Diagnosis and management of behavioral variant frontotemporal dementia.

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Pressman, Peter S; Miller, Bruce L

2014-04-01

Frontotemporal dementia was documented over a century ago. The last decade, however, has seen substantial changes in our conceptions of this increasingly recognized disorder. Different clinical variants have been delineated, the most common of which is the behavioral variant (bvFTD). Updated diagnostic criteria have been established. New histopathological findings and genetic etiologies have been discovered. Research continues to uncover molecular mechanisms by which abnormal proteins accumulate in degenerating brain tissue. Novel neuroimaging techniques suggest that functional networks are diminished in bvFTD that might be relevant to empathy and social behavior. Despite rapid advances in our understanding of bvFTD, the disease is still under-recognized and commonly misdiagnosed. The result is inappropriate patient care. Recognizing the various presentations of bvFTD and its histological and genetic subtypes might further diagnosis, treatment, and research. © 2013 Society of Biological Psychiatry Published by Society of Biological Psychiatry All rights reserved.

False recognition in behavioural variant frontotemporal dementia and Alzheimer’s disease – disinhibition or amnesia?

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Emma C Flanagan

2016-07-01

Full Text Available Episodic memory recall processes in Alzheimer’s disease (AD and behavioural variant frontotemporal dementia (bvFTD can be similarly impaired, whereas recognition performance is more variable. A potential reason for this variability could be false-positive errors made on recognition trials and whether these errors are due to amnesia per se or a general over-endorsement of recognition items regardless of memory. The current study addressed this issue by analysing recognition performance on the Rey Auditory Verbal Learning Test (RAVLT in 39 bvFTD, 77 AD and 61 control participants from two centres (India, Australia, as well as disinhibition assessed using the Hayling test. Whereas both AD and bvFTD patients were comparably impaired on delayed recall, bvFTD patients showed intact recognition performance in terms of the number of correct hits. However, both patient groups endorsed significantly more false-positives than controls, and bvFTD and AD patients scored equally poorly on a sensitivity index (correct hits - false-positives. Furthermore, measures of disinhibition were significantly associated with false positives in both groups, with a stronger relationship with false-positives in bvFTD. Voxel-based morphometry analyses revealed similar neural correlates of false positive endorsement across bvFTD and AD, with both patient groups showing involvement of prefrontal and Papez circuitry regions, such as medial temporal and thalamic regions, and a DTI analysis detected an emerging but non-significant trend between false positives and decreased fornix integrity in bvFTD only. These findings suggest that false-positive errors on recognition tests relate to similar mechanisms in bvFTD and AD, reflecting deficits in episodic memory processes and disinhibition. These findings highlight that current memory tests are not sufficient to accurately distinguish between bvFTD and AD patients.

Brain Serotonergic and Noradrenergic Deficiencies in Behavioral Variant Frontotemporal Dementia Compared to Early-Onset Alzheimer's Disease

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Vermeiren, Yannick; Janssens, Jana; Aerts, Tony; Martin, Jean-Jacques; Sieben, Anne; Van Dam, Debby; De Deyn, Peter P.

2016-01-01

Routinely prescribed psychoactive drugs in behavioral variant frontotemporal dementia (FTD) for improvement of (non) cognitive symptoms are primarily based on monoamine replacement or augmentation strategies. These were, however, initially intended to symptomatically treat other degenerative,

Social influence on associative learning: double dissociation in high-functioning autism, early-stage behavioural variant frontotemporal dementia and Alzheimer's disease.

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Kéri, Szabolcs

2014-05-01

Most of our learning activity takes place in a social context. I examined how social interactions influence associative learning in neurodegenerative diseases and atypical neurodevelopmental conditions primarily characterised by social cognitive and memory dysfunctions. Participants were individuals with high-functioning autism (HFA, n = 18), early-stage behavioural variant frontotemporal dementia (bvFTD, n = 16) and Alzheimer's disease (AD, n = 20). The leading symptoms in HFA and bvFTD were social and behavioural dysfunctions, whereas AD was characterised by memory deficits. Participants received three versions of a paired associates learning task. In the game with boxes test, objects were hidden in six candy boxes placed in different locations on the computer screen. In the game with faces, each box was labelled by a photo of a person. In the real-life version of the game, participants played with real persons. Individuals with HFA and bvFTD performed well in the computer games, but failed on the task including real persons. In contrast, in patients with early-stage AD, social interactions boosted paired associates learning up to the level of healthy control volunteers. Worse performance in the real life game was associated with less successful recognition of complex emotions and mental states in the Reading the Mind in the Eyes Test. Spatial span did not affect the results. When social cognition is impaired, but memory systems are less compromised (HFA and bvFTD), real-life interactions disrupt associative learning; when disease process impairs memory systems but social cognition is relatively intact (early-stage AD), social interactions have a beneficial effect on learning and memory. Copyright © 2014 Elsevier Ltd. All rights reserved.

Prosocial deficits in behavioral variant frontotemporal dementia relate to reward network atrophy

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Sturm, Virginia E.; Perry, David C.; Wood, Kristie; Hua, Alice Y.; Alcantar, Oscar; Datta, Samir; Rankin, Katherine P.; Rosen, Howard J.; Miller, Bruce L.; Kramer, Joel H.

2017-01-01

Abstract Introduction Empathy and shared feelings of reward motivate individuals to share resources with others when material gain is not at stake. Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disease that affects emotion‐ and reward‐relevant neural systems. Although there is diminished empathy and altered reward processing in bvFTD, how the disease impacts prosocial behavior is less well understood. Methods A total of 74 participants (20 bvFTD, 15 Alzheimer's dis...

Sensitivity of current criteria for the diagnosis of behavioral variant frontotemporal dementia

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Piguet, O; Hornberger, M; Shelley, B P.; Kipps, C M.; Hodges, J R.

2009-01-01

Background: Diagnosis of behavioral variant frontotemporal dementia (bvFTD) relies on criteria that are constraining and potentially ambiguous. Some features are open to clinical interpretation and their prevalence unknown. This study investigated the sensitivity of current diagnostic criteria in a large group of patients with bvFTD. Methods: Forty-five patients with clear evidence of bvFTD as judged by progressive clinical decline (>3 years) with marked frontal features and significant frontal brain atrophy on brain MRI were included. Thirty-two have died; pathologic confirmation of frontotemporal lobar degeneration was found in all 18 coming to autopsy. We established the prevalence of core and supportive diagnostic features at presentation and with disease progression. Results: Only 25/45 patients (56%) showed all five core features necessary for a diagnosis of bvFTD at initial presentation and 33/45 (73%) as their disease progressed. Two core features, emotional blunting and loss of insight, were never observed in 25% and 13% of cases. Executive dysfunction, hyperorality, mental inflexibility, and distractibility were the only supportive features present in >50% of cases at initial presentation. Although not a diagnostic feature, impaired activities of daily living was present in 33/45 patients (73%). Conclusions: Strict application of the criteria misses a significant proportion of patients. Many supportive features have low prevalence and are clinically not useful. Revision of the criteria to include level of certainty (definite, probable, possible) dependent on the number of features present and the presence of ancillary information (e.g., brain atrophy, neuropsychological abnormalities, impaired activities of daily living) is encouraged. GLOSSARY ACE = Addenbrooke’s Cognitive Examination; ADL = activities of daily living; bvFTD = behavioral variant frontotemporal dementia; MMSE = Mini-Mental State Examination. PMID:19237702

Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia

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Cuyvers, Elise; Bettens, Karolien; Philtjens, Stephanie; Van Langenhove, Tim; Gijselinck, Ilse; van der Zee, Julie; Engelborghs, Sebastiaan; Vandenbulcke, Mathieu; Van Dongen, Jasper; Geerts, Nathalie; Maes, Githa; Mattheijssens, Maria; Peeters, Karin; Cras, Patrick; Vandenberghe, Rik; De Deyn, Peter P.; Van Broeckhoven, Christine; Cruts, Marc; Sleegers, Kristel

Homozygous mutations in exon 2 of TREM2, a gene involved in Nasu-Hakola disease, can cause frontotemporal dementia (FTD). Moreover, a rare TREM2 exon 2 variant (p.R47H) was reported to increase the risk of Alzheimer's disease (AD) with an odds ratio as strong as that for APOE epsilon 4. We

Correlated patterns of neuropsychological and behavioral symptoms in frontal variant of Alzheimer disease and behavioral variant frontotemporal dementia: a comparative case study.

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Li, Pan; Zhou, Yu-Ying; Lu, Da; Wang, Yan; Zhang, Hui-Hong

2016-05-01

Although the neuropathologic changes and diagnostic criteria for the neurodegenerative disorder Alzheimer's disease (AD) are well-established, the clinical symptoms vary largely. Symptomatically, frontal variant of AD (fv-AD) presents very similarly to behavioral variant frontotemporal dementia (bvFTD), which creates major challenges for differential diagnosis. Here, we report two patients who present with progressive cognitive impairment, early and prominent behavioral features, and significant frontotemporal lobe atrophy on magnetic resonance imaging, consistent with an initial diagnosis of probable bvFTD. However, multimodal functional neuroimaging revealed neuropathological data consistent with a diagnosis of probable AD for one patient (pathology distributed in the frontal lobes) and a diagnosis of probable bvFTD for the other patient (hypometabolism in the bilateral frontal lobes). In addition, the fv-AD patient presented with greater executive impairment and milder behavioral symptoms relative to the bvFTD patient. These cases highlight that recognition of these atypical syndromes using detailed neuropsychological tests, biomarkers, and multimodal neuroimaging will lead to greater accuracy in diagnosis and patient management.

Frontal and temporal lobe contributions to emotional enhancement of memory in behavioural-variant frontotemporal dementia and Alzheimer's disease

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Fiona eKumfor

2014-06-01

Full Text Available Emotional events gain special priority in how they are remembered, with emotionally arousing events typically recalled more vividly and with greater confidence than non-emotional events. In dementia, memory and emotion processing are affected to varying degrees, however, whether emotional enhancement of memory for complex ecologically valid events is differentially affected across dementia syndromes remains unclear, with previous studies examining effects of emotion on simple visual recognition only. Here, we examined memory for an emotionally arousing short story and a closely matched, emotionally neutral story in behavioural-variant frontotemporal dementia (bvFTD (n = 13 and Alzheimer’s disease (AD (n = 14, and contrasted their performance with healthy controls (n = 12. Multiple-choice recognition memory for specific details of the story was assessed after a 1-hour delay. While AD and control groups showed enhanced memory for the emotional story, the bvFTD group recalled a similar number of details from the emotional and neutral stories. Voxel-based morphometry analyses revealed emotional enhancement of memory correlated with distinct brain regions in each patient group. In AD, emotional enhancement was associated with integrity of the bilateral hippocampus, parahippocampal gyri, temporal fusiform gyrus and frontal pole, regions implicated in memory processes. In contrast in bvFTD, integrity of emotion processing regions, including the orbitofrontal cortex, right amygdala and right insula, correlated with the extent emotion enhanced memory. Our results reveal that integrity of frontal and temporal regions determine the quality and nature of emotional memories. While emotional enhancement of memory is present in mild AD, in bvFTD emotion does not facilitate memory retrieval for complex realistic events. This attenuation of emotional enhancement is due to degradation of emotion processing regions, which may be important for modulating levels

Can cognitive assessment really discriminate early stages of Alzheimer's and behavioural variant frontotemporal dementia at initial clinical presentation?

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Reul, Sophia; Lohmann, Hubertus; Wiendl, Heinz; Duning, Thomas; Johnen, Andreas

2017-08-09

Neuropsychological testing is considered crucial for differential diagnosis of Alzheimer's disease (AD) and behavioural variant frontotemporal dementia (bvFTD). In-depth neuropsychological assessment revealed specific dysfunctions in the two dementia syndromes. However, a significant overlap of cognitive impairments exists in early disease stages. We questioned whether a standard neuropsychological assessment at initial clinical presentation can delineate patients with AD versus bvFTD. In a retrospective approach, we evaluated and compared how cognitive profiles assessed at initial clinical presentation predicted the diagnosis of later verified AD (n = 43) and bvFTD (n = 26). Additionally, the neuropsychological standard domains memory, language, visuospatial skills, executive functions, praxis and social cognition were subjected to stepwise discriminant analysis to compare their differential contribution to diagnosis. Regardless of diagnosis, a percentage of patients presented with major deterioration in a wide range of cognitive domains when compared with age-matched normative data. Only few significant differences were detected on the group level: Patients with AD were relatively more impaired in the verbal recall, verbal recognition, figure copy, and surprisingly in the executive subdomains, set shifting and processing speed whereas bvFTD was characterised by more deficits in imitation of face postures. A combination of tests for verbal recall, imitation of limb and face postures, and figure copy showed the greatest discriminatory power. Our results imply that the contribution of a standard neuropsychological assessment is limited for differential diagnosis of AD and bvFTD at initial presentation. In contrast to current clinical guidelines, executive functions are neither particularly nor exclusively impaired in patients with bvFTD when assessed within a standard clinical neuropsychological test battery. The significant overlap of bvFTD and AD

Auditory conflict and congruence in frontotemporal dementia.

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Clark, Camilla N; Nicholas, Jennifer M; Agustus, Jennifer L; Hardy, Christopher J D; Russell, Lucy L; Brotherhood, Emilie V; Dick, Katrina M; Marshall, Charles R; Mummery, Catherine J; Rohrer, Jonathan D; Warren, Jason D

2017-09-01

Impaired analysis of signal conflict and congruence may contribute to diverse socio-emotional symptoms in frontotemporal dementias, however the underlying mechanisms have not been defined. Here we addressed this issue in patients with behavioural variant frontotemporal dementia (bvFTD; n = 19) and semantic dementia (SD; n = 10) relative to healthy older individuals (n = 20). We created auditory scenes in which semantic and emotional congruity of constituent sounds were independently probed; associated tasks controlled for auditory perceptual similarity, scene parsing and semantic competence. Neuroanatomical correlates of auditory congruity processing were assessed using voxel-based morphometry. Relative to healthy controls, both the bvFTD and SD groups had impaired semantic and emotional congruity processing (after taking auditory control task performance into account) and reduced affective integration of sounds into scenes. Grey matter correlates of auditory semantic congruity processing were identified in distributed regions encompassing prefrontal, parieto-temporal and insular areas and correlates of auditory emotional congruity in partly overlapping temporal, insular and striatal regions. Our findings suggest that decoding of auditory signal relatedness may probe a generic cognitive mechanism and neural architecture underpinning frontotemporal dementia syndromes. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Late onset bipolar disorder and frontotemporal dementia with mutation in progranulin gene: a case report.

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Rubino, Elisa; Vacca, Alessandro; Gallone, Salvatore; Govone, Flora; Zucca, Milena; Gai, Annalisa; Ferrero, Patrizia; Fenoglio, Pierpaola; Giordana, Maria Teresa; Rainero, Innocenzo

2017-11-01

Bipolar disorder is a chronic psychiatric illness characterised by fluctuation in mood state, with a relapsing and remitting course. Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous syndrome, with the most frequent phenotype being behavioural variant frontotemporal dementia (bvFTD). Here, we report the case of an Italian male presenting with late-onset bipolar disorder that developed into bvFTD over time, carrying a mutation in the GRN gene. Interestingly, the patient carried the c.1639 C > T variant in the GRN gene, resulting in a R547C substitution. Our case report further corroborates the notion that, in addition to FTD, progranulin may be involved in the neurobiology of bipolar disorder type 1, and suggests to screen patients with late-onset bipolar disorder for GRN mutations.

Judgments about moral responsibility and determinism in patients with behavioural variant of frontotemporal dementia: still compatibilists.

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Cova, Florian; Bertoux, Maxime; Bourgeois-Gironde, Sacha; Dubois, Bruno

2012-06-01

Do laypeople think that moral responsibility is compatible with determinism? Recently, philosophers and psychologists trying to answer this question have found contradictory results: while some experiments reveal people to have compatibilist intuitions, others suggest that people could in fact be incompatibilist. To account for this contradictory answers, Nichols and Knobe (2007) have advanced a 'performance error model' according to which people are genuine incompatibilist that are sometimes biased to give compatibilist answers by emotional reactions. To test for this hypothesis, we investigated intuitions about determinism and moral responsibility in patients suffering from behavioural frontotemporal dementia. Patients suffering from bvFTD have impoverished emotional reaction. Thus, the 'performance error model' should predict that bvFTD patients will give less compatibilist answers. However, we found that bvFTD patients give answers quite similar to subjects in control group and were mostly compatibilist. Thus, we conclude that the 'performance error model' should be abandoned in favour of other available model that best fit our data. Copyright © 2012 Elsevier Inc. All rights reserved.

Clinical Utility of Short Social Cognitive Tests in Early Differentiation of Behavioral Variant Frontotemporal Dementia from Alzheimer’s Disease

DEFF Research Database (Denmark)

Buhl, Christian; Stokholm, Jette; Gade, Anders

2013-01-01

Traditional cognitive tests used in clinical practice may not be sensitive enough for the early differentiation of behavioral variant frontotemporal dementia (bvFTD) from Alzheimer's disease (AD). A growing body of literature has shown that deficits in various aspects of social cognition can be f...

Psychosis in behavioral variant frontotemporal dementia

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Gossink FT

2017-04-01

Full Text Available Flora T Gossink,1,2 Everard GB Vijverberg,2,3 Welmoed Krudop,2 Philip Scheltens,2 Max L Stek,1 Yolande AL Pijnenburg,1,2 Annemiek Dols1,2 1Department of Old Age Psychiatry, GGZinGeest, 2Alzheimer Center & Department of Neurology, VU University Medical Center, Amsterdam, 3Department of Neurology, HagaZiekenhuis, The Hague, the Netherlands Background: Dementia is generally characterized by cognitive impairment that can be accompanied by psychotic symptoms; for example, visual hallucinations are a core feature of dementia with Lewy bodies, and delusions are often seen in Alzheimer’s disease. However, for behavioral variant of frontotemporal dementia (bvFTD, studies on the broad spectrum of psychotic symptoms are still lacking. The aim of this study was to systematically and prospectively subtype the wide spectrum of psychotic symptoms in probable and definite bvFTD.Methods: In this study, a commonly used and validated clinical scale that quantifies the broad spectrum of psychotic symptoms (Positive and Negative Symptom Scale was used in patients with probable and definite bvFTD (n=22 and with a primary psychiatric disorder (n=35 in a late-onset frontal lobe cohort. Median symptom duration was 2.8 years, and the patients were prospectively followed for 2 years.Results: In total, 22.7% of bvFTD patients suffered from delusions, hallucinatory behavior, and suspiciousness, although the majority of the patients exhibited negative psychotic symptoms such as social and emotional withdrawal and blunted affect (95.5% and formal thought disorders (81.8%. “Difficulty in abstract thinking” and “stereotypical thinking” (formal thought disorders differentiated bvFTD from psychiatric disorders. The combined predictors difficulty in abstract thinking, stereotypical thinking, “anxiety”, “guilt feelings,” and “tension” explained 75.4% of variance in the diagnosis of bvFTD versus psychiatric diagnoses (P<0.001.Conclusion: Delusions

Observing conversational laughter in frontotemporal dementia.

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Pressman, Peter S; Simpson, Michaela; Gola, Kelly; Shdo, Suzanne M; Spinelli, Edoardo G; Miller, Bruce L; Gorno-Tempini, Maria Luisa; Rankin, Katherine; Levenson, Robert W

2017-05-01

We performed an observational study of laughter during seminaturalistic conversations between patients with dementia and familial caregivers. Patients were diagnosed with (1) behavioural variant frontotemporal dementia (bvFTD), (2) right temporal variant frontotemporal dementia (rtFTD), (3) semantic variant of primary progressive aphasia (svPPA), (4) non-fluent variant primary progressive aphasia (nfvPPA) or (5) early onset Alzheimer's disease (eoAD). We hypothesised that those with bvFTD would laugh less in response to their own speech than other dementia groups or controls, while those with rtFTD would laugh less regardless of who was speaking. Patients with bvFTD (n=39), svPPA (n=19), rtFTD (n=14), nfvPPA (n=16), eoAD (n=17) and healthy controls (n=156) were recorded (video and audio) while discussing a problem in their relationship with a healthy control companion. Using the audio track only, laughs were identified by trained coders and then further classed by an automated algorithm as occurring during or shortly after the participant's own vocalisation ('self' context) or during or shortly after the partner's vocalisation ('partner' context). Individuals with bvFTD, eoAD or rtFTD laughed less across both contexts of self and partner than the other groups. Those with bvFTD laughed less relative to their own speech comparedwith healthy controls. Those with nfvPPA laughed more in the partner context compared with healthy controls. Laughter in response to one's own vocalisations or those of a conversational partner may be a clinically useful measure in dementia diagnosis. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Reconocimiento facial de emociones básicas y complejas en una población de pacientes con demencia frontotemporal variante frontal Facial recognition of basic and complex emotions in a population of patients with frontal variant of frontotemporal dementia

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María Eugenia Tabernero

2011-12-01

Full Text Available La variante frontal de la Demencia Frontotemporal (DFTvf se caracteriza por un severo trastorno de la conducta y la personalidad, explicado por alteraciones en el procesamiento emocional y/o en la Teoría de la Mente (TdM. Objetivo: Evaluar los procesos cognitivos involucrados en a resolución del Test de Caras (Baron-Cohen et al., 1997 en comparación con el test Lectura de la Mente en los Ojos (LMO (Baron-Cohen et al., 2001 y la utilidad de ambos para el diagnóstico de alteraciones en la TdM en pacientes con DFTvf. Población: 20 pacientes con diagnóstico de DFTvf, media de edad 66,9 años y escolaridad 6,25 años. Resultados: Correlación significativa entre LMO y el Test de Caras. Doble disociación entre ambas pruebas. Conclusión: La presencia de correlaciones indica que ambas pruebas se afectan en esta demencia, resultando herramientas de igual valor clínico. El hallazgo de disociaciones indica que cada una de ellas evalúa procesos cognitivos parcialmente independientesThe frontal variant of frontotemporal dementia (FTDfv is characterized by a severe behavioural and personality impairment, explained by alterations in the emotional process and/or in Theory of Mind (ToM. Objective: To assess the cognitive processes involved in performing the Faces Test (Baron-Cohen et al., 1997 in comparison with Reading de Mind in the Eyes Test (RME (Baron-Cohen et al., 2001, and the utility of both in the diagnosis of ToM alterations in FTDfv patients. Subjects: 20 patients diagnosed with FTDfv, mean age 66,9 years and mean education 6,25 years. Results: Significative correlation between RME and Faces Test. Double dissociation between these tests. Conclusion: The presence of correlations indicates that both tests are affected in this dementia, being both useful as clinical tools. The dissociations founded indicates that each one assesses partially-independent cognitive processes.

Discrete Neural Correlates for the Recognition of Negative Emotions: Insights from Frontotemporal Dementia

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Kumfor, Fiona; Irish, Muireann; Hodges, John R.; Piguet, Olivier

2013-01-01

Patients with frontotemporal dementia have pervasive changes in emotion recognition and social cognition, yet the neural changes underlying these emotion processing deficits remain unclear. The multimodal system model of emotion proposes that basic emotions are dependent on distinct brain regions, which undergo significant pathological changes in frontotemporal dementia. As such, this syndrome may provide important insight into the impact of neural network degeneration upon the innate ability to recognise emotions. This study used voxel-based morphometry to identify discrete neural correlates involved in the recognition of basic emotions (anger, disgust, fear, sadness, surprise and happiness) in frontotemporal dementia. Forty frontotemporal dementia patients (18 behavioural-variant, 11 semantic dementia, 11 progressive nonfluent aphasia) and 27 healthy controls were tested on two facial emotion recognition tasks: The Ekman 60 and Ekman Caricatures. Although each frontotemporal dementia group showed impaired recognition of negative emotions, distinct associations between emotion-specific task performance and changes in grey matter intensity emerged. Fear recognition was associated with the right amygdala; disgust recognition with the left insula; anger recognition with the left middle and superior temporal gyrus; and sadness recognition with the left subcallosal cingulate, indicating that discrete neural substrates are necessary for emotion recognition in frontotemporal dementia. The erosion of emotion-specific neural networks in neurodegenerative disorders may produce distinct profiles of performance that are relevant to understanding the neurobiological basis of emotion processing. PMID:23805313

Dissociation between controlled and automatic processes in the behavioral variant of fronto-temporal dementia.

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Collette, Fabienne; Van der Linden, Martial; Salmon, Eric

2010-01-01

A decline of cognitive functioning affecting several cognitive domains was frequently reported in patients with frontotemporal dementia. We were interested in determining if these deficits can be interpreted as reflecting an impairment of controlled cognitive processes by using an assessment tool specifically developed to explore the distinction between automatic and controlled processes, namely the process dissociation procedure (PDP) developed by Jacoby. The PDP was applied to a word stem completion task to determine the contribution of automatic and controlled processes to episodic memory performance and was administered to a group of 12 patients with the behavioral variant of frontotemporal dementia (bv-FTD) and 20 control subjects (CS). Bv-FTD patients obtained a lower performance than CS for the estimates of controlled processes, but no group differences was observed for estimates of automatic processes. The between-groups comparison of the estimates of controlled and automatic processes showed a larger contribution of automatic processes to performance in bv-FTD, while a slightly more important contribution of controlled processes was observed in control subjects. These results are clearly indicative of an alteration of controlled memory processes in bv-FTD.

Right Limbic FDG-PET Hypometabolism Correlates with Emotion Recognition and Attribution in Probable Behavioral Variant of Frontotemporal Dementia Patients.

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Chiara Cerami

Full Text Available The behavioural variant of frontotemporal dementia (bvFTD is a rare disease mainly affecting the social brain. FDG-PET fronto-temporal hypometabolism is a supportive feature for the diagnosis. It may also provide specific functional metabolic signatures for altered socio-emotional processing. In this study, we evaluated the emotion recognition and attribution deficits and FDG-PET cerebral metabolic patterns at the group and individual levels in a sample of sporadic bvFTD patients, exploring the cognitive-functional correlations. Seventeen probable mild bvFTD patients (10 male and 7 female; age 67.8±9.9 were administered standardized and validated version of social cognition tasks assessing the recognition of basic emotions and the attribution of emotions and intentions (i.e., Ekman 60-Faces test-Ek60F and Story-based Empathy task-SET. FDG-PET was analysed using an optimized voxel-based SPM method at the single-subject and group levels. Severe deficits of emotion recognition and processing characterized the bvFTD condition. At the group level, metabolic dysfunction in the right amygdala, temporal pole, and middle cingulate cortex was highly correlated to the emotional recognition and attribution performances. At the single-subject level, however, heterogeneous impairments of social cognition tasks emerged, and different metabolic patterns, involving limbic structures and prefrontal cortices, were also observed. The derangement of a right limbic network is associated with altered socio-emotional processing in bvFTD patients, but different hypometabolic FDG-PET patterns and heterogeneous performances on social tasks at an individual level exist.

Hippocampal sclerosis dementia: An amnesic variant of frontotemporal degeneration

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Chiadi U. Onyike

Full Text Available ABSTRACT Objective: To describe characteristics of hippocampal sclerosis dementia. Methods: Convenience sample of Hippocampal sclerosis dementia (HSD recruited from the Johns Hopkins University Brain Resource Center. Twenty-four cases with post-mortem pathological diagnosis of hippocampal sclerosis dementia were reviewed for clinical characterization. Results: The cases showed atrophy and neuronal loss localized to the hippocampus, amygdala and entorrhinal cortex. The majority (79.2% had amnesia at illness onset, and many (54.2% showed abnormal conduct and psychiatric disorder. Nearly 42% presented with an amnesic state, and 37.5% presented with amnesia plus abnormal conduct and psychiatric disorder. All eventually developed a behavioral or psychiatric disorder. Disorientation, executive dysfunction, aphasia, agnosia and apraxia were uncommon at onset. Alzheimer disease (AD was the initial clinical diagnosis in 89% and the final clinical diagnosis in 75%. Diagnosis of frontotemporal dementia (FTD was uncommon (seen in 8%. Conclusion: HSD shows pathological characteristics of FTD and clinical features that mimic AD and overlap with FTD. The findings, placed in the context of earlier work, support the proposition that HSD belongs to the FTD family, where it may be identified as an amnesic variant.

Hippocampal sclerosis dementia: an amnesic variant of frontotemporal degeneration

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Onyike, Chiadi U.; Pletnikova, Olga; Sloane, Kelly L.; Sullivan, Campbell; Troncoso, Juan C.; Rabins, Peter V.

2013-01-01

OBJECTIVE To describe characteristics of hippocampal sclerosis dementia. METHODS Convenience sample of Hippocampal sclerosis dementia (HSD) recruited from the Johns Hopkins University Brain Resource Center. Twenty-four cases with post-mortem pathological diagnosis of hippocampal sclerosis dementia were reviewed for clinical characterization. RESULTS The cases showed atrophy and neuronal loss localized to the hippocampus, amygdala and entorrhinal cortex. The majority (79.2%) had amnesia at illness onset, and many (54.2%) showed abnormal conduct and psychiatric disorder. Nearly 42% presented with an amnesic state, and 37.5% presented with amnesia plus abnormal conduct and psychiatric disorder. All eventually developed a behavioral or psychiatric disorder. Disorientation, executive dysfunction, aphasia, agnosia and apraxia were uncommon at onset. Alzheimer disease (AD) was the initial clinical diagnosis in 89% and the final clinical diagnosis in 75%. Diagnosis of frontotemporal dementia (FTD) was uncommon (seen in 8%). CONCLUSION HSD shows pathological characteristics of FTD and clinical features that mimic AD and overlap with FTD. The findings, placed in the context of earlier work, support the proposition that HSD belongs to the FTD family, where it may be identified as an amnesic variant. PMID:24363834

White matter tract signatures of impaired social cognition in frontotemporal lobar degeneration

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Laura E. Downey

2015-01-01

Full Text Available Impairments of social cognition are often leading features in frontotemporal lobar degeneration (FTLD and likely to reflect large-scale brain network disintegration. However, the neuroanatomical basis of impaired social cognition in FTLD and the role of white matter connections have not been defined. Here we assessed social cognition in a cohort of patients representing two core syndromes of FTLD, behavioural variant frontotemporal dementia (bvFTD; n = 29 and semantic variant primary progressive aphasia (svPPA; n = 15, relative to healthy older individuals (n = 37 using two components of the Awareness of Social Inference Test, canonical emotion identification and sarcasm identification. Diffusion tensor imaging (DTI was used to derive white matter tract correlates of social cognition performance and compared with the distribution of grey matter atrophy on voxel-based morphometry. The bvFTD and svPPA groups showed comparably severe deficits for identification of canonical emotions and sarcasm, and these deficits were correlated with distributed and overlapping white matter tract alterations particularly affecting frontotemporal connections in the right cerebral hemisphere. The most robust DTI associations were identified in white matter tracts linking cognitive and evaluative processing with emotional responses: anterior thalamic radiation, fornix (emotion identification and uncinate fasciculus (sarcasm identification. DTI associations of impaired social cognition were more consistent than corresponding grey matter associations. These findings delineate a brain network substrate for the social impairment that characterises FTLD syndromes. The findings further suggest that DTI can generate sensitive and functionally relevant indexes of white matter damage in FTLD, with potential to transcend conventional syndrome boundaries.

The Cambridge Behavioural Inventory revised.

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Wear, Helen J; Wedderburn, Catherine J; Mioshi, Eneida; Williams-Gray, Caroline H; Mason, Sarah L; Barker, Roger A; Hodges, John R

2008-01-01

Neurobehavioural and psychiatric symptoms are common in a range of neurodegenerative disorders with distinct profiles which are helpful in the diagnosis and monitoring of these disorders. The Cambridge Behavioural Inventory (CBI) has been shown to distinguish frontotemporal dementia (FTD), Alzheimer's disease (AD), Huntington's disease (HD) and Parkinson's disease (PD), but it is lengthy. To develop a shorter version of the 81 item CBI. CBI data from 450 participants with behavioural variant frontotemporal dementia (bv-FTD) (64), AD (96), PD (215) and HD (75) were analysed using Principal Components Analysis and measures of internal consistency (Cronbach alpha). A reduced 45-item questionnaire was developed. The instrument identified distinct behavioural profiles and performed as well as the original version. A shorter (45 item) version of the CBI is capable of differentiating bv-FTD and AD from PD and HD. It may be useful in delineating the type and extent of problems in these disorders as well as monitoring therapeutic interventions.

Processing emotion from abstract art in frontotemporal lobar degeneration.

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Cohen, Miriam H; Carton, Amelia M; Hardy, Christopher J; Golden, Hannah L; Clark, Camilla N; Fletcher, Phillip D; Jaisin, Kankamol; Marshall, Charles R; Henley, Susie M D; Rohrer, Jonathan D; Crutch, Sebastian J; Warren, Jason D

2016-01-29

art may signal emotions independently of a biological or social carrier: it might therefore constitute a test case for defining brain mechanisms of generic emotion decoding and the impact of disease states on those mechanisms. This is potentially of particular relevance to diseases in the frontotemporal lobar degeneration (FTLD) spectrum. These diseases are often led by emotional impairment despite retained or enhanced artistic interest in at least some patients. However, the processing of emotion from art has not been studied systematically in FTLD. Here we addressed this issue using a novel emotional valence matching task on abstract paintings in patients representing major syndromes of FTLD (behavioural variant frontotemporal dementia, n=11; sematic variant primary progressive aphasia (svPPA), n=7; nonfluent variant primary progressive aphasia (nfvPPA), n=6) relative to healthy older individuals (n=39). Performance on art emotion valence matching was compared between groups taking account of perceptual matching performance and assessed in relation to facial emotion matching using customised control tasks. Neuroanatomical correlates of art emotion processing were assessed using voxel-based morphometry of patients' brain MR images. All patient groups had a deficit of art emotion processing relative to healthy controls; there were no significant interactions between syndromic group and emotion modality. Poorer art emotion valence matching performance was associated with reduced grey matter volume in right lateral occopitotemporal cortex in proximity to regions previously implicated in the processing of dynamic visual signals. Our findings suggest that abstract art may be a useful model system for investigating mechanisms of generic emotion decoding and aesthetic processing in neurodegenerative diseases. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Analysis on early clinical features of behavioral variant frontotemporal dementia

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Guan-jun LI

2017-11-01

Full Text Available Background Although the early behavioral symptoms of behavioral variant frontotemporal dementia (bvFTD are prominent, early diagnosis for bvFTD is difficult due to confusion with other mental disorders, and lack of sensitivity and specificity of diagnostic criteria, etc. In this paper, we summarized the important reviews in recent years and analyzed the clinical characteristics of bvFTD patients to improve the detection of early symptoms in bvFTD. Methods Twenty-three possible or probable bvFTD patients were diagnosed according to International Behavioral Variant Frontotemporal Dementia Criteria Consortium (FTDC. Self-designed questionnaires designed by Shanghai Mental Health Center were used to collect sociodemographic data and general information of patients. Their clinical characteristics were summarized, including abnormal behaviors, cognitive impairment, psychotic symptoms and other symptoms. Mini-Mental State Examination (MMSE, Activities of Daily Living (ADL and Clinical Dementia Rating Scale (CDR were used to make neuropsychological tests and compare with similar overseas studies (control group, N = 66. Results Eleven male patients and 12 female patients were included in our study. Compared with control group, the average age of onset [(50.83 ± 11.55 years vs. (57.00 ± 10.00 years; t = 3.863, P = 0.000] and average age of diagnosis [(53.22 ± 11.55 years vs. (61.00 ± 9.00 years; t = 13.423, P = 0.000] of bvFTD patients were smaller. The study showed that bvFTD patients had more apathy or indolence [95.65% (22/23 vs. 65.15% (43/66; χ2 = 8.057, P = 0.005], loss of sympathy or empathy [95.65% (22/23 vs. 33.33% (22/66; χ2 = 26.499, P = 0.000], while patients in control group showed more derepression behavior [98.48% (65/66 vs. 52.17% (12/23; χ2 = 27.514, P = 0.000] and continuous, stiff, obsessive and/or ritualized behavior [95.45% (63/66 vs. 30.43% (7/23; adjusted χ2 = 39.159, P = 0.000]. For cognitive impairment, bvFTD patients

Behavioral variant frontotemporal dementia patients do not succumb to the Allais paradox.

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Bertoux, Maxime; Cova, Florian; Pessiglione, Mathias; Hsu, Ming; Dubois, Bruno; Bourgeois-Gironde, Sacha

2014-01-01

The Allais Paradox represents one of the earliest empirical challenges to normative models of decision-making, and suggests that choices in one part of a gamble may depend on the possible outcome in another, independent, part of the gamble-a violation of the so-called "independence axiom." To account for Allaisian behavior, one well-known class of models propose that individuals' choices are influenced not only by possible outcomes resulting from one's choices, but also the anticipation of regret for foregone options. Here we test the regret hypothesis using a population of patients with behavioral variant frontotemporal dementia (bvFTD), a clinical population known to present ventromedial prefrontal cortex dysfunctions and associated with impaired regret processing in previous studies of decision-making. Compared to matched controls and Alzheimer's disease (AD) patients, we found a striking diminution of Allaisian behavior among bvFTD patients. These results are consistent with the regret hypothesis and furthermore suggest a crucial role for prefrontal regions in choices that typically stands in contradiction with a basic axiom of rational decision-making.

The structural neuroanatomy of music emotion recognition: evidence from frontotemporal lobar degeneration.

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Omar, Rohani; Henley, Susie M D; Bartlett, Jonathan W; Hailstone, Julia C; Gordon, Elizabeth; Sauter, Disa A; Frost, Chris; Scott, Sophie K; Warren, Jason D

2011-06-01

Despite growing clinical and neurobiological interest in the brain mechanisms that process emotion in music, these mechanisms remain incompletely understood. Patients with frontotemporal lobar degeneration (FTLD) frequently exhibit clinical syndromes that illustrate the effects of breakdown in emotional and social functioning. Here we investigated the neuroanatomical substrate for recognition of musical emotion in a cohort of 26 patients with FTLD (16 with behavioural variant frontotemporal dementia, bvFTD, 10 with semantic dementia, SemD) using voxel-based morphometry. On neuropsychological evaluation, patients with FTLD showed deficient recognition of canonical emotions (happiness, sadness, anger and fear) from music as well as faces and voices compared with healthy control subjects. Impaired recognition of emotions from music was specifically associated with grey matter loss in a distributed cerebral network including insula, orbitofrontal cortex, anterior cingulate and medial prefrontal cortex, anterior temporal and more posterior temporal and parietal cortices, amygdala and the subcortical mesolimbic system. This network constitutes an essential brain substrate for recognition of musical emotion that overlaps with brain regions previously implicated in coding emotional value, behavioural context, conceptual knowledge and theory of mind. Musical emotion recognition may probe the interface of these processes, delineating a profile of brain damage that is essential for the abstraction of complex social emotions. Copyright © 2011 Elsevier Inc. All rights reserved.

Automatic MRI Quantifying Methods in Behavioral-Variant Frontotemporal Dementia Diagnosis

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Antti Cajanus

2018-02-01

Full Text Available Aims: We assessed the value of automated MRI quantification methods in the differential diagnosis of behavioral-variant frontotemporal dementia (bvFTD from Alzheimer disease (AD, Lewy body dementia (LBD, and subjective memory complaints (SMC. We also examined the role of the C9ORF72-related genetic status in the differentiation sensitivity. Methods: The MRI scans of 50 patients with bvFTD (17 C9ORF72 expansion carriers were analyzed using 6 quantification methods as follows: voxel-based morphometry (VBM, tensor-based morphometry, volumetry (VOL, manifold learning, grading, and white-matter hyperintensities. Each patient was then individually compared to an independent reference group in order to attain diagnostic suggestions. Results: Only VBM and VOL showed utility in correctly identifying bvFTD from our set of data. The overall classification sensitivity of bvFTD with VOL + VBM achieved a total sensitivity of 60%. Using VOL + VBM, 32% were misclassified as having LBD. There was a trend of higher values for classification sensitivity of the C9ORF72 expansion carriers than noncarriers. Conclusion: VOL, VBM, and their combination are effective in differential diagnostics between bvFTD and AD or SMC. However, MRI atrophy profiles for bvFTD and LBD are too similar for a reliable differentiation with the quantification methods tested in this study.

Behavioral variant frontotemporal dementia patients do not succumb to the Allais paradox

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Maxime eBertoux

2014-09-01

Full Text Available The Allais Paradox represents on of the earliest empirical challenges to normative models of decision-making, and suggests that choices in one part of a gamble may depend on the possible outcome in another, independent, part of the gamble—a violation of the so-called independence axiom. To account for Allaisian behavior, one well-known class of models propose that individuals’ choices are influenced not only by possible outcomes resulting from one’s choices, but also the anticipation of regret for foregone options. Here we test the regret hypothesis using a population of patients with behavioral variant frontotemporal dementia (bvFTD, a clinical population known to present ventromedial prefrontal cortex dysfunctions and associated with impaired regret processing in previous studies of decision-making. Compared to behavior of matched controls and Alzheimer (AD patients that has no ventromedial prefrontal atrophy, we found a striking diminution of Allaisian behavior among bvFTD patients. These results are consistent with the regret hypothesis and furthermore suggest a crucial role for prefrontal regions in choices that typically stands in contradiction with a basic axiom of rational decision-making.

Mentalising music in frontotemporal dementia.

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Downey, Laura E; Blezat, Alice; Nicholas, Jennifer; Omar, Rohani; Golden, Hannah L; Mahoney, Colin J; Crutch, Sebastian J; Warren, Jason D

2013-01-01

Despite considerable recent interest, the biological basis and clinical diagnosis of behavioural variant frontotemporal dementia (bvFTD) pose unresolved problems. Mentalising (the cognitive capacity to interpret the behaviour of oneself and others in terms of mental states) is impaired as a prominent feature of bvFTD, consistent with involvement of brain regions including ventro-medial prefrontal cortex (PFC), orbitofrontal cortex and anterior temporal lobes. Here, we investigated mentalising ability in a cohort of patients with bvFTD using a novel modality: music. We constructed a novel neuropsychological battery requiring attribution of affective mental or non-mental associations to musical stimuli. Mentalising performance of patients with bvFTD (n = 20) was assessed in relation to matched healthy control subjects (n = 20); patients also had a comprehensive assessment of behaviour and general neuropsychological functions. Neuroanatomical correlates of performance on the experimental tasks were investigated using voxel-based morphometry of patients' brain magnetic resonance imaging (MRI) scans. Compared to healthy control subjects, patients showed impaired ability to attribute mental states but not non-mental characteristics to music, and this deficit correlated with performance on a standard test of social inference and with carer ratings of patients' empathic capacity, but not with other potentially relevant measures of general neuropsychological function. Mentalising performance in the bvFTD group was associated with grey matter changes in anterior temporal lobe and ventro-medial PFC. These findings suggest that music can represent surrogate mental states and the ability to construct such mental representations is impaired in bvFTD, with potential implications for our understanding of the biology of bvFTD and human social cognition more broadly. Copyright © 2012 Elsevier Ltd. All rights reserved.

Kraepelin’s description of chronic mania: a clinical picture that meets the behavioral variant frontotemporal dementia phenotype

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Leandro Boson Gambogi

Full Text Available ABSTRACT Chronic mania is an under-investigated condition and few reports have associated this disorder with an organic background. The present work examines Kraepelin’s reliable description of chronic mania from a current behavioral neurology viewpoint. Kraepelin had described a cluster of symptoms that are now recognized as core manifestations of the behavioral variant frontotemporal dementia (bvFTD clinical phenotype. We also carried out additional reviews of original manuscripts from Kraepelin’s peers, in order to find any case reports that might fulfill the current diagnostic proposal for bvFTD. Even though we failed to find an ideal case, we found some scholars who seemed to agree that chronic mania should be considered a special form of dementia. The present work highlights, through historical data, the possible overlapping features between primary psychiatric disorders and neuropsychiatric symptoms secondary to neurodegenerative conditions.

Cortical function in Alzheimer’s disease and frontotemporal dementia

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Wang Pan

2016-01-01

Full Text Available Alzheimer’s disease (AD and the behavioral variant of frontotemporal dementia (bvFTD are the most common causes of dementia; however, their overlapping clinical syndromes and involved brain regions make a differential diagnosis difficult. We aimed to identify the differences in the cognition and motor cortex excitability between AD and bvFTD patients.

Restoring neuronal progranulin reverses deficits in a mouse model of frontotemporal dementia.

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Arrant, Andrew E; Filiano, Anthony J; Unger, Daniel E; Young, Allen H; Roberson, Erik D

2017-05-01

Loss-of-function mutations in progranulin (GRN), a secreted glycoprotein expressed by neurons and microglia, are a common autosomal dominant cause of frontotemporal dementia, a neurodegenerative disease commonly characterized by disrupted social and emotional behaviour. GRN mutations are thought to cause frontotemporal dementia through progranulin haploinsufficiency, therefore, boosting progranulin expression from the intact allele is a rational treatment strategy. However, this approach has not been tested in an animal model of frontotemporal dementia and it is unclear if boosting progranulin could correct pre-existing deficits. Here, we show that adeno-associated virus-driven expression of progranulin in the medial prefrontal cortex reverses social dominance deficits in Grn+/- mice, an animal model of frontotemporal dementia due to GRN mutations. Adeno-associated virus-progranulin also corrected lysosomal abnormalities in Grn+/- mice. The adeno-associated virus-progranulin vector only transduced neurons, suggesting that restoring neuronal progranulin is sufficient to correct deficits in Grn+/- mice. To further test the role of neuronal progranulin in the development of frontotemporal dementia-related deficits, we generated two neuronal progranulin-deficient mouse lines using CaMKII-Cre and Nestin-Cre. Measuring progranulin levels in these lines indicated that most brain progranulin is derived from neurons. Both neuronal progranulin-deficient lines developed social dominance deficits similar to those in global Grn+/- mice, showing that neuronal progranulin deficiency is sufficient to disrupt social behaviour. These data support the concept of progranulin-boosting therapies for frontotemporal dementia and highlight an important role for neuron-derived progranulin in maintaining normal social function. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Relación entre el feedback emocional, feedback cognitivo-verbal y percepción emocional en la variante frontal de demencia frontotemporal resultados preliminares Relationship Between Emotional Feedback, Verbal-Cognitive Feedback And Emotional Perception In The Frontal Variant Of Frontotemporal Dementia Preliminary Results

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Florencia Calodolce

2008-12-01

Full Text Available Numerosos estudios hallaron disociaciones, tanto entre las pruebas de cognición social entre sí, como entre éstas y las que evalúan funciones ejecutivas, lo cual apoya la idea de que el feedback emocional, la percepción emocional y el feedback cognitivo-verbal constituyen dominios cognitivos independientes. Sin embargo en la literatura actual existe controversia respecto de aquella disociación. Con el objetivo de estudiar dicha relación se evaluaron 15 sujetos con variante frontal de Demencia Frontotemporal (DFTvf con una batería neuropsicológica, y además utilizando: Wisconsin Card Sorting Test (WCST, Iowa Gamblig Task (IGT y Test de Lectura de Mente en Ojos (LMO. Se encontró un correlación inversa entre IGT y WCST, correlación directa entre LMO y WCST y falta de correlación entre IGT y LMO. Estos resultados apoyan la hipótesis de que los dominios cognitivos estudiados se encuentran disociados (Bechara, A., Damasio, A.R. y Lough, S..Several studies found dissociations, both between social cognition tests among themselves, and between these and those evaluating executive functions, which supports the idea that emotional feedback, emotional perception and verbal-cognitive feedback are independent cognitive domains. Nevertheless in present literature there is a controversy respect to that dissosciation. With the objective to study the relation between these processes a group of 15 subjects with frontal variant of Frontotemporal Dementia (DFTvf, was evaluated with a neuropsycological battery and in addition using: Wisconsin Card Sorting Test (WCST, Iowa Gamblig Task (IGT and The Reading the mind in Eyes Test (LMO. There was found: an inverse correlation between IGT and WCST, a direct correlation between LMO and WCST and a lack of correlation between IGT and LMO. These results support the hypothesis that the studied cognitive domains are dissociated (Bechara,A., Damasio, A.R. y Lough, S..

Frontotemporal dementia and primary progressive aphasia, a review

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Kirshner HS

2014-06-01

Full Text Available Howard S KirshnerDepartment of Neurology, Vanderbilt University Medical Center, Nashville, TN, USAAbstract: Frontotemporal dementias are neurodegenerative diseases in which symptoms of frontal and/or temporal lobe disease are the first signs of the illness, and as the diseases progress, they resemble a focal left hemisphere process such as stroke or traumatic brain injury, even more than a neurodegenerative disease. Over time, some patients develop a more generalized dementia. Four clinical subtypes characterize the predominant presentations of this illness: behavioral or frontal variant FTD, progressive nonfluent aphasia, semantic dementia, and logopenic primary progressive aphasia. These clinical variants correlate with regional patterns of atrophy on brain imaging studies such as MRI and PET scanning, as well as with biochemical and molecular genetic variants of the disorder. The treatment is as yet only symptomatic, but advances in molecular genetics promise new therapies.Keywords: FTD, behavior variant or frontal variant FTD, pick's disease, PPA, progressive nonfluent aphasia

Frontotemporal dementias: Recent advances and current controversies

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Leyton Cristian

2010-10-01

Full Text Available Frontotemporal dementia (FTD syndromes comprise a heterogeneous group of neurodegenerative conditions characterized by atrophy in the frontal and temporal lobes. Three main clinical variants are recognized: Behavioral variant (bv-FTD, Semantic dementia (SD, and Progressive nonfluent aphasia (PNFA. However, logopenic/phonological (LPA variant has been recently described, showing a distinctive pattern of brain atrophy and often associated to Alzheimer′s disease pathology. The diagnosis of FTD is challenging, since there is clinical, pathological, and genetic overlap between the variants and other neurodegenerative diseases, such as motoneuron disease (MND and corticobasal degeneration (CBD. In addition, patients with gene mutations (tau and progranulin display an inconsistent clinical phenotype and the correspondence between the clinical variant and its pathology is unpredictable. New cognitive tests based on social cognition and emotional recognition together with advances in molecular pathology and genetics have contributed to an improved understanding. There is now a real possibility of accurate biomarkers for early diagnosis. The present review concentrates on new insights and debates in FTD.

Motor speech signature of behavioral variant frontotemporal dementia: Refining the phenotype.

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Vogel, Adam P; Poole, Matthew L; Pemberton, Hugh; Caverlé, Marja W J; Boonstra, Frederique M C; Low, Essie; Darby, David; Brodtmann, Amy

2017-08-22

To provide a comprehensive description of motor speech function in behavioral variant frontotemporal dementia (bvFTD). Forty-eight individuals (24 bvFTD and 24 age- and sex-matched healthy controls) provided speech samples. These varied in complexity and thus cognitive demand. Their language was assessed using the Progressive Aphasia Language Scale and verbal fluency tasks. Speech was analyzed perceptually to describe the nature of deficits and acoustically to quantify differences between patients with bvFTD and healthy controls. Cortical thickness and subcortical volume derived from MRI scans were correlated with speech outcomes in patients with bvFTD. Speech of affected individuals was significantly different from that of healthy controls. The speech signature of patients with bvFTD is characterized by a reduced rate (75%) and accuracy (65%) on alternating syllable production tasks, and prosodic deficits including reduced speech rate (45%), prolonged intervals (54%), and use of short phrases (41%). Groups differed on acoustic measures derived from the reading, unprepared monologue, and diadochokinetic tasks but not the days of the week or sustained vowel tasks. Variability of silence length was associated with cortical thickness of the inferior frontal gyrus and insula and speech rate with the precentral gyrus. One in 8 patients presented with moderate speech timing deficits with a further two-thirds rated as mild or subclinical. Subtle but measurable deficits in prosody are common in bvFTD and should be considered during disease management. Language function correlated with speech timing measures derived from the unprepared monologue only. © 2017 American Academy of Neurology.

Meta-analytic Review of Memory Impairment in Behavioral Variant Frontotemporal Dementia.

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Poos, Jackie M; Jiskoot, Lize C; Papma, Janne M; van Swieten, John C; van den Berg, Esther

2018-03-19

A meta-analysis of the extent, nature and pattern of memory performance in behavioral variant frontotemporal dementia (bvFTD). Multiple observational studies have challenged the relative sparing of memory in bvFTD as stated in the current diagnostic criteria. We performed a meta-analytic review covering the period 1967 to February 2017 of case-control studies on episodic memory in bvFTD versus control participants (16 studies, 383 patients, 603 control participants), and patients with bvFTD versus those with Alzheimer's disease (AD) (20 studies, 452 bvFTD, 874 AD). Differences between both verbal and non-verbal working memory, episodic memory learning and recall, and recognition memory were examined. Data were extracted from the papers and combined into a common metric measure of effect, Hedges' d. Patients with bvFTD show large deficits in memory performance compared to controls (Hedges' d -1.10; 95% confidence interval [CI] [-1.23, -0.95]), but perform significantly better than patients with AD (Hedges' d 0.85; 95% CI [0.69, 1.03]). Learning and recall tests differentiate best between patients with bvFTD and AD (p<.01). There is 37-62% overlap in test scores between the two groups. This study points to memory disorders in patients with bvFTD, with performance at an intermediate level between controls and patients with AD. This indicates that, instead of being an exclusion criterion for bvFTD diagnosis, memory deficits should be regarded as a potential integral part of the clinical spectrum. (JINS, 2018, 24, 1-13).

The behavioral variant of frontotemporal dementia: An analysis of the literature and a case report.

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Birkhoff, Jutta Maria; Garberi, Cesare; Re, Laura

2016-01-01

The aim of this case report is to underline the importance of possible legal consequences of the behavioral variant of frontotemporal dementia (bvFTD). This disease is associated with antisocial behavior, impulse control disorder and cognitive and personality impairment, which are often the earliest manifestations of the bvFTD. One of the antisocial behaviors possibly associated with this neurodegenerative disease is pathological stealing. This case report is about a 50-year-old Italian man who had a regular life until 2010. In 2010 and 2011, some critical events occurred: he lost his job, his father-in-law, to whom he was particularly close, died, and his wife had a serious illness. He began to show symptoms of depression, a significant weight loss, apathy, poor self-care, and lack of interest in the activities of his family. He became disengaged from his prior activities, emotionally detached from his family and developed compulsive hoarding. Moreover, he had uninhibited behaviors, a memory retrieval deficit, executive dysfunctions and impulsive behaviors. In January 2012, the subject began stealing objects, particularly components of computer, without premeditation or concern for resulting legal actions. He was then diagnosed affected by bvFTD. He was charged with theft and attempted theft and the Court asked for a psychiatric evaluation, in order to analyze the effect of the neurodegenerative disease on his behavior. To answer to the Court, the Authors analyzed his history of life and made a mental examination. The subject was considered mentally insane at the time of his crimes. This is an example of the practical application in judicial cases of the latest knowledge and evidence in the literature about the frontotemporal dementia, a disease associated with antisocial behaviors that could create tensions with the criminal law. The focus of the paper is to explain how the behavioral symptoms of bvFTD can have legal implications and how to deal with legal

Unclassified cases of behavioral variant of major frontotemporal neurocognitive disorder in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition.

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Fukuda, Koji; Hattori, Hideyuki

2014-04-01

In the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), the behavioral variant of major frontotemporal neurocognitive disorder (bvFT-NCD) is subclassified into "probable bvFT-NCD" or "possible bvFT-NCD." When genetic evidence is unavailable, cases without clinical neuroimaging are subclassified into "possible bvFT-NCD," whereas cases whose clinical images show the typical characteristics are subclassified into "probable bvFT-NCD." Thus, the cases that meet the diagnostic criteria of bvFT-NCD based on their symptoms, but lack the neuroimaging characteristics, fall between the two categories of probable and possible bvFT-NCD. These cases herein are defined as "unclassified bvFT-NCD," and the present study aims at considering an appropriate diagnostic approach to such cases, that is, whether unclassified bvFT-NCD should be included in bvFT-NCD as a third subcategory, or whether it should be classified into diseases other than bvFT-NCD. All patients who presented at the Department of Psychiatry of the National Center for Geriatrics and Gerontology with suspicion of the behavioral variant of frontotemporal dementia between 1 May 2011 and 30 April 2013 were retrospectively rediagnosed based on the DSM-5 criteria. A total of 16 cases met the criteria of bvFT-NCD, and among them, eight cases corresponded to unclassified bvFT-NCD. From a cross-sectional and clinical perspective, all eight cases of unclassified bvFT-NCD fulfilled the symptomatic criteria for bvFT-NCD, although the possibilities of Alzheimer's disease and other mental disorders could not be ruled out completely. To establish clinical diagnostic criteria for unclassified bvFT-NCD, accumulation of cases and evidence will be required along with longitudinal observation using various diagnostic technologies and post-mortem examination. © 2014 Japan Geriatrics Society.

Comparing the driving behaviours of individuals with frontotemporal lobar degeneration and those with Alzheimer's disease.

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Fujito, Ryoko; Kamimura, Naoto; Ikeda, Manabu; Koyama, Asuka; Shimodera, Shinji; Morinobu, Shigeru; Inoue, Shimpei

2016-01-01

Assessing driving aptitude in dementia patients is critically important for both patient and public safety. However, there have been only a few reports on the driving behaviours and accident risk of patients with dementia, especially frontotemporal lobar degeneration (FTLD). Therefore, we compared the characteristics of driving behaviours in patients with FTLD and those with Alzheimer's disease (AD). The subjects were 28 FTLD and 67 AD patients who visited the Department of Psychiatry, Kochi Medical School Hospital. We conducted semi-structured interviews with their families and caregivers about traffic accident history and changes in patient driving behaviours after dementia onset and then compared the findings between the two groups. Overall changes in driving behaviours were reported in 89% (25/28) and 76% (51/67) of the FTLD and AD patients, respectively (P = 0.17). In the FTLD group, difficulty in judging inter-vehicle distances, ignoring road signs and traffic signals, and distraction were reported in 50% (14/28), 61% (17/28), and 50% (14/28) of patients, respectively, and 75% (21/28) patients had caused a traffic accident after dementia onset. The risk of causing an accident was higher in the FTLD group than in the AD group (odds ratio = 10.4, 95% confidence interval = 3.7-29.1). In addition, the mean duration between dementia onset and a traffic accident was 1.35 years in the FTLD group compared with 3.0 years in the AD group (P driving behaviours than those with AD, and the risk of causing a traffic accident may be higher in patients with FTLD from an early disease stage. © 2015 The Authors. Psychogeriatrics © 2015 Japanese Psychogeriatric Society.

Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features

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Mahoney, Colin J.; Beck, Jon; Rohrer, Jonathan D.; Lashley, Tammaryn; Mok, Kin; Shakespeare, Tim; Yeatman, Tom; Warrington, Elizabeth K.; Schott, Jonathan M.; Fox, Nick C.; Rossor, Martin N.; Hardy, John; Collinge, John; Revesz, Tamas; Mead, Simon

2012-01-01

An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43–68 years) and duration (1.7–22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases

Frontotemporal lobar degeneration: current perspectives

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Riedl L

2014-02-01

Full Text Available Lina Riedl,1 Ian R Mackenzie,2 Hans Förstl,1 Alexander Kurz,1 Janine Diehl-Schmid1 1Center for Cognitive Disorders, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; 2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada Abstract: The term frontotemporal lobar degeneration (FTLD refers to a group of progressive brain diseases, which preferentially involve the frontal and temporal lobes. Depending on the primary site of atrophy, the clinical manifestation is dominated by behavior alterations or impairment of language. The onset of symptoms usually occurs before the age of 60 years, and the mean survival from diagnosis varies between 3 and 10 years. The prevalence is estimated at 15 per 100,000 in the population aged between 45 and 65 years, which is similar to the prevalence of Alzheimer's disease in this age group. There are two major clinical subtypes, behavioral-variant frontotemporal dementia and primary progressive aphasia. The neuropathology underlying the clinical syndromes is also heterogeneous. A common feature is the accumulation of certain neuronal proteins. Of these, the microtubule-associated protein tau (MAPT, the transactive response DNA-binding protein, and the fused in sarcoma protein are most important. Approximately 10% to 30% of FTLD shows an autosomal dominant pattern of inheritance, with mutations in the genes for MAPT, progranulin (GRN, and in the chromosome 9 open reading frame 72 (C9orf72 accounting for more than 80% of familial cases. Although significant advances have been made in recent years regarding diagnostic criteria, clinical assessment instruments, neuropsychological tests, cerebrospinal fluid biomarkers, and brain imaging techniques, the clinical diagnosis remains a challenge. To date, there is no specific pharmacological treatment for FTLD. Some evidence has been provided for serotonin reuptake

Facial Emotion Recognition Performance Differentiates Between Behavioral Variant Frontotemporal Dementia and Major Depressive Disorder.

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Chiu, Isabelle; Piguet, Olivier; Diehl-Schmid, Janine; Riedl, Lina; Beck, Johannes; Leyhe, Thomas; Holsboer-Trachsler, Edith; Kressig, Reto W; Berres, Manfred; Monsch, Andreas U; Sollberger, Marc

Misdiagnosis of early behavioral variant frontotemporal dementia (bvFTD) with major depressive disorder (MDD) is not uncommon due to overlapping symptoms. The aim of this study was to improve the discrimination between these disorders using a novel facial emotion perception task. In this prospective cohort study (July 2013-March 2016), we compared 25 patients meeting Rascovsky diagnostic criteria for bvFTD, 20 patients meeting DSM-IV criteria for MDD, 21 patients meeting McKhann diagnostic criteria for Alzheimer's disease dementia, and 31 healthy participants on a novel emotion intensity rating task comprising morphed low-intensity facial stimuli. Participants were asked to rate the intensity of morphed faces on the congruent basic emotion (eg, rating on sadness when sad face is shown) and on the 5 incongruent basic emotions (eg, rating on each of the other basic emotions when sad face is shown). While bvFTD patients underrated congruent emotions (P dementia patients perceived emotions similarly to healthy participants, indicating no impact of cognitive impairment on rating scores. Our congruent and incongruent facial emotion intensity rating task allows a detailed assessment of facial emotion perception in patient populations. By using this simple task, we achieved an almost complete discrimination between bvFTD and MDD, potentially helping improve the diagnostic certainty in early bvFTD. © Copyright 2018 Physicians Postgraduate Press, Inc.

Resting state functional connectivity differences between behavioral variant frontotemporal dementia and Alzheimer’s disease

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Anne eHafkemeijer

2015-09-01

Full Text Available Alzheimer’s disease (AD and behavioral variant frontotemporal dementia (bvFTD are the most common types of early-onset dementia. Here, we apply resting state functional magnetic resonance imaging (fMRI to study functional brain connectivity differences between AD and bvFTD.We used resting state fMRI data of 31 AD patients, 25 bvFTD patients, and 29 controls. We studied functional connectivity throughout the entire brain, applying two different analysis techniques, studying network-to-region and region-to-region connectivity. A general linear model approach was used to study group differences, while controlling for physiological noise, age, gender, study center, and regional gray matter volume. Given gray matter differences, we observed decreased network-to-region connectivity in bvFTD between a lateral visual cortical network and lateral occipital and cuneal cortex, and b auditory system network and angular gyrus. In AD, we found decreased network-to-region connectivity between the dorsal visual stream network and lateral occipital and parietal opercular cortex. Region-to-region connectivity was decreased in bvFTD between superior temporal gyrus and cuneal, supracalcarine, intracalcarine cortex, and lingual gyrus. We showed that the pathophysiology of functional brain connectivity is different between AD and bvFTD. However, the group differences in functional connectivity are less abundant than has been shown in previous studies.

Manic behavior and asymmetric right frontotemporal dementia from a novel progranulin mutation

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Mendez MF

2018-02-01

Full Text Available Mario F Mendez1–3 1Department of Neurology, 2Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA; 3Neurology Service, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA Abstract: Studies suggest a relationship of manic behavior and bipolar disorder (BD with behavioral variant frontotemporal dementia (bvFTD. The nature of this relationship is unclear. This report presents a patient with initial manic behavior as the main manifestation of familial bvFTD from a novel progranulin (GRN mutation. In contrast, there are other reports of a long background of BD preceding a diagnosis of bvFTD. A review of the literature and this patient suggest that manic symptoms result from damage to right frontotemporal neural structures from longstanding BD, as well as from bvFTD and other focal neurological disorders. In addition, there is a subgroup of patients with a probable genetic predisposition to both BD and bvFTD. Keywords: frontotemporal dementia, mania, bipolar disorder, progranulin mutation

Face shape and face identity processing in behavioral variant fronto-temporal dementia: A specific deficit for familiarity and name recognition of famous faces.

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De Winter, François-Laurent; Timmers, Dorien; de Gelder, Beatrice; Van Orshoven, Marc; Vieren, Marleen; Bouckaert, Miriam; Cypers, Gert; Caekebeke, Jo; Van de Vliet, Laura; Goffin, Karolien; Van Laere, Koen; Sunaert, Stefan; Vandenberghe, Rik; Vandenbulcke, Mathieu; Van den Stock, Jan

2016-01-01

Deficits in face processing have been described in the behavioral variant of fronto-temporal dementia (bvFTD), primarily regarding the recognition of facial expressions. Less is known about face shape and face identity processing. Here we used a hierarchical strategy targeting face shape and face identity recognition in bvFTD and matched healthy controls. Participants performed 3 psychophysical experiments targeting face shape detection (Experiment 1), unfamiliar face identity matching (Experiment 2), familiarity categorization and famous face-name matching (Experiment 3). The results revealed group differences only in Experiment 3, with a deficit in the bvFTD group for both familiarity categorization and famous face-name matching. Voxel-based morphometry regression analyses in the bvFTD group revealed an association between grey matter volume of the left ventral anterior temporal lobe and familiarity recognition, while face-name matching correlated with grey matter volume of the bilateral ventral anterior temporal lobes. Subsequently, we quantified familiarity-specific and name-specific recognition deficits as the sum of the celebrities of which respectively only the name or only the familiarity was accurately recognized. Both indices were associated with grey matter volume of the bilateral anterior temporal cortices. These findings extent previous results by documenting the involvement of the left anterior temporal lobe (ATL) in familiarity detection and the right ATL in name recognition deficits in fronto-temporal lobar degeneration.

Meta-Analysis of Facial Emotion Recognition in Behavioral Variant Frontotemporal Dementia: Comparison With Alzheimer Disease and Healthy Controls.

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Bora, Emre; Velakoulis, Dennis; Walterfang, Mark

2016-07-01

Behavioral disturbances and lack of empathy are distinctive clinical features of behavioral variant frontotemporal dementia (bvFTD) in comparison to Alzheimer disease (AD). The aim of this meta-analytic review was to compare facial emotion recognition performances of bvFTD with healthy controls and AD. The current meta-analysis included a total of 19 studies and involved comparisons of 288 individuals with bvFTD and 329 healthy controls and 162 bvFTD and 147 patients with AD. Facial emotion recognition was significantly impaired in bvFTD in comparison to the healthy controls (d = 1.81) and AD (d = 1.23). In bvFTD, recognition of negative emotions, especially anger (d = 1.48) and disgust (d = 1.41), were severely impaired. Emotion recognition was significantly impaired in bvFTD in comparison to AD in all emotions other than happiness. Impairment of emotion recognition is a relatively specific feature of bvFTD. Routine assessment of social-cognitive abilities including emotion recognition can be helpful in better differentiating between cortical dementias such as bvFTD and AD. © The Author(s) 2016.

Emergence of artistic talent in frontotemporal dementia.

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Miller, B L; Cummings, J; Mishkin, F; Boone, K; Prince, F; Ponton, M; Cotman, C

1998-10-01

To describe the clinical, neuropsychological, and imaging features of five patients with frontotemporal dementia (FTD) who acquired new artistic skills in the setting of dementia. Creativity in the setting of dementia has recently been reported. We describe five patients who became visual artists in the setting of FTD. Sixty-nine FTD patients were interviewed regarding visual abilities. Five became artists in the early stages of FTD. Their history, artistic process, neuropsychology, and anatomy are described. On SPECT or pathology, four of the five patients had the temporal variant of FTD in which anterior temporal lobes are involved but the dorsolateral frontal cortex is spared. Visual skills were spared but language and social skills were devastated. Loss of function in the anterior temporal lobes may lead to the "facilitation" of artistic skills. Patients with the temporal lobe variant of FTD offer a window into creativity.

Behavioral variant frontotemporal dementia: advanced disease stages and death. A step to palliative care.

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Diehl-Schmid, J; Richard-Devantoy, S; Grimmer, T; Förstl, H; Jox, R

2017-08-01

The aim of the present study was to gain insight into the living and care situation in advanced behavioral variant frontotemporal dementia (bvFTD), to describe symptoms and findings in advanced bvFTD, and to evaluate somatic comorbidities and circumstances of death. Standardized interviews were conducted with family caregivers of 83 patients with bvFTD. Forty-four percent of the patients were already deceased at the time of the interview. At the time of the interview or death, respectively, 47% of the patients lived in a nursing home. The median time between symptom onset and nursing home admission was 5.0 ± 5.5 years. In moderate and severe dementia stages almost all patients suffered from severe disabilities including impairment of language, gait, swallowing, and of the ability to care for themselves. Sixteen percent of the patients had got enteral tube feeding. Comorbid somatic diseases were diagnosed in 46% of the patients. Twenty-three percent of the deceased patients had been admitted into a hospital before death. Cardiovascular disease and respiratory disease, mostly pneumonia, were the most frequent causes of death. Advanced bvFTD is characterized by severe cognitive impairment and physical disabilities. BvFTD leads to a premature death. Our findings stress the importance of strategies that maximize patient comfort in advanced disease stages and allow for a peaceful death. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

[Pathological gambling and epilepsy in patients with frontotemporal dementia: Two case reports].

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Castro-Suarez, Sheila; Martinez, Peggy; Meza, María

2016-01-01

Frontotemporal dementia is a neurodegenerative disorder of which the behavioral variant is most common. This condition is currently considered the most common cause of dementia in people younger than 60 years. Here, we present two unrelated cases in which the typical symptoms were cognitive and behavioral progressive deterioration and psychiatric disorders such as disinhibition, impulsive acts, apathy, lack of empathy, stereotypies, and changes in eating habits. The first case exhibited pathological gambling as the initial symptom and resided in a psychiatric facility for a year. Notably, this was the second such case in Latin America and one of only a few such cases reported worldwide. The second case presented with epileptic seizures during evolution. In both cases, brain magnetic resonance revealed left-predominant frontotemporal atrophy, and alterations in executive function were evident during neuropsychological assessments.

Frontotemporal Dementias: A Review

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Wilkins Kirsten

2007-06-01

Full Text Available Abstract Dementia is a clinical state characterized by loss of function in multiple cognitive domains. It is a costly disease in terms of both personal suffering and economic loss. Frontotemporal dementia (FTD is the term now preferred over Picks disease to describe the spectrum of non-Alzheimers dementias characterized by focal atrophy of the frontal and anterior temporal regions of the brain. The prevalence of FTD is considerable, though specific figures vary among different studies. It occurs usually in an age range of 35–75 and it is more common in individuals with a positive family history of dementia. The risk factors associated with this disorder include head injury and family history of FTD. Although there is some controversy regarding the further syndromatic subdivision of the different types of FTD, the three major clinical presentations of FTD include: 1 a frontal or behavioral variant (FvFTD, 2 a temporal, aphasic variant, also called Semantic dementia (SD, and 3 a progressive aphasia (PA. These different variants differ in their clinical presentation, cognitive deficits, and affected brain regions. Patients with FTD should have a neuropsychiatric assessment, neuropsychological testing and neuroimaging studies to confirm and clarify the diagnosis. Treatment for this entity consists of behavioral and pharmacological approaches. Medications such as serotonin reuptake inhibitors, antipsychotics, mood stabilizer and other novel treatments have been used in FTD with different rates of success. Further research should be directed at understanding and developing new diagnostic and therapeutic modalities to improve the patients' prognosis and quality of life.

Brain perfusion SPECT with Brodmann areas analysis in differentiating frontotemporal dementia subtypes.

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Valotassiou, Varvara; Papatriantafyllou, John; Sifakis, Nikolaos; Tzavara, Chara; Tsougos, Ioannis; Psimadas, Dimitrios; Kapsalaki, Eftychia; Fezoulidis, Ioannis; Hadjigeorgiou, George; Georgoulias, Panagiotis

2014-01-01

Despite the known validity of clinical diagnostic criteria, significant overlap of clinical symptoms between Frontotemporal dementia (FTD) subtypes exists in several cases, resulting in great uncertainty of the diagnostic boundaries. We evaluated the perfusion between FTD subtypes using brain perfusion (99m)Tc-HMPAO SPECT with Brodmann areas (BA) mapping. NeuroGam software was applied on single photon emission computed tomographic (SPECT) studies for the semi-quantitative evaluation of perfusion in BA and the comparison with the software's normal database. We studied 91 consecutive FTD patients: 21 with behavioural variants (bvFTD), 39 with language variants (lvFTD) [12 with progressive non-fluent aphasia (PNFA), 27 with semantic dementia (SD)], and 31 patients with progressive supranuclear palsy (PSP)/corticobasal degeneration (CBD). Stepwise logistic regression analyses showed that the BA 28L and 32R could independently differentiate bvFTD from lvFTD, while the BA 8R and 25R could discriminate bvFTD from SD and PNFA, respectively. Additionally, BA 7R and 32R were found to discriminate bvFTD from CBD/PSP. The only BA that could differentiate SD from PNFA was 6L. BA 6R and 20L were found to independently differentiate CBD/PSP from lvFTD. Moreover, BA 20L and 22R could discriminate CBD/PSP from PNFA, while BA 6R, 20L and 45R were found to independently discriminate CBD/PSP from SD. Brain perfusion SPECT with BA mapping can be a useful additional tool in differentiating FTD variants by improving the definition of brain areas that are specifically implicated, resulting in a more accurate differential diagnosis in atypical or uncertain forms of FTD.

Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia

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van Swieten, J.C.; Heutink, P.

2008-01-01

Background: Frontotemporal dementia (FTD) is predominantly a presenile disorder that is characterised by behavioural changes and cognitive impairment, particularly in language and executive functions, and is associated with neurodegeneration in the frontal or temporal cortices, or both. Research

The Relationship between Subclinical Asperger’s Syndrome and Frontotemporal Lobar Degeneration

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Akira Midorikawa

2012-04-01

Full Text Available Background/Aims: The existence of the behavioral variant of frontotemporal dementia (bv-FTD, including senile Asperger’s syndrome (AS, has been proposed. However, there are no empirical case reports to support the proposal. In this report, we present 3 patients who showed symptoms of bv-FTD and demonstrated signs of autistic spectrum disorder, especially AS. Methods: We evaluated 3 subjects using the diagnostic criteria for bv-FTD, and their caregivers retrospectively provided data to calculate the Autism-Spectrum Quotient, Japanese version [Wakabayashi et al.: Shinrigaku Kenkyu 2004;75:78–84]. We also compared these data with those obtained from 3 individuals with Alzheimer’s disease. Results: All 3 patients met the criteria for bv-FTD and had a higher Autism-Spectrum Quotient score than did comparable Alzheimer’s disease subjects. Conclusion: It is possible that some senile persons with frontotemporal lobar degeneration-like maladaptive behavior may suffer from subclinical AS.

Coexistence of Schizophrenia and Frontotemporal Dementia: A Case Report

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Zafer Subasi

2014-01-01

With this case, it is aimed to present a patient who was followed up with a diagnosis of schizophrenia nearly 30 years, had personality and behaviour changes added to clinical course for the last 4-5 years, had diagnostic confusion and was finally diagnosed with frontotemporal dementia superimposed on schizophrenia.Neurodegenerative diseases should be considered as either differential diagnosis or coexistence in case of symptoms such as cognitive decline or personality and behavior changes oc...

Frontotemporal Degeneration in a Child.

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Terrill, Tyler; Pascual, Juan M

2017-07-01

There is a predilection for the frontal and temporal lobes in certain cases of dementia in the adult, leading to the syndrome of frontotemporal dementia. However, this syndrome has seemed to elude the developing brain until now. We describe an example of apparently selective neurodegeneration of the frontal and temporal regions during development associated with some of the clinical, magnetic resonance imaging, and fludeoxyglucose positron emission tomography (FDG PET) scan features of canonical frontotemporal dementia in the adult. This patient does not have any of the common frontotemporal dementia-causing mutations or known progressive brain disorders of children. This patient illustrates that symptomatic, selective, and progressive vulnerability of the frontal and temporal lobes is not restricted to adulthood, expanding the phenotype of frontotemporal degeneration. Copyright © 2017 Elsevier Inc. All rights reserved.

Enhanced Positive Emotional Reactivity Undermines Empathy in Behavioral Variant Frontotemporal Dementia

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Alice Y. Hua

2018-06-01

Full Text Available Behavioral variant frontotemporal dementia (bvFTD is a neurodegenerative disease characterized by profound changes in emotions and empathy. Although most patients with bvFTD become less sensitive to negative emotional cues, some patients become more sensitive to positive emotional stimuli. We investigated whether dysregulated positive emotions in bvFTD undermine empathy by making it difficult for patients to share (emotional empathy, recognize (cognitive empathy, and respond (real-world empathy to emotions in others. Fifty-one participants (26 patients with bvFTD and 25 healthy controls viewed photographs of neutral, positive, negative, and self-conscious emotional faces and then identified the emotions displayed in the photographs. We used facial electromyography to measure automatic, sub-visible activity in two facial muscles during the task: Zygomaticus major (ZM, which is active during positive emotional reactions (i.e., smiling, and Corrugator supercilii (CS, which is active during negative emotional reactions (i.e., frowning. Participants rated their baseline positive and negative emotional experience before the task, and informants rated participants' real-world empathic behavior on the Interpersonal Reactivity Index. The majority of participants also underwent structural magnetic resonance imaging. A mixed effects model found a significant diagnosis X trial interaction: patients with bvFTD showed greater ZM reactivity to neutral, negative (disgust and surprise, self-conscious (proud, and positive (happy faces than healthy controls. There was no main effect of diagnosis or diagnosis X trial interaction on CS reactivity. Compared to healthy controls, patients with bvFTD had impaired emotion recognition. Multiple regression analyses revealed that greater ZM reactivity predicted worse negative emotion recognition and worse real-world empathy. At baseline, positive emotional experience was higher in bvFTD than healthy controls and also

Early vs late age at onset frontotemporal dementia and frontotemporal lobar degeneration.

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Seo, Sang Won; Thibodeau, Marie-Pierre; Perry, David C; Hua, Alice; Sidhu, Manu; Sible, Isabel; Vargas, Jose Norberto S; Gaus, Stephanie E; Rabinovici, Gil D; Rankin, Katherine D; Boxer, Adam L; Kramer, Joel H; Rosen, Howard J; Gorno-Tempini, Maria Luisa; Grinberg, Lea T; Huang, Eric J; DeArmond, Stephen J; Trojanowski, John Q; Miller, Bruce L; Seeley, William W

2018-03-20

To examine clinicopathologic correlations in early vs late age at onset frontotemporal dementia (FTD) and frontotemporal lobar degeneration (FTLD). All patients were clinically evaluated and prospectively diagnosed at the UCSF Memory and Aging Center. Two consecutive series were included: (1) patients with a clinically diagnosed FTD syndrome who underwent autopsy (cohort 1) and (2) patients with a primary pathologic diagnosis of FTLD, regardless of the clinical syndrome (cohort 2). These series were divided by age at symptom onset (cutoff 65 years). In cohort 1, 48 (25.3%) were 65 years or older at symptom onset. Pathologic causes of behavioral variant FTD (bvFTD) were similar in the early age at onset (EO) and late age at onset (LO) bvFTD groups. In corticobasal syndrome (CBS), however, the most common pathologic substrate differed according to age at onset: progressive supranuclear palsy (42.9%) in LO-CBS and Alzheimer disease (AD; 40.7%) in EO-CBS. In cohort 2, 57 (28.4%) were classified as LO-FTLD. Regarding FTLD major molecular classes, FTLD with transactive response DNA-binding protein of 43 kDa was most common in EO-FTLD (44.4%), whereas FTLD-tau (58.3%) was most common in LO-FTLD. Antemortem diagnosis of a non-FTD syndrome, usually AD-type dementia, was more frequent in LO-FTLD than EO-FTLD (19.3% vs 7.7%, p = 0.017). LO-FTLD was also associated with more prevalent comorbid pathologic changes. Of these, moderate to severe AD neuropathologic change and argyrophilic grain disease were overrepresented among patients who received an antemortem diagnosis of AD-type dementia. Patients with FTD and FTLD often develop symptoms after age 65, and age at onset represents an important consideration when making antemortem neuropathologic predictions. © 2018 American Academy of Neurology.

Impaired Interoceptive Accuracy in Semantic Variant Primary Progressive Aphasia

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Charles R. Marshall

2017-11-01

Full Text Available BackgroundInteroception (the perception of internal bodily sensations is strongly linked to emotional experience and sensitivity to the emotions of others in healthy subjects. Interoceptive impairment may contribute to the profound socioemotional symptoms that characterize frontotemporal dementia (FTD syndromes, but remains poorly defined.MethodsPatients representing all major FTD syndromes and healthy age-matched controls performed a heartbeat counting task as a measure of interoceptive accuracy. In addition, patients had volumetric MRI for voxel-based morphometric analysis, and their caregivers completed a questionnaire assessing patients’ daily-life sensitivity to the emotions of others.ResultsInteroceptive accuracy was impaired in patients with semantic variant primary progressive aphasia relative to healthy age-matched individuals, but not in behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. Impaired interoceptive accuracy correlated with reduced daily-life emotional sensitivity across the patient cohort, and with atrophy of right insula, cingulate, and amygdala on voxel-based morphometry in the impaired semantic variant group, delineating a network previously shown to support interoceptive processing in the healthy brain.ConclusionInteroception is a promising novel paradigm for defining mechanisms of reduced emotional reactivity, empathy, and self-awareness in neurodegenerative syndromes and may yield objective measures for these complex symptoms.

Dissociation in Rating Negative Facial Emotions between Behavioral Variant Frontotemporal Dementia and Major Depressive Disorder.

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Chiu, Isabelle; Piguet, Olivier; Diehl-Schmid, Janine; Riedl, Lina; Beck, Johannes; Leyhe, Thomas; Holsboer-Trachsler, Edith; Berres, Manfred; Monsch, Andreas U; Sollberger, Marc

2016-11-01

Features of behavioral variant frontotemporal dementia (bvFTD) such as executive dysfunction, apathy, and impaired empathic abilities are also observed in major depressive disorder (MDD). This may contribute to the reason why early stage bvFTD is often misdiagnosed as MDD. New assessment tools are thus needed to improve early diagnosis of bvFTD. Although emotion processing is affected in bvFTD and MDD, growing evidence indicates that the pattern of emotion processing deficits varies between the two disorders. As such, emotion processing paradigms have substantial potentials to distinguish bvFTD from MDD. The current study compared 25 patients with bvFTD, 21 patients with MDD, 21 patients with Alzheimer disease (AD) dementia, and 31 healthy participants on a novel facial emotion intensity rating task. Stimuli comprised morphed faces from the Ekman and Friesen stimulus set containing faces of each sex with two different degrees of emotion intensity for each of the six basic emotions. Analyses of covariance uncovered a significant dissociation between bvFTD and MDD patients in rating the intensity of negative emotions overall (i.e., bvFTD patients underrated negative emotions overall, whereas MDD patients overrated negative emotions overall compared with healthy participants). In contrast, AD dementia patients rated negative emotions similarly to healthy participants, suggesting no impact of cognitive deficits on rating facial emotions. By strongly differentiating bvFTD and MDDpatients through negative facial emotions, this sensitive and short rating task might help improve the early diagnosis of bvFTD. Copyright © 2016 American Association for Geriatric Psychiatry. All rights reserved.

The frontal-anatomic specificity of design fluency repetitions and their diagnostic relevance for behavioral variant frontotemporal dementia.

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Possin, Katherine L; Chester, Serana K; Laluz, Victor; Bostrom, Alan; Rosen, Howard J; Miller, Bruce L; Kramer, Joel H

2012-09-01

On tests of design fluency, an examinee draws as many different designs as possible in a specified time limit while avoiding repetition. The neuroanatomical substrates and diagnostic group differences of design fluency repetition errors and total correct scores were examined in 110 individuals diagnosed with dementia, 53 with mild cognitive impairment (MCI), and 37 neurologically healthy controls. The errors correlated significantly with volumes in the right and left orbitofrontal cortex (OFC), the right and left superior frontal gyrus, the right inferior frontal gyrus, and the right striatum, but did not correlate with volumes in any parietal or temporal lobe regions. Regression analyses indicated that the lateral OFC may be particularly crucial for preventing these errors, even after excluding patients with behavioral variant frontotemporal dementia (bvFTD) from the analysis. Total correct correlated more diffusely with volumes in the right and left frontal and parietal cortex, the right temporal cortex, and the right striatum and thalamus. Patients diagnosed with bvFTD made significantly more repetition errors than patients diagnosed with MCI, Alzheimer's disease, semantic dementia, progressive supranuclear palsy, or corticobasal syndrome. In contrast, total correct design scores did not differentiate the dementia patients. These results highlight the frontal-anatomic specificity of design fluency repetitions. In addition, the results indicate that the propensity to make these errors supports the diagnosis of bvFTD. (JINS, 2012, 18, 1-11).

The 5-HTTLPR variant in the serotonin transporter gene modifies degeneration of brain regions important for emotion in behavioral variant frontotemporal dementia

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Jennifer S. Yokoyama

2015-01-01

Full Text Available The serotonin transporter length polymorphism (5-HTTLPR short allele (5-HTTLPR-s has been associated with differential susceptibility for anxiety and depression in multiple psychiatric disorders. 5-HTTLPR-s modifies the serotonergic systems that support emotion and behavioral regulation by reducing gene expression, which slows the reuptake of serotonin, and is associated with distinct morphological and functional effects. Serotonergic systems are also shown to be dysfunctional in behavioral variant frontotemporal dementia (bvFTD, a disease characterized by marked socioemotional dysfunction. However, studies of 5-HTTLPR-s effects in bvFTD have been inconsistent. Our objective was to investigate the patterns of gray matter volume by 5-HTTLPR-s genotype in both healthy older controls and bvFTD patients. We performed voxel-based morphometry of 179 cognitively normal older adults and 24 bvFTD cases to determine brain changes associated with dose (0/1/2 of 5-HTTLPR-s allele. 5-HTTLPR-s frequency did not differ between controls and bvFTD. We found a significant interaction effect whereby carrying more 5-HTTLPR-s alleles in bvFTD was associated with smaller volume in left inferior frontal gyrus (T = 4.86, PFWE = 0.03 and larger volume in right temporal lobe (T = 5.01, PFWE = 0.01. These results suggest that the 5-HTTLPR-s allele differentially influences brain morphology in bvFTD. We propose that patients with bvFTD and 5-HTTLPR-s have altered volumes in regions that support socioemotional behavior, which may be a developmental or disease-related compensation for altered serotonergic activity.

Gene variants associated with antisocial behaviour: a latent variable approach.

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Bentley, Mary Jane; Lin, Haiqun; Fernandez, Thomas V; Lee, Maria; Yrigollen, Carolyn M; Pakstis, Andrew J; Katsovich, Liliya; Olds, David L; Grigorenko, Elena L; Leckman, James F

2013-10-01

The aim of this study was to determine if a latent variable approach might be useful in identifying shared variance across genetic risk alleles that is associated with antisocial behaviour at age 15 years. Using a conventional latent variable approach, we derived an antisocial phenotype in 328 adolescents utilizing data from a 15-year follow-up of a randomized trial of a prenatal and infancy nurse-home visitation programme in Elmira, New York. We then investigated, via a novel latent variable approach, 450 informative genetic polymorphisms in 71 genes previously associated with antisocial behaviour, drug use, affiliative behaviours and stress response in 241 consenting individuals for whom DNA was available. Haplotype and Pathway analyses were also performed. Eight single-nucleotide polymorphisms (SNPs) from eight genes contributed to the latent genetic variable that in turn accounted for 16.0% of the variance within the latent antisocial phenotype. The number of risk alleles was linearly related to the latent antisocial variable scores. Haplotypes that included the putative risk alleles for all eight genes were also associated with higher latent antisocial variable scores. In addition, 33 SNPs from 63 of the remaining genes were also significant when added to the final model. Many of these genes interact on a molecular level, forming molecular networks. The results support a role for genes related to dopamine, norepinephrine, serotonin, glutamate, opioid and cholinergic signalling as well as stress response pathways in mediating susceptibility to antisocial behaviour. This preliminary study supports use of relevant behavioural indicators and latent variable approaches to study the potential 'co-action' of gene variants associated with antisocial behaviour. It also underscores the cumulative relevance of common genetic variants for understanding the aetiology of complex behaviour. If replicated in future studies, this approach may allow the identification of a

Molecular Pathways Bridging Frontotemporal Lobar Degeneration and Psychiatric Disorders

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Roberta eZanardini

2016-02-01

Full Text Available The overlap of symptoms between neurodegenerative and psychiatric diseases has been reported. Neuropsychiatric alterations are commonly observed in dementia, especially in the behavioral variant of frontotemporal dementia (bvFTD, which is the most common clinical FTD subtype. At the same time, psychiatric disorders, like schizophrenia, can display symptoms of dementia, including features of frontal dysfunction with relative sparing of memory. In the present review we discuss common molecular features in these pathologies with a special focus on FTD. Molecules like Brain Derived Neurotrophic Factor (BDNF and progranulin are linked to the pathophysiology of both neurodegenerative and psychiatric diseases. In these brain-associated illnesses, the presence of disease-associated variants in BDNF and progranulin (GRN genes cause a reduction of circulating proteins levels, through alterations in proteins expression or secretion. For these reasons, we believe that prevention and therapy of psychiatric and neurological disorders could be achieved enhancing both BDNF and progranulin levels thanks to drug discovery efforts.

Emotional quotient in frontotemporal dementia vs. Alzheimer's disease: the role of socioemotional agnosia.

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Carr, Andrew R; Samimi, Mersal S; Paholpak, Pongsatorn; Jimenez, Elvira E; Mendez, Mario F

2017-01-01

Socioemotional dysfunction distinguishes behavioural variant frontotemporal dementia (bvFTD) from other dementias. Patients with bvFTD not only have early social impairment and emotional blunting, but they also have agnosia of their socioemotional dysfunction. To investigate the relationship between agnosia and dysfunction, we assessed self-knowledge of socioemotional dysfunction with an emotional quotient (EQ) scale administered to 12 patients with bvFTD and a comparison group of 12 age-matched patients with Alzheimer's disease (AD), and compared these self-ratings to caregiver ratings of social dysfunction and emotional blunting. The bvFTD patients self-rated as having higher EQs than the AD patients, particularly higher self-ratings of their Social Skills, an EQ subscale which correlated with increased emotional blunting. On within-groups analysis, the bvFTD patients' high self-ratings of their EQ Appraisal of Emotions correlated with increased socioemotional dysfunction, whereas all of the AD patients' self-ratings correlated appropriately with their degree of dysfunction. Large socioemotional agnosia scores (EQ minus function) distinguishes bvFTD from AD. Additionally, in bvFTD, agnosia specifically for their ability to appreciate others' emotions correlates with the degree of socioemotional dysfunction, suggesting a role for socioemotional agnosia in increasing socioemotional dysfunction.

Episodic Memory Dysfunction in Behavioral Variant Frontotemporal Dementia: A Clinical And FDG-PET Study.

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Fernández-Matarrubia, Marta; Matías-Guiu, Jordi A; Cabrera-Martín, María Nieves; Moreno-Ramos, Teresa; Valles-Salgado, María; Carreras, José Luis; Matías-Guiu, Jorge

2017-01-01

Episodic memory disturbance is still considered as an exclusion criterion for behavioral variant frontotemporal dementia (bvFTD), but growing evidence suggests that memory can be impaired. Our main purposes were to assess episodic memory in a group of bvFTD patients comparatively with Alzheimer's disease (AD) patients, and analyze the relationship between episodic memory and brain metabolism measured using positron emission tomography imaging with 18F-fluorodeoxyglucose (FDG-PET). Twenty-six bvFTD, 29 AD, and 24 healthy controls were included. Episodic memory was assessed by the Free and Cued Selective Reminding Test (FCSRT), which controls for effective encoding and measures memory consolidation processing. All participants underwent FDG-PET brain scans to provide data for voxel-based brain mapping analysis. Half of bvFTD patients had a deficit of total, free delayed, and total free delayed recall as severe as AD patients (amnestic-FTD). The other half had FCSRT scores similar to controls (non-amnestic-FTD). Imaging analyses revealed that amnestic-FTD showed bilateral lower metabolism than non-amnestic-FTD in anterior parahippocampal and inferior temporal gyri. Additionally, FCSRT total and total delayed scores were inversely correlated with parahippocampal metabolism in both bvFTD and AD. Besides, bvFTD showed an inverse association among FCSRT and inferior temporal metabolism. Our findings support that bvFTD could present a genuine amnesia affecting storage and consolidation abilities, which involves structures implicated in the Papez circuit, as occurs in AD, and also inferior temporal regions. These results contribute to understanding the mechanisms underpinning memory dysfunction in bvFTD, and may be relevant to further revisions of the current diagnostic criteria.

The behavioural/dysexecutive variant of Alzheimer's disease: clinical, neuroimaging and pathological features

NARCIS (Netherlands)

Ossenkoppele, R.; Pijnenburg, Y.A.L.; Perry, D.C.; Cohn-Sheehy, B.I.; Scheltens, N.M.E.; Vogel, J.W.; Kramer, J.H.; van der Vlies, A.E.; La Joie, R.; Rosen, H.J.; van der Flier, W.M.; Grinberg, L.T.; Rozemuller, A.J.M.; Huang, E.J.; van Berckel, B.N.M.; Miller, B.L.; Barkhof, F.; Jagust, W.J.; Scheltens, P.; Seeley, W.W.; Rabinovici, G.D.

2015-01-01

A 'frontal variant of Alzheimer's disease' has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimer's disease pathology. The description of this rare Alzheimer's disease phenotype has been limited to case reports and small series, and many clinical,

Demência fronto-temporal: aspectos clínicos e terapêuticos Demencia frontotemporal: aspectos clínicos y terapéuticos Frontotemporal dementia: clinical and therapeutic features

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Antônio Lúcio Teixeira-Jr

2006-04-01

Full Text Available A demência fronto-temporal é uma importante causa de demência no período pré-senil. Caracteriza-se por significativas modificações do comportamento e da personalidade, enquanto o funcionamento cognitivo avaliado por testes psicométricos tradicionais encontra-se relativamente preservado. Muitos pacientes buscam o psiquiatra em virtude dos sintomas comportamentais proeminentes, como apatia, desinibição e comportamentos perseverativos ou estereotipados. O tratamento racional da demência fronto-temporal é atualmente limitado. Os sintomas comportamentais são controlados principalmente por inibidores seletivos da recaptação de serotonina.La demencia frontotemporal es una importante causa de demencia en el período presenil de la vida. Se caracteriza por alteraciones significativas en el comportamiento y en la personalidad, mientras la función cognitiva evaluada por pruebas psicométricas convencionales resulta relativamente preservada. Muchos pacientes recurren al psiquiatra en función de síntomas comportamentales sobresalientes como apatía, desinhibición y comportamientos perseverantes o estereotipados. El tratamiento racional de la demencia frontotemporal aún se encuentra bastante limitado. Los síntomas comportamentales se controlan principalmente con inhibidores selectivos de la recaptación de serotonina.Frontotemporal dementia is a major cause of dementia in the presenium. It is characterized by significant changes in behavior and personality, while cognitive functioning as assessed by traditional psychometric tests is relatively preserved. Thus, many patients present to the psychiatrist because of the prominence of behavioral symptoms, such as apathy, disinhibition, perseverative or stereotyped behaviors. Rational treatment for frontotemporal dementia is currently limited. The behavioral symptoms are controlled mainly with selective serotonin reuptake inhibitors.

Reversal of pathology in CHMP2B-mediated frontotemporal dementia patient cells using RNA interference

DEFF Research Database (Denmark)

Nielsen, Troels Tolstrup; Mizielinska, Sarah; Hasholt, Lis

2012-01-01

role in the pathogenesis of the disease. METHODS: In the present study, we used lentiviral vectors to efficiently knockdown CHMP2B by delivering microRNA embedded small hairpin RNAs. RESULTS: We show that CHMP2B can be efficiently knocked down in patient fibroblasts using an RNA interference approach......BACKGROUND: Frontotemporal dementia is the second most common form of young-onset dementia after Alzheimer's disease, and several genetic forms of frontotemporal dementia are known. A rare genetic variant is caused by a point mutation in the CHMP2B gene. CHMP2B is a component of the ESCRT......-III complex, which is involved in endosomal trafficking of proteins targeted for degradation in lysosomes. Mutations in CHMP2B result in abnormal endosomal structures in patient fibroblasts and patient brains, probably through a gain-of-function mechanism, suggesting that the endosomal pathway plays a central...

Screening UBQLN-2 in French frontotemporal lobar degeneration and frontotemporal lobar degeneration-amyotrophic lateral sclerosis patients.

Science.gov (United States)

Lattante, Serena; Le Ber, Isabelle; Camuzat, Agnès; Pariente, Jérémie; Brice, Alexis; Kabashi, Edor

2013-08-01

The ubiquilin-2 gene (UBQLN-2) is the only amyotrophic lateral sclerosis (ALS)-related gene mapping on the X chromosome. Mutations in the PXX domain of UBQLN-2 have been first described in ALS patients with a mutational frequency of 2.6% in familial ALS cases with no evidence of male-to-male transmission. Different populations have been further tested with mutations largely distributed in the gene and lower frequency of positive cases. To determine the genetic contribution of UBQLN-2 in frontotemporal lobar degeneration (FTLD) and FTLD-ALS, we screened a cohort of 136 French patients, identifying a missense variant (c.1006A>G; p.T336A) in 1 FTLD patient whose biological relevance to disease is questionable. We conclude that UBQLN-2 mutations related to ALS/FTLD are extremely rare in French FTLD and FTLD-ALS patients and should not be analyzed systematically. Copyright © 2013. Published by Elsevier Inc.

Difficulties in detecting behavioral symptoms of frontotemporal lobar degeneration across cultures.

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Papatriantafyllou, John D; Viskontas, Indre V; Papageorgiou, Sokratis G; Miller, Bruce L; Pavlic, Danijela; Bingol, Ayse; Yener, Gorsev

2009-01-01

Cross-cultural studies of neurodegenerative disorders are especially important when the disease in question is difficult to diagnose, particularly if symptoms of the illness include behavioral disturbances that may be interpreted differently in different cultures. One such disease is frontotemporal lobar degeneration (FTLD), an early-age-of-onset dementia that disproportionately affects social behavior. We report the demographic and neuropsychologic characteristics of more than 300 patients diagnosed with FTLD in the United States, Greece, and Turkey. We find that patients with the frontal variant of frontotemporal dementia (FTD) are diagnosed at an earlier age and report earlier symptom onset in the United States than in Greece or Turkey. Furthermore, neuropsychologic measures indicate that at diagnosis, FTD patients in the United States are less impaired than patients in Greece and Turkey. Patients with FTD in Greece and Turkey are diagnosed later in the disease, presumably because their behavioral symptoms are not easily detected by the medical system in these countries. Our study underscores the need to create culturally appropriate indices of the behavioral symptoms of FTLD, so that patients may be diagnosed and treated at an earlier stage.

Bilingualism delays the onset of behavioral but not aphasic forms of frontotemporal dementia.

Science.gov (United States)

Alladi, Suvarna; Bak, Thomas H; Shailaja, Mekala; Gollahalli, Divyaraj; Rajan, Amulya; Surampudi, Bapiraju; Hornberger, Michael; Duggirala, Vasanta; Chaudhuri, Jaydip Ray; Kaul, Subhash

2017-05-01

Bilingualism has been found to delay onset of dementia and this has been attributed to an advantage in executive control in bilinguals. However, the relationship between bilingualism and cognition is complex, with costs as well as benefits to language functions. To further explore the cognitive consequences of bilingualism, the study used Frontotemporal dementia (FTD) syndromes, to examine whether bilingualism modifies the age at onset of behavioral and language variants of Frontotemporal dementia (FTD) differently. Case records of 193 patients presenting with FTD (121 of them bilingual) were examined and the age at onset of the first symptoms were compared between monolinguals and bilinguals. A significant effect of bilingualism delaying the age at onset of dementia was found in behavioral variant FTD (5.7 years) but not in progressive nonfluent aphasia (0.7 years), semantic dementia (0.5 years), corticobasal syndrome (0.4 years), progressive supranuclear palsy (4.3 years) and FTD-motor neuron disease (3 years). On dividing all patients predominantly behavioral and predominantly aphasic groups, age at onset in the bilingual behavioral group (62.6) was over 6 years higher than in the monolingual patients (56.5, p=0.006), while there was no difference in the aphasic FTD group (60.9 vs. 60.6 years, p=0.851). The bilingual effect on age of bvFTD onset was shown independently of other potential confounding factors such as education, gender, occupation, and urban vs rural dwelling of subjects. To conclude, bilingualism delays the age at onset in the behavioral but not in the aphasic variants of FTD. The results are in line with similar findings based on research in stroke and with the current views of the interaction between bilingualism and cognition, pointing to advantages in executive functions and disadvantages in lexical tasks. Copyright © 2017 Elsevier Ltd. All rights reserved.

The influence of singing on social engagement for persons with severe frontotemporal dementia

DEFF Research Database (Denmark)

Ridder, Hanne Mette Ochsner

2010-01-01

Panksepp (2010) describes how the pain of social loss opens the gateway to depression, and how the chronic sense of aloneness pervades many mental health illnesses and pathologies. In relation to this, psychological and behavioural symptoms of neurodegenerative diseases like dementia are reported...... to increase when psychosocial needs are not met (Kitwood 1997). Thus there is a growing need to address psychosocial needs, while at the same time psychosocial needs are increasing difficult to help as a result of frontotemporal dementia. In frontotemporal dementia the progressive loss of cognitive...... functioning (e.g. the lost ability to process language, to focus attention, to remember and to act in what is defined as a socially appropriate manner) makes it very challenging to engage in social interaction, especially in groups. Music therapy is applied as a non-pharmacological treatment of psychological...

Longitudinal Diffusion Tensor Imaging Resembles Patterns of Pathology Progression in Behavioral Variant Frontotemporal Dementia (bvFTD

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Jan Kassubek

2018-03-01

Full Text Available Objective: Recently, the characteristic longitudinal distribution pattern of the underlying phosphorylated TDP-43 (pTDP-43 pathology in the behavioral variant of frontotemporal dementia (bvFTD excluding Pick's disease (PiD across specific brain regions was described. The aim of the present study was to investigate whether in vivo investigations of bvFTD patients by use of diffusion tensor imaging (DTI were consistent with these proposed patterns of progression.Methods: Sixty-two bvFTD patients and 47 controls underwent DTI in a multicenter study design. Of these, 49 bvFTD patients and 34 controls had a follow-up scan after ~12 months. Cross-sectional and longitudinal alterations were assessed by a two-fold analysis, i.e., voxelwise comparison of fractional anisotropy (FA maps and a tract of interest-based (TOI approach, which identifies tract structures that could be assigned to brain regions associated with disease progression.Results: Whole brain-based spatial statistics showed white matter alterations predominantly in the frontal lobes cross-sectionally and longitudinally. The TOIs of bvFTD neuroimaging stages 1 and 2 (uncinate fascicle—bvFTD pattern I; corticostriatal pathway—bvFTD pattern II showed highly significant differences between bvFTD patients and controls. The corticospinal tract-associated TOI (bvFTD pattern III did not differ between groups, whereas the differences in the optic radiation (bvFTD pattern IV reached significance. The findings in the corticospinal tract were due to a “dichotomous” behavior of FA changes there.Conclusion: Longitudinal TOI analysis demonstrated a pattern of white matter pathways alterations consistent with patterns of pTDP-43 pathology.

Functional connectivity and microstructural white matter changes in phenocopy frontotemporal dementia

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Meijboom, R.; Steketee, R.M.E.; Lugt, A. van der; Smits, M. [Erasmus MC - University Medical Centre, Radiology and Nuclear Medicine, Rotterdam (Netherlands); Koning, I. de [Erasmus MC - University Medical Centre, Neuropsychology, Rotterdam (Netherlands); Osse, R.J. [Erasmus MC - University Medical Centre, Psychiatry, Rotterdam (Netherlands); Jiskoot, L.C. [Erasmus MC - University Medical Centre, Neuropsychology, Rotterdam (Netherlands); Erasmus MC - University Medical Centre, Neurology, Rotterdam (Netherlands); Jong, F.J. de; Swieten, J.C. van [Erasmus MC - University Medical Centre, Neurology, Rotterdam (Netherlands)

2017-04-15

Phenocopy frontotemporal dementia (phFTD) is a rare and poorly understood clinical syndrome. PhFTD shows core behavioural variant FTD (bvFTD) symptoms without associated cognitive deficits and brain abnormalities on conventional MRI and without progression. In contrast to phFTD, functional connectivity and white matter (WM) microstructural abnormalities have been observed in bvFTD. We hypothesise that phFTD belongs to the same disease spectrum as bvFTD and investigated whether functional connectivity and microstructural WM changes similar to bvFTD are present in phFTD. Seven phFTD patients without progression or alternative psychiatric diagnosis, 12 bvFTD patients and 17 controls underwent resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI). Default mode network (DMN) connectivity and WM measures were compared between groups. PhFTD showed subtly increased DMN connectivity and subtle microstructural changes in frontal WM tracts. BvFTD showed abnormalities in similar regions as phFTD, but had lower increased DMN connectivity and more extensive microstructural WM changes. Our findings can be interpreted as neuropathological changes in phFTD and are in support of the hypothesis that phFTD and bvFTD may belong to the same disease spectrum. Advanced MRI techniques, objectively identifying brain abnormalities, would therefore be potentially suited to improve the diagnosis of phFTD. (orig.)

Functional connectivity and microstructural white matter changes in phenocopy frontotemporal dementia

International Nuclear Information System (INIS)

Meijboom, R.; Steketee, R.M.E.; Lugt, A. van der; Smits, M.; Koning, I. de; Osse, R.J.; Jiskoot, L.C.; Jong, F.J. de; Swieten, J.C. van

2017-01-01

Phenocopy frontotemporal dementia (phFTD) is a rare and poorly understood clinical syndrome. PhFTD shows core behavioural variant FTD (bvFTD) symptoms without associated cognitive deficits and brain abnormalities on conventional MRI and without progression. In contrast to phFTD, functional connectivity and white matter (WM) microstructural abnormalities have been observed in bvFTD. We hypothesise that phFTD belongs to the same disease spectrum as bvFTD and investigated whether functional connectivity and microstructural WM changes similar to bvFTD are present in phFTD. Seven phFTD patients without progression or alternative psychiatric diagnosis, 12 bvFTD patients and 17 controls underwent resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI). Default mode network (DMN) connectivity and WM measures were compared between groups. PhFTD showed subtly increased DMN connectivity and subtle microstructural changes in frontal WM tracts. BvFTD showed abnormalities in similar regions as phFTD, but had lower increased DMN connectivity and more extensive microstructural WM changes. Our findings can be interpreted as neuropathological changes in phFTD and are in support of the hypothesis that phFTD and bvFTD may belong to the same disease spectrum. Advanced MRI techniques, objectively identifying brain abnormalities, would therefore be potentially suited to improve the diagnosis of phFTD. (orig.)

C9orf72 and UNC13A Are Shared Risk Loci for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: A Genome-Wide Meta-Analysis

NARCIS (Netherlands)

Diekstra, F.P.; Van Deerlin, V.M.; van Swieten, J.C.; Al-Chalabi, A.; Ludolph, A.C.; Weishaupt, J.H.; Hardiman, O.; Landers, J.E.; Brown, R.H.; Es, M.A.; Pasterkamp, R.J.; Koppers, M.; Andersen, P.M.; Estrada, K.; Rivadeneira, F.; Hofman, A.; Uitterlinden, A. G.; Van Damme, P.; Melki, J.; Meininger, V.; Shatunov, A.; Shaw, C.E.; Leigh, P.N.; Shaw, P.J.; Morrison, K.E.; Fogh, I.; Chio, A.; Traynor, B.J.; Czell, D.; Weber, M.; Heutink, P.; Bakker, P.I.W.; Silani, V.; Robberecht, W.; Van den Berg, L.H.; Veldink, J.H.

2014-01-01

Objective Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant

Frontotemporal dementia: An updated overview

OpenAIRE

Mohandas, E.; Rajmohan, V.

2009-01-01

Frontotemporal dementia (FTD) is a progressive neurodegenerative syndrome occurring between 45 and 65 years. The syndrome is also called frontotemporal lobar degeneration (FTLD). However, FTLD refers to a larger group of disorders FTD being one of its subgroups. The other subgroups of FTLD are progressive nonfluent aphasia (PFNA), and semantic dementia (SD). FTLD is characterized by atrophy of prefrontal and anterior temporal cortices. FTD occurs in 5-15% of patients with dementia and it is t...

Ludopatía y epilepsia en demencia frontotemporal: Reporte de dos casos

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Sheila Castro-Suarez

Full Text Available RESUMEN La demencia frontotemporal es un trastorno neurodegenerativo cuyo subtipo más común es la variante conductual. Es considerada la causa de demencia más frecuente en menores de 60 años. Se presentan dos casos no emparentados cuyos síntomas típicos fueron: deterioro progresivo de la cognición, del comportamiento, alteraciones psiquiátricas como desinhibición, actos impulsivos, apatía, falta de empatía, estereotipias y cambios en los hábitos de alimentación. La resonancia magnética cerebral, en ambos casos, mostró atrofia frontotemporal a predominio izquierdo; en la evaluación neuropsicológica se evidenció alteraciones de las funciones ejecutivas. El primer caso cursó con ludopatía como síntoma inicial, motivo por el cual permaneció por un año en un centro psiquiátrico, siendo el segundo en Latinoamérica y uno de los pocos casos reportados en el mundo. El segundo caso presentó crisis epilépticas en su evolución.

History, Present, and Progress of Frontotemporal Dementia in China: A Systematic Review

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Ru-Jing Ren

2012-01-01

Full Text Available We aim to provide an overview of clinical and demographical features and neuropathological research on frontotemporal dementia (FTD from China over the past decade. We reviewed the demographic features, clinical presentations, and neuropathology of the FTD-spectrum disorders from the 49 cases in China published since 1998. On the basis of these findings, we retrospect the history and speculate on future progress in terms of FTD in China. We found that most published papers comprise case reports with a few retrospective studies with small sample sizes. Behavior variant FTD (bvFTD was the most common diagnostic subtype, of which 35% were associated with amyotrophic lateral sclerosis or Parkinsonian syndrome. More than 47% patients with FTD had age onset before 65. There were no differences in age of onset and sex distribution between diagnostic subtypes. The spectrum of neuropathological diagnosis of bvFTD was frontotemporal lobe degeneration (FTLD with tau protein or ubiquitin-immunopositive inclusions, and FTLD without intracellular inclusions. Median survival in bvFTD was 14 years. This paper provides an overview of the current status and pointers for future research directions of FTD in China.

Functional neuroimaging and presenting psychiatric features in frontotemporal dementia

Science.gov (United States)

Mendez, M F; McMurtray, A; Chen, A K; Shapira, J S; Mishkin, F; Miller, B L

2006-01-01

Background Frontotemporal dementia (FTD) is a behavioural syndrome caused by degeneration of the frontal and anterior temporal lobes. Behavioural disturbances include psychiatric features. Whether patients with FTD present with psychiatric features varies with the initial neuroanatomical variability of FTD. Objective To identify presenting psychiatric changes not part of diagnostic criteria of FTD and contrast them with the degree of hemispheric asymmetry and frontal and temporal hypoperfusion on single photon emission computed tomography (SPECT) imaging. Methods 74 patients who met consensus criteria for FTD were evaluated at a two year follow up. All had brain SPECT on initial presentation. Results of an FTD psychiatric checklist were contrasted with ratings of regional hypoperfusion. Results The regions of predominant hypoperfusion did not correlate with differences on FTD demographic variables but were associated with presenting psychiatric features. Dysthymia and anxiety were associated with right temporal hypoperfusion. “Moria” or frivolous behaviour also occurred with temporal lobe changes, especially on the right. The only significant frontal lobe feature was the presence of a peculiar physical bearing in association with right frontal hypoperfusion. Conclusions Patients with FTD may present with psychiatric changes distinct from the behavioural diagnostic criteria for this disorder. Early temporal involvement is associated with frivolous behaviour and right temporal involvement is associated with emotional disturbances. In contrast, those with right frontal disease may present with alterations in non‐verbal behaviour. PMID:16043457

Longitudinal grey and white matter changes in frontotemporal dementia and Alzheimer's disease.

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Lars Frings

Full Text Available Behavioural variant frontotemporal dementia (bvFTD and Alzheimer's disease (AD dementia are characterised by progressive brain atrophy. Longitudinal MRI volumetry may help to characterise ongoing structural degeneration and support the differential diagnosis of dementia subtypes. Automated, observer-independent atlas-based MRI volumetry was applied to analyse 102 MRI data sets from 15 bvFTD, 14 AD, and 10 healthy elderly control participants with consecutive scans over at least 12 months. Anatomically defined targets were chosen a priori as brain structures of interest. Groups were compared regarding volumes at clinic presentation and annual change rates. Baseline volumes, especially of grey matter compartments, were significantly reduced in bvFTD and AD patients. Grey matter volumes of the caudate and the gyrus rectus were significantly smaller in bvFTD than AD. The bvFTD group could be separated from AD on the basis of caudate volume with high accuracy (79% cases correct. Annual volume decline was markedly larger in bvFTD and AD than controls, predominantly in white matter of temporal structures. Decline in grey matter volume of the lateral orbitofrontal gyrus separated bvFTD from AD and controls. Automated longitudinal MRI volumetry discriminates bvFTD from AD. In particular, greater reduction of orbitofrontal grey matter and temporal white matter structures after 12 months is indicative of bvFTD.

Orbitofrontal and limbic signatures of empathic concern and intentional harm in the behavioral variant frontotemporal dementia.

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Baez, Sandra; Morales, Juan P; Slachevsky, Andrea; Torralva, Teresa; Matus, Cristian; Manes, Facundo; Ibanez, Agustin

2016-02-01

Perceiving and evaluating intentional harms in an interpersonal context engages both cognitive and emotional domains. This process involves inference of intentions, moral judgment, and, crucially, empathy towards others' suffering. This latter skill is notably impaired in behavioral variant frontotemporal dementia (bvFTD). However, the relationship between regional brain atrophy in bvFTD and deficits in the above-mentioned abilities is not well understood. The present study investigated how gray matter (GM) atrophy in bvFTD patients correlates with the perception and evaluation of harmful actions (attribution of intentionality, evaluation of harmful behavior, empathic concern, and moral judgment). First, we compared the behavioral performance of 26 bvFTD patients and 23 healthy controls on an experimental task (ET) indexing intentionality, empathy, and moral cognition during evaluation of harmful actions. Second, we compared GM volume in patients and controls using voxel-based morphometry (VBM). Third, we examined brain regions where atrophy might be associated with specific impairments in the patient group. Finally, we explored whether the patients' deficits in intentionality comprehension and empathic concern could be partially explained by regional GM atrophy or impairments in other relevant factors, such as executive functions (EFs). In bvFTD patients, atrophy of limbic structures (amygdala and anterior paracingulate cortex--APC) was related to impairments in intentionality comprehension, while atrophy of the orbitofrontal cortex (OFC) was associated with empathic concern deficits. Intentionality comprehension impairments were predicted by EFs and orbitofrontal atrophy predicted deficits in empathic concern. Thus, although the perception and evaluation of harmful actions are variously compromised in bvFTD, deficits in empathic concern may be central to this syndrome as they are associated with one of the earliest atrophied region. More generally, our results

A Longitudinal Study on Resting State Functional Connectivity in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease.

Science.gov (United States)

Hafkemeijer, Anne; Möller, Christiane; Dopper, Elise G P; Jiskoot, Lize C; van den Berg-Huysmans, Annette A; van Swieten, John C; van der Flier, Wiesje M; Vrenken, Hugo; Pijnenburg, Yolande A L; Barkhof, Frederik; Scheltens, Philip; van der Grond, Jeroen; Rombouts, Serge A R B

2017-01-01

Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. We applied longitudinal resting state functional magnetic resonance imaging (fMRI) to delineate functional brain connections relevant for disease progression and diagnostic accuracy. We used two-center resting state fMRI data of 20 AD patients (65.1±8.0 years), 12 bvFTD patients (64.7±5.4 years), and 22 control subjects (63.8±5.0 years) at baseline and 1.8-year follow-up. We used whole-network and voxel-based network-to-region analyses to study group differences in functional connectivity at baseline and follow-up, and longitudinal changes in connectivity within and between groups. At baseline, connectivity between paracingulate gyrus and executive control network, between cuneal cortex and medial visual network, and between paracingulate gyrus and salience network was higher in AD compared with controls. These differences were also present after 1.8 years. At follow-up, connectivity between angular gyrus and right frontoparietal network, and between paracingulate gyrus and default mode network was lower in bvFTD compared with controls, and lower compared with AD between anterior cingulate gyrus and executive control network, and between lateral occipital cortex and medial visual network. Over time, connectivity decreased in AD between precuneus and right frontoparietal network and in bvFTD between inferior frontal gyrus and left frontoparietal network. Longitudinal changes in connectivity between supramarginal gyrus and right frontoparietal network differ between both patient groups and controls. We found disease-specific brain regions with longitudinal connectivity changes. This suggests the potential of longitudinal resting state fMRI to delineate regions relevant for disease progression and for diagnostic accuracy, although no group differences in longitudinal changes in the direct comparison of AD and bvFTD were found.

Trajectories of Behavioural Disturbances Across Dementia Types.

Science.gov (United States)

Linds, Alexandra B; Kirstein, Alana B; Freedman, Morris; Verhoeff, Nicolaas P L G; Wolf, Uri; Chow, Tiffany W

2015-11-01

To replicate a previous finding that the trajectory of the Neuropsychiatric Inventory (NPI) shifts in the sixth year of behavioural variant frontotemporal dementia (bvFTD). We evaluated longitudinal tracking with both the Frontal Behavioural Inventory (FBI) and NPI, comparing bvFTD against other dementias. Chart reviews over two to five years for patients with bvFTD (n=30), primary progressive aphasia (PPA, n=13) and Alzheimer's disease (AD, n=118) at an urban Canadian tertiary clinic specializing in dementia. Linear regressions of the longitudinal data tested predictors of annualized rates of change (ROC) in NPI and FBI total and subscales for apathy and disinhibition among dementia groups. The mode of the overall sample for the most advanced duration of illness observed was 5 years, with the median at 7 years. We did not find a crescendo-decrescendo pattern in scores although, for bvFTD and AD, high initial scores correlated with ensuing downward ROCs on the NPI and FBI. Educational level showed an influence on disinhibition ROCs. The FBI was no more revealing than the NPI for apathy and disinhibition scores in these dementias. A cognitive reserve effect on behavioural disturbance was supported but it may take longer than our 4 years of observing the clinical sample to record inflection points in the behavioural and psychiatric symptoms seen in bvFTD. The current data only imply that both apathy and disinhibition will diminish over the course of dementia.

Frontotemporal dementia caused by CHMP2B mutations

DEFF Research Database (Denmark)

Isaacs, A M; Johannsen, P; Holm, I

2011-01-01

CHMP2B mutations are a rare cause of autosomal dominant frontotemporal dementia (FTD). The best studied example is frontotemporal dementia linked to chromosome 3 (FTD-3) which occurs in a large Danish family, with a further CHMP2B mutation identified in an unrelated Belgian familial FTD patient. ...

Examining the language and behavioural profile in FTD and ALS-FTD.

Science.gov (United States)

Saxon, Jennifer A; Thompson, Jennifer C; Jones, Matthew; Harris, Jennifer M; Richardson, Anna Mt; Langheinrich, Tobias; Neary, David; Mann, David Ma; Snowden, Julie S

2017-08-01

A proportion of patients with behavioural variant frontotemporal dementia (bvFTD) develop amyotrophic lateral sclerosis (ALS). It is currently unknown whether the behavioural and cognitive syndrome in bvFTD with ALS (ALS-FTD) is indistinguishable from that of bvFTD alone. A retrospective cohort of 241 patients with clinical diagnoses of bvFTD (n=185) or ALS-FTD (n=56) was examined with respect to behavioural, cognitive and neuropsychiatric symptoms. Features were rated as present or absent based on information recorded from clinical interviews and detailed neuropsychological assessment. A number of behavioural and affective changes were reported more frequently in bvFTD than ALS-FTD: social disinhibition (pALS-FTD than bvFTD (pALS-FTD than bvFTD: agrammatism (pALS-FTD. In particular, while changes in social behaviour are prominent in bvFTD alone, there may be a comparatively greater degree of language impairment in ALS-FTD. Prospective exploration of the pattern of differences between these groups will be essential. Identification of a distinct neuropsychological phenotype in ALS-FTD may have clinical implications for early diagnosis, disease management and care planning and theoretical implications for our understanding of the relationship between ALS and FTD. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Moral processing deficit in behavioral variant frontotemporal dementia is associated with facial emotion recognition and brain changes in default mode and salience network areas.

Science.gov (United States)

Van den Stock, Jan; Stam, Daphne; De Winter, François-Laurent; Mantini, Dante; Szmrecsanyi, Benedikt; Van Laere, Koen; Vandenberghe, Rik; Vandenbulcke, Mathieu

2017-12-01

Behavioral variant frontotemporal dementia (bvFTD) is associated with abnormal emotion recognition and moral processing. We assessed emotion detection, discrimination, matching, selection, and categorization as well as judgments of nonmoral, moral impersonal, moral personal low- and high-conflict scenarios. bvFTD patients gave more utilitarian responses on low-conflict personal moral dilemmas. There was a significant correlation between a facial emotion processing measure derived through principal component analysis and utilitarian responses on low-conflict personal scenarios in the bvFTD group (controlling for MMSE-score and syntactic abilities). Voxel-based morphometric multiple regression analysis in the bvFTD group revealed a significant association between the proportion of utilitarian responses on personal low-conflict dilemmas and gray matter volume in ventromedial prefrontal areas ( p height  emotions in moral cognition and suggest a common basis for deficits in both abilities, possibly related to reduced experience of emotional sensations. At the neural level abnormal moral cognition in bvFTD is related to structural integrity of the medial prefrontal cortex and functional characteristics of the anterior insula. The present findings provide a common basis for emotion recognition and moral reasoning and link them with areas in the default mode and salience network.

New Perspective on Parkinsonism in Frontotemporal Lobar Degeneration

Directory of Open Access Journals (Sweden)

Hee Kyung Park

2013-04-01

Full Text Available Frontotemporal dementia (FTD is the second most common type of presenile dementia. Three clinical prototypes have been defined; behavioral variant FTD, semantic dementia, and progressive nonfluent aphasia. Progressive supranuclear palsy, corticobasal degeneration, and motor neuron disease may possess clinical and pathological characteristics that overlap with FTD, and it is possible that they may all belong to the same clinicopathological spectrum. Frontotemporal lobar degeneration (FTLD is a clinicopathological syndrome that encompasses a heterogenous group of neurodegenerative disorders. Owing to the advancement in the field of molecular genetics, diagnostic imaging, and pathology, FTLD has been the focus of great interest. Nevertheless, parkinsonism in FTLD has received relatively less attention. Parkinsonism is found in approximately 20–30% of patients in FTLD. Furthermore, parkinsonism can be seen in all FTLD subtypes, and some patients with familial and sporadic FTLD can present with prominent parkinsonism. Therefore, there is a need to understand parkinsonism in FTLD in order to obtain a better understanding of the disease. With regard to the clinical characteristics, the akinetic rigid type of parkinsonism has predominantly been described. Parkinsonism is frequently observed in familial FTD, more specifically, in FTD with parkinsonism linked to chromosome 17q (FTDP-17. The genes associated with parkinsonism are microtubule associated protein tau (MAPT, progranulin (GRN or PGRN, and chromosome 9 open reading frame 72 (C9ORF72 repeat expansion. The neural substrate of parkinsonism remains to be unveiled. Dopamine transporter (DAT imaging revealed decreased uptake of DAT, and imaging findings indicated atrophic changes of the basal ganglia. Parkinsonism can be an important feature in FTLD and, therefore, increased attention is needed on the subject.

Frontotemporal dementia and its subtypes: a genome-wide association study

Science.gov (United States)

Ferrari, Raffaele; Hernandez, Dena G; Nalls, Michael A; Rohrer, Jonathan D; Ramasamy, Adaikalavan; Kwok, John B J; Dobson-Stone, Carol; Brooks, William S; Schofield, Peter R; Halliday, Glenda M; Hodges, John R; Piguet, Olivier; Bartley, Lauren; Thompson, Elizabeth; Haan, Eric; Hernández, Isabel; Ruiz, Agustín; Boada, Mercè; Borroni, Barbara; Padovani, Alessandro; Cruchaga, Carlos; Cairns, Nigel J; Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta; Forloni, Gianluigi; Galimberti, Daniela; Fenoglio, Chiara; Serpente, Maria; Scarpini, Elio; Clarimón, Jordi; Lleó, Alberto; Blesa, Rafael; Waldö, Maria Landqvist; Nilsson, Karin; Nilsson, Christer; Mackenzie, Ian R A; Hsiung, Ging-Yuek R; Mann, David M A; Grafman, Jordan; Morris, Christopher M; Attems, Johannes; Griffiths, Timothy D; McKeith, Ian G; Thomas, Alan J; Pietrini, P; Huey, Edward D; Wassermann, Eric M; Baborie, Atik; Jaros, Evelyn; Tierney, Michael C; Pastor, Pau; Razquin, Cristina; Ortega-Cubero, Sara; Alonso, Elena; Perneczky, Robert; Diehl-Schmid, Janine; Alexopoulos, Panagiotis; Kurz, Alexander; Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo; Rogaeva, Ekaterina; George-Hyslop, Peter St; Rossi, Giacomina; Tagliavini, Fabrizio; Giaccone, Giorgio; Rowe, James B; Schlachetzki, J C M; Uphill, James; Collinge, John; Mead, S; Danek, Adrian; Van Deerlin, Vivianna M; Grossman, Murray; Trojanowsk, John Q; van der Zee, Julie; Deschamps, William; Van Langenhove, Tim; Cruts, Marc; Van Broeckhoven, Christine; Cappa, Stefano F; Le Ber, Isabelle; Hannequin, Didier; Golfier, Véronique; Vercelletto, Martine; Brice, Alexis; Nacmias, Benedetta; Sorbi, Sandro; Bagnoli, Silvia; Piaceri, Irene; Nielsen, Jørgen E; Hjermind, Lena E; Riemenschneider, Matthias; Mayhaus, Manuel; Ibach, Bernd; Gasparoni, Gilles; Pichler, Sabrina; Gu, Wei; Rossor, Martin N; Fox, Nick C; Warren, Jason D; Spillantini, Maria Grazia; Morris, Huw R; Rizzu, Patrizia; Heutink, Peter; Snowden, Julie S; Rollinson, Sara; Richardson, Anna; Gerhard, Alexander; Bruni, Amalia C; Maletta, Raffaele; Frangipane, Francesca; Cupidi, Chiara; Bernardi, Livia; Anfossi, Maria; Gallo, Maura; Conidi, Maria Elena; Smirne, Nicoletta; Rademakers, Rosa; Baker, Matt; Dickson, Dennis W; Graff-Radford, Neill R; Petersen, Ronald C; Knopman, David; Josephs, Keith A; Boeve, Bradley F; Parisi, Joseph E; Seeley, William W; Miller, Bruce L; Karydas, Anna M; Rosen, Howard; van Swieten, John C; Dopper, Elise G P; Seelaar, Harro; Pijnenburg, Yolande AL; Scheltens, Philip; Logroscino, Giancarlo; Capozzo, Rosa; Novelli, Valeria; Puca, Annibale A; Franceschi, M; Postiglione, Alfredo; Milan, Graziella; Sorrentino, Paolo; Kristiansen, Mark; Chiang, Huei-Hsin; Graff, Caroline; Pasquier, Florence; Rollin, Adeline; Deramecourt, Vincent; Lebert, Florence; Kapogiannis, Dimitrios; Ferrucci, Luigi; Pickering-Brown, Stuart; Singleton, Andrew B; Hardy, John; Momeni, Parastoo

2014-01-01

Summary Background Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. All participants had European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) and suggestive single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8) that encompassed the HLA locus at 6p21.3 in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC, for the behavioural FTD subtype. Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation incis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and possibly to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of

Is the Frontal Assessment Battery reliable in ALS patients?

NARCIS (Netherlands)

Raaphorst, J.; Beeldman, E.; Jaeger, B.; Schmand, B.A.; Berg, L.H. van den; Weikamp, J.G.; Schelhaas, H.J.; Visser, M. de; Haan, R.J. de

2013-01-01

The assessment of frontal functions in ALS patients is important because of the overlap with the behavioural variant of frontotemporal dementia (bvFTD). We investigated the applicability and reliability of the Frontal Assessment Battery (FAB) within a cohort of predominantly prevalent ALS patients.

Perfusion SPECT studies with mapping of Brodmann areas in differentiating Alzheimer's disease from frontotemporal degeneration syndromes.

Science.gov (United States)

Valotassiou, Varvara; Papatriantafyllou, John; Sifakis, Nikolaos; Tzavara, Chara; Tsougos, Ioannis; Kapsalaki, Eftychia; Hadjigeorgiou, George; Georgoulias, Panagiotis

2012-12-01

The aim of this study was to evaluate the contribution of brain perfusion single-photon emission computed tomography (SPECT) studies with mapping of Brodmann areas (BAs) in the differential diagnosis between Alzheimer's disease (AD) and frontotemporal degeneration (FTLD) syndromes. Thirty-nine patients with AD and 73 patients with FTLD syndromes [behavioural variant FTLD (bvFTLD); language variant FTLD (lvFTLD), including semantic dementia (SD) and progressive nonfluent aphasia (PNFA); and corticobasal degeneration (CBD)/progressive supranuclear palsy (PSP) syndromes] underwent brain perfusion SPECT. The NeuroGam software was used for the semiquantitative evaluation of perfusion in BAs of the left (L) and right (R) hemispheres. Compared with those in AD patients, BAs with statistically significant hypoperfusion were found in the prefrontal, orbitofrontal and cingulated cortices and Broca's areas of FTLD and bvFTLD patients; in the temporal and prefrontal cortices and Broca's areas of lvFTLD patients; in the left temporal gyrus of SD patients; in premotor and supplementary motor, prefrontal, orbitofrontal, temporal and anterior cingulated cortices and Broca's areas of PNFA patients; and in the prefrontal, temporal, posterior cingulated and primary and secondary visual cortices of CBD/PSP patients. BA 46R could differentiate AD patients from FTLD and bvFTLD patients; 21L and 25L were found to be independent predictors for lvFTLD in comparison with AD, and 25R, 21L and 23R could differentiate AD patients from PNFA, SD and CBD/PSP patients, respectively. Brain perfusion SPECT with BA mapping in AD and FTLD patients could improve the definition of brain areas that are specifically implicated in these disorders, resulting in a more accurate differential diagnosis.

Social Cognition Deficits: The Key to Discriminate Behavioral Variant Frontotemporal Dementia from Alzheimer's Disease Regardless of Amnesia?

Science.gov (United States)

Bertoux, Maxime; de Souza, Leonardo Cruz; O'Callaghan, Claire; Greve, Andrea; Sarazin, Marie; Dubois, Bruno; Hornberger, Michael

2016-01-01

Relative sparing of episodic memory is a diagnostic criterion of behavioral variant frontotemporal dementia (bvFTD). However, increasing evidence suggests that bvFTD patients can show episodic memory deficits at a similar level as Alzheimer's disease (AD). Social cognition tasks have been proposed to distinguish bvFTD, but no study to date has explored the utility of such tasks for the diagnosis of amnestic bvFTD. Here, we contrasted social cognition performance of amnestic and non-amnestic bvFTD from AD, with a subgroup having confirmed in vivo pathology markers. Ninety-six participants (38 bvFTD and 28 AD patients as well as 30 controls) performed the short Social-cognition and Emotional Assessment (mini-SEA). BvFTD patients were divided into amnestic versus non-amnestic presentation using the validated Free and Cued Selective Reminding Test (FCSRT) assessing episodic memory. As expected, the accuracy of the FCSRT to distinguish the overall bvFTD group from AD was low (69.7% ) with ∼50% of bvFTD patients being amnestic. By contrast, the diagnostic accuracy of the mini-SEA was high (87.9% ). When bvFTD patients were split on the level of amnesia, mini-SEA diagnostic accuracy remained high (85.1% ) for amnestic bvFTD versus AD and increased to very high (93.9% ) for non-amnestic bvFTD versus AD. Social cognition deficits can distinguish bvFTD and AD regardless of amnesia to a high degree and provide a simple way to distinguish both diseases at presentation. These findings have clear implications for the diagnostic criteria of bvFTD. They suggest that the emphasis should be on social cognition deficits with episodic memory deficits not being a helpful diagnostic criterion in bvFTD.

Family caregivers of patients with frontotemporal dementia: An integrative review.

Science.gov (United States)

Caceres, Billy A; Frank, Mayu O; Jun, Jin; Martelly, Melissa T; Sadarangani, Tina; de Sales, Paloma Cesar

2016-03-01

The purpose of this integrative review is to: (1) identify the characteristics of family caregivers of patients with frontotemporal dementia, (2) explore the impact of providing care on family caregivers' health and well-being, and (3) identify coping strategies used by family caregivers. Frontotemporal dementia is thought to be the second most common form of dementia after Alzheimer's disease. Family caregivers of patients with frontotemporal dementia face unique challenges due to its early onset, behavioral symptoms, and slow progression of decline. However, there is a dearth of research evaluating the health and wellbeing of family caregivers of patients with frontotemporal dementia. An integrative review was conducted using the Whittemore and Knafl methodology. An electronic search of the literature was conducted using four electronic databases: PubMed, Embase, CINAHL, and Web of Science. The Crowe Critical Appraisal tool was used to evaluate the quality of the selected articles. Findings of 11 articles informed this integrative review. Family caregivers of patients with frontotemporal dementia identify behavioral disturbances as most troubling. Spouses and female caregivers experience greater caregiver burden, distress, increased rates of depression, as well as decreased sleep related to behavior disturbances. Though less explored, providing care to those with behavioral disturbances may also impact caregiver physical health. Additionally, female caregivers are most likely to employ coping strategies, most commonly, adaptation and reframing. Effective interventions to reduce family caregiver burden are poorly understood but family caregivers suggest education and internet-based support groups are most helpful. Family caregivers of patients with frontotemporal dementia experience significant distress, which impacts their health and wellbeing. It is important for healthcare providers who care for patients with frontotemporal dementia to recognize the unique

Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration

NARCIS (Netherlands)

Chen-Plotkin, A.S.; Martinez-Lage, M.; Sleiman, P.M.A.; Hu, W.; Greene, R.; Wood, E.M.; Bing, S.X.; Grossman, M.; Schellenberg, G.D.; Hatanpaa, K.J.; Weiner, M.F.; White, C.L.; Brooks, W.S.; Halliday, G.M.; Kril, J.J.; Gearing, M.; Beach, T.G.; Graff-Radford, N.R.; Dickson, D.W.; Rademakers, R.; Boeve, B.F.; Pickering-Brown, S.M.; Snowden, J.; van Swieten, J.C.; Heutink, P.; Seelaar, H.; Murrell, J.R.; Ghetti, B.; Spina, S.; Grafman, J.; Kaye, J.A.; Woltjer, R.L.; Mesulam, M.; Bigio, E.; Llado, A.; Miller, B.L.; Alzualde, A.; Moreno, F.; Rohrer, J.D.; Mackenzie, I.R.A.; Feldman, H.H.; Hamilton, R.L.; Cruts, M.; Engelborghs, S.; de Deyn, P.P.; Van Broeckhoven, C.; Bird, T.D.; Cairns, N.J.; Goate, A.; Frosch, M.P.; Riederer, P.F.; Bogdanovic, N.; Lee, V.M.Y.; Trojanowski, J.Q.; Van Deerlin, V.M.

2011-01-01

Objective: To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD). Participants and Design: A 46-site International Frontotemporal Lobar

Parsing cognitive and emotional empathy deficits for negative and positive stimuli in frontotemporal dementia.

Science.gov (United States)

Oliver, Lindsay D; Mitchell, Derek G V; Dziobek, Isabel; MacKinley, Julia; Coleman, Kristy; Rankin, Katherine P; Finger, Elizabeth C

2015-01-01

Behavioural variant frontotemporal dementia (bvFTD) is a debilitating neurodegenerative disorder characterized by frontal and temporal lobe atrophy primarily affecting social cognition and emotion, including loss of empathy. Many consider empathy to be a multidimensional construct, including cognitive empathy (the ability to adopt and understand another's perspective) and emotional empathy (the capacity to share another's emotional experience). Cognitive and emotional empathy deficits have been associated with bvFTD; however, little is known regarding the performance of patients with bvFTD on behavioural measures of emotional empathy, and whether empathic responses differ for negative versus positive stimuli. 24 patients with bvFTD and 24 healthy controls completed the Multifaceted Empathy Test (MET; Dziobek et al., 2008), a performance-based task that taps both cognitive and emotional facets of empathy, and allows for the discrimination of responses to negative versus positive realistic images. MET scores were also compared with caregiver ratings of patient behaviour on the Interpersonal Reactivity Index, which assesses patients' everyday demonstrations of perspective taking and empathic concern. Patients with bvFTD were less accurate than controls at inferring mental states for negative and positive stimuli. They also demonstrated lower levels of shared emotional experience, more positive emotional reactions, and diminished arousal to negative social stimuli relative to controls. Patients showed reduced emotional reactions to negative non-social stimuli as well. Lastly, the MET and IRI measures of emotional empathy were found to be significantly correlated within the bvFTD group. The results suggest that patients with bvFTD show a global deficit in cognitive empathy, and deficient emotional empathy for negative, but not positive, experiences. Further, a generalized emotional processing impairment for negative stimuli was observed, which could contribute to the

A Modified Reading the Mind in the Eyes Test Predicts Behavioral Variant Frontotemporal Dementia Better Than Executive Function Tests

Directory of Open Access Journals (Sweden)

Matthias L. Schroeter

2018-01-01

Full Text Available Behavioral variant frontotemporal dementia (bvFTD is characterized by deep alterations in behavior and personality. Although revised diagnostic criteria agree for executive dysfunction as most characteristic, impairments in social cognition are also suggested. The study aimed at identifying those neuropsychological and behavioral parameters best discriminating between bvFTD and healthy controls. Eighty six patients were diagnosed with possible or probable bvFTD according to Rascovsky et al. (2011 and compared with 43 healthy age-matched controls. Neuropsychological performance was assessed with a modified Reading the Mind in the Eyes Test (RMET, Stroop task, Trail Making Test (TMT, Hamasch-Five-Point Test (H5PT, and semantic and phonemic verbal fluency tasks. Behavior was assessed with the Apathy Evaluation Scale, Frontal Systems Behavioral Scale, and Bayer Activities of Daily Living Scale. Each test’s discriminatory power was investigated by Receiver Operating Characteristic curves calculating the area under the curve (AUC. bvFTD patients performed significantly worse than healthy controls in all neuropsychological tests. Discriminatory power (AUC was highest in behavioral questionnaires, high in verbal fluency tasks and the RMET, and lower in executive function tests such as the Stroop task, TMT and H5PT. As fluency tasks depend on several cognitive functions, not only executive functions, results suggest that the RMET discriminated better between bvFTD and control subjects than other executive tests. Social cognition should be incorporated into diagnostic criteria for bvFTD in the future, such as in the International Classification of Diseases (ICD-11, as already suggested in the Diagnostic and Statistical Manual for Mental Disorders (DSM-5.

The ALS-FTD-Q: a new screening tool for behavioural disturbances in ALS

NARCIS (Netherlands)

Raaphorst, J.; Beeldman, E.; Schmand, B.; Berkhout, J.; Linssen, W.H.J.P.; van den Berg, L.H.; Pijnenburg, Y.A.; Grupstra, H.F.; Weikamp, J.G.; Schelhaas, H.J.; Papma, J.M.; van Swieten, J.C.; de Visser, M.; de Haan, R.J.

2012-01-01

Objective: The assessment of behavioral disturbances in amyotrophic lateral sclerosis (ALS) is important because of the overlap with the behavioral variant of frontotemporal dementia (ALS-bvFTD). Motor symptoms and dysarthria are not taken into account in currently used behavioral questionnaires. We

The Use of Profanity During Letter Fluency Tasks in Frontotemporal Dementia and Alzheimer's Disease

Science.gov (United States)

Ringman, John M.; Kwon, Eunice; Flores, Deborah L.; Rotko, Carol; Mendez, Mario F.; Lu, Po

2012-01-01

Objective To assess whether the production of profanity during letter fluency testing distinguishes frontotemporal dementia (FTD) and Alzheimer's disease (AD) patients. Background Alterations in language and social behavior typify FTD spectrum disorders. Nonetheless, in can be difficult to distinguish pathologically-defined frontotemporal lobar degeneration (FTLD) from AD clinically. Assessing verbal fluency by having patients generate as many words as they can beginning with specific letters in a given period of time can yield diverse information of diagnostic utility. Method Words produced during FAS letter fluency testing were reviewed and instances of the use of "f*ck", "*ss", and "sh*t" and other words felt to be inappropriate were sought. The frequency of these words was compared between clinically diagnosed FTD and AD patients using chi-square tests. Results We found that 6/32 (18.8%) patients with FTD generated the word "f*ck" during the "F" trial as opposed to none of 38 patients with AD (p = 0.007). Patients who said "f*ck" had diagnoses of either behavioral variant FTD (3/15), progressive non-fluent aphasia (2/8), or semantic dementia (1/3). Conclusions Though the specific neuropathology in these cases is uncertain, generation of "f*ck" during letter fluency testing appears to have utility in differentiating FTD from AD. PMID:20829665

The atrophy pattern in the subtypes of frontotemporal lobar degeneration and Alzheimer disease by structural MRI

International Nuclear Information System (INIS)

Zhang Bing; Zhang Xin; Li Ming; Chen Fei; Xu Jun; Wang Huiting; Qian Lai; Zhao Hui; Xu Yun; Zhu Bin

2012-01-01

Objective: To analyze the patterns of cortical atrophy of the two subtypes of frontotemporal lobar degeneration (FTLD), behavioural-variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA). And to compare them with that of Alzheimer disease (AD) to provide an objective basis for early diagnosis and differential diagnosis. Methods: A total of 83 patients were enrolled in this study and there were 30 patients with cognitively normal controls (CN), 30 with AD and 23 with FTLD (10 with bvFTD, 13 with PPA). Philips 3.0 T TX scanner and 8 channel head coil was employed. Three dimensional turbo fast echo (3D-TFE) T 1 WI sequence with high resolution was used to collect the volume data of gray matter. 3D-TFE T 1 WI images were normalized and segmented into gray matter map for statistical analysis by SPM 8 and VBM 8. The false discovery rate (FDR) was adopted in P value adjustment, P<0.001, and the cluster size was set at 5. The full width at half maximum (FWHM) was set at 4 mm for the smoothing. Paired t test was used for statistics. Results: In bvFTD, PPA and AD groups,there were diffuse regions with reduced volume in cerebral cortex and subcortical structures (such as the hippocampus, the amygdala, the caudate nuclei, et al). The most obvious atrophic region in bvFTD and PPA group was found in the frontotemporal. Compared with AD, gray matter atrophy in bvFTD was found in brain regions including bilateral temporal lobes, bilateral superior temporal pole gyri, bilateral middle temporal pole gyri, right fusiform gyrus and bilateral frontal lobes. Among them, temporal and frontal lobes atrophy had obvious right partial lateralizing, with 14 301 voxels in right temporal lobe and 5105 in left (t=-5.03, P<0.05). The number of atrophy voxels in right and left frontal lobe were 1344 and 125 (t=3.45, P<0.05). The left temporooccipital lobe atrophy was more obvious than the right in PPA,with 15 637 voxels in left and 10 723 in right (t=-2.65, P<0

Frontotemporal White Matter in Adolescents with, and at-Risk for, Bipolar Disorder

Directory of Open Access Journals (Sweden)

Sonja M. C. de Zwarte

2014-03-01

Full Text Available Frontotemporal neural systems are highly implicated in the emotional dysregulation characteristic of bipolar disorder (BD. Convergent genetic, postmortem, behavioral and neuroimaging evidence suggests abnormalities in the development of frontotemporal white matter (WM in the pathophysiology of BD. This review discusses evidence for the involvement of abnormal WM development in BD during adolescence, with a focus on frontotemporal WM. Findings from diffusion tensor imaging (DTI studies in adults and adolescents are reviewed to explore possible progressive WM abnormalities in the disorder. Intra- and interhemispheric frontotemporal abnormalities were reported in adults with BD. Although evidence in children and adolescents with BD to date has been limited, similar intrahemispheric and interhemispheric findings have also been reported. The findings in youths suggest that these abnormalities may represent a trait marker present early in the course of BD. Functional connectivity studies, demonstrating a relationship between WM abnormalities and frontotemporal dysfunction in BD, and DTI studies of vulnerability in first-degree relatives of individuals with BD, are discussed. Together, findings suggest the involvement of abnormal frontotemporal WM development in the pathophysiology of BD and that these abnormalities may be early trait markers of vulnerability; however, more studies are critically needed.

Functional dissociation between anterior temporal lobe and inferior frontal gyrus in the processing of dynamic body expressions: Insights from behavioral variant frontotemporal dementia.

Science.gov (United States)

Jastorff, Jan; De Winter, Francois-Laurent; Van den Stock, Jan; Vandenberghe, Rik; Giese, Martin A; Vandenbulcke, Mathieu

2016-12-01

Several brain regions are involved in the processing of emotional stimuli, however, the contribution of specific regions to emotion perception is still under debate. To investigate this issue, we combined behavioral testing, structural and resting state imaging in patients diagnosed with behavioral variant frontotemporal dementia (bvFTD) and age matched controls, with task-based functional imaging in young, healthy volunteers. As expected, bvFTD patients were impaired in emotion detection as well as emotion categorization tasks, testing dynamic emotional body expressions as stimuli. Interestingly, their performance in the two tasks correlated with gray matter volume in two distinct brain regions, the left anterior temporal lobe for emotion detection and the left inferior frontal gyrus (IFG) for emotion categorization. Confirming this observation, multivoxel pattern analysis in healthy volunteers demonstrated that both ROIs contained information for emotion detection, but that emotion categorization was only possible from the pattern in the IFG. Furthermore, functional connectivity analysis showed reduced connectivity between the two regions in bvFTD patients. Our results illustrate that the mentalizing network and the action observation network perform distinct tasks during emotion processing. In bvFTD, communication between the networks is reduced, indicating one possible cause underlying the behavioral symptoms. Hum Brain Mapp 37:4472-4486, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Alzheimer Disease and Behavioral Variant Frontotemporal Dementia: Automatic Classification Based on Cortical Atrophy for Single-Subject Diagnosis.

Science.gov (United States)

Möller, Christiane; Pijnenburg, Yolande A L; van der Flier, Wiesje M; Versteeg, Adriaan; Tijms, Betty; de Munck, Jan C; Hafkemeijer, Anne; Rombouts, Serge A R B; van der Grond, Jeroen; van Swieten, John; Dopper, Elise; Scheltens, Philip; Barkhof, Frederik; Vrenken, Hugo; Wink, Alle Meije

2016-06-01

Purpose To investigate the diagnostic accuracy of an image-based classifier to distinguish between Alzheimer disease (AD) and behavioral variant frontotemporal dementia (bvFTD) in individual patients by using gray matter (GM) density maps computed from standard T1-weighted structural images obtained with multiple imagers and with independent training and prediction data. Materials and Methods The local institutional review board approved the study. Eighty-four patients with AD, 51 patients with bvFTD, and 94 control subjects were divided into independent training (n = 115) and prediction (n = 114) sets with identical diagnosis and imager type distributions. Training of a support vector machine (SVM) classifier used diagnostic status and GM density maps and produced voxelwise discrimination maps. Discriminant function analysis was used to estimate suitability of the extracted weights for single-subject classification in the prediction set. Receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) were calculated for image-based classifiers and neuropsychological z scores. Results Training accuracy of the SVM was 85% for patients with AD versus control subjects, 72% for patients with bvFTD versus control subjects, and 79% for patients with AD versus patients with bvFTD (P ≤ .029). Single-subject diagnosis in the prediction set when using the discrimination maps yielded accuracies of 88% for patients with AD versus control subjects, 85% for patients with bvFTD versus control subjects, and 82% for patients with AD versus patients with bvFTD, with a good to excellent AUC (range, 0.81-0.95; P ≤ .001). Machine learning-based categorization of AD versus bvFTD based on GM density maps outperforms classification based on neuropsychological test results. Conclusion The SVM can be used in single-subject discrimination and can help the clinician arrive at a diagnosis. The SVM can be used to distinguish disease-specific GM patterns in patients with AD

Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation

DEFF Research Database (Denmark)

Clayton, Emma L.; Mancuso, Renzo; Nielsen, Troels Tolstrup

2017-01-01

Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like c...

Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia.

Science.gov (United States)

Dermody, Nadene; Wong, Stephanie; Ahmed, Rebekah; Piguet, Olivier; Hodges, John R; Irish, Muireann

2016-05-30

Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer's disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information.

The Power of Neuroimaging Biomarkers for Screening Frontotemporal Dementia

OpenAIRE

McMillan, Corey T.; Avants, Brian B.; Cook, Philip; Ungar, Lyle; Trojanowski, John Q.; Grossman, Murray

2014-01-01

Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative disease that can result from either frontotemporal lobar degeneration (FTLD) or Alzheimer’s disease (AD) pathology. It is critical to establish statistically powerful biomarkers that can achieve substantial cost-savings and increase feasibility of clinical trials. We assessed three broad categories of neuroimaging methods to screen underlying FTLD and AD pathology in a clinical FTD series: global ...

Sensitivity of the Wechsler Abbreviated Scale of Intelligence-Second Edition (WASI-II) to the neurocognitive deficits associated with the semantic dementia variant of frontotemporal lobar degeneration: A case study.

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Gontkovsky, Samuel T

2017-01-01

This case study of a 71-year-old woman illustrates the clinical utility of the Wechsler Abbreviated Scale of Intelligence-Second Edition (WASI-II) in assessing the neurocognitive sequelae of the semantic dementia variant of frontotemporal lobar degeneration. Obtained scores revealed a decline in estimated Full Scale IQ from the patient's expected premorbid level. Consistent with her initial onset of neuropathology in the left temporal lobe, the WASI-II yielded a difference of 53 standard score points between the Perceptual Reasoning and Verbal Comprehension composites, reflecting the patient's intact capabilities in visuospatial perception and construction in conjunction with marked disturbances of language. The similarities subtest was particularly sensitive to the patient's neurocognitive deficits. WASI-II scores corresponded well with the results obtained from other administered measures, in particular those from the Repeatable Battery for the Assessment of Neuropsychological Status. Findings provide support for use of the WASI-II in the clinical evaluation of semantic dementia and offer preliminary evidence that the test may be helpful in both lateralization and localization of brain lesions.

Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations.

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Luis, Elkin; Ortiz, Alexandra; Eudave, Luis; Ortega-Cubero, Sara; Borroni, Barbara; van der Zee, Julie; Gazzina, Stefano; Caroppo, Paola; Rubino, Elisa; D'Agata, Federico; Le Ber, Isabelle; Santana, Isabel; Cunha, Gil; Almeida, Maria R; Boutoleau-Bretonnière, Claire; Hannequin, Didier; Wallon, David; Rainero, Innocenzo; Galimberti, Daniela; Van Broeckhoven, Christine; Pastor, Maria A; Pastor, Pau

2016-05-07

Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1), among other genes. Rare SQSTM1 gene mutations have been associated with Paget's disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD). The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction. We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 pathogenic variants (FTD/SQSTM1 mutation carriers; n = 10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD; n = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n = 20). The groups were matched according to current age, disease duration, and gender. After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres. These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineatinga specific gene-linked atrophy pattern.

Fronto-striatal atrophy correlates of neuropsychiatric dysfunction in frontotemporal dementia (FTD and Alzheimer's disease (AD

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Dong Seok Yi

Full Text Available ABSTRACT Behavioural disturbances in frontotemporal dementia (FTD are thought to reflect mainly atrophy of cortical regions. Recent studies suggest that subcortical brain regions, in particular the striatum, are also significantly affected and this pathology might play a role in the generation of behavioural symptoms. Objective: To investigate prefrontal cortical and striatal atrophy contributions to behavioural symptoms in FTD. Methods: One hundred and eighty-two participants (87 FTD patients, 39 AD patients and 56 controls were included. Behavioural profiles were established using the Cambridge Behavioural Inventory Revised (CBI-R and Frontal System Behaviour Scale (FrSBe. Atrophy in prefrontal (VMPFC, DLPFC and striatal (caudate, putamen regions was established via a 5-point visual rating scale of the MRI scans. Behavioural scores were correlated with atrophy rating scores. Results: Behavioural and atrophy ratings demonstrated that patients were significantly impaired compared to controls, with bvFTD being most severely affected. Behavioural-anatomical correlations revealed that VMPFC atrophy was closely related to abnormal behaviour and motivation disturbances. Stereotypical behaviours were associated with both VMPFC and striatal atrophy. By contrast, disturbance of eating was found to be related to striatal atrophy only. Conclusion: Frontal and striatal atrophy contributed to the behavioural disturbances seen in FTD, with some behaviours related to frontal, striatal or combined fronto-striatal pathology. Consideration of striatal contributions to the generation of behavioural disturbances should be taken into account when assessing patients with potential FTD.

Defining the association of TMEM106B variants among frontotemporal lobar degeneration patients with GRN mutations and C9orf72 repeat expansions.

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Lattante, Serena; Le Ber, Isabelle; Galimberti, Daniela; Serpente, Maria; Rivaud-Péchoux, Sophie; Camuzat, Agnès; Clot, Fabienne; Fenoglio, Chiara; Scarpini, Elio; Brice, Alexis; Kabashi, Edor

2014-11-01

TMEM106B was identified as a risk factor for frontotemporal lobar degeneration (FTD) with TAR DNA-binding protein 43 kDa inclusions. It has been reported that variants in this gene are genetic modifiers of the disease and that this association is stronger in patients carrying a GRN mutation or a pathogenic expansion in chromosome 9 open reading frame 72 (C9orf72) gene. Here, we investigated the contribution of TMEM106B polymorphisms in cohorts of FTD and FTD with amyotrophic lateral sclerosis patients from France and Italy. Patients carrying the C9orf72 expansion (n = 145) and patients with GRN mutations (n = 76) were compared with a group of FTD patients (n = 384) negative for mutations and to a group of healthy controls (n = 552). In our cohorts, the presence of the C9orf72 expansion did not correlate with TMEM106B genotypes but the association was very strong in individuals with pathogenic GRN mutations (p = 9.54 × 10(-6)). Our data suggest that TMEM106B genotypes differ in FTD patient cohorts and strengthen the protective role of TMEM106B in GRN carriers. Further studies are needed to determine whether TMEM106B polymorphisms are associated with other genetic causes for FTD, including C9orf72 repeat expansions. Copyright © 2014 Elsevier Inc. All rights reserved.

Frontotemporal dementia and its subtypes

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Ferrari, Raffaele; Hernandez, Dena G; Nalls, Michael A

2014-01-01

BACKGROUND: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel gene...

Are we comparing frontotemporal dementia and Alzheimer disease patients with the right measures?

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Deutsch, Mariel B; Liang, Li-Jung; Jimenez, Elvira E; Mather, Michelle J; Mendez, Mario F

2016-09-01

Clinical research studies of behavioral variant frontotemporal dementia (bvFTD) often use Alzheimer disease (AD) as a comparison group for control of dementia variables, using tests of cognitive function to match the groups. These two dementia syndromes, however, are very different in clinical manifestations, and the comparable severity of these dementias may not be reflected by commonly used cognitive scales such as the Mini-Mental State Examination (MMSE). We evaluated different measures of dementia severity and symptoms among 20 people with bvFTD compared to 24 with early-onset AD. Despite similar ages, disease-duration, education, and cognitive performance on two tests of cognitive function, the MMSE and the Montreal Cognitive Assessment (MoCA), the bvFTD participants, compared to the AD participants, were significantly more impaired on other measures of disease severity, including function (Functional Assessment Questionnaire (FAQ)), neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI)), and global dementia stage (Clinical Dementia Rating Scales (CDRs)). However, when we adjusted for the frontotemporal lobar degeneration-CDR (FTLD-CDR) in the analyses, the two dementia groups were comparable across all measures despite significant differences on the cognitive scales. We found tests of cognitive functions (MMSE and MoCA) to be insufficient measures for ensuring comparability between bvFTD and AD groups. In clinical studies, the FTLD-CDR, which includes additional language and behavior items, may be a better overall way to match bvFTD and AD groups on dementia severity.

Neuropsychological and Behavioural Phenotype of Dandy-Walker Variant Presenting in Chromosome 22 Trisomy: A Case Study

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Searson, Ruth; Hare, Dougal Julian; Sridharan, Sridhar

2013-01-01

In this study, a case of Dandy-Walker variant syndrome associated with trisomy 22 in a 17-year-old man is described. This is the first account of this combination in a person surviving into adulthood, and the neuropsychological and behavioural presentation is described in detail and a clinical formulation is presented for the benefit of…

Usefulness of the pterion plate in frontotemporal craniotomy

International Nuclear Information System (INIS)

Goto, Akiko; Aoki, Yoshinori; Kano, Toshiyuki

2008-01-01

The objective of this study was to evaluate the usefulness of the pterion plate in preventing depression of the lateral side of the orbita after frontotemporal craniotomy. Forty patients who underwent frontotemporal craniotomy at our facility were studied: 20 received pterion plates during surgery (pterion plate group) and 20 did not (non-pterion plate group). In all patients, postoperative bone window CT was used to confirm the presence or absence of a depression (≥5 mm) on the lateral side of the orbita. Patient satisfaction was assessed by a questionnaire. Depression of the lateral side of the orbita on postoperative bone window CT was noted in none of the subjects in the pterion plate group and in 12 (60%) of the subjects in the non-pterion plate group (p<0.01). Patient satisfaction was higher in the pterion plate than in the non-pterion plate group (p<0.01). Findings from bone window CT and the questionnaire indicate that the pterion plate is effective in preventing postoperative depression of the lateral side of the orbita during frontotemporal craniotomy. (author)

The cognitive profile of behavioural variant FTD and its similarities with ALS: a systematic review and meta-analysis.

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Beeldman, Emma; Raaphorst, Joost; Klein Twennaar, Michelle; Govaarts, Rosanne; Pijnenburg, Yolande A L; de Haan, Rob J; de Visser, Marianne; Schmand, Ben A

2018-02-09

Approximately 30% of patients with amyotrophic lateral sclerosis (ALS) have cognitive impairment and 8%-14% fulfil the criteria for behavioural variant frontotemporal dementia (bv-FTD). The cognitive profiles of ALS and bv-FTD have been reported to be comparable, but this has never been systematically investigated. We aimed to determine the cognitive profile of bv-FTD and examine its similarities with that of ALS, to provide evidence for the existence of a cognitive disease continuum encompassing bv-FTD and ALS. We therefore systematically reviewed neuropsychological studies on bv-FTD patients and healthy volunteers. Neuropsychological tests were divided in 10 cognitive domains and effect sizes were calculated for all domains and compared with the cognitive profile of ALS by means of a visual comparison and a Pearson's r correlation coefficient. We included 120 studies, totalling 2425 bv-FTD patients and 2798 healthy controls. All cognitive domains showed substantial effect sizes, indicating cognitive impairment in bv-FTD patients compared to healthy controls. The cognitive domains with the largest effect sizes were social cognition, verbal memory and fluency (1.77-1.53). The cognitive profiles of bv-FTD and ALS (10 cognitive domains, 1287 patients) showed similarities on visual comparison and a moderate correlation 0.58 (p=0.13). When social cognition, verbal memory, fluency, executive functions, language and visuoperception were considered, i.e. the cognitive profile of ALS, Pearson's r was 0.73 (p=0.09), which raised to 0.92 (p=0.03), when language was excluded in this systematic analysis of patients with a non-language subtype of FTD. The cognitive profile of bv-FTD consists of deficits in social cognition, verbal memory, fluency and executive functions and shows similarities with the cognitive profile of ALS. These findings support a cognitive continuum encompassing ALS and bv-FTD. © Article author(s) (or their employer(s) unless otherwise stated in the text

Profiling Speech and Pausing in Amyotrophic Lateral Sclerosis (ALS and Frontotemporal Dementia (FTD.

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Yana Yunusova

Full Text Available This study examines reading aloud in patients with amyotrophic lateral sclerosis (ALS and those with frontotemporal dementia (FTD in order to determine whether differences in patterns of speaking and pausing exist between patients with primary motor vs. primary cognitive-linguistic deficits, and in contrast to healthy controls.136 participants were included in the study: 33 controls, 85 patients with ALS, and 18 patients with either the behavioural variant of FTD (FTD-BV or progressive nonfluent aphasia (FTD-PNFA. Participants with ALS were further divided into 4 non-overlapping subgroups--mild, respiratory, bulbar (with oral-motor deficit and bulbar-respiratory--based on the presence and severity of motor bulbar or respiratory signs. All participants read a passage aloud. Custom-made software was used to perform speech and pause analyses, and this provided measures of speaking and articulatory rates, duration of speech, and number and duration of pauses. These measures were statistically compared in different subgroups of patients.The results revealed clear differences between patient groups and healthy controls on the passage reading task. A speech-based motor function measure (i.e., articulatory rate was able to distinguish patients with bulbar ALS or FTD-PNFA from those with respiratory ALS or FTD-BV. Distinguishing the disordered groups proved challenging based on the pausing measures.This study demonstrated the use of speech measures in the identification of those with an oral-motor deficit, and showed the usefulness of performing a relatively simple reading test to assess speech versus pause behaviors across the ALS-FTD disease continuum. The findings also suggest that motor speech assessment should be performed as part of the diagnostic workup for patients with FTD.

Criminal behavior in frontotemporal dementia and Alzheimer disease.

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Liljegren, Madeleine; Naasan, Georges; Temlett, Julia; Perry, David C; Rankin, Katherine P; Merrilees, Jennifer; Grinberg, Lea T; Seeley, William W; Englund, Elisabet; Miller, Bruce L

2015-03-01

Neurodegenerative diseases can cause dysfunction of neural structures involved in judgment, executive function, emotional processing, sexual behavior, violence, and self-awareness. Such dysfunctions can lead to antisocial and criminal behavior that appears for the first time in the adult or middle-aged individual or even later in life. To investigate the frequency and type of criminal behavior among patients with a diagnosed dementing disorder. We conducted a retrospective medical record review of 2397 patients who were seen at the University of California, San Francisco, Memory and Aging Center between 1999 and 2012, including 545 patients with Alzheimer disease (AD), 171 patients with behavioral variant of frontotemporal dementia (bvFTD), 89 patients with semantic variant of primary progressive aphasia, and 30 patients with Huntington disease. Patient notes containing specific keywords denoting criminal behavior were reviewed. Data were stratified by criminal behavior type and diagnostic groups. Frequencies of criminal behavior and χ² statistics were calculated. Of the 2397 patients studied, 204 (8.5%) had a history of criminal behavior that emerged during their illness. Of the major diagnostic groups, 42 of 545 patients (7.7%) with AD, 64 of 171 patients (37.4%) with bvFTD, 24 of 89 patients (27.0%) with semantic variant of primary progressive aphasia, and 6 of 30 patients (20%) with Huntington disease exhibited criminal behavior. A total of 14% of patients with bvFTD were statistically significantly more likely to present with criminal behavior compared with 2% of patients with AD (P violence compared with 2% of patients with AD (P = .003). Common manifestations of criminal behavior in the bvFTD group included theft, traffic violations, sexual advances, trespassing, and public urination in contrast with those in the AD group, who commonly committed traffic violations, often related to cognitive impairment. Criminal behavior is more common in patients

The Relationship between Acquired Impairments of Executive Function and Behaviour Change in Adults with Down Syndrome

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Adams, Dawn; Oliver, C.

2010-01-01

Background: The latter stages of dementia in individuals with Down syndrome are well documented; however, earlier cognitive and behavioural changes have only recently been described. Holland et al. suggested such early signs of dementia in this population are behavioural and are similar to those seen in frontotemporal dementia, but there is, as…

Genetics Home Reference: GRN-related frontotemporal dementia

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... making a protein called granulin (also known as progranulin). Granulin is active in many different tissues in ... Boeve B, Feldman H, Hutton M. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome ...

Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia.

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Wilke, Carlo; Gillardon, Frank; Deuschle, Christian; Hobert, Markus A; Jansen, Iris E; Metzger, Florian G; Heutink, Peter; Gasser, Thomas; Maetzler, Walter; Blauwendraat, Cornelis; Synofzik, Matthis

2017-01-01

Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene (GRN). However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to GRN mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in GRN-negative FTD. Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls). All FTD patients were assessed by whole-exome sequencing for GRN mutations, yielding a target cohort of 34 patients without pathogenic mutations in GRN (GRN-negative cohort) and 3 GRN mutation carriers (2 LoF variants and 1 novel missense variant). Not only the GRN mutation carriers but also the GRN-negative patients showed decreased CSF levels of progranulin (serum levels in GRN-negative patients were normal). The decreased CSF progranulin levels were unrelated to patients' increased CSF levels of total tau, possibly indicating different destructive neuronal processes within FTD neurodegeneration. The patient with the novel GRN missense variant (c.1117C>T, p.P373S) showed substantially decreased CSF levels of progranulin, comparable to the 2 patients with GRN LoF mutations, suggesting a pathogenic effect of this missense variant. Our results indicate that central nervous progranulin reduction is not restricted to the relatively rare cases of FTD caused by GRN LoF mutations, but also contributes to the more common GRN-negative forms of FTD. Central nervous progranulin reduction might reflect a partially distinct pathogenic mechanism underlying FTD neurodegeneration and is not directly linked to tau alterations. © 2016 S. Karger AG, Basel.

Person-Based Versus Generalized Impulsivity Disinhibition in Frontotemporal Dementia and Alzheimer Disease.

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Paholpak, Pongsatorn; Carr, Andrew R; Barsuglia, Joseph P; Barrows, Robin J; Jimenez, Elvira; Lee, Grace J; Mendez, Mario F

2016-09-19

While much disinhibition in dementia results from generalized impulsivity, in behavioral variant frontotemporal dementia (bvFTD) disinhibition may also result from impaired social cognition. To deconstruct disinhibition and its neural correlates in bvFTD vs. early-onset Alzheimer's disease (eAD). Caregivers of 16 bvFTD and 21 matched-eAD patients completed the Frontal Systems Behavior Scale disinhibition items. The disinhibition items were further categorized into (1) "person-based" subscale which predominantly associated with violating social propriety and personal boundary and (2) "generalized-impulsivity" subscale which included nonspecific impulsive acts. Subscale scores were correlated with grey matter volumes from tensor-based morphometry on magnetic resonance images. In comparison to the eAD patients, the bvFTD patients developed greater person-based disinhibition (P dementia, violations of social propriety and personal boundaries involved fronto-parieto-temporal network of Theory of Mind, whereas nonspecific disinhibition involved the OFC and aTL. © The Author(s) 2016.

Dominant hemisphere lateralization of cortical parasympathetic control as revealed by frontotemporal dementia

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Guo, Christine C.; Sturm, Virginia E.; Zhou, Juan; Gennatas, Efstathios D.; Trujillo, Andrew J.; Hua, Alice Y.; Crawford, Richard; Stables, Lara; Kramer, Joel H.; Rankin, Katherine; Levenson, Robert W.; Rosen, Howard J.; Miller, Bruce L.; Seeley, William W.

2016-01-01

The brain continuously influences and perceives the physiological condition of the body. Related cortical representations have been proposed to shape emotional experience and guide behavior. Although previous studies have identified brain regions recruited during autonomic processing, neurological lesion studies have yet to delineate the regions critical for maintaining autonomic outflow. Even greater controversy surrounds hemispheric lateralization along the parasympathetic–sympathetic axis. The behavioral variant of frontotemporal dementia (bvFTD), featuring progressive and often asymmetric degeneration that includes the frontoinsular and cingulate cortices, provides a unique lesion model for elucidating brain structures that control autonomic tone. Here, we show that bvFTD is associated with reduced baseline cardiac vagal tone and that this reduction correlates with left-lateralized functional and structural frontoinsular and cingulate cortex deficits and with reduced agreeableness. Our results suggest that networked brain regions in the dominant hemisphere are critical for maintaining an adaptive level of baseline parasympathetic outflow. PMID:27071080

C9ORF72 G4C2-repeat expansion and frontotemporal dementia first reported case in Argentina.

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Fernández Suarez, M; Surace, Ezequiel; Harris, P; Tapajoz, F; Sevlever, G; Allegri, R; Russo, G N

2016-06-01

We present a female patient aged 51 who developed behavioral disorders followed by cognitive impairment over 3 years. Neuropsychological, neuropsychiatric, and radiological features suggested a probable behavioral variant of frontotemporal dementia (bvFTD). A family history of amyotrophic lateral sclerosis and parkinsonism suggested the hexanucleotide repeat expansion G4C2 in C9ORF72 . We set up a two-step genotyping algorithm for the detection of the expansion using fragment-length analysis polymerase chain reaction (PCR) and repeat-primed PCR with fluorescent primers. We confirmed the presence of an expanded G4C2 allele in the patient. This represents the first documented case of bvFTD due to a C9ORF72 expansion in Argentina.

Primary ectopic frontotemporal extradural craniopharyngioma

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Reza Pourkhalili

2016-01-01

Full Text Available We present a case of primary ectopic frontotemporal extradural craniopharyngioma. Primary ectopic craniopharyngiomas are very rare and have been reported involving the fourth ventricle, infrasellar region, lateral ventricle, temporal area, cerebellopontine angle, clivus, corpus callosum, and prepontine cistern. There was just 1 case of craniopharyngioma previously presented in the literature, with nearly same location as the presenting case.

Regional cerebral glucose metabolism in frontotemporal lobar degeneration

International Nuclear Information System (INIS)

Park, J.M.; Cho, S.S.; Lee, K.-H.; Choi, Y.; Choe, Y.S.; Kim, B.-T.; Kim, S.E.; Kwon, J.C.; Na, D.L.

2002-01-01

Purpose: Frontotemporal lobar degeneration (FTLD) is the third most common cause of dementia, following Alzheimer's disease and Lewy body disease. Four prototypic neuro behavioral syndromes can be produced by FTLD: frontotemporal dementia (FTD), frontotemporal dementia with motor neuron disease (MND), semantic dementia (SD), and progressive aphasia (PA). We investigated patterns of metabolic impairment in patients with FTLD presented with four different clinical syndromes. Methods: We analyzed glucose metabolic patterns on FDG PET images obtained from 34 patients with a clinical diagnosis of FTLD (19 FTD, 6 MND, 6 SD, and 3 PA, according to a consensus criteria for clinical syndromes associated with FTLD) and 7 age-matched healthy controls using SPM99. Results: Patients with FTD had metabolic deficit in the left frontal cortex and bilateral anterior temporal cortex. Hypometabolism in the bilateral pre-motor area was shown in patients with MND. Patients with SD had metabolic deficit in the left posterior temporal cortex including Wernicke's area, while hypometabolism in the bilateral inferior frontal gyrus including Broca's area and left angular gyrus was seen in patients with PA. These metabolic patterns were well correlated with clinical and neuropsychological features of FTLD syndromes. Conclusion: These data provide a biochemical basis of clinical classification of FTLD. FDG PET may help evaluate and classify patients with FTLD

Eyetracking metrics reveal impaired spatial anticipation in behavioural variant frontotemporal dementia.

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Primativo, Silvia; Clark, Camilla; Yong, Keir X X; Firth, Nicholas C; Nicholas, Jennifer; Alexander, Daniel; Warren, Jason D; Rohrer, Jonathan D; Crutch, Sebastian J

2017-11-01

Eyetracking technology has had limited application in the dementia field to date, with most studies attempting to discriminate syndrome subgroups on the basis of basic oculomotor functions rather than higher-order cognitive abilities. Eyetracking-based tasks may also offer opportunities to reduce or ameliorate problems associated with standard paper-and-pencil cognitive tests such as the complexity and linguistic demands of verbal test instructions, and the problems of tiredness and attention associated with lengthy tasks that generate few data points at a slow rate. In the present paper we adapted the Brixton spatial anticipation test to a computerized instruction-less version where oculomotor metrics, rather than overt verbal responses, were taken into account as indicators of high level cognitive functions. Twelve bvFTD (in whom spatial anticipation deficits were expected), six SD patients (in whom deficits were predicted to be less frequent) and 38 healthy controls were presented with a 10 × 7 matrix of white circles. During each trial (N = 24) a black dot moved across seven positions on the screen, following 12 different patterns. Participants' eye movements were recorded. Frequentist statistical analysis of standard eye movement metrics were complemented by a Bayesian machine learning (ML) approach in which raw eyetracking time series datasets were examined to explore the ability to discriminate diagnostic group performance not only on the overall performance but also on individual trials. The original pen and paper Brixton test identified a spatial anticipation deficit in 7/12 (58%) of bvFTD and in 2/6 (33%) of SD patients. The eyetracking frequentist approach reported the deficit in 11/12 (92%) of bvFTD and in none (0%) of the SD patients. The machine learning approach had the main advantage of identifying significant differences from controls in 24/24 individual trials for bvFTD patients and in only 12/24 for SD patients. Results indicate that the fine grained rich datasets obtained from eyetracking metrics can inform us about high level cognitive functions in dementia, such as spatial anticipation. The ML approach can help identify conditions where subtle deficits are present and, potentially, contribute to test optimisation and the reduction of testing times. The absence of instructions also favoured a better distinction between different clinical groups of patients and can help provide valuable disease-specific markers. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

An investigation of care-based vs. rule-based morality in frontotemporal dementia, Alzheimer's disease, and healthy controls.

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Carr, Andrew R; Paholpak, Pongsatorn; Daianu, Madelaine; Fong, Sylvia S; Mather, Michelle; Jimenez, Elvira E; Thompson, Paul; Mendez, Mario F

2015-11-01

Behavioral changes in dementia, especially behavioral variant frontotemporal dementia (bvFTD), may result in alterations in moral reasoning. Investigators have not clarified whether these alterations reflect differential impairment of care-based vs. rule-based moral behavior. This study investigated 18 bvFTD patients, 22 early onset Alzheimer's disease (eAD) patients, and 20 healthy age-matched controls on care-based and rule-based items from the Moral Behavioral Inventory and the Social Norms Questionnaire, neuropsychological measures, and magnetic resonance imaging (MRI) regions of interest. There were significant group differences with the bvFTD patients rating care-based morality transgressions less severely than the eAD group and rule-based moral behavioral transgressions more severely than controls. Across groups, higher care-based morality ratings correlated with phonemic fluency on neuropsychological tests, whereas higher rule-based morality ratings correlated with increased difficulty set-shifting and learning new rules to tasks. On neuroimaging, severe care-based reasoning correlated with cortical volume in right anterior temporal lobe, and rule-based reasoning correlated with decreased cortical volume in the right orbitofrontal cortex. Together, these findings suggest that frontotemporal disease decreases care-based morality and facilitates rule-based morality possibly from disturbed contextual abstraction and set-shifting. Future research can examine whether frontal lobe disorders and bvFTD result in a shift from empathic morality to the strong adherence to conventional rules. Published by Elsevier Ltd.

Frontotemporal Dementia Complicated by Comorbid Borderline Personality Disorder: A Case Report

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Salzbrenner, LCDR Stephen; Brown, Jaime; Hart, Gavin; Dettmer, Ens Jonathan; Williams, LT Raquel; Ormeno, LT Monica; O’Neal, LCDR Ethel; Shippy, LT Jennifer

2009-01-01

Frontotemporal dementia is the fourth most common cause of dementia in the United States and characteristically presents with an early decline in social conduct, impaired regulation of interpersonal conduct, emotional blunting, and general loss of insight, with relative preservation of memory. This a case of frontotemporal dementia in a 46-year-old woman who presented with existing diagnoses of borderline personality disorder and major depressive disorder. She had been repeatedly evaluated fo...

Combined Socio-Behavioral Evaluation Improves the Differential Diagnosis Between the Behavioral Variant of Frontotemporal Dementia and Alzheimer's Disease: In Search of Neuropsychological Markers.

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Dodich, Alessandra; Cerami, Chiara; Cappa, Stefano F; Marcone, Alessandra; Golzi, Valeria; Zamboni, Michele; Giusti, Maria Cristina; Iannaccone, Sandro

2018-01-01

Current diagnostic criteria for behavioral variant of frontotemporal dementia (bvFTD) and typical Alzheimer's disease (AD) include a differential pattern of neuropsychological impairments (episodic memory deficit in typical AD and dysexecutive syndrome in bvFTD). There is, however, large evidence of a frequent overlap in neuropsychological features, making the differential diagnosis extremely difficult. In this retrospective study, we evaluated the diagnostic value of different cognitive and neurobehavioral markers in bvFTD and AD patient groups. We included 95 dementia patients with a clinical and biomarker evidence of bvFTD (n = 48) or typical AD (n = 47) pathology. A clinical 2-year follow-up confirmed clinical classification. Performances at basic cognitive tasks (memory, executive functions, visuo-spatial, language) as well as social cognition skills and neurobehavioral profiles have been recorded. A stepwise logistic regression model compared the neuropsychological profiles between groups and assessed the accuracy of cognitive and neurobehavioral markers in discriminating bvFTD from AD. Statistical comparison between patient groups proved social cognition and episodic memory impairments as main cognitive signatures of bvFTD and AD neuropsychological profiles, respectively. Only half of bvFTD patients showed attentive/executive deficits, questioning their role as cognitive marker of bvFTD. Notably, the large majority of bvFTD sample (i.e., 70%) poorly performed at delayed recall tasks. Logistic regression analysis identified social cognition performances, Frontal Behavioral Inventory and Mini-Mental State Examination scores as the best combination in distinguishing bvFTD from AD. Social cognition tasks and socio-behavioral questionnaires are recommended in clinical settings to improve the accuracy of early diagnosis of bvFTD.

Functional MRI of music emotion processing in frontotemporal dementia.

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Agustus, Jennifer L; Mahoney, Colin J; Downey, Laura E; Omar, Rohani; Cohen, Miriam; White, Mark J; Scott, Sophie K; Mancini, Laura; Warren, Jason D

2015-03-01

Frontotemporal dementia is an important neurodegenerative disorder of younger life led by profound emotional and social dysfunction. Here we used fMRI to assess brain mechanisms of music emotion processing in a cohort of patients with frontotemporal dementia (n = 15) in relation to healthy age-matched individuals (n = 11). In a passive-listening paradigm, we manipulated levels of emotion processing in simple arpeggio chords (mode versus dissonance) and emotion modality (music versus human emotional vocalizations). A complex profile of disease-associated functional alterations was identified with separable signatures of musical mode, emotion level, and emotion modality within a common, distributed brain network, including posterior and anterior superior temporal and inferior frontal cortices and dorsal brainstem effector nuclei. Separable functional signatures were identified post-hoc in patients with and without abnormal craving for music (musicophilia): a model for specific abnormal emotional behaviors in frontotemporal dementia. Our findings indicate the potential of music to delineate neural mechanisms of altered emotion processing in dementias, with implications for future disease tracking and therapeutic strategies. © 2014 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.

Definite behavioral variant of frontotemporal dementia with C9ORF72 expansions despite positive Alzheimer's disease cerebrospinal fluid biomarkers.

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Wallon, David; Rovelet-Lecrux, Anne; Deramecourt, Vincent; Pariente, Jeremie; Auriacombe, Sophie; Le Ber, Isabelle; Schraen, Suzanna; Pasquier, Florence; Campion, Dominique; Hannequin, Didier

2012-01-01

Hexanucleotide expansion repeats in the C9ORF72 gene are a major cause of familial and, to a lesser extent, sporadic frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and FTLD-ALS. To examine whether C9ORF72 expansions could be involved in early-onset Alzheimer's disease (EOAD), we genotyped the hexanucleotide repeat region in a large cohort of 114 EOAD patients who all had positive AD cerebrospinal fluid (CSF) biomarkers. We found hexanucleotide expansion repeats of the C9ORF72 gene in 3 out of 114 patients (2.6%). We raise several hypotheses to explain our results and discuss the current status of AD CSF biomarkers in the dementia diagnostic algorithm.

Frontotemporal dementia with severe thalamic involvement : a clinical and neuropathological study

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Radanovic Márcia

2003-01-01

Full Text Available Frontotemporal dementia (FTD is the third-leading cause of cortical dementia after Alzheimer's disease and Lewy body dementia, and is characterized by a dementia where behavioral disturbances are prominent and appear early in the course of the disease. We report the case of a 58 year-old man affected by dementia with behavioral disturbances, in addition to rigid-hypokinetic and a lower motor neuron syndrome that were present at later stages of the illness. Neuroimaging studies showed frontotemporal atrophy. Neuropathological studies revealed intense thalamic neuronal loss and astrocytic gliosis, as well as moderate frontotemporal neuronal loss, astrocytosis and spongiform degeneration. Thalamic degeneration has previously been described among the wide group of neuropathological features of FTD. The aim of the present study is to show the clinical and neuropathological aspects of thalamic degeneration in FTD, along with its role in behavioral disturbances, a common finding in this condition.

Grey and white matter changes across the amyotrophic lateral sclerosis-frontotemporal dementia continuum.

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Patricia Lillo

Full Text Available There is increasing evidence that amyotrophic lateral sclerosis (ALS and frontotemporal dementia (FTD lie on a clinical, pathological and genetic continuum with patients of one disease exhibiting features of the other. Nevertheless, to date, the underlying grey matter and white matter changes across the ALS-FTD disease continuum have not been explored. In this study fifty-three participants with ALS (n = 10, ALS-FTD (n = 10 and behavioural variant FTD (bvFTD; n = 15 as well as controls (n = 18, underwent detailed clinical assessment plus structural imaging using voxel-based morphometry (VBM and diffusion tensor imaging (DTI analysis of magnetic resonance brain imaging to examine grey and white matter differences and commonalities across the continuum. Importantly, patient groups were matched for age, education, gender and disease duration. VBM and DTI results showed that changes in the ALS group were confined mainly to the motor cortex and anterior cingulate as well as their underlying white matter tracts. ALS-FTD and bvFTD showed widespread grey matter and white matter changes involving frontal and temporal lobes. Extensive prefrontal cortex changes emerged as a marker for bvFTD compared to other subtypes, while ALS-FTD could be distinguished from ALS by additional temporal lobe grey and white matter changes. Finally, ALS could be mainly distinguished from the other two groups by corticospinal tract degeneration. The present study shows for the first time that FTD and ALS overlap in anterior cingulate, motor cortex and related white matter tract changes across the whole continuum. Nevertheless, frontal and temporal atrophy as well as corticospinal tract degeneration emerged as marker for subtype classification, which will inform future diagnosis and target disease management across the continuum.

Profiling Speech and Pausing in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)

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Yunusova, Yana; Graham, Naida L.; Shellikeri, Sanjana; Phuong, Kent; Kulkarni, Madhura; Rochon, Elizabeth; Tang-Wai, David F.; Chow, Tiffany W.; Black, Sandra E.; Zinman, Lorne H.; Green, Jordan R.

2016-01-01

Objective This study examines reading aloud in patients with amyotrophic lateral sclerosis (ALS) and those with frontotemporal dementia (FTD) in order to determine whether differences in patterns of speaking and pausing exist between patients with primary motor vs. primary cognitive-linguistic deficits, and in contrast to healthy controls. Design 136 participants were included in the study: 33 controls, 85 patients with ALS, and 18 patients with either the behavioural variant of FTD (FTD-BV) or progressive nonfluent aphasia (FTD-PNFA). Participants with ALS were further divided into 4 non-overlapping subgroups—mild, respiratory, bulbar (with oral-motor deficit) and bulbar-respiratory—based on the presence and severity of motor bulbar or respiratory signs. All participants read a passage aloud. Custom-made software was used to perform speech and pause analyses, and this provided measures of speaking and articulatory rates, duration of speech, and number and duration of pauses. These measures were statistically compared in different subgroups of patients. Results The results revealed clear differences between patient groups and healthy controls on the passage reading task. A speech-based motor function measure (i.e., articulatory rate) was able to distinguish patients with bulbar ALS or FTD-PNFA from those with respiratory ALS or FTD-BV. Distinguishing the disordered groups proved challenging based on the pausing measures. Conclusions and Relevance This study demonstrated the use of speech measures in the identification of those with an oral-motor deficit, and showed the usefulness of performing a relatively simple reading test to assess speech versus pause behaviors across the ALS—FTD disease continuum. The findings also suggest that motor speech assessment should be performed as part of the diagnostic workup for patients with FTD. PMID:26789001

An Investigation of Care-Based vs. Rule-Based Morality in Frontotemporal Dementia, Alzheimer’s Disease, and Healthy Controls

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Carr, Andrew R.; Paholpak, Pongsatorn; Daianu, Madelaine; Fong, Sylvia S.; Mather, Michelle; Jimenez, Elvira E.; Thompson, Paul; Mendez, Mario F.

2015-01-01

Behavioral changes in dementia, especially behavioral variant frontotemporal dementia (bvFTD), may result in alterations in moral reasoning. Investigators have not clarified whether these alterations reflect differential impairment of care-based vs. rule-based moral behavior. This study investigated 18 bvFTD patients, 22 early onset Alzheimer’s disease (eAD) patients, and 20 healthy age-matched controls on care-based and rule-based items from the Moral Behavioral Inventory and the Social Norms Questionnaire, neuropsychological measures, and magnetic resonance imaging (MRI) regions of interest. There were significant group differences with the bvFTD patients rating care-based morality transgressions less severely than the eAD group and rule-based moral behavioral transgressions more severely than controls. Across groups, higher care-based morality ratings correlated with phonemic fluency on neuropsychological tests, whereas higher rule-based morality ratings correlated with increased difficulty set-shifting and learning new rules to tasks. On neuroimaging, severe care-based reasoning correlated with cortical volume in right anterior temporal lobe, and rule-based reasoning correlated with decreased cortical volume in the right orbitofrontal cortex. Together, these findings suggest that frontotemporal disease decreases care-based morality and facilitates rule-based morality possibly from disturbed contextual abstraction and set-shifting. Future research can examine whether frontal lobe disorders and bvFTD result in a shift from empathic morality to the strong adherence to conventional rules. PMID:26432341

[Specificities of the logopenic variant of primary progressive aphasia].

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Magnin, E; Teichmann, M; Martinaud, O; Moreaud, O; Ryff, I; Belliard, S; Pariente, J; Moulin, T; Vandel, P; Démonet, J-F

2015-01-01

The logopenic variant of primary progressive aphasia is a syndrome with neuropsychological and linguistic specificities, including phonological loop impairment for which diagnosis is currently mainly based on the exclusion of the two other variants, semantic and nonfluent/agrammatic primary progressive aphasia. The syndrome may be underdiagnosed due (1) to mild language difficulties during the early stages of the disease or (2) to being mistaken for mild cognitive impairment or Alzheimer's disease when the evaluation of episodic memory is based on verbal material and (3) finally, it is not uncommon that the disorders are attributed to psychiatric co-morbidities such as, for example, anxiety. Moreover, compared to other variants of primary progressive aphasia, brain abnormalities are different. The left temporoparietal junction is initially affected. Neuropathology and biomarkers (cerebrospinal fluid, molecular amyloid nuclear imaging) frequently reveal Alzheimer's disease. Consequently this variant of primary progressive aphasia does not fall under the traditional concept of frontotemporal lobar degeneration. These distinctive features highlight the utility of correct diagnosis, classification, and use of biomarkers to show the neuropathological processes underlying logopenic primary progressive aphasia. The logopenic variant of primary progressive aphasia is a specific form of Alzheimer's disease frequently presenting a rapid decline; specific linguistic therapies are needed. Further investigation of this syndrome is needed to refine screening, improve diagnostic criteria and better understand the epidemiology and the biological mechanisms involved. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Demencia frontotemporal no familiar y epilepsia generalizada Frontotemporal dementia non familial and generalized epilepsy

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Patricio Fuentes

2005-12-01

Full Text Available Se presenta un paciente de 62 años, sin antecedentes familiares de demencia, que a los 45 años debuta con crisis súbitas de disnea, visión borrosa, caída al suelo y movimientos repetitivos de brazos. Tratado por epilepsia con fenitoína y ácido valproico, repite esporádicamente crisis semejantes. Hace 4 años sus familiares notan cambios de personalidad, irritabilidad y conductas obsesivas. Hace 2 años aparecen episodios de desorientación de días de duración, algunos con alucinaciones auditivas y también fenómenos convulsivos. Ultimamente presenta crisis polimorfas, algunas con prolongada alteración de conciencia, estados catatoniformes y relajación esfinteriana. Examen físico y neurológico sin anormalidades. Evaluación neuropsicológica evidenció consistentes defectos en funciones frontales. EEG mostraron lentitud generalizada y actividad irritativa esporádica en regiones frontotemporales. Atrofia cortical de predominio anterior en CT scan e hipoperfusión fronto-temporal bilateral en SPECT. Exámenes de laboratorio y LCR normales. CONCLUSIÓN: La asociación de DFT con epilepsia, en forma no familiar, sugiere un síndrome neurodegenerativo cortical diferente.A 62 year-old patient is presented, without family antecedents of dementia who begins with 45 years of age with sudden crisis of dyspnea, blurred vision, fall to the floor and repetitive jerks of arms. Tried by epilepsy with phenytoin and valproate repeats similar crisis sporadically. Four years ago their relatives began to notice changes of personality, irritability and obsessive behaviors. Later on, are added episodes of disorientation of days of duration, some with auditory hallucinations and also convulsive manifestations. Finally appear polymorphic crisis, some with continue alteration of consciousness, catatonic states and sphincteric incontinence. Physical and neurological examination without abnormalities. Neuropsychological evaluation evidenced consistent

Genetics Home Reference: frontotemporal dementia with parkinsonism-17

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... FTDP-17 . These changes include a loss of inhibition, inappropriate emotional responses, restlessness, neglect of personal hygiene, ... California, San Fransisco Memory and Aging Center Patient Support and Advocacy Resources (4 links) Association for Frontotemporal ...

Mistakes, Too Few to Mention? Impaired Self-conscious Emotional Processing of Errors in the Behavioral Variant of Frontotemporal Dementia

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Carole S. Scherling

2017-10-01

Full Text Available Anosognosia, or lack of awareness of one's deficits, is a core feature of the behavioral variant of frontotemporal dementia (bvFTD. We hypothesized that this deficit has its origins in failed emotional processing of errors. We studied autonomic and facial emotional reactivity to errors in patients with bvFTD (n = 17, Alzheimer's disease (AD, n = 20, and healthy controls (HC, n = 35 during performance of a timed two-alternative-choice button press task. Performance-related behavioral responses to errors were quantified using rates of error correction and post-error slowing of reaction times. Facial emotional responses were measured by monitoring facial reactivity via video and subsequently coding the type, duration and intensity of all emotional reactions. Skin conductance response (SCR was measured via noninvasive sensors. SCR and total score for each facial emotion expression were quantified for each trial. Facial emotions were grouped into self-conscious (amusement, embarrassment and negative (fear, sadness, anger, disgust, contempt emotions. HCs corrected 99.4% of their errors. BvFTD patients corrected 94% (not statistically different compared with HC and AD corrected 74.8% of their errors (p < 0.05 compared with HC and bvFTD. All groups showed similar post-error slowing. Errors in HCs were associated with greater facial reactivity and SCRs compared with non-error trials, including both negative and self-conscious emotions. BvFTD patients failed to produce self-conscious emotions or an increase in SCR for errors, although they did produce negative emotional responses to a similar degree as HCs. AD showed no deficit in facial reactivity to errors. Although, SCR was generally reduced in AD during error trials, they showed a preserved increase in SCR for errors relative to correct trials. These results demonstrate a specific deficit in emotional responses to errors in bvFTD, encompassing both physiological response and a specific deficit in self

Detection of genetic variants affecting cattle behaviour and their impact on milk production: a genome-wide association study.

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Friedrich, Juliane; Brand, Bodo; Ponsuksili, Siriluck; Graunke, Katharina L; Langbein, Jan; Knaust, Jacqueline; Kühn, Christa; Schwerin, Manfred

2016-02-01

Behaviour traits of cattle have been reported to affect important production traits, such as meat quality and milk performance as well as reproduction and health. Genetic predisposition is, together with environmental stimuli, undoubtedly involved in the development of behaviour phenotypes. Underlying molecular mechanisms affecting behaviour in general and behaviour and productions traits in particular still have to be studied in detail. Therefore, we performed a genome-wide association study in an F2 Charolais × German Holstein cross-breed population to identify genetic variants that affect behaviour-related traits assessed in an open-field and novel-object test and analysed their putative impact on milk performance. Of 37,201 tested single nucleotide polymorphism (SNPs), four showed a genome-wide and 37 a chromosome-wide significant association with behaviour traits assessed in both tests. Nine of the SNPs that were associated with behaviour traits likewise showed a nominal significant association with milk performance traits. On chromosomes 14 and 29, six SNPs were identified to be associated with exploratory behaviour and inactivity during the novel-object test as well as with milk yield traits. Least squares means for behaviour and milk performance traits for these SNPs revealed that genotypes associated with higher inactivity and less exploratory behaviour promote higher milk yields. Whether these results are due to molecular mechanisms simultaneously affecting behaviour and milk performance or due to a behaviour predisposition, which causes indirect effects on milk performance by influencing individual reactivity, needs further investigation. © 2015 Stichting International Foundation for Animal Genetics.

The frontotemporal syndrome of ALS is associated with poor survival.

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Govaarts, Rosanne; Beeldman, Emma; Kampelmacher, Mike J; van Tol, Marie-Jose; van den Berg, Leonard H; van der Kooi, Anneke J; Wijkstra, Peter J; Zijnen-Suyker, Marianne; Cobben, Nicolle A M; Schmand, Ben A; de Haan, Rob J; de Visser, Marianne; Raaphorst, Joost

2016-12-01

Thirty percent of ALS patients have a frontotemporal syndrome (FS), defined as behavioral changes or cognitive impairment. Despite previous studies, there are no firm conclusions on the effect of the FS on survival and the use of non-invasive ventilation (NIV) in ALS. We examined the effect of the FS on survival and the start and duration of NIV in ALS. Behavioral changes were defined as >22 points on the ALS-Frontotemporal-Dementia-Questionnaire or ≥3 points on ≥2 items of the Neuropsychiatric Inventory. Cognitive impairment was defined as below the fifth percentile on ≥2 tests of executive function, memory or language. Classic ALS was defined as ALS without the frontotemporal syndrome. We performed survival analyses from symptom onset and time from NIV initiation, respectively, to death. The impact of the explanatory variables on survival and NIV initiation were examined using Cox proportional hazards models. We included 110 ALS patients (76 men) with a mean age of 62 years. Median survival time was 4.3 years (95 % CI 3.53-5.13). Forty-seven patients (43 %) had an FS. Factors associated with shorter survival were FS, bulbar onset, older age at onset, short time to diagnosis and a C9orf72 repeat expansion. The adjusted hazard ratio (HR) for the FS was 2.29 (95 % CI 1.44-3.65, p NIV initiation (adjusted HR 2.70, 95 % CI 1.04-4.67, p = 0.04). In conclusion, there is an association between the frontotemporal syndrome and poor survival in ALS, which remains present after initiation of NIV.

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: A cross-sectional analysis

NARCIS (Netherlands)

J.D. Rohrer (Jonathan D); J.M. Nicholas (Jennifer M); D.M. Cash (David M); J.C. van Swieten (John); E.G.P. Dopper (Elise); L.C. Jiskoot (Lize); R. van Minkelen (Rick); S.A.R.B. Rombouts (Serge); M.J. Cardoso (Manuel Jorge); S. Clegg (Shona); M. Espak (Miklos); S. Mead (Simon); D.L. Thomas (David L); E. De Vita (Enrico); M. Masellis (Mario); S.E. Black (Sandra); M. Freedman (Morris); R. Keren (Ron); B.J. MacIntosh (Bradley J); E. Rogaeva (Ekaterina); D. Tang-Wai (David); M.C. Tartaglia (Maria Carmela); R. Laforce (Robert); F. Tagliavini (Fabrizio); P. Tiraboschi (Pietro); V. Redaelli (Veronica); S. Prioni (Sara); M. Grisoli (Marina); B. Borroni (Barbara); A. Padovani (Alessandro); D. Galimberti (Daniela); E. Scarpini (Elio); A. Arighi (Andrea); G. Fumagalli (Giorgio); J.B. Rowe (James); I. Coyle-Gilchrist (Ian); C. Graff (Caroline); M. Fallström (Marie); S. Jelic (Svetislav Svetislav); A.K. Ståhlbom (Anne Kinhult); C. Andersson (Christin); H. Thonberg (Håkan); L. Lilius (Lena); G.B. Frisoni (Giovanni B.); M. Pievani (Michela); M. Bocchetta (Martina); L. Benussi (Luisa); R. Ghidoni (Roberta); E. Finger (Elizabeth); S. Sorbi (Sandro); B. Nacmias (Benedetta); G. Lombardi (Gemma); C. Polito (Cristina); J.D. Warren (Jason); S. Ourselin (Sebastien); N.C. Fox (Nick); M. Rossor (Martin)

2015-01-01

textabstractBackground: Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (. GRN), microtubule-associated protein tau (. MAPT), or chromosome

Self-awareness in neurodegenerative disease relies on neural structures mediating reward-driven attention.

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Shany-Ur, Tal; Lin, Nancy; Rosen, Howard J; Sollberger, Marc; Miller, Bruce L; Rankin, Katherine P

2014-08-01

Accurate self-awareness is essential for adapting one's tasks and goals to one's actual abilities. Patients with neurodegenerative diseases, particularly those with right frontal involvement, often present with poor self-awareness of their functional limitations that may exacerbate their already jeopardized decision-making and behaviour. We studied the structural neuroanatomical basis for impaired self-awareness among patients with neurodegenerative disease and healthy older adults. One hundred and twenty-four participants (78 patients with neurodegenerative diseases including Alzheimer's disease, behavioural variant frontotemporal dementia, right-temporal frontotemporal dementia, semantic variant and non-fluent variant primary progressive aphasia, and 46 healthy controls) described themselves on the Patient Competency Rating Scale, rating observable functioning across four domains (daily living activities, cognitive, emotional control, interpersonal). All participants underwent structural magnetic resonance imaging. Informants also described subjects' functioning on the same scale. Self-awareness was measured by comparing self and informant ratings. Group differences in discrepancy scores were analysed using general linear models, controlling for age, sex and disease severity. Compared with controls, patients with behavioural variant frontotemporal dementia overestimated their functioning in all domains, patients with Alzheimer's disease overestimated cognitive and emotional functioning, patients with right-temporal frontotemporal dementia overestimated interpersonal functioning, and patients with non-fluent aphasia overestimated emotional and interpersonal functioning. Patients with semantic variant aphasia did not overestimate functioning on any domain. To examine the neuroanatomic correlates of impaired self-awareness, discrepancy scores were correlated with brain volume using voxel-based morphometry. To identify the unique neural correlates of overlooking

The prevalence of depressive symptoms in frontotemporal dementia: a meta-analysis.

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Chakrabarty, Trisha; Sepehry, Amir A; Jacova, Claudia; Hsiung, Ging-Yuek Robin

2015-01-01

Depression is common in Alzheimer's and vascular dementia and is associated with poorer outcomes; however, less is known about the impact of depression on frontotemporal dementia (FTD). Here, we conducted a meta-analysis of diagnostic methods and the prevalence of depressive symptoms in FTD. PubMed, EMBASE and PsychINFO were queried for 'depression' and/or 'depressive mood' in behavioral- and language-variant FTD. The prevalence and diagnosis of depressive symptoms were extracted from relevant studies and the results pooled using a random-effects model. We included 29 studies in this meta-analysis, with sample sizes ranging from 3 to 73 (n = 870). The omnibus estimated event rate of depressed mood was 0.334 (33%; 95% CI: 0.268-0.407). Symptoms were most commonly assessed via standardized neuropsychiatric rating scales, with other methods including subjective caregiver reports and chart reviews. The study results were heterogeneous due to the variability in diagnostic methods. Depressive symptoms similar to those in other dementias are commonly detected in FTD. However, the diagnostic methods are heterogeneous, and symptoms of depression often overlap with manifestations of FTD. Having a standardized diagnostic approach to depression in FTD will greatly facilitate future research in this area.

Neurocognitive differential diagnosis of dementing diseases: Alzheimer's Dementia, Vascular Dementia, Frontotemporal Dementia, and Major Depressive Disorder.

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Braaten, Alyssa J; Parsons, Thomas D; McCue, Robert; Sellers, Alfred; Burns, William J

2006-11-01

Similarities in presentation of Dementia of Alzheimer's Type, Vascular Dementia, Frontotemporal Dementia, and Major Depressive Disorder, pose differential diagnosis challenges. The current study identifies specific neuropsychological patterns of scores for Dementia of Alzheimer's Type, Vascular Dementia, Frontotemporal Dementia, and Major Depressive Disorder. Neuropsychological domains directly assessed in the study included: immediate memory, delayed memory, confrontational naming, verbal fluency, attention, concentration, and executive functioning. The results reveal specific neuropsychological comparative profiles for Dementia of Alzheimer's Type, Vascular Dementia, Frontotemporal Dementia, and Major Depressive Disorder. The identification of these profiles will assist in the differential diagnosis of these disorders and aid in patient treatment.

Montreal Cognitive Assessment (MoCA): validation study for frontotemporal dementia.

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Freitas, Sandra; Simões, Mário R; Alves, Lara; Duro, Diana; Santana, Isabel

2012-09-01

The Montreal Cognitive Assessment (MoCA) is a brief instrument developed for the screening of milder forms of cognitive impairment, having surpassed the well-known limitations of the Mini-Mental State Examination (MMSE). The aim of the present study was to validate the MoCA as a cognitive screening test for behavioral-variant frontotemporal dementia (bv-FTD) by examining its psychometric properties and diagnostic accuracy. Three matched subgroups of participants were considered: bv-FTD (n = 50), Alzheimer disease (n = 50), and a control group of healthy adults (n = 50). Compared with the MMSE, the MoCA demonstrated consistently superior psychometric properties and discriminant capacity, providing comprehensive information about the patients' cognitive profiles. The diagnostic accuracy of MoCA for bv-FTD was extremely high (area under the curve AUC [MoCA] = 0.934, 95% confidence interval [CI] = 0.866-.974; AUC [MMSE] = 0.772, 95% CI = 0.677-0.850). With a cutoff below 17 points, the MoCA results for sensitivity, specificity, positive predictive value, negative predictive value, and classification accuracy were significantly superior to those of the MMSE. The MoCA is a sensitive and accurate instrument for screening the patients with bv-FTD and represents a better option than the MMSE.

Frontotemporal correlates of impulsivity and machine learning in retired professional athletes with a history of multiple concussions.

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Goswami, R; Dufort, P; Tartaglia, M C; Green, R E; Crawley, A; Tator, C H; Wennberg, R; Mikulis, D J; Keightley, M; Davis, Karen D

2016-05-01

The frontotemporal cortical network is associated with behaviours such as impulsivity and aggression. The health of the uncinate fasciculus (UF) that connects the orbitofrontal cortex (OFC) with the anterior temporal lobe (ATL) may be a crucial determinant of behavioural regulation. Behavioural changes can emerge after repeated concussion and thus we used MRI to examine the UF and connected gray matter as it relates to impulsivity and aggression in retired professional football players who had sustained multiple concussions. Behaviourally, athletes had faster reaction times and an increased error rate on a go/no-go task, and increased aggression and mania compared to controls. MRI revealed that the athletes had (1) cortical thinning of the ATL, (2) negative correlations of OFC thickness with aggression and task errors, indicative of impulsivity, (3) negative correlations of UF axial diffusivity with error rates and aggression, and (4) elevated resting-state functional connectivity between the ATL and OFC. Using machine learning, we found that UF diffusion imaging differentiates athletes from healthy controls with significant classifiers based on UF mean and radial diffusivity showing 79-84 % sensitivity and specificity, and 0.8 areas under the ROC curves. The spatial pattern of classifier weights revealed hot spots at the orbitofrontal and temporal ends of the UF. These data implicate the UF system in the pathological outcomes of repeated concussion as they relate to impulsive behaviour. Furthermore, a support vector machine has potential utility in the general assessment and diagnosis of brain abnormalities following concussion.

Mutations in the PFN1 gene are not a common cause in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration in France.

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Lattante, Serena; Le Ber, Isabelle; Camuzat, Agnès; Brice, Alexis; Kabashi, Edor

2013-06-01

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are 2 adult onset neurological disorders with overlapping symptoms and clinical characteristics. It is well established that they share a common pathologic and genetic background. Recently, mutations in profilin 1 gene (PFN1) have been identified in patients with familial ALS, suggesting a role for this gene in the pathogenesis of the disease. Based on this, we hypothesized that mutations in PFN1 might also contribute to FTLD disease. We studied a French cohort of 165 ALS/FTLD patients, without finding any variant. We conclude that mutations in PFN1 are not a common cause for ALS/FTLD in France. Copyright © 2013 Elsevier Inc. All rights reserved.

Frontotemporal dementia and its subtypes: a genome-wide association study.

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Ferrari, Raffaele; Hernandez, Dena G; Nalls, Michael A; Rohrer, Jonathan D; Ramasamy, Adaikalavan; Kwok, John B J; Dobson-Stone, Carol; Brooks, William S; Schofield, Peter R; Halliday, Glenda M; Hodges, John R; Piguet, Olivier; Bartley, Lauren; Thompson, Elizabeth; Haan, Eric; Hernández, Isabel; Ruiz, Agustín; Boada, Mercè; Borroni, Barbara; Padovani, Alessandro; Cruchaga, Carlos; Cairns, Nigel J; Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta; Forloni, Gianluigi; Galimberti, Daniela; Fenoglio, Chiara; Serpente, Maria; Scarpini, Elio; Clarimón, Jordi; Lleó, Alberto; Blesa, Rafael; Waldö, Maria Landqvist; Nilsson, Karin; Nilsson, Christer; Mackenzie, Ian R A; Hsiung, Ging-Yuek R; Mann, David M A; Grafman, Jordan; Morris, Christopher M; Attems, Johannes; Griffiths, Timothy D; McKeith, Ian G; Thomas, Alan J; Pietrini, P; Huey, Edward D; Wassermann, Eric M; Baborie, Atik; Jaros, Evelyn; Tierney, Michael C; Pastor, Pau; Razquin, Cristina; Ortega-Cubero, Sara; Alonso, Elena; Perneczky, Robert; Diehl-Schmid, Janine; Alexopoulos, Panagiotis; Kurz, Alexander; Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo; Rogaeva, Ekaterina; St George-Hyslop, Peter; Rossi, Giacomina; Tagliavini, Fabrizio; Giaccone, Giorgio; Rowe, James B; Schlachetzki, Johannes C M; Uphill, James; Collinge, John; Mead, Simon; Danek, Adrian; Van Deerlin, Vivianna M; Grossman, Murray; Trojanowski, John Q; van der Zee, Julie; Deschamps, William; Van Langenhove, Tim; Cruts, Marc; Van Broeckhoven, Christine; Cappa, Stefano F; Le Ber, Isabelle; Hannequin, Didier; Golfier, Véronique; Vercelletto, Martine; Brice, Alexis; Nacmias, Benedetta; Sorbi, Sandro; Bagnoli, Silvia; Piaceri, Irene; Nielsen, Jørgen E; Hjermind, Lena E; Riemenschneider, Matthias; Mayhaus, Manuel; Ibach, Bernd; Gasparoni, Gilles; Pichler, Sabrina; Gu, Wei; Rossor, Martin N; Fox, Nick C; Warren, Jason D; Spillantini, Maria Grazia; Morris, Huw R; Rizzu, Patrizia; Heutink, Peter; Snowden, Julie S; Rollinson, Sara; Richardson, Anna; Gerhard, Alexander; Bruni, Amalia C; Maletta, Raffaele; Frangipane, Francesca; Cupidi, Chiara; Bernardi, Livia; Anfossi, Maria; Gallo, Maura; Conidi, Maria Elena; Smirne, Nicoletta; Rademakers, Rosa; Baker, Matt; Dickson, Dennis W; Graff-Radford, Neill R; Petersen, Ronald C; Knopman, David; Josephs, Keith A; Boeve, Bradley F; Parisi, Joseph E; Seeley, William W; Miller, Bruce L; Karydas, Anna M; Rosen, Howard; van Swieten, John C; Dopper, Elise G P; Seelaar, Harro; Pijnenburg, Yolande A L; Scheltens, Philip; Logroscino, Giancarlo; Capozzo, Rosa; Novelli, Valeria; Puca, Annibale A; Franceschi, Massimo; Postiglione, Alfredo; Milan, Graziella; Sorrentino, Paolo; Kristiansen, Mark; Chiang, Huei-Hsin; Graff, Caroline; Pasquier, Florence; Rollin, Adeline; Deramecourt, Vincent; Lebert, Florence; Kapogiannis, Dimitrios; Ferrucci, Luigi; Pickering-Brown, Stuart; Singleton, Andrew B; Hardy, John; Momeni, Parastoo

2014-07-01

Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms. We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data

Frontotemporal dementia and neurocysticercosis: a case report

Directory of Open Access Journals (Sweden)

Corina Satler

Full Text Available ABSTRACT We report a case of a 67-year-old woman with frontotemporal dementia (FTD and a history of neurocysticercosis. After her retirement she showed progressive behavioral changes and neuropsychiatric symptoms with relative preservation of cognitive functioning. During the next three years, the patient manifested progressive deterioration of verbal communication gradually evolving to mutism, a hallmark of cases of progressive nonfluent aphasia.

Frontotemporal Lobar Degeneration and microRNAs

Directory of Open Access Journals (Sweden)

Paola ePiscopo

2016-02-01

Full Text Available Frontotemporal lobar degeneration (FTLD includes a spectrum of disorders characterized by changes of personality and social behaviour and, often, a gradual and progressive language dysfunction. In the last years, several efforts have been fulfilled in identifying both genetic mutations and pathological proteins associated with FTLD. The molecular bases undergoing the onset and progression of the disease remain still unknown. Recent literature prompts an involvement of RNA metabolism in FTLD, particularly miRNAs. Dysregulation of miRNAs in several disorders, including neurodegenerative diseases, and increasing importance of circulating miRNAs in different pathologies has suggested to implement the study of their possible application as biological markers and new therapeutic targets; moreover, miRNA-based therapy is becoming a powerful tool to deepen the function of a gene, the mechanism of a disease, and validate therapeutic targets. Regarding FTLD, different studies showed that miRNAs are playing an important role. For example, several reports have evaluated miRNA regulation of the progranulin gene suggesting that it is under their control, as described for miR-29b, miR-107 and miR-659. More recently, it has been demonstrated that TMEM106B gene, which protein is elevated in FTLD-TDP brains, is repressed by miR-132/212 cluster; this post-transcriptional mechanism increases intracellular levels of progranulin, affecting its pathways. These findings if confirmed could suggest that these microRNAs have a role as potential targets for some related-FTLD genes. In this review, we focus on the emerging roles of the miRNAs in the pathogenesis of FTLD.

Which behaviours? Identifying the most common and burdensome behaviour changes in amyotrophic lateral sclerosis.

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Andrews, Sophie Claire; Pavlis, Alexia; Staios, Mathew; Fisher, Fiona

2017-04-01

Behaviour change is increasingly recognised as a common feature of amyotrophic lateral sclerosis (ALS), and may be similar to that seen in frontotemporal dementia (FTD). The behaviours most disturbed in ALS, and those that relate most significantly to caregiver burden, however, have not been well established. Forty ALS participants and their caregivers, and 27 age- and gender-matched healthy controls and their relatives, participated in this study. ALS participants were assessed on a disease rating scale, and caregivers and control informants completed the revised version of the Cambridge Behaviour Inventory and a measure of burden. ALS caregivers reported significantly more disturbance than healthy control informants on the functional domains of everyday skills, self-care, and sleep, and in the behavioural domains of mood and motivation. There were no differences between groups in frequency of memory and orientation difficulties, or behaviours characteristic of FTD, such as changes to eating habits or stereotypic and motor behaviour, indicating that the behavioural profile in ALS may differ from FTD. In the ALS group, the domains with the strongest relationship to caregiver burden were everyday skills, motivation and memory, likely because poor motivation, memory dysfunction and difficulties completing activities of daily living require more carer support via direct supervision, prompting or hands on care. Services to support ALS patients and caregivers need to provide targeted interventions for those functional and behavioural changes which are most burdensome in the disease.

Individual Music Therapy with Persons with Frontotemporal Dementia

DEFF Research Database (Denmark)

Ridder, Hanne Mette Ochsner; Aldridge, David

2005-01-01

It is possible to slow down the progression of Alzheimer’s disease with pharmacological treatment. When this treatment is given to people with types of dementia that affect the frontal and temporal lobes (Frontotemporal Dementia) the results are discouraging. It is observed that the patients show...... is an integration of a relational music therapy approach and a more physiologically based arousal model, and is here illustrated in a case study research that integrated both qualitative and quantitative data in a flexible research design.......It is possible to slow down the progression of Alzheimer’s disease with pharmacological treatment. When this treatment is given to people with types of dementia that affect the frontal and temporal lobes (Frontotemporal Dementia) the results are discouraging. It is observed that the patients show...... pronounced restlessness and mania. In this article we describe a non-pharmacological psychosocial approach, music therapy, and how it is possible to work with this method when constitutional, regulative, dialogical, and integrative aspects are included. The focus is on therapeutic singing where well known...

Impaired affective and cognitive theory of mind and behavioural change in amyotrophic lateral sclerosis.

Science.gov (United States)

van der Hulst, Egberdina-Józefa; Bak, Thomas H; Abrahams, Sharon

2015-11-01

Executive and behavioural changes are well-recognised in classical amyotrophic lateral sclerosis (ALS), indicating a subclinical behavioural-variant frontotemporal dementia (bvFTD) in some patients. Social cognitive deficits in ALS have been recently described and an impairment was identified on a simple Theory of Mind (ToM) test, which assesses the judgement of the preference of another through direction of eye gaze. The present study further delineated this deficit, by distinguishing between Affective and Cognitive subcomponents, and determining the relationship to behavioural change, levels of empathy and self-awareness. The Cognitive-Affective Judgement of Preference Test was administered to 33 patients with ALS and 26 controls. Furthermore, a comprehensive neuropsychological battery and detailed behavioural assessment, with measures of empathy and awareness, were included. Patients with ALS showed a significant impairment in Affective ToM only when compared with healthy controls, with a deficit in 36% of patients; 12% showed an isolated Affective ToM deficit while 24% showed more generic ToM dysfunction. A Cognitive ToM deficit was found in 27% of patients, with 3% showing an isolated Cognitive ToM deficit. The patients with ALS showed reduced empathy (Fantasy scale) and increased behavioural dysfunction with high levels of apathy. In addition, patients with either an Affective and/or Cognitive ToM deficit exhibited poor self-awareness of their performance and abnormalities on verbal fluency, while those with an Affective ToM deficit also displayed higher levels of apathy and a naming deficit. Dysfunctional ToM is a prominent feature of the cognitive profile of ALS. This specific difficulty in identifying and distinguishing the feelings and thoughts of another from a self-perspective may underpin the social behavioural abnormalities present in some patients with ALS, manifest as apathy and loss of awareness. Published by the BMJ Publishing Group Limited. For

Screening for the C9ORF72 repeat expansion in a greek frontotemporal dementia cohort.

Science.gov (United States)

Kartanou, Chrisoula; Karadima, Georgia; Koutsis, Georgios; Breza, Marianthi; Papageorgiou, Sokratis G; Paraskevas, George P; Kapaki, Elisabeth; Panas, Marios

2018-02-01

The C9orf72 repeat expansion is a common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in European populations. A previous study has reported a high frequency of the expansion in Greek ALS. However, no data have been reported on the frequency of the expansion in Greek FTD. Currently, we investigated the frequency of the C9orfF72 expansion in a well-characterized cohort of 64 Greek FTD patients. We detected the C9orf72 repeat expansion in 9.3% of cases. Overall, 27.7% of familial and 2.2% of sporadic cases were expansion-positive. Five out of 6 cases had a diagnosis of behavioral variant FTD. All expansion-positive cases had fairly typical FTD presentations. Clinical features included motor neuron disease, Parkinsonism and hallucinations. We conclude that the overall frequency of C9orf72-positive cases in Greek FTD is high, comparable to Greek ALS, similar to some Western European, but significantly higher than some Mediterranean FTD populations.

Clinical update on frontotemporal dementia: diagnosis and treatment.

Science.gov (United States)

Mocellin, Ramon; Scholes, Amelia; Walterfang, Mark; Looi, Jeffrey C L; Velakoulis, Dennis

2015-10-01

To provide a clinical update for general psychiatrists on frontotemporal dementias (FTDs) using a selective narrative review of recent findings and advances in conceptualising, diagnosing and treating FTD. General psychiatrists can apply their skills to support patients, carers, GPs and allied health workers in comprehensive care of persons with FTD. © The Royal Australian and New Zealand College of Psychiatrists 2015.

Frontotemporal dementia and its subtypes: A genome-wide association study

NARCIS (Netherlands)

R. Ferrari (Roberto); D.G. Hernandez (Dena); M.A. Nalls (Michael); J.D. Rohrer (Jonathan Daniel); A. Ramasamy (Adaikalavan); J.B.J. Kwok (John); C. Dobson-Stone (Carol); Brooks Brooks William S. (W.S.); C.J. Schofield (Christopher); G.M. Halliday (Glenda Margaret); J. Hodges (John); O. Piguet (Olivier); L. Bartley (Lauren); E. Thompson (Elizabeth); E. Haan (Eric); I. Hernández (Isabel); A. Ruiz (Agustin); M. Boada (Mercè); B. Borroni (Barbara); A. Padovani (Alessandro); C. Cruchaga (Carlos); N.J. Cairns (Nigel); L. Benussi (Luisa); G. Binetti (Giuliano); R. Ghidoni (Roberta); G. Forloni (Gianluigi); D. Galimberti (Daniela); C. Fenoglio (Chiara); M. Serpente (Maria); E. Scarpini (Elio); J. Clarimon (Jordi); A. Lleo (Alberto); R. Blesa (Rafael); M.L. Waldö (Maria Landqvist); K. Nilsson (Karin); C. Nilsson (Christer); I.R.A. Mackenzie (Ian); G.Y.R. Hsiung (Ging-Yuek); D.M.A. Mann (David); J. Grafman (Jordan); C.M. Morris (Chris); J. Attems (Johannes); T.D. Griffiths (Timothy); I.G. McKeith (Ian); A.W. Thomas (Alan); P. Pietrini (P.); E.D. Huey (Edward); E.M. Wassermann (Eric); A. Baborie (Atik); J.A.J. Jaros (Julian); M.C. Tierney (Michael); P. Pastor (Pau); C. Razquin (Cristina); S. Ortega-Cubero (Sara); E. Alonso (Elena); R. Perneczky (Robert); J. Diehl-Schmid (Janine); E.C. Alexopoulos (Evangelos); A. Kurz; I. Rainero (Innocenzo); M. Rubino (Maurizio); L. Pinessi (Lorenzo); E. Rogaeva (Ekaterina); P.H. St George-Hyslop (Peter); G. de Rossi (Giulio); F. Tagliavini (Fabrizio); G. Giaccone (Giuseppe); J.B. Rowe (James); J.C.M. Schlachetzki (Johannes C.); J. Uphill (James); J. Collinge (John); S. Mead (Simon); A. Danek (Adrian); V.M. Deerlin (Vivianna); M. Grossman (Murray); J.Q. Trojanowski (John); J. van der Zee (Jill); J. Deschamps (Jacqueline); T. van Langenhove (Tim); M. Cruts (Marc); C. van Broeckhoven (Christine); S.F. Cappa (Stefano); I. Le Ber (Isabelle); D. Hannequin (Didier); V. Golfier (Véronique); M. Vercelletto (Martine); A. Brice; B. Nacmias (Benedetta); S. Sorbi (Sandro); S. Bagnoli (Silvia); I. Piaceri (Irene); J.E. Nielsen (Jorgen); L.E. Hjermind (Lena); M. Riemenschneider (Matthias); M. Mayhaus (Manuel); B. Ibach (Bernd); G. Gasparoni (Gilles); I. Pichler (Irene); W. Gu (Wei); M. Rossor (Martin); N.C. Fox (Nick); J.D. Warren (Jason); M.G. Spillantini; H. Morris (Huw); P. Rizzu (Patrizia); P. Heutink (Peter); J. Snowden (Julie); S. Rollinson (Sara); A. Richardson (Anna); A. Gerhard (Alex); A.C. Bruni (Amalia); R. Maletta (Raffaele); F. Frangipane (Francesca); C. Cupidi (Chiara); L. Bernardi (Livia); M. Anfossi (Maria); V. Gallo (Valentina); A. Conidi (Andrea); N. Smirne (Nicoletta); S. Rademakers (Suzanne); M.C. Baker (Matthew); D.W. Dickson (Dennis); N.R. Graff-Radford (Neill); R.C. Petersen (Ronald); D.S. Knopman (David); K.A. Josephs (Keith); B.F. Boeve (Bradley); J.E. Parisi (Joseph); W. Seeley (William); B.L. Miller (Bruce Lars); A. Karydas (Anna); H. Rosen (Howard); J.C. van Swieten (John); E.G.P. Dopper (Elise); H. Seelaar (Harro); Y. Pijnenburg (Yolande); P. Scheltens (Philip); G. Logroscino (Giancarlo); R. Capozzo (Rosa); V. Novelli (Valeria); A.A. Puca (Annibale); C. Franceschi (Claudio); A. Postiglione (Alfredo); D.J. Milan (David); D. Sorrentino (Dario); M. Kristiansen (Mark); Y.T. Chiang; M.J. Graff (Maud J.L.); F. Pasquier (Florence); P.E. Rollin (Pierre); V. Deramecourt (Vincent); F. Lebert (Florence); D. Kapogiannis (Dimitrios); L. Ferrucci (Luigi); S. Pickering-Brown (Stuart); A. Singleton (Andrew); J. Hardy (John); M. Momeni (Mona)

2014-01-01

textabstractBackground: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify

Recognition of Facial Expressions of Different Emotional Intensities in Patients with Frontotemporal Lobar Degeneration

Directory of Open Access Journals (Sweden)

Roy P. C. Kessels

2007-01-01

Full Text Available Behavioural problems are a key feature of frontotemporal lobar degeneration (FTLD. Also, FTLD patients show impairments in emotion processing. Specifically, the perception of negative emotional facial expressions is affected. Generally, however, negative emotional expressions are regarded as more difficult to recognize than positive ones, which thus may have been a confounding factor in previous studies. Also, ceiling effects are often present on emotion recognition tasks using full-blown emotional facial expressions. In the present study with FTLD patients, we examined the perception of sadness, anger, fear, happiness, surprise and disgust at different emotional intensities on morphed facial expressions to take task difficulty into account. Results showed that our FTLD patients were specifically impaired at the recognition of the emotion anger. Also, the patients performed worse than the controls on recognition of surprise, but performed at control levels on disgust, happiness, sadness and fear. These findings corroborate and extend previous results showing deficits in emotion perception in FTLD.

Right Frontotemporal Cortex Mediates the Relationship between Cognitive Insight and Subjective Quality of Life in Patients with Schizophrenia.

Science.gov (United States)

Pu, Shenghong; Nakagome, Kazuyuki; Itakura, Masashi; Ohtachi, Hiroaki; Iwata, Masaaki; Nagata, Izumi; Kaneko, Koichi

2018-01-01

Although prior studies identified a relationship between cognitive insight and subjective quality of life (QOL) in patients with schizophrenia, the brain regions mediating this relationship remain unknown. Recent studies have shown that the ventrolateral prefrontal cortex may be particularly important for cognitive insight in individuals with schizophrenia. Here, we examined whether frontotemporal function mediates the relationship between cognitive insight and QOL in 64 participants, including 32 patients with schizophrenia and 32 healthy controls. Cognitive insight was measured using the Beck Cognitive Insight Scale (BCIS), while participants' subjective QOL was assessed using the Medical Outcomes Study 36-item Short-form Health Survey. Frontotemporal function was evaluated during a verbal fluency task using multichannel near-infrared spectroscopy. Consistent with previous findings, we found that frontotemporal function was impaired in patients with schizophrenia. Interestingly, our data also revealed that the right ventrolateral PFC and the right anterior part of the temporal cortex significantly mediated the relationship between the self-reflectiveness (SR) subscale of the BCIS and subjective QOL. These findings suggest that cognitive insight, particularly SR, is associated with subjective QOL in patients with schizophrenia via right frontotemporal function. The findings of this study provide important insight into a QOL model of schizophrenia, which may guide the development of cost-effective interventions that target frontotemporal function in patients with schizophrenia.

Effects of brand variants on smokers' choice behaviours and risk perceptions.

Science.gov (United States)

Hoek, Janet; Gendall, Philip; Eckert, Christine; Kemper, Joya; Louviere, Jordan

2016-03-01

Australian tobacco companies have introduced evocative variant names that could re-create the aspirational connotations plain packaging aims to remove. To inform future regulation, we explored how brand descriptors affected smokers' responses to plain packs featuring different variant name combinations. An online survey of 254 daily smokers or social smokers aged between 18 and 34 used a within-subjects best-worst experiment to estimate the relative effects of variant names. A 2×4×4×4 design contained four attributes: quality (premium or none), taste (smooth, fine, rich or none) connotation (classic, midnight, infinite or none) and colour (red, blue, white or none). In a between-subjects component, respondents evaluated one of two alternative packs according to its perceived harm and ease of quitting. The most important variant attribute was connotation, followed by taste, colour and quality; within these attributes, the most attractive descriptors were 'classic' and 'smooth'. We identified four distinct segments that differed significantly in their sociodemographic attributes and variant preferences, although not in their perceptions of the harm or quitting ease associated with two different variants. Some descriptors significantly enhance the appeal of tobacco products among different groups of smokers and may undermine plain packaging's dissuasive intent. Policymakers should explicitly regulate variant names to avoid the 'poetry on a package' evident in Australia. Options include disallowing new descriptors, limiting the number of descriptors permitted or banning descriptors altogether. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

A novel network analysis approach reveals DNA damage, oxidative stress and calcium/cAMP homeostasis-associated biomarkers in frontotemporal dementia

Science.gov (United States)

Ferrari, Raffaele; Graziano, Francesca; Novelli, Valeria; Rossi, Giacomina; Galimberti, Daniela; Rainero, Innocenzo; Benussi, Luisa; Nacmias, Benedetta; Bruni, Amalia C.; Cusi, Daniele; Salvi, Erika; Borroni, Barbara; Grassi, Mario

2017-01-01

Frontotemporal Dementia (FTD) is the form of neurodegenerative dementia with the highest prevalence after Alzheimer’s disease, equally distributed in men and women. It includes several variants, generally characterized by behavioural instability and language impairments. Although few mendelian genes (MAPT, GRN, and C9orf72) have been associated to the FTD phenotype, in most cases there is only evidence of multiple risk loci with relatively small effect size. To date, there are no comprehensive studies describing FTD at molecular level, highlighting possible genetic interactions and signalling pathways at the origin FTD-associated neurodegeneration. In this study, we designed a broad FTD genetic interaction map of the Italian population, through a novel network-based approach modelled on the concepts of disease-relevance and interaction perturbation, combining Steiner tree search and Structural Equation Model (SEM) analysis. Our results show a strong connection between Calcium/cAMP metabolism, oxidative stress-induced Serine/Threonine kinases activation, and postsynaptic membrane potentiation, suggesting a possible combination of neuronal damage and loss of neuroprotection, leading to cell death. In our model, Calcium/cAMP homeostasis and energetic metabolism impairments are primary causes of loss of neuroprotection and neural cell damage, respectively. Secondly, the altered postsynaptic membrane potentiation, due to the activation of stress-induced Serine/Threonine kinases, leads to neurodegeneration. Our study investigates the molecular underpinnings of these processes, evidencing key genes and gene interactions that may account for a significant fraction of unexplained FTD aetiology. We emphasized the key molecular actors in these processes, proposing them as novel FTD biomarkers that could be crucial for further epidemiological and molecular studies. PMID:29020091

A novel network analysis approach reveals DNA damage, oxidative stress and calcium/cAMP homeostasis-associated biomarkers in frontotemporal dementia.

Directory of Open Access Journals (Sweden)

Fernando Palluzzi

Full Text Available Frontotemporal Dementia (FTD is the form of neurodegenerative dementia with the highest prevalence after Alzheimer's disease, equally distributed in men and women. It includes several variants, generally characterized by behavioural instability and language impairments. Although few mendelian genes (MAPT, GRN, and C9orf72 have been associated to the FTD phenotype, in most cases there is only evidence of multiple risk loci with relatively small effect size. To date, there are no comprehensive studies describing FTD at molecular level, highlighting possible genetic interactions and signalling pathways at the origin FTD-associated neurodegeneration. In this study, we designed a broad FTD genetic interaction map of the Italian population, through a novel network-based approach modelled on the concepts of disease-relevance and interaction perturbation, combining Steiner tree search and Structural Equation Model (SEM analysis. Our results show a strong connection between Calcium/cAMP metabolism, oxidative stress-induced Serine/Threonine kinases activation, and postsynaptic membrane potentiation, suggesting a possible combination of neuronal damage and loss of neuroprotection, leading to cell death. In our model, Calcium/cAMP homeostasis and energetic metabolism impairments are primary causes of loss of neuroprotection and neural cell damage, respectively. Secondly, the altered postsynaptic membrane potentiation, due to the activation of stress-induced Serine/Threonine kinases, leads to neurodegeneration. Our study investigates the molecular underpinnings of these processes, evidencing key genes and gene interactions that may account for a significant fraction of unexplained FTD aetiology. We emphasized the key molecular actors in these processes, proposing them as novel FTD biomarkers that could be crucial for further epidemiological and molecular studies.

The frontotemporal syndrome of ALS is associated with poor survival

NARCIS (Netherlands)

Govaarts, R. (Rosanne); E. Beeldman (Emma); M.J. Kampelmacher (Mike J.); M.J.D. van Tol (Marie-José); L.H. van den Berg (Leonard); A.J. Kooj (Anneke); P.J. Wijkstra (Peter); Zijnen-Suyker, M. (Marianne); N.A.M. Cobben (Nicolle); B. Schmand (Ben); R.J. de Haan (Rob); M. de Visser (Marianne); J. Raaphorst

2016-01-01

textabstractThirty percent of ALS patients have a frontotemporal syndrome (FS), defined as behavioral changes or cognitive impairment. Despite previous studies, there are no firm conclusions on the effect of the FS on survival and the use of non-invasive ventilation (NIV) in ALS. We examined the

The social and economic burden of frontotemporal degeneration.

Science.gov (United States)

Galvin, James E; Howard, David H; Denny, Sharon S; Dickinson, Susan; Tatton, Nadine

2017-11-14

To quantify the socioeconomic burden of frontotemporal degeneration (FTD) compared to previously published data for Alzheimer disease (AD). A 250-item internet survey was administered to primary caregivers of patients with behavioral-variant FTD (bvFTD), primary progressive aphasia, FTD with motor neuron disease, corticobasal syndrome, or progressive supranuclear palsy. The survey included validated scales for disease staging, behavior, activities of daily living, caregiver burden, and health economics, as well as investigator-designed questions to capture patient and caregiver experience with FTD. The entire survey was completed by 674 of 956 respondents (70.5%). Direct costs (2016 US dollars) equaled $47,916 and indirect costs $71,737, for a total annual per-patient cost of $119,654, nearly 2 times higher than reported costs for AD. Patients ≥65 years of age, with later stages of disease, and with bvFTD correlated with higher direct costs, while patients <65 years of age and men were associated with higher indirect costs. An FTD diagnosis produced a mean decrease in household income from $75,000 to $99,000 12 months before diagnosis to $50,000 to $59,999 12 months after diagnosis, resulting from lost days of work and early departure from the workforce. The economic burden of FTD is substantial. Counting productivity-related costs, per-patient costs for FTD appear to be greater than per-patient costs reported for AD. There is a need for biomarkers for accurate and timely diagnosis, effective treatments, and services to reduce this socioeconomic burden. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

The frontotemporal syndrome of ALS is associated with poor survival

NARCIS (Netherlands)

Govaarts, Rosanne; Beeldman, Emma; Kampelmacher, Mike J; van Tol, Marie-Jose; van den Berg, Leonard H; van der Kooi, Anneke J; Wijkstra, Peter J; Zijnen-Suyker, Marianne; Cobben, Nicolle A M; Schmand, Ben A; de Haan, Rob J; de Visser, Marianne; Raaphorst, Joost

2016-01-01

Thirty percent of ALS patients have a frontotemporal syndrome (FS), defined as behavioral changes or cognitive impairment. Despite previous studies, there are no firm conclusions on the effect of the FS on survival and the use of non-invasive ventilation (NIV) in ALS. We examined the effect of the

Caregiver burden in atypical dementias: comparing frontotemporal dementia, Creutzfeldt-Jakob disease, and Alzheimer's disease.

Science.gov (United States)

Uflacker, Alice; Edmondson, Mary C; Onyike, Chiadi U; Appleby, Brian S

2016-02-01

Caregiver burden is a significant issue in the treatment of dementia and a known contributor to institutionalization of patients with dementia. Published data have documented increased caregiver burden in behavioral variant frontotemporal dementia (bvFTD) compared to Alzheimer's disease (AD). Another atypical dementia with high-perceived caregiver burden is sporadic Creutzfeldt-Jakob disease (sCJD), but no formal studies have assessed this perception. The aim of this study was to compare caregiver burden across atypical dementia etiologies. 76 adults with atypical dementia (young-onset AD [YOAD], bvFTD, language variant FTD [lvFTD], and sCJD) were administered an abbreviated version of the Zarit Burden Interview (ZBI), Neuropsychiatric Inventory (NPI-Q), and other assessment instruments during a five-year time period at Johns Hopkins Hospital (JHH). A Cox regression model examined differences between disease categories that impact mean ZBI scores. Mean ZBI scores were significantly different between dementia etiologies, with bvFTD and sCJD having the highest caregiver burden (p = 0.026). Mean NPI-Q caregiver distress scores were highest in bvFTD and sCJD (p = 0.002), with sCJD and bvFTD also having the highest number of endorsed symptom domains (p = 0.012). On regression analyses, an interactive variable combining final diagnosis category and NPI-Q total severity score demonstrated statistically significant differences in mean ZBI scores for sCJD and bvFTD. This study demonstrates that bvFTD and sCJD have increased levels of caregiver burden, NPI-Q caregiver distress, total severity scores, and number of endorsed symptom domains. These results suggest that higher caregiver burden in bvFTD and sCJD are disease specific and possibly related to neuropsychiatric symptoms.

Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease

NARCIS (Netherlands)

Pottier, C.; Bieniek, K.F.; Finch, N.; Vorst, M. van de; Baker, M.; Perkersen, R.; Brown, P.; Ravenscroft, T.; Blitterswijk, M. van; Nicholson, A.M.; DeTure, M.; Knopman, D.S.; Josephs, K.A.; Parisi, J.E.; Petersen, R.C.; Boylan, K.B.; Boeve, B.F.; Graff-Radford, N.R.; Veltman, J.A.; Gilissen, C.; Murray, M.E.; Dickson, D.W.; Rademakers, R.

2015-01-01

Frontotemporal lobar degeneration with TAR DNA-binding protein 43 inclusions (FTLD-TDP) is the most common pathology associated with frontotemporal dementia (FTD). Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) and mutations in progranulin (GRN) are the major known genetic causes

TDP-43 protein variants as biomarkers in amyotrophic lateral sclerosis.

Science.gov (United States)

Williams, Stephanie M; Khan, Galam; Harris, Brent T; Ravits, John; Sierks, Michael R

2017-01-25

TDP-43 aggregates accumulate in individuals affected by amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, representing potential diagnostic and therapeutic targets. Using an atomic force microscopy based biopanning protocol developed in our lab, we previously isolated 23 TDP-43 reactive antibody fragments with preference for human ALS brain tissue relative to frontotemporal dementia, a related neurodegeneration, and healthy samples from phage-displayed single chain antibody fragment (scFv) libraries. Here we further characterize the binding specificity of these different scFvs and identify which ones have promise for detecting ALS biomarkers in human brain tissue and plasma samples. We developed a sensitive capture ELISA for detection of different disease related TDP-43 variants using the scFvs identified from the ALS biopanning. We show that a wide variety of disease selective TDP-43 variants are present in ALS as the scFvs show different reactivity profiles amongst the ALS cases. When assaying individual human brain tissue cases, three scFvs (ALS-TDP6, ALS-TDP10 and ALS-TDP14) reacted with all the ALS cases and 12 others reacted with the majority of the ALS cases, and none of the scFvs reacted with any control samples. When assaying individual human plasma samples, 9 different scFvs reacted with all the sporadic ALS samples and again none of them reacted with any control samples. These 9 different scFvs had different patterns of reactivity with plasma samples obtained from chromosome 9 open reading frame 72 (c9orf72) cases indicating that these familial ALS genetic variants may display different TDP-43 pathology than sporadic ALS cases. These results indicated that a range of disease specific TDP-43 variants are generated in ALS patients with different variants being generated in sporadic and familial cases. We show that a small panel of scFvs recognizing different TDP-43 variants can generate a neuropathological and plasma biomarker

Behavioral and autonomic reactivity to moral dilemmas in frontotemporal dementia versus Alzheimer's disease.

Science.gov (United States)

Fong, Sylvia S; Navarrete, Carlos David; Perfecto, Sean E; Carr, Andrew R; Jimenez, Elvira E; Mendez, Mario F

2017-08-01

The personal/impersonal distinction of moral decision-making postulates intuitive emotional responses from medial frontal activity and rational evaluation from lateral frontal activity. This model can be analyzed in behavioral variant frontotemporal dementia (bvFTD), a disorder characterized by impaired emotional intuitions, ventromedial prefrontal cortex (vmPFC) involvement, and relative sparing of lateral frontal regions. Moral dilemmas were presented to 10 bvFTD, 11 Alzheimer's disease (AD), and 9 healthy control (HC) participants while recording skin conductance responses, a measure of emotional arousal. We evaluated their personal versus impersonal conflict, subjective discomfort, and adherence to social norms. Replicating prior work, bvFTD participants were more willing to harm in the personal, but not the impersonal, dilemma compared to AD and HC groups. BvFTD participants had lower arousal and less of an increase in conflict on the personal versus the impersonal dilemma, in contrast to increased arousal and conflict for the AD and HC groups. Furthermore, bvFTD participants verbalized less discomfort, a correlate of low adherence to social norms. These findings support impaired emotional reactions to moral dilemmas in bvFTD and vmPFC lesions and the personal/impersonal model. It suggests a reversion to utilitarian-like considerations when emotional intuition is impaired in the brain.

Reconocimiento facial de emociones básicas y su Relación con la teoría de la mente en la variante conductual de la demencia frontotemporal

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María Eugenia Tabernero

2016-01-01

Full Text Available Las emociones básicas están biológicamente determinadas y ligadas a conductas fundamenta- les para la supervivencia. Las emociones secun- darias son aquellas que para su reconocimiento, requieren la elaboración cognitiva de un contexto social, por lo tanto, de la Teoría de la Mente (TdM. La TdM fue definida como la habilidad de conceptualizar estados mentales de otros indi- viduos para explicar y predecir gran parte de su comportamiento. No es un concepto unitario, exis ten disociaciones entre los componentes cog- nitivo y el emocional de la TdM. Han sido esta- blecidas las alteraciones en el reconocimiento facial de emociones básicas (RFEB y en las ta- reas de TdM en la variante conductual de la de- mencia frontotemporal (DFTvc. El objetivo del trabajo que se informa fue estudiar el reconoci- miento de emociones básicas o primarias y su re- lación con la TdM en pacientes con DFTvc. El 81% de los pacientes mostró alteraciones en por lo menos uno de los tests de RFEB y el 35% en el reconocimiento de la prosodia emocional. El subtest Denominación y el Puntaje Total Emo- ciones mostraron correlaciones con el Test Lec- tura de la Mente en los Ojos, mientras que todas las tareas de RFEB correlacionaron con la tarea de falsa creencia. Se encontraron dobles disocia- ciones entre TdM emocional y cognitiva, con mayor afectación del componente emocional. Como conclusión se corrobora la presencia de alteraciones en el RFEB con prosodia emocional conservada en la DFTvc. La ausencia de correlaciones entre emociones básicas y secundarias pa- recería indicar que se trata de procesos independientes entre sí.

Creep Behaviour of Modified Mar-247 Superalloy

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Cieśla M.

2016-06-01

Full Text Available The paper presents the results of analysis of creep behaviour in short term creep tests of cast MAR-247 nickel-based superalloy samples made using various modification techniques and heat treatment. The accelerated creep tests were performed under temperature of 982 °C and the axial stresses of σ = 150 MPa (variant I and 200 MPa (variant II. The creep behaviour was analysed based on: creep durability (creep rupture life, steady-state creep rate and morphological parameters of macro- and microstructure. It was observed that the grain size determines the creep durability in case of test conditions used in variant I, durability of coarse-grained samples was significantly higher.

Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease

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Laura Ibanez

2018-04-01

Full Text Available Background: The prevalence of dementia in Parkinson disease (PD increases dramatically with advancing age, approaching 80% in patients who survive 20 years with the disease. Increasing evidence suggests clinical, pathological and genetic overlap between Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia with PD. However, the contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established.Objective: To assess the contribution of coding variants in Mendelian dementia-causing genes on the risk of developing PD and the effect on cognitive performance of PD patients.Methods: We analyzed the coding regions of the amyloid-beta precursor protein (APP, Presenilin 1 and 2 (PSEN1, PSEN2, and Granulin (GRN genes from 1,374 PD cases and 973 controls using pooled-DNA targeted sequence, human exome-chip and whole-exome sequencing (WES data by single variant and gene base (SKAT-O and burden tests analyses. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE or the Montreal Cognitive Assessment (MoCA. The effect of coding variants in dementia-causing genes on cognitive performance was tested by multiple regression analysis adjusting for gender, disease duration, age at dementia assessment, study site and APOE carrier status.Results: Known AD pathogenic mutations in the PSEN1 (p.A79V and PSEN2 (p.V148I genes were found in 0.3% of all PD patients. There was a significant burden of rare, likely damaging variants in the GRN and PSEN1 genes in PD patients when compared with frequencies in the European population from the ExAC database. Multiple regression analysis revealed that PD patients carrying rare variants in the APP, PSEN1, PSEN2, and GRN genes exhibit lower cognitive tests scores than non-carrier PD patients (p = 2.0 × 10−4, independent of age at PD diagnosis, age at evaluation, APOE status or recruitment site.Conclusions: Pathogenic mutations in

Risk and protective genetic variants in suicidal behaviour: association with SLC1A2, SLC1A3, 5-HTR1B &NTRK2 polymorphisms.

LENUS (Irish Health Repository)

Murphy, Therese M

2012-02-01

BACKGROUND: Suicidal behaviour is known to aggregate in families. Patients with psychiatric disorders are at higher risk for suicide attempts (SA), however protective and risk genetic variants for suicide appear to be independent of underlying psychiatric disorders. Here we investigate genetic variants in genes important for neurobiological pathways linked to suicidal behaviour and\\/or associated endophenotypes, for association with SA among patients with co-existing psychiatric illness. Selected gene-gene and gene-environment interactions were also tested. METHODS: DNA was obtained from bloods of 159 patients (76 suicide attempters and 83 non-attempters), who were profiled for DSM-IV Axis I psychiatric diagnosis. Twenty-eight single nucleotide polymorphisms (SNPs) from 18 candidate genes (COMT, 5-HT2A, 5-HT1A, 5-HTR1B, TPH1, MAO-A, TPH2, DBH, CNR1, BDNF, ABCG1, GABRA5, GABRG2, GABRB2, SLC1A2, SLC1A3, NTRK2, CRHR1) were genotyped. Genotyping was performed by KBioscience. Tests of association between genetic variants and SA were conducted using Chi squared and Armitage Trend tests. Binary logistical regression analyses were performed to evaluate the contribution of individual genetic variants to the prediction of SA, and to examine SNPs for potential gene-gene and gene-environment interactions. RESULTS: Our analysis identified 4 SNPs (rs4755404, rs2269272, rs6296 and rs1659400), which showed evidence of association with SA compared to a non-attempter control group. We provide evidence of a 3-locus gene-gene interaction, and a putative gene-environment interaction, whereby genetic variation at the NTRK2 locus may moderate the risk associated with history of childhood abuse. CONCLUSION: Preliminary findings suggest that allelic variability in SLC1A2\\/3, 5-HTR1B and NTRK2 may be relevant to the underlying diathesis for suicidal acts.

Factors Underpinning Caregiver Burden in Frontotemporal Dementia Differ in Spouses and their Children

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Kaizik, Cassandra; Caga, Jashelle; Camino, Julieta; O’Connor, Claire M.; McKinnon, Colleen; Oyebode, Jan R.; Piguet, Olivier; Hodges, John R.; Mioshi, Eneida

2017-01-01

The objectives of this observational study were to (1) compare spousal and child caregiver burden; (2) compare co-resident and live-out child caregiver burden; and (3) investigate factors influencing spousal and child caregiver burden. Data was collected from 90 caregivers of people with frontotemporal degeneration (FTD) recruited from the Frontotemporal Dementia Research Group (Frontier) at Neuroscience Research, Australia. Of this caregiver group, 43 were spousal caregivers and 47 were child caregivers. Caregiver burden and emotional state were evaluated using the short Zarit Burden Interview and the short version of the Depression, Anxiety and Stress Scale-21. The Social Network Index was applied to ascertain the social network of the caregiver, while the Intimate Bond Measure was used to evaluate the current quality of the relationship between the caregiver and the person with dementia. The Frontotemporal Dementia Rating Scale was used to assess severity of dementia. Spousal and child caregivers experienced similar levels of burden, depression, anxiety, and stress, regardless of disease severity. Co-resident child caregivers had smaller social networks and greater burden than live-out caregivers. Dementia severity was key in spousal caregiver burden, whereas caregiver depression was most important in child caregiver burden. Child and spousal caregivers of individuals with FTD share similar levels of burden, influenced by different factors. Future interventions need to account for these differences. PMID:28106550

Neuroanatomical profiles of personality change in frontotemporal lobar degeneration.

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Mahoney, Colin J; Rohrer, Jonathan D; Omar, Rohani; Rossor, Martin N; Warren, Jason D

2011-05-01

The neurobiological basis of personality is poorly understood. Frontotemporal lobar degeneration (FTLD) frequently presents with complex behavioural changes, and therefore potentially provides a disease model in which to investigate brain substrates of personality. To assess neuroanatomical correlates of personality change in a cohort of individuals with FTLD using voxel-based morphometry (VBM). Thirty consecutive individuals fulfilling consensus criteria for FTLD were assessed. Each participant's carer completed a Big Five Inventory (BFI) questionnaire on five key personality traits; for each trait, a change score was derived based on current compared with estimated premorbid characteristics. All participants underwent volumetric brain magnetic resonance imaging. A VBM analysis was implemented regressing change score for each trait against regional grey matter volume across the FTLD group. The FTLD group showed a significant decline in extraversion, agreeableness, conscientiousness and openness and an increase in neuroticism. Change in particular personality traits was associated with overlapping profiles of grey matter loss in more anterior cortical areas and relative preservation of grey matter in more posterior areas; the most robust neuroanatomical correlate was identified for reduced conscientiousness in the region of the posterior superior temporal gyrus. Quantitative measures of personality change in FTLD can be correlated with changes in regional grey matter. The neuroanatomical profiles for particular personality traits overlap brain circuits previously implicated in aspects of social cognition and suggest that dysfunction at the level of distributed cortical networks underpins personality change in FTLD.

Examining frontotemporal connectivity and rTMS in healthy controls: implications for auditory hallucinations in schizophrenia.

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Gromann, Paula M; Tracy, Derek K; Giampietro, Vincent; Brammer, Michael J; Krabbendam, Lydia; Shergill, Sukhwinder S

2012-01-01

Repetitive transcranial magnetic stimulation (rTMS) has been shown to have clinically beneficial effects in altering the perception of auditory hallucinations (AH) in patients with schizophrenia. However, the mode of action is not clear. Recent neuroimaging findings indicate that rTMS has the potential to induce not only local effects but also changes in remote, functionally connected brain regions. Frontotemporal dysconnectivity has been proposed as a mechanism leading to psychotic symptoms in schizophrenia. The current study examines functional connectivity between temporal and frontal brain regions after rTMS and the implications for AH in schizophrenia. A connectivity analysis was conducted on the fMRI data of 11 healthy controls receiving rTMS, compared with 11 matched subjects receiving sham TMS, to the temporoparietal junction, before engaging in a task associated with robust frontotemporal activation. Compared to the control group, the rTMS group showed an altered frontotemporal connectivity with stronger connectivity between the right temporoparietal cortex and the dorsolateral prefrontal cortex and the angular gyrus. This finding provides preliminary evidence for the hypothesis that normalizing the functional connectivity between the temporoparietal and frontal brain regions may underlie the therapeutic effect of rTMS on AH in schizophrenia.

Sortilin-Mediated Endocytosis Determines Levels of the Fronto-Temporal Dementia Protein, Progranulin

DEFF Research Database (Denmark)

Hu, Fenghua; Padukkavidana, Thihan; Vægter, Christian Bjerggaard

2010-01-01

The most common inherited form of Fronto-Temporal Lobar Degeneration (FTLD) known stems from Progranulin (GRN) mutation, and exhibits TDP-43 plus ubiquitin protein aggregates in brain. Despite the causative role of GRN haploinsufficiency in FTLD-TDP, the neurobiology of this secreted glycoprotein...

A Single-Centre, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Investigate the Efficacy and Safety of Minoxidil Topical Foam in Frontotemporal and Vertex Androgenetic Alopecia in Men.

Science.gov (United States)

Hillmann, Kathrin; Garcia Bartels, Natalie; Kottner, Jan; Stroux, Andrea; Canfield, Douglas; Blume-Peytavi, Ulrike

2015-01-01

5% minoxidil formulations twice daily are effective in treating vertex male androgenetic alopecia (AGA); however, efficacy and safety data in frontotemporal regions are lacking. To assess the efficacy of 5% minoxidil topical foam (5% MTF) in the frontotemporal region of male AGA patients after 24 weeks of treatment compared to placebo treatment and to the vertex region. Seventy males with moderate AGA applied 5% MTF or placebo foam (plaTF) twice daily for 24 weeks in frontotemporal and vertex regions. Target area non-vellus hair count (TAHC) was the primary end point. Frontotemporal and vertex TAHC and target area cumulative non-vellus hair width (TAHW) showed similar responses to 5% MTF with significant increases up to week 16 compared to baseline (p < 0.001). After 24 weeks of treatment, frontotemporal TAHW increased significantly in the 5% MTF group compared to the plaTF group (p = 0.017), while TAHC showed a similar non-significant increase from baseline in both regions. At 24 weeks, 5% MTF users rated a significant improvement in scalp coverage for the frontotemporal (p = 0.016) and vertex areas (p = 0.027). 5% MTF twice a day promotes hair density and width in both frontotemporal and vertex regions in men with moderate stages of AGA. © 2015 S. Karger AG, Basel.

Processing emotion from abstract art in frontotemporal lobar degeneration

OpenAIRE

Cohen, Miriam H.; Carton, Amelia M.; Hardy, Christopher J.; Golden, Hannah L.; Clark, Camilla N.; Fletcher, Phillip D.; Jaisin, Kankamol; Marshall, Charles R.; Henley, Susie M.D.; Rohrer, Jonathan D.; Crutch, Sebastian J.; Warren, Jason D.

2016-01-01

Abstract art may signal emotions independently of a biological or social carrier: it might therefore constitute a test case for defining brain mechanisms of generic emotion decoding and the impact of disease states on those mechanisms. This is potentially of particular relevance to diseases in the frontotemporal lobar degeneration (FTLD) spectrum. These diseases are often led by emotional impairment despite retained or enhanced artistic interest in at least some patients. However, the process...

TDP-43 in Familial and Sporadic Frontotemporal Lobar Degeneration with Ubiquitin Inclusions

NARCIS (Netherlands)

Cairns, Nigel J.; Neumann, Manuela; Bigio, Eileen H.; Holm, Ida E.; Troost, Dirk; Hatanpaa, Kimmo J.; Foong, Chan; White, Charles L.; Schneider, Julie A.; Kretzschmar, Hans A.; Carter, Deborah; Taylor-Reinwald, Lisa; Paulsmeyer, Katherine; Strider, Jeffrey; Gitcho, Michael; Goate, Alison M.; Morris, John C.; Mishrall, Manjari; Kwong, Linda K.; Stieber, Anna; Xu, Yan; Forman, Mark S.; Trojanowski, John Q.; Lee, Virginia M.-Y.; Mackenzie, Ian R. A.

2007-01-01

TAR DNA-binding protein 43 (TDP-43) is a major pathological protein of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Thus, TDP-43 defines a novel class of neurodegenerative diseases called

PROGRANULIN MUTATIONS AFFECTS BRAIN OSCILLATORY ACTIVITY IN FRONTO-TEMPORAL DEMENTIA

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Davide Vito Moretti

2016-02-01

Full Text Available Background: mild cognitive impairment (MCI is a clinical stage indicating a prodromal phase of dementia. This practical concept could be used also for fronto-temporal dementia (FTD. Progranulin (PGRN has been recently recognized as a useful diagnostic biomarker for fronto-temporal lobe degeneration (FTLD due to GRN null mutations. Electroencephalography (EEG is a reliable tool in detecting brain networks changes. The working hypothesis of the present study is that EEG oscillations could detect different modifications among FTLD stages (FTD-MCI versus overt FTD as well as differences between GRN mutation carriers versus non carriers in patients with overt FTD. Methods: EEG in all patients and PGRN dosage in patients with a clear FTD were detected. The cognitive state has been investigated through mini mental state examination (MMSE. Results: MCI-FTD showed a significant lower spectral power in both alpha and theta oscillations as compared to overt FTD. GRN mutations carriers affected by FTLD show an increase in high alpha and decrease in theta oscillations as compared to non-carriers.Conclusion: EEG frequency rhythms are sensible to different stage of FTD and could detect changes in brain oscillatory activity affected by GRN mutations

Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

DEFF Research Database (Denmark)

Ferrari, Raffaele; Wang, Yunpeng; Vandrovcova, Jana

2017-01-01

BACKGROUND: Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer's disease (AD) and Parkinson's disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between...

A Case of Morvan Syndrome Mimicking Amyotrophic Lateral Sclerosis With Frontotemporal Dementia.

Science.gov (United States)

Freund, Brin; Maddali, Manoj; Lloyd, Thomas E

2016-06-01

Morvan syndrome is a rare autoimmune/paraneoplastic disorder involving antibodies to the voltage-gated potassium channel complex. It is defined by subacute encephalopathy, neuromuscular hyperexcitability, dysautonomia, and sleep disturbance. It may present a diagnostic dilemma when trying to differentiate from amyotrophic lateral sclerosis with frontotemporal dementia. A 76-year-old man with a history of untreated prostate adenocarcinoma was evaluated for subacute cognitive decline, diffuse muscle cramps, and hyponatremia. MRI demonstrated atrophy most prominent in the frontal and temporal regions. Electromyography (EMG) demonstrated diffuse myokymia/neuromyotonia. Polysomnography lacked REM and N3 sleep. Paraneoplastic panel detected antibodies to voltage-gated potassium channel complex (CASPR2 subtype). It is difficult to differentiate between Morvan syndrome and amyotrophic lateral sclerosis with frontotemporal dementia with examination and neuroimaging alone. There may be a link between Morvan syndrome and prostate adenocarcinoma which could help with screening/diagnosis. The authors found that laboratory and neurophysiological tests are indispensable in diagnosing and treating Morvan syndrome.

A 43-kDa TDP-43 species is present in aggregates associated with frontotemporal lobar degeneration.

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Patrick J Bosque

Full Text Available The transactive response DNA-binding protein (TDP-43 is a major component of the abnormal intracellular inclusions that occur in two common neurodegenerative diseases of humans: (1 a subtype of frontotemporal lobar degeneration and (2 amyotrophic lateral sclerosis. Genetics, experiments in cultured cells and animals, and analogy with other neurodegenerative diseases indicate that the process of TDP-43 aggregation is fundamental to the pathogenesis of these 2 diseases, but the process by which this aggregation occurs is not understood. Biochemical fractionation has revealed truncated, phosphorylated and ubiquitinated forms of TDP-43 in a detergent-insoluble fraction from diseased CNS tissue, while these forms are absent from controls. However, a large amount of the normally predominant 43-kDa form of TDP-43 is present in the detergent-insoluble fraction even from control brains, so it has not been possible to determine if this form of TDP-43 is part of pathological aggregates in frontotemporal lobe degeneration. We used semi-denaturing detergent-agarose gel electrophoresis to isolate high molecular weight aggregates containing TDP-43 that are present in the cerebral cortex of individuals with frontotemporal lobar degeneration but not that of controls. These aggregates include the same covalently modified forms of TDP-43 seen in detergent-insoluble extracts. In addition, aggregates include a 43-kDa TDP-43 species. This aggregated 43-kDa form of TDP-43 is absent or present only at low levels in controls. The presence of 43-kDa TDP-43 in aggregates raises the possibility that covalent modification is not a primary step in the pathogenic aggregation of TDP-43 associated with frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

Efficacy of Electroconvulsive Therapy for Comorbid Frontotemporal Dementia with Bipolar Disorder

OpenAIRE

Paul, Sean; Goetz, Jennifer; Bennett, Jeffrey; Korah, Tessy

2013-01-01

Challenges encountered in the diagnosis and treatment of frontotemporal dementia (FTD) are further confounded when presented with comorbid psychiatric disorder. Here we report a case of progressive FTD in a patient with a long history of bipolar affective disorder (BAD) 1, depressed type. We also report beneficial effects of electroconvulsive therapy and its potential application in similar comorbid disorders.

Atrophy in distinct corticolimbic networks in frontotemporal dementia relates to social impairments measured using the Social Impairment Rating Scale

Science.gov (United States)

Bickart, Kevin C; Brickhouse, Michael; Negreira, Alyson; Sapolsky, Daisy

2015-01-01

Patients with frontotemporal dementia (FTD) often exhibit prominent, early and progressive impairments in social behaviour. We developed the Social Impairment Rating Scale (SIRS), rated by a clinician after a structured interview, which grades the types and severity of social behavioural symptoms in seven domains. In 20 FTD patients, we used the SIRS to study the anatomic basis of social impairments. In support of hypotheses generated from a prior study of healthy adults, we found that the relative magnitude of brain atrophy in three partially dissociable corticolimbic networks anchored in the amygdala predicted the severity of distinct social impairments measured using the SIRS. Patients with the greatest atrophy in a mesolimbic, reward-related (affiliation) network exhibited the most severe socioemotional detachment, whereas patients with the greatest atrophy in an interoceptive, pain-related (aversion) network exhibited the most severe lack of social apprehension. Patients with the greatest atrophy in a perceptual network exhibited the most severe lack of awareness or understanding of others’ social and emotional behaviour. Our findings underscore observations that FTD is associated with heterogeneous social symptoms that can be understood in a refined manner by measuring impairments in component processes subserved by dissociable neural networks. Furthermore, these findings support the validity of the SIRS as an instrument to measure the social symptoms of patients with FTD. Ultimately, we hope it will be useful as a longitudinal outcome measure in natural history studies and in clinical trials of putative interventions to improve social functioning. PMID:24133285

The neural correlates and clinical characteristics of psychosis in the frontotemporal dementia continuum and the C9orf72 expansion

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Emma M Devenney

2017-01-01

Conclusions: This study underlines the need to consider and assess for psychotic symptoms in the frontotemporal dementia-amyotrophic lateral sclerosis continuum particularly in those with C9orf72 gene expansions. The network of brain regions identified in this study is strikingly similar to that identified in other psychotic disorders such as schizophrenia, which suggests that treatment strategies in psychiatry may be beneficial for the management of psychotic symptoms in frontotemporal dementia.

Efficacy of Electroconvulsive Therapy for Comorbid Frontotemporal Dementia with Bipolar Disorder

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Sean Paul

2013-01-01

Full Text Available Challenges encountered in the diagnosis and treatment of frontotemporal dementia (FTD are further confounded when presented with comorbid psychiatric disorder. Here we report a case of progressive FTD in a patient with a long history of bipolar affective disorder (BAD 1, depressed type. We also report beneficial effects of electroconvulsive therapy and its potential application in similar comorbid disorders.

Epidemiological Survey of Frontotemporal Lobar Degeneration in Tottori Prefecture, Japan

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Kenji Wada-Isoe

2012-09-01

Full Text Available Background: The prevalence of frontotemporal lobar degeneration (FTLD in Japan is unknown. An epidemiological survey study of FTLD was undertaken in Tottori Prefecture, a district in the western region of Japan. Methods: Hospitals in Tottori Prefecture were surveyed by a two-step questionnaire in 2010, and the prevalence of FTLD per 100,000 inhabitants was calculated using the actual number of patients and inhabitants in Tottori Prefecture on the prevalence day of October 1, 2010. Results: In this survey, 66 patients were diagnosed with FTLD. The subtypes of FTLD were as follows: 62 cases of frontotemporal dementia (FTD, 3 cases of progressive nonfluent aphasia, and 1 case of semantic dementia. Among the FTD cases, 5 cases were FTD with motor neuron disease and 1 case was FTD with parkinsonism linked to chromosome 17. The prevalence of FTD in the total population of Tottori Prefecture was 11.2 per 100,000 inhabitants. Based on these results, the prevalence of FTLD in Japan in 2008 was estimated to be 9.5 per 100,000 individuals. Conclusions: Our epidemiological survey results suggest that there are at least 12,000 FTLD patients in Japan, indicating that FTLD is not a rare disease.

Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability

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M. Catarina Silva

2016-09-01

Full Text Available Frontotemporal dementia (FTD and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of neuronal loss is not fully understood. To identify molecular events associated with tauopathy, we studied induced pluripotent stem cell (iPSC-derived neurons from individuals carrying the tau-A152T variant. We highlight the potential of in-depth phenotyping of human neuronal cell models for pre-clinical studies and identification of modulators of endogenous tau toxicity. Through a panel of biochemical and cellular assays, A152T neurons showed accumulation, redistribution, and decreased solubility of tau. Upregulation of tau was coupled to enhanced stress-inducible markers and cell vulnerability to proteotoxic, excitotoxic, and mitochondrial stressors, which was rescued upon CRISPR/Cas9-mediated targeting of tau or by pharmacological activation of autophagy. Our findings unmask tau-mediated perturbations of specific pathways associated with neuronal vulnerability, revealing potential early disease biomarkers and therapeutic targets for FTD and other tauopathies.

Dementias show differential physiological responses to salient sounds

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Phillip David Fletcher

2015-03-01

Full Text Available Abnormal responsiveness to salient sensory signals is often a prominent feature of dementia diseases, particularly the frontotemporal lobar degenerations, but has been little studied. Here we assessed processing of one important class of salient signals, looming sounds, in canonical dementia syndromes. We manipulated tones using intensity cues to create percepts of salient approaching (‘looming’ or less salient withdrawing sounds. Pupil dilatation responses and behavioural rating responses to these stimuli were compared in patients fulfilling consensus criteria for dementia syndromes (semantic dementia, n=10; behavioural variant frontotemporal dementia, n=16, progressive non-fluent aphasia, n=12; amnestic Alzheimer’s disease, n=10 and a cohort of 26 healthy age-matched individuals. Approaching sounds were rated as more salient than withdrawing sounds by healthy older individuals but this behavioural response to salience did not differentiate healthy individuals from patients with dementia syndromes. Pupil responses to approaching sounds were greater than responses to withdrawing sounds in healthy older individuals and in patients with semantic dementia: this differential pupil response was reduced in patients with progressive nonfluent aphasia and Alzheimer’s disease relative both to the healthy control and semantic dementia groups, and did not correlate with nonverbal auditory semantic function. Autonomic responses to auditory salience are differentially affected by dementias and may constitute a novel biomarker of these diseases.

The clinical differentiation of fronto-temporal dementia from psychiatric disease

OpenAIRE

Panegyres, Peter K; Graves, Angela; Frencham, Kate AR

2007-01-01

Objective Frontal and/or temporal lobar atrophy (F/TA) is sometimes detected on neuroimaging in patients with psychiatric disease. This observation leads to difficulty in distinguishing whether patients have fronto-temporal dementia (FTD) or psychiatric illness. This paper sets out to develop clinical profiles that might be useful at first presentation to distinguish these two populations. Methods 29 patients were selected from a database of 250 current patients attending young onset dementia...

The brain basis of musicophilia: evidence from frontotemporal lobar degeneration

OpenAIRE

Phillip David Fletcher; Laura eDowney; Pirada eWitoonpanich; Jason eWarren

2013-01-01

Musicophilia, or abnormal craving for music, is a poorly understood phenomenon that has been associated in particular with focal degeneration of the temporal lobes. Here we addressed the brain basis of musicophilia using voxel-based morphometry (VBM) on MR volumetric brain images in a retrospectively ascertained cohort of patients meeting clinical consensus criteria for frontotemporal lobar degeneration: of 37 cases ascertained, 12 had musicophilia and 25 did not exhibit the phenomenon. The s...

Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations

DEFF Research Database (Denmark)

Urwin, Hazel; Authier, Astrid; Nielsen, Jørgen Erik

2010-01-01

Mutations in CHMP2B cause frontotemporal dementia (FTD) in a large Danish pedigree, which is termed FTD linked to chromosome 3 (FTD-3), and also in an unrelated familial FTD patient. CHMP2B is a component of the ESCRT-III complex, which is required for function of the multivesicular body (MVB), a...

TDP-43 pathology in familial frontotemporal dementia and motor neuron disease without Progranulin mutations.

NARCIS (Netherlands)

Seelaar, H.; Schelhaas, H.J.; Azmani, A.; Kusters, B.; Rosso, S.; Majoor-Krakauer, D.F.; Rijik, M.C. de; Rizzu, P.; Brummelhuis, M. Ten; Doorn, P.A. van; Kamphorst, W.; Willemsen, R.; Swieten, J. van

2007-01-01

Frontotemporal dementia is accompanied by motor neuron disease (FTD + MND) in approximately 10% of cases. There is accumulating evidence for a clinicopathological overlap between FTD and MND based on observations of familial aggregation and neuropathological findings of ubiquitin-positive neuronal

TDP-43 pathology in familial frontotemporal dementia and motor neuron disease without Progranulin mutations

NARCIS (Netherlands)

H. Seelaar (Harro); H. Jurgen Schelhaas; A. Azmani (Asma); B. Küsters (Benno); S.M. Rosso (Sonia); D.F. Majoor-Krakauer (Danielle); M.C. de Rijik (Maarten); P. Rizzu (Patrizia); M. ten Brummelhuis (Ming); P.A. van Doorn (Pieter); W. Kamphorst (Wouter); R. Willemsen (Rob); J.C. van Swieten (John)

2007-01-01

textabstractFrontotemporal dementia is accompanied by motor neuron disease (FTD + MND) in ∼10% of cases. There is accumulating evidence for a clinicopathological overlap between FTD and MND based on observations of familial aggregation and neuropathological findings of ubiquitin-positive neuronal

Self-perception in a clinical sample of gender variant children.

Science.gov (United States)

Rijn, Anouk Balleur-van; Steensma, Thomas D; Kreukels, Baudewijntje P C; Cohen-Kettenis, Peggy T

2013-07-01

Gender variance (GV) in childhood has a negative impact on the self-concept of children in the general population and can lead to mental health problems and even suicidal ideation in adulthood. This study explored the self-concept of clinically referred gender variant children and examined potential risk factors. The Self-Perception Profile for Children was administered to 147 children, who were referred to a gender identity clinic. Their parents completed the Child Behaviour Checklist and the Gender Identity Questionnaire to assess the degree of GV. The referred children were at risk of developing a negative self-concept; more specifically gender variant girls had low scores on 'global self-worth', 'physical appearance' and 'behavioural conduct' compared to Dutch norms for girls. Gender variant boys had low scores on 'global self-worth', 'scholastic competence', 'athletic competence' and 'physical appearance' compared to Dutch norms for boys. Within the group of referred children, sex differences, but no age effects, were found. The referred girls felt more competent than the referred boys on 'athletic competence' and 'scholastic functioning'. For both boys and girls poor peer relations had a significant negative relationship with self-concept and more GV was related to a lower global self-worth. Clinically referred gender variant children seemed vulnerable to developing a negative self-concept. Poor peer relations and extreme GV might be mediating variables. Interventions might focus on enhancing acceptance of the environment and improving social skills of gender variant children.

[The interactive neuroanatomical simulation and practical application of frontotemporal transsylvian exposure in neurosurgery].

Science.gov (United States)

Balogh, Attila; Czigléczki, Gábor; Papal, Zsolt; Preul, Mark C; Banczerowski, Péter

2014-11-30

There is an increased need for new digital education tools in neurosurgical training. Illustrated textbooks offer anatomic and technical reference but do not substitute hands-on experience provided by surgery or cadaver dissection. Due to limited availability of cadaver dissections the need for development of simulation tools has been augmented. We explored simulation technology for producing virtual reality-like reconstructions of simulated surgical approaches on cadaver. Practical application of the simulation tool has been presented through frontotemporal transsylvian exposure. The dissections were performed on two cadaveric heads. Arteries and veins were prepared and injected with colorful silicon rubber. The heads were rigidly fixed in Mayfield headholder. A robotic microscope with two digital cameras in inverted cone method of image acquisition was used to capture images around a pivot point in several phases of dissections. Multilayered, high-resolution images have been built into interactive 4D environment by custom developed software. We have developed the simulation module of the frontotemporal transsylvian approach. The virtual specimens can be rotated or tilted to any selected angles and examined from different surgical perspectives at any stage of dissections. Important surgical issues such as appropriate head positioning or surgical maneuvers to expose deep situated neuroanatomic structures can be simulated and studied by using the module. The simulation module of the frontotemporal transsylvian exposure helps to examine effect of head positioning on the visibility of deep situated neuroanatomic structures and study surgical maneuvers required to achieve optimal exposure of deep situated anatomic structures. The simulation program is a powerful tool to study issues of preoperative planning and well suited for neurosurgical training.

Lost and forgotten? Orientation versus memory in Alzheimer's disease and frontotemporal dementia.

Science.gov (United States)

Yew, Belinda; Alladi, Suvarna; Shailaja, Mekala; Hodges, John R; Hornberger, Michael

2013-01-01

Recent studies suggest that significant memory problems are not specific to Alzheimer's disease (AD) but can be also observed in other neurodegenerative conditions, such as behavioral variant frontotemporal dementia (bvFTD). We investigated whether orientation (spatial & temporal) information is a better diagnostic marker for AD compared to memory and whether their atrophy correlates of orientation and memory differ. A large sample (n = 190) of AD patients (n = 73), bvFTD patients (n = 54), and healthy controls (n = 63) underwent testing. A subset of the patients (n = 72) underwent structural imaging using voxel-based morphometry analysis of magnetic resonance brain imaging. Orientation and memory scores from the Addenbrooke's Cognitive Examination showed that AD patients had impaired orientation and memory, while bvFTD patients performing at control level for orientation but had impaired memory. A logistic regression showed that 78% of patients could be classified on the basis of orientation and memory scores alone at clinic presentation. Voxel-based morphometry analysis was conducted using orientation and memory scores as covariates, which showed that the neural correlates for orientation and memory also dissociated with posterior hippocampus cortex being related to orientation in AD, while the anterior hippocampus was associated with memory performance in the AD and bvFTD patients. Orientation and memory measures discriminate AD and bvFTD to a high degree and tap into different hippocampal regions. Disorientation and posterior hippocampus appears therefore specific to AD and will allow clinicians to discriminate AD patients from other neurodegenerative conditions with similar memory deficits at clinic presentation.

FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration

DEFF Research Database (Denmark)

Urwin, Hazel; Josephs, Keith A; Rohrer, Jonathan D

2010-01-01

Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92...

The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

DEFF Research Database (Denmark)

Lill, Christina M; Rengmark, Aina; Pihlstrøm, Lasse

2015-01-01

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we......) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10......(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628...

Frontotemporal dementia with trans-activation response DNA-binding protein 43 presenting with catatonic syndrome.

Science.gov (United States)

Watanabe, Ryohei; Kawakami, Ito; Onaya, Mitsumoto; Higashi, Shinji; Arai, Nobutaka; Akiyama, Haruhiko; Hasegawa, Masato; Arai, Tetsuaki

2017-11-07

Catatonia is a clinical syndrome characterized by symptoms such as immobility, mutism, stupor, stereotypy, echophenomena, catalepsy, automatic obedience, posturing, negativism, gegenhalten and ambitendency. This syndrome occurs mostly in mood disorder and schizophrenic patients, and is related to neuronal dysfunction involving the frontal lobe. Some cases of frontotemporal dementia (FTD) with catatonia have been reported, but these cases were not examined by autopsy. Here, we report on a FTD case which showed catatonia after the first episode of brief psychotic disorder. At the age of 58, the patient had a sudden onset of disorganized behavior and meaningless speech. Psychotropic drugs were effective for catatonic symptoms. However, after remission apathy, hyperorality, socially inappropriate behavior, hoarding, and an instinctive grasp reaction appeared and persisted. Brain MRI showed significant atrophy of the bilateral fronto-temporal lobes. A neuropathological examination revealed extensive trans-activation response DNA-binding protein 43 (TDP-43) positive neurocytoplasmic inclusions and dystrophic neurites in the brain, including the cerebral cortex, basal ganglia, and brainstem. Pathological diagnosis was frontotemporal lobar degeneration (FTLD) with TDP-43 (FTLD-TDP) type C, which was also confirmed by the band pattern of C-terminal fragments of TDP-43 on western blotting of sarkosyl-insoluble fractions extracted from the frozen brain. Dysfunction of the thalamus, globus pallidus, supplementary motor area, amygdala and cingulate cortex have been said to be related to the catatonic syndrome. In this case, these areas were affected, showing abnormal TDP-43-positive structures. Further studies are expected to confirm further clinical - pathological correlations to FTLD. © 2017 Japanese Society of Neuropathology.

Association between smoking behaviour and genetic variants of ...

Indian Academy of Sciences (India)

ESZTER KOTYUK

behaviour (never smoked, quit, occasional, or regular smokers) and level of nicotine addiction (Hooked on Nicotine ..... versus quit, never smoker versus occasional, never smoker .... pared to the nonsmokers (see figure 1), suggesting that the.

Clinical and Neuropsychological Characteristics of a Nationwide Hospital-Based Registry of Frontotemporal Dementia Patients in Korea: A CREDOS-FTD Study

Directory of Open Access Journals (Sweden)

Eun-Joo Kim

2014-07-01

Full Text Available Background: We investigated the demographic, clinical, and neuropsychological characteristics of frontotemporal dementia (FTD from the Clinical Research Center for Dementia of South Korea (CREDOS-FTD registry. Methods: A total of 200 consecutive patients with FTD recruited from 16 neurological clinics in Korea were evaluated by cognitive and functional assessments, a screening test for aphasia, behavioral questionnaires, motor assessments, and brain MRI or PET. Results: In our registry, 78 patients were classified as having been diagnosed with behavioral-variant FTD (bvFTD, 70 with semantic dementia (SD, 33 with progressive nonfluent aphasia (PNFA, and 8 with motor neuron disease plus syndrome (MND-plus. The patients with language variants of dementia were older than those with bvFTD. There were no differences in sex ratio, duration of illness, or level of education among the four subgroups. Overall, the patients with bvFTD showed a significantly better performance in cognitive tests. A higher frequency of motor symptoms and a lower frequency of behavioral symptoms were found in PNFA than in bvFTD and SD. The Global Language Index was significantly lower in SD than in bvFTD and PNFA. The MND-plus group had a poorer performance than all the others in all cognitive domains. Conclusion: The neuropsychological, behavioral, motor, and language characteristics of the four subtypes are comparable with those from other series. However, the proportion of SD (37.0%, which was similar to that of bvFTD (41.3%, was higher in our registry than in other series.

Association between smoking behaviour and genetic variants of ...

Indian Academy of Sciences (India)

rs1981844, rs3812047, rs3096140, rs2973041, rs2910702, rs1549250, rs2973050 and rs11111). Allele-wise association analyses of the eight GDNF SNPs provided a significant association between smoking behaviour and rs3096140 (P ...

Computerized assessment of the acoustics of primary progressive aphasia.

NARCIS (Netherlands)

Ossewaarde, Roelant; Jalvingh, Fedor; Jonkers, Roel; Bastiaanse, Yvonne

2016-01-01

There are two variants of fronto-temporal dementia: a behavioral variant (behavioral FTD, bvFTD, Neary et al. (1998)), which causes changes in behavior and personality but leaves syntax, phonology and semantics relatively intact, and a variant that causes impairments in the language processing

Differential regional cerebral glucose metabolism in clinical syndromes of frontotemporal lobar degeneration: a study with FDG PET

International Nuclear Information System (INIS)

Park, J. M.; Cho, S. S.; Na, D. L.; Lee, K. H.; Choi, Y.; Choe, Y. S.; Kim, B. T.; Kim, S. E.

2001-01-01

Frontotemporal lobar degeneration( FTLD) is the third most common dementia, following Alzheimer's disease and Lewy body disease. Four prototypic neurobehavioral syndromes can be produced by FTLD: frontotemporal dementia (FTD), frontotemporal dementia with motor neuron disease (MND), semantic dementia (SD), and progressive aphasia (PA). We investigated patterns of metabolic impairment in patient with FTLD presented with four different clinical syndromes. We analysed glucose metabolic patterns on FDG PET images obtained from 34 patients with a clinical diagnosis of FTLD (19 FTD, 6 MND, 6 SD, and 3 PA, according to a consensus criteria for clinical syndromes associated with FTLD) and 7 age-matched healthy controls using SPM99. Patients with FTD had metabolic deficit in the left frontal cortex and bilateral anterior temporal cortex. Hypometabolism in the bilateral premotor are was shown in patients with MND. Patients with SD had metabolic deficit in the left posterior temporal cortex including Wernicke's area, while hypometabolism in the bilateral inferior frontal gyrus including Broca's area and left angular gyrus was seen in patients with PA. These metabolic patterns were well correlated with clinical features of FTLD syndromes. These data provide a biochemical basis of clinical classification of FTLD. FDG PET may help evaluate and classify patients with FTLD

Differential regional cerebral glucose metabolism in clinical syndromes of frontotemporal lobar degeneration: a study with FDG PET

Energy Technology Data Exchange (ETDEWEB)

Park, J. M.; Cho, S. S.; Na, D. L.; Lee, K. H.; Choi, Y.; Choe, Y. S.; Kim, B. T.; Kim, S. E. [College of Medicine, Sungkyunkwan Univ., Seoul (Korea, Republic of)

2001-07-01

Frontotemporal lobar degeneration( FTLD) is the third most common dementia, following Alzheimer's disease and Lewy body disease. Four prototypic neurobehavioral syndromes can be produced by FTLD: frontotemporal dementia (FTD), frontotemporal dementia with motor neuron disease (MND), semantic dementia (SD), and progressive aphasia (PA). We investigated patterns of metabolic impairment in patient with FTLD presented with four different clinical syndromes. We analysed glucose metabolic patterns on FDG PET images obtained from 34 patients with a clinical diagnosis of FTLD (19 FTD, 6 MND, 6 SD, and 3 PA, according to a consensus criteria for clinical syndromes associated with FTLD) and 7 age-matched healthy controls using SPM99. Patients with FTD had metabolic deficit in the left frontal cortex and bilateral anterior temporal cortex. Hypometabolism in the bilateral premotor are was shown in patients with MND. Patients with SD had metabolic deficit in the left posterior temporal cortex including Wernicke's area, while hypometabolism in the bilateral inferior frontal gyrus including Broca's area and left angular gyrus was seen in patients with PA. These metabolic patterns were well correlated with clinical features of FTLD syndromes. These data provide a biochemical basis of clinical classification of FTLD. FDG PET may help evaluate and classify patients with FTLD.

Souvenaid reduces behavioral deficits and improves social cognition skills in frontotemporal dementia: a proof-of-concept study.

Science.gov (United States)

Pardini, Matteo; Serrati, Carlo; Guida, Silvia; Mattei, Chiara; Abate, Lucia; Massucco, Davide; Sassos, Davide; Amore, Mario; Krueger, Frank; Cocito, Leonardo; Emberti Gialloreti, Leonardo

2015-01-01

Souvenaid™ is a nutraceutical compound thought to positively enhance synaptic function. In line with this mechanism of action, Souvenaid™ has been shown to improve cognitive function in subjects with mild Alzheimer's disease in randomized clinical trials. To date, however, the potential of Souvenaid™ to improve cognitive functioning in subjects with other neurodegenerative conditions also characterized by synaptic loss has not been explored. To evaluate the impact of Souvenaid™ on executive functions, social cognition and behavioral disturbances in subjects with the behavioral variant of frontotemporal dementia (bv-FTD). Twenty-six subjects with bv-FTD were enrolled in the study and randomized to Souvenaid™ (125 ml/day) or placebo groups. After 12 weeks, subjects were switched between the two groups. All subjects, blinded to treatment, underwent clinical and cognitive evaluations at enrollment, after 12 weeks and after 24 weeks. Treatment with Souvenaid™ was associated with a significant reduction of behavioral symptoms and an increase in Theory of Mind skills compared to placebo, which both returned to baseline when Souvenaid™ was discontinued. Souvenaid™ did not have an effect on executive functions. Our results provide evidence of the potential of Souvenaid™ therapy for the treatment of behavioral disturbances and social cognition skills in FTD. © 2015 S. Karger AG, Basel.

Verb Agreements during On-Line Sentence Processing in Alzheimer's Disease and Frontotemporal Dementia

Science.gov (United States)

Price, C.C.; Grossman, M.

2005-01-01

An on-line ''word detection'' paradigm was used to assess the comprehension of thematic and transitive verb agreements during sentence processing in individuals diagnosed with probable Alzheimer's Disease (AD, n=15) and Frontotemporal Dementia (FTD, n=14). AD, FTD, and control participants (n=17) were asked to listen for a word in a sentence.…

The Power of Neuroimaging Biomarkers for Screening Frontotemporal Dementia

Science.gov (United States)

McMillan, Corey T.; Avants, Brian B.; Cook, Philip; Ungar, Lyle; Trojanowski, John Q.; Grossman, Murray

2014-01-01

Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative disease that can result from either frontotemporal lobar degeneration (FTLD) or Alzheimer’s disease (AD) pathology. It is critical to establish statistically powerful biomarkers that can achieve substantial cost-savings and increase feasibility of clinical trials. We assessed three broad categories of neuroimaging methods to screen underlying FTLD and AD pathology in a clinical FTD series: global measures (e.g., ventricular volume), anatomical volumes of interest (VOIs) (e.g., hippocampus) using a standard atlas, and data-driven VOIs using Eigenanatomy. We evaluated clinical FTD patients (N=93) with cerebrospinal fluid, gray matter (GM) MRI, and diffusion tensor imaging (DTI) to assess whether they had underlying FTLD or AD pathology. Linear regression was performed to identify the optimal VOIs for each method in a training dataset and then we evaluated classification sensitivity and specificity in an independent test cohort. Power was evaluated by calculating minimum sample sizes (mSS) required in the test classification analyses for each model. The data-driven VOI analysis using a multimodal combination of GM MRI and DTI achieved the greatest classification accuracy (89% SENSITIVE; 89% SPECIFIC) and required a lower minimum sample size (N=26) relative to anatomical VOI and global measures. We conclude that a data-driven VOI approach employing Eigenanatomy provides more accurate classification, benefits from increased statistical power in unseen datasets, and therefore provides a robust method for screening underlying pathology in FTD patients for entry into clinical trials. PMID:24687814

Motor Speech Phenotypes of Frontotemporal Dementia, Primary Progressive Aphasia, and Progressive Apraxia of Speech

Science.gov (United States)

Poole, Matthew L.; Brodtmann, Amy; Darby, David; Vogel, Adam P.

2017-01-01

Purpose: Our purpose was to create a comprehensive review of speech impairment in frontotemporal dementia (FTD), primary progressive aphasia (PPA), and progressive apraxia of speech in order to identify the most effective measures for diagnosis and monitoring, and to elucidate associations between speech and neuroimaging. Method: Speech and…

Characterization of Movement Disorder Phenomenology in Genetically Proven, Familial Frontotemporal Lobar Degeneration: A Systematic Review and Meta-Analysis

Science.gov (United States)

Gasca-Salas, Carmen; Masellis, Mario; Khoo, Edwin; Shah, Binit B.; Fisman, David; Lang, Anthony E.; Kleiner-Fisman, Galit

2016-01-01

Background Mutations in granulin (PGRN) and tau (MAPT), and hexanucleotide repeat expansions near the C9orf72 genes are the most prevalent genetic causes of frontotemporal lobar degeneration. Although behavior, language and movement presentations are common, the relationship between genetic subgroup and movement disorder phenomenology is unclear. Objective We conducted a systematic review and meta-analysis of the literature characterizing the spectrum and prevalence of movement disorders in genetic frontotemporal lobar degeneration. Methods Electronic databases were searched using terms related to frontotemporal lobar degeneration and movement disorders. Articles were included when cases had a proven genetic cause. Study-specific prevalence estimates for clinical features were transformed using Freeman-Tukey arcsine transformation, allowing for pooled estimates of prevalence to be generated using random-effects models. Results The mean age at onset was earlier in those with MAPT mutations compared to PGRN (p<0.001) and C9orf72 (p = 0.024). 66.5% of subjects had an initial non-movement presentation that was most likely a behavioral syndrome (35.7%). At any point during the disease, parkinsonism was the most common movement syndrome reported in 79.8% followed by progressive supranuclear palsy (PSPS) and corticobasal (CBS) syndromes in 12.2% and 10.7%, respectively. The prevalence of movement disorder as initial presentation was higher in MAPT subjects (35.8%) compared to PGRN subjects (10.1). In those with a non-movement presentation, language disorder was more common in PGRN subjects (18.7%) compared to MAPT subjects (5.4%). Summary This represents the first systematic review and meta-analysis of the occurrence of movement disorder phenomenology in genetic frontotemporal lobar degeneration. Standardized prospective collection of clinical information in conjunction with genetic characterization will be crucial for accurate clinico-genetic correlation. PMID:27100392

Grey and white matter correlates of recent and remote autobiographical memory retrieval--insights from the dementias.

Directory of Open Access Journals (Sweden)

Muireann Irish

Full Text Available The capacity to remember self-referential past events relies on the integrity of a distributed neural network. Controversy exists, however, regarding the involvement of specific brain structures for the retrieval of recently experienced versus more distant events. Here, we explored how characteristic patterns of atrophy in neurodegenerative disorders differentially disrupt remote versus recent autobiographical memory. Eleven behavioural-variant frontotemporal dementia, 10 semantic dementia, 15 Alzheimer's disease patients and 14 healthy older Controls completed the Autobiographical Interview. All patient groups displayed significant remote memory impairments relative to Controls. Similarly, recent period retrieval was significantly compromised in behavioural-variant frontotemporal dementia and Alzheimer's disease, yet semantic dementia patients scored in line with Controls. Voxel-based morphometry and diffusion tensor imaging analyses, for all participants combined, were conducted to investigate grey and white matter correlates of remote and recent autobiographical memory retrieval. Neural correlates common to both recent and remote time periods were identified, including the hippocampus, medial prefrontal, and frontopolar cortices, and the forceps minor and left hippocampal portion of the cingulum bundle. Regions exclusively implicated in each time period were also identified. The integrity of the anterior temporal cortices was related to the retrieval of remote memories, whereas the posterior cingulate cortex emerged as a structure significantly associated with recent autobiographical memory retrieval. This study represents the first investigation of the grey and white matter correlates of remote and recent autobiographical memory retrieval in neurodegenerative disorders. Our findings demonstrate the importance of core brain structures, including the medial prefrontal cortex and hippocampus, irrespective of time period, and point towards the

Real-life helping behaviours in North America: A genome-wide association approach.

Directory of Open Access Journals (Sweden)

Georg Primes

Full Text Available In humans, prosocial behaviour is essential for social functioning. Twin studies suggest this distinct human trait to be partly hardwired. In the last decade research on the genetics of prosocial behaviour focused on neurotransmitters and neuropeptides, such as oxytocin, dopamine, and their respective pathways. Recent trends towards large scale medical studies targeting the genetic basis of complex diseases such as Alzheimer's disease and schizophrenia pave the way for new directions also in behavioural genetics. Based on data from 10,713 participants of the American Health and Retirement Study we estimated heritability of helping behaviour-its total variance explained by 1.2 million single nucleotide polymorphisms-to be 11%. Both, fixed models and mixed linear models identified rs11697300, an intergene variant on chromosome 20, as a candidate variant moderating this particular helping behaviour. We assume that this so far undescribed area is worth further investigation in association with human prosocial behaviour.

The attribution of animacy and agency in frontotemporal dementia versus Alzheimer's disease.

Science.gov (United States)

Fong, Sylvia S; Paholpak, Pongsatorn; Daianu, Madelaine; Deutsch, Mariel B; Riedel, Brandalyn C; Carr, Andrew R; Jimenez, Elvira E; Mather, Michelle M; Thompson, Paul M; Mendez, Mario F

2017-07-01

Impaired attribution of animacy (state of living or being sentient) and of agency (capability of intrinsically-driven action) may underlie social behavior disturbances in behavioral variant frontotemporal dementia (bvFTD). We presented the Heider and Simmel film of moving geometric shapes to 11 bvFTD patients, 11 Alzheimer's disease (AD) patients, and 12 healthy controls (HCs) and rated their recorded verbal responses for animacy attribution and agency attribution. All participants had skin conductance (SC) continuously recorded while viewing the film, and all dementia participants underwent magnetic resonance imaging (MRI) for regions of interest. The bvFTD patients, but not the AD patients, were impaired in animacy attribution, compared to the HCs. In contrast, both bvFTD and AD groups were impaired in agency attribution, compared to the HCs, and only the HCs had increasing SC responsiveness during viewing of the film. On MRI analysis of cortical thicknesses, animacy scores significantly correlated across groups with the right pars orbitalis and opercularis; agency scores with the left inferior and superior parietal cortices and the supramarginal gyrus; and both scores with the left cingulate isthmus involved in visuospatial context. These findings suggest that bvFTD is specifically associated with impaired animacy attribution from right inferior frontal atrophy. In contrast, both dementias may have impaired agency attribution from left parietal cortical atrophy and absent SC increases during the film, a sympathetic indicator of attribution of a social "story" to the moving shapes. These findings clarify disease-related changes in social attribution and corroborate the neuroanatomical origins of animacy and agency. Copyright © 2017 Elsevier Ltd. All rights reserved.

Association of GSK3B With Alzheimer Disease and Frontotemporal Dementia

Science.gov (United States)

Schaffer, Barbara A. J.; Bertram, Lars; Miller, Bruce L.; Mullin, Kristina; Weintraub, Sandra; Johnson, Nancy; Bigio, Eileen H.; Mesulam, Marsel; Wiedau-Pazos, Martina; Jackson, George R.; Cummings, Jeffrey L.; Cantor, Rita M.; Levey, Allan I.; Tanzi, Rudolph E.; Geschwind, Daniel H.

2009-01-01

Background Deposits of abnormally hyperphosphorylated tau are a hallmark of several dementias, including Alzheimer disease (AD), and about 10% of familial frontotemporal dementia (FTD) cases are caused by mutations in the tau gene. As a known tau kinase, GSK3B is a promising candidate gene in the remaining cases of FTD and in AD, for which tau mutations have not been found. Objective To examine the promoter of GSK3B and all 12 exons, including the surrounding intronic sequence, in patients with FTD, patients with AD, and aged healthy subjects to identify single-nucleotide polymorphisms associated with disease. Design, Setting, and Participants Single-nucleotide polymorphism frequency was examined in a case-control cohort of 48 patients with probable AD, 102 patients with FTD, 38 patients with primary progressive aphasia, and 85 aged healthy subjects. Results were followed up in 2 independent AD family samples consisting of 437 multiplex families with AD (National Institute of Mental Health Genetics Initiative AD Study) or 150 sibships discordant for AD (Consortium on Alzheimer’s Genetics Study). Results Several rare sequence variants in GSK3B were identified in the case-control study. An intronic polymorphism (IVS2−68G>A) occurred at more than twice the frequency among patients with FTD (10.8%) and patients with AD (14.6%) than in aged healthy subjects (4.1%). The polymorphism showed association with disease in both follow-up samples independently, although only the Consortium on Alzheimer’s Genetics sample showed the same direction of association as the case-control sample. Conclusions To our knowledge, this is the first evidence that a gene known to be involved in tau phosphorylation, GSK3B, is associated with risk for primary neurodegenerative dementias. This supports previous work in animal models suggesting that such genes are therapeutic targets. PMID:18852354

The Genetics of Monogenic Frontotemporal Dementia

Directory of Open Access Journals (Sweden)

Leonel T. Takada

Full Text Available ABSTRACTAround 10-15% of patients diagnosed with frontotemporal dementia (FTD have a positive family history for FTD with an autosomal dominant pattern of inheritance. Since the identification of mutations in MAPT(microtubuleassociated protein tau gene in 1998, over 10 other genes have been associated with FTD spectrum disorders, discussed in this review. Along with MAPT, mutations in GRN(progranulin and C9orf72(chromosome 9 open reading frame 72 are the most commonly identified in FTD cohorts. The association of FTD and motor neuron disease (MND can be caused by mutations in C9orf72and other genes, such as TARDBP(TAR DNA-binding protein, FUS(fused in sarcoma, UBQLN2(ubiquilin 2. Multisystem proteinopathy is a complex phenotype that includes FTD, Paget disease of the bone, inclusion body myopathy and MND, and can be due to mutations in VCP(valosing containing protein and other recently identified genes.

Listeners' processing of a given reduced word pronunciation variant directly reflects their exposure to this variant: Evidence from native listeners and learners of French.

Science.gov (United States)

Brand, Sophie; Ernestus, Mirjam

2018-05-01

In casual conversations, words often lack segments. This study investigates whether listeners rely on their experience with reduced word pronunciation variants during the processing of single segment reduction. We tested three groups of listeners in a lexical decision experiment with French words produced either with or without word-medial schwa (e.g., /ʀvy/ and /ʀvy/ for revue). Participants also rated the relative frequencies of the two pronunciation variants of the words. If the recognition accuracy and reaction times (RTs) for a given listener group correlate best with the frequencies of occurrence holding for that given listener group, recognition is influenced by listeners' exposure to these variants. Native listeners' relative frequency ratings correlated well with their accuracy scores and RTs. Dutch advanced learners' accuracy scores and RTs were best predicted by their own ratings. In contrast, the accuracy and RTs from Dutch beginner learners of French could not be predicted by any relative frequency rating; the rating task was probably too difficult for them. The participant groups showed behaviour reflecting their difference in experience with the pronunciation variants. Our results strongly suggest that listeners store the frequencies of occurrence of pronunciation variants, and consequently the variants themselves.

C9orf72 expansion presenting as an eating disorder.

Science.gov (United States)

Sanders, Peter; Ewing, Isobel; Ahmad, Kate

2016-03-01

This report describes a 64-year-old woman with a strong family history of motor neuron disease, whose diagnosis of behavioural variant frontotemporal dementia was delayed due to her initial presentation with atypical manifestations, including restriction of oral intake resulting in low weight, disordered eating and anxiety. Upon investigation, she was found to be a carrier of the C9orf72 hexanucleotide repeat expansion. Our case supports previous publications asserting that C9orf72 mutation carriers manifest with diverse clinical syndromes, and expands the phenotype to include anorexia and food refusal as potential features of the condition. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Early-stage differentiation between presenile Alzheimer’s disease and frontotemporal dementia using arterial spin labeling MRI

NARCIS (Netherlands)

R.M.E. Steketee (Rebecca); E.E. Bron (Esther); R. Meijboom (Rozanna); G.C. Houston (Gavin); S. Klein (Stefan); H.J.M.M. Mutsaerts (Henri J. M.); C. Méndez Orellana (Carolina); F.J. De Jong (Frank J.); J.C. van Swieten (John); A. van der Lugt (Aad); M. Smits (Marion)

2016-01-01

textabstractObjective: To investigate arterial spin labeling (ASL)-MRI for the early diagnosis of and differentiation between the two most common types of presenile dementia: Alzheimer’s disease (AD) and frontotemporal dementia (FTD), and for distinguishing age-related from pathological perfusion

Early-stage differentiation between presenile Alzheimer’s disease and frontotemporal dementia using arterial spin labeling MRI

NARCIS (Netherlands)

R.M.E. Steketee (Rebecca); E.E. Bron (Esther); Meijboom, R. (Rozanna); Houston, G.C. (Gavin C.); Klein, S. (Stefan); H.J.M.M. Mutsaerts (Henri J. M.); Orellana, C.P.M. (Carolina P. Mendez); F.J. de Jong (Fransina); J.C. van Swieten (John); A. van der Lugt (Aad); M. Smits (Marion)

2015-01-01

textabstractObjective: To investigate arterial spin labeling (ASL)-MRI for the early diagnosis of and differentiation between the two most common types of presenile dementia: Alzheimer’s disease (AD) and frontotemporal dementia (FTD), and for distinguishing age-related from pathological perfusion

Effect of minoxidil topical foam on frontotemporal and vertex androgenetic alopecia in men: a 104-week open-label clinical trial.

Science.gov (United States)

Kanti, V; Hillmann, K; Kottner, J; Stroux, A; Canfield, D; Blume-Peytavi, U

2016-07-01

Topical minoxidil formulations have been shown to be effective in treating androgenetic alopecia (AGA) for 12 months. Efficacy and safety in both frontotemporal and vertex regions over longer application periods have not been studied so far. To evaluate the effect of 5% minoxidil topical foam (5% MTF) in the frontotemporal and vertex areas in patients with moderate AGA over 104 weeks. An 80-week, open-label extension phase was performed, following a 24-week randomized, double-blind, placebo-controlled study in men with AGA grade IIIvertex to VI. Group 1 (n = 22) received ongoing 5% MTF for 104 weeks, Group 2 (n = 23) received placebo topical foam (plaTF) until week 24, followed by 5% MTF until week 104 during the extension phase. Frontotemporal and vertex target area non-vellus hair counts (f-TAHC, v-TAHC) and cumulative hair width (f-TAHW, v-TAHW) were assessed at baseline and at weeks 24, 52, 76 and 104. In Group 1, f-TAHW and f-TAHC showed a statistically significant increase from baseline to week 52 and week 76, respectively, returning to values comparable to baseline at week 104. No significant differences were found between baseline and week 104 in v-TAHC in Group 1 as well as f-TAHC, v-TAHC, f-TAHW and v-TAHW values in Group 2. 5% MTF is effective in stabilizing hair density, hair width and scalp coverage in both frontotemporal and vertex areas over an application period of 104 weeks, while showing a good safety and tolerability profile with a low rate of irritant contact dermatitis. © 2015 European Academy of Dermatology and Venereology.

Fronto-parietal and fronto-temporal theta phase synchronization for visual and auditory-verbal working memory.

Science.gov (United States)

Kawasaki, Masahiro; Kitajo, Keiichi; Yamaguchi, Yoko

2014-01-01

In humans, theta phase (4-8 Hz) synchronization observed on electroencephalography (EEG) plays an important role in the manipulation of mental representations during working memory (WM) tasks; fronto-temporal synchronization is involved in auditory-verbal WM tasks and fronto-parietal synchronization is involved in visual WM tasks. However, whether or not theta phase synchronization is able to select the to-be-manipulated modalities is uncertain. To address the issue, we recorded EEG data from subjects who were performing auditory-verbal and visual WM tasks; we compared the theta synchronizations when subjects performed either auditory-verbal or visual manipulations in separate WM tasks, or performed both two manipulations in the same WM task. The auditory-verbal WM task required subjects to calculate numbers presented by an auditory-verbal stimulus, whereas the visual WM task required subjects to move a spatial location in a mental representation in response to a visual stimulus. The dual WM task required subjects to manipulate auditory-verbal, visual, or both auditory-verbal and visual representations while maintaining auditory-verbal and visual representations. Our time-frequency EEG analyses revealed significant fronto-temporal theta phase synchronization during auditory-verbal manipulation in both auditory-verbal and auditory-verbal/visual WM tasks, but not during visual manipulation tasks. Similarly, we observed significant fronto-parietal theta phase synchronization during visual manipulation tasks, but not during auditory-verbal manipulation tasks. Moreover, we observed significant synchronization in both the fronto-temporal and fronto-parietal theta signals during simultaneous auditory-verbal/visual manipulations. These findings suggest that theta synchronization seems to flexibly connect the brain areas that manipulate WM.

Fronto-parietal and fronto-temporal theta phase synchronization for visual and auditory-verbal working memory

Directory of Open Access Journals (Sweden)

Masahiro eKawasaki

2014-03-01

Full Text Available In humans, theta phase (4–8 Hz synchronization observed on electroencephalography (EEG plays an important role in the manipulation of mental representations during working memory (WM tasks; fronto-temporal synchronization is involved in auditory-verbal WM tasks and fronto-parietal synchronization is involved in visual WM tasks. However, whether or not theta phase synchronization is able to select the to-be-manipulated modalities is uncertain. To address the issue, we recorded EEG data from subjects who were performing auditory-verbal and visual WM tasks; we compared the theta synchronizations when subjects performed either auditory-verbal or visual manipulations in separate WM tasks, or performed both two manipulations in the same WM task. The auditory-verbal WM task required subjects to calculate numbers presented by an auditory-verbal stimulus, whereas the visual WM task required subjects to move a spatial location in a mental representation in response to a visual stimulus. The dual WM task required subjects to manipulate auditory-verbal, visual, or both auditory-verbal and visual representations while maintaining auditory-verbal and visual representations. Our time-frequency EEG analyses revealed significant fronto-temporal theta phase synchronization during auditory-verbal manipulation in both auditory-verbal and auditory-verbal/visual WM tasks, but not during visual manipulation tasks. Similarly, we observed significant fronto-parietal theta phase synchronization during visual manipulation tasks, but not during auditory-verbal manipulation tasks. Moreover, we observed significant synchronization in both the fronto-temporal and fronto-parietal theta signals during simultaneous auditory-verbal/visual manipulations. These findings suggest that theta synchronization seems to flexibly connect the brain areas that manipulate WM.

From narcissistic personality disorder to frontotemporal dementia: a case report.

Science.gov (United States)

Poletti, Michele; Bonuccelli, Ubaldo

2011-01-01

Premorbid personality characteristics could have a pathoplastic effect on behavioral symptoms and personality changes related to neurodegenerative diseases. Patients with personality disorders, in particular of the dramatic cluster, may present functional frontolimbic abnormalities. May these neurobiological vulnerabilities linked to a premorbid personality disorder predispose or represent a risk factor to subsequently develop a neurodegenerative disorder? Are subjects with personality disorders more at risk to develop a dementia than mentally healthy subjects? This topic is discussed presenting the clinical case of a patient who suffered of a probable Narcissistic Personality Disorder and subsequently developed a clinically diagnosed Frontotemporal Dementia.

Emotion Recognition in Frontotemporal Dementia and Alzheimer's Disease: A New Film-Based Assessment

Science.gov (United States)

Goodkind, Madeleine S.; Sturm, Virginia E.; Ascher, Elizabeth A.; Shdo, Suzanne M.; Miller, Bruce L.; Rankin, Katherine P.; Levenson, Robert W.

2015-01-01

Deficits in recognizing others' emotions are reported in many psychiatric and neurological disorders, including autism, schizophrenia, behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). Most previous emotion recognition studies have required participants to identify emotional expressions in photographs. This type of assessment differs from real-world emotion recognition in important ways: Images are static rather than dynamic, include only 1 modality of emotional information (i.e., visual information), and are presented absent a social context. Additionally, existing emotion recognition batteries typically include multiple negative emotions, but only 1 positive emotion (i.e., happiness) and no self-conscious emotions (e.g., embarrassment). We present initial results using a new task for assessing emotion recognition that was developed to address these limitations. In this task, respondents view a series of short film clips and are asked to identify the main characters' emotions. The task assesses multiple negative, positive, and self-conscious emotions based on information that is multimodal, dynamic, and socially embedded. We evaluate this approach in a sample of patients with bvFTD, AD, and normal controls. Results indicate that patients with bvFTD have emotion recognition deficits in all 3 categories of emotion compared to the other groups. These deficits were especially pronounced for negative and self-conscious emotions. Emotion recognition in this sample of patients with AD was indistinguishable from controls. These findings underscore the utility of this approach to assessing emotion recognition and suggest that previous findings that recognition of positive emotion was preserved in dementia patients may have resulted from the limited sampling of positive emotion in traditional tests. PMID:26010574

Emotion recognition in frontotemporal dementia and Alzheimer's disease: A new film-based assessment.

Science.gov (United States)

Goodkind, Madeleine S; Sturm, Virginia E; Ascher, Elizabeth A; Shdo, Suzanne M; Miller, Bruce L; Rankin, Katherine P; Levenson, Robert W

2015-08-01

Deficits in recognizing others' emotions are reported in many psychiatric and neurological disorders, including autism, schizophrenia, behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). Most previous emotion recognition studies have required participants to identify emotional expressions in photographs. This type of assessment differs from real-world emotion recognition in important ways: Images are static rather than dynamic, include only 1 modality of emotional information (i.e., visual information), and are presented absent a social context. Additionally, existing emotion recognition batteries typically include multiple negative emotions, but only 1 positive emotion (i.e., happiness) and no self-conscious emotions (e.g., embarrassment). We present initial results using a new task for assessing emotion recognition that was developed to address these limitations. In this task, respondents view a series of short film clips and are asked to identify the main characters' emotions. The task assesses multiple negative, positive, and self-conscious emotions based on information that is multimodal, dynamic, and socially embedded. We evaluate this approach in a sample of patients with bvFTD, AD, and normal controls. Results indicate that patients with bvFTD have emotion recognition deficits in all 3 categories of emotion compared to the other groups. These deficits were especially pronounced for negative and self-conscious emotions. Emotion recognition in this sample of patients with AD was indistinguishable from controls. These findings underscore the utility of this approach to assessing emotion recognition and suggest that previous findings that recognition of positive emotion was preserved in dementia patients may have resulted from the limited sampling of positive emotion in traditional tests. (c) 2015 APA, all rights reserved).

The Functional Organisation of the Fronto-Temporal Language System: Evidence from Syntactic and Semantic Ambiguity

Science.gov (United States)

Rodd, Jennifer M.; Longe, Olivia A.; Randall, Billi; Tyler, Lorraine K.

2010-01-01

Spoken language comprehension is known to involve a large left-dominant network of fronto-temporal brain regions, but there is still little consensus about how the syntactic and semantic aspects of language are processed within this network. In an fMRI study, volunteers heard spoken sentences that contained either syntactic or semantic ambiguities…

Adaptation and validation of a Spanish-language version of the Frontotemporal Dementia Rating Scale (FTD-FRS).

Science.gov (United States)

Turró-Garriga, O; Hermoso Contreras, C; Olives Cladera, J; Mioshi, E; Pelegrín Valero, C; Olivera Pueyo, J; Garre-Olmo, J; Sánchez-Valle, R

2017-06-01

The Frontotemporal Dementia Rating Scale (FTD-FRS) is a tool designed to aid with clinical staging and assessment of the progression of frontotemporal dementia (FTD-FRS). Present a multicentre adaptation and validation study of a Spanish version of the FRS. The adapted version was created using 2 translation-back translation processes (English to Spanish, Spanish to English) and verified by the scale's original authors. We validated the adapted version in a sample of consecutive patients diagnosed with FTD. The procedure included evaluating internal consistency, testing unidimensionality with the Rasch model, analysing construct validity and discriminant validity, and calculating the degree of agreement between the Clinical Dementia Rating scale (CDR) and FTD-FRS for FTD cases. The study included 60 patients with DFT. The mean score on the FRS was 12.1 points (SD=6.5; range, 2-25) with inter-group differences (F=120.3; df=3; Pde Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Behavioural agency theory and the family business

OpenAIRE

Kumeto, Gershon

2015-01-01

The behavioural agency theory was developed to provide a more comprehensive explanation and prediction of managerial risk taking, in response to some shortcomings of agency theory. In general, the theory offers explanations of why decision makers prefer some strategic choices to others. The use of behavioural agency theory in family business research has, however, been very limited. Family business scholars recently adapted this theory to construct the family business variant, the ‘socioemoti...

Right Fronto-Temporal EEG can Differentiate the Affective Responses to Award-Winning Advertisements.

Science.gov (United States)

Wang, Regina W Y; Huarng, Shy-Peih; Chuang, Shang-Wen

2018-04-01

Affective engineering aims to improve service/product design by translating the customer's psychological feelings. Award-winning advertisements (AAs) were selected on the basis of the professional standards that consider creativity as a prerequisite. However, it is unknown if AA is related to satisfactory advertising performance among customers or only to the experts' viewpoints towards the advertisements. This issue in the field of affective engineering and design merits in-depth evaluation. We recruited 30 subjects and performed an electroencephalography (EEG) experiment while watching AAs and non-AAs (NAAs). The event-related potential (ERP) data showed that AAs evoked larger positive potentials 250-1400 [Formula: see text]ms after stimulus onset, particularly in the right fronto-temporal regions. The behavioral results were consistent with the professional recognition given to AAs by experts. The perceived levels of creativity and "product-like" quality were higher for the AAs than for the NAAs. Event-related spectral perturbation (ERSP) analysis further revealed statistically significant differences in the theta, alpha, beta, and gamma band activity in the right fronto-temporal regions between the AAs and NAAs. Our results confirm that EEG features from the time/frequency domains can differentiate affective responses to AAs at a neural circuit level, and provide scientific evidence to support the identification of AAs.

Common genetic variants influence human subcortical brain structures

Science.gov (United States)

Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Olde Loohuis, Loes M.; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Nöthen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdés Hernández, Maria C.; van ’t Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Jönsson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

2015-01-01

The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. PMID:25607358

Common genetic variants influence human subcortical brain structures.

Science.gov (United States)

Hibar, Derrek P; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S; Armstrong, Nicola J; Bernard, Manon; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brown, Andrew A; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Olde Loohuis, Loes M; Luciano, Michelle; Macare, Christine; Mather, Karen A; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rose, Emma J; Salami, Alireza; Sämann, Philipp G; Schmaal, Lianne; Schork, Andrew J; Shin, Jean; Strike, Lachlan T; Teumer, Alexander; van Donkelaar, Marjolein M J; van Eijk, Kristel R; Walters, Raymond K; Westlye, Lars T; Whelan, Christopher D; Winkler, Anderson M; Zwiers, Marcel P; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M H; Hartberg, Cecilie B; Haukvik, Unn K; Heister, Angelien J G A M; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C M; Lopez, Lorna M; Makkinje, Remco R R; Matarin, Mar; Naber, Marlies A M; McKay, D Reese; Needham, Margaret; Nugent, Allison C; Pütz, Benno; Royle, Natalie A; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S L; van Hulzen, Kimm J E; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A; Bastin, Mark E; Brodaty, Henry; Bulayeva, Kazima B; Carless, Melanie A; Cichon, Sven; Corvin, Aiden; Curran, Joanne E; Czisch, Michael; de Zubicaray, Greig I; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fedko, Iryna O; Ferrucci, Luigi; Foroud, Tatiana M; Fox, Peter T; Fukunaga, Masaki; Gibbs, J Raphael; Göring, Harald H H; Green, Robert C; Guelfi, Sebastian; Hansell, Narelle K; Hartman, Catharina A; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G; Heslenfeld, Dirk J; Hoekstra, Pieter J; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Liu, Xinmin; Longo, Dan L; McMahon, Katie L; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W; Mostert, Jeanette C; Mühleisen, Thomas W; Nalls, Michael A; Nichols, Thomas E; Nilsson, Lars G; Nöthen, Markus M; Ohi, Kazutaka; Olvera, Rene L; Perez-Iglesias, Rocio; Pike, G Bruce; Potkin, Steven G; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D; Rujescu, Dan; Schnell, Knut; Schofield, Peter R; Smith, Colin; Steen, Vidar M; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Valdés Hernández, Maria C; van 't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J A; van Tol, Marie-Jose; Veltman, Dick J; Wassink, Thomas H; Westman, Eric; Zielke, Ronald H; Zonderman, Alan B; Ashbrook, David G; Hager, Reinmar; Lu, Lu; McMahon, Francis J; Morris, Derek W; Williams, Robert W; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Cahn, Wiepke; Calhoun, Vince D; Cavalleri, Gianpiero L; Crespo-Facorro, Benedicto; Dale, Anders M; Davies, Gareth E; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C; Espeseth, Thomas; Gollub, Randy L; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W J H; Roffman, Joshua L; Sisodiya, Sanjay M; Smoller, Jordan W; van Bokhoven, Hans; van Haren, Neeltje E M; Völzke, Henry; Walter, Henrik; Weiner, Michael W; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A; Blangero, John; Boomsma, Dorret I; Brouwer, Rachel M; Cannon, Dara M; Cookson, Mark R; de Geus, Eco J C; Deary, Ian J; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E; Francks, Clyde; Glahn, David C; Grabe, Hans J; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E; Jönsson, Erik G; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S; Saykin, Andrew J; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M; Weale, Michael E; Weinberger, Daniel R; Adams, Hieab H H; Launer, Lenore J; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L; Becker, James T; Yanek, Lisa; van der Lee, Sven J; Ebling, Maritza; Fischl, Bruce; Longstreth, W T; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N; van Duijn, Cornelia M; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M Arfan; Martin, Nicholas G; Wright, Margaret J; Schumann, Gunter; Franke, Barbara; Thompson, Paul M; Medland, Sarah E

2015-04-09

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Translation, cross-cultural adaptation and applicability of the Brazilian version of the Frontotemporal Dementia Rating Scale (FTD-FRS

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Thais Bento Lima-Silva

Full Text Available ABSTRACT Background: Staging scales for dementia have been devised for grading Alzheimer's disease (AD but do not include the specific symptoms of frontotemporal lobar degeneration (FTLD. Objective: To translate and adapt the Frontotemporal Dementia Rating Scale (FTD-FRS to Brazilian Portuguese. Methods: The cross-cultural adaptation process consisted of the following steps: translation, back-translation (prepared by independent translators, discussion with specialists, and development of a final version after minor adjustments. A pilot application was carried out with 12 patients diagnosed with bvFTD and 11 with AD, matched for disease severity (CDR=1.0. The evaluation protocol included: Addenbrooke's Cognitive Examination-Revised (ACE-R, Mini-Mental State Examination (MMSE, Executive Interview (EXIT-25, Neuropsychiatric Inventory (NPI, Frontotemporal Dementia Rating Scale (FTD-FRS and Clinical Dementia Rating scale (CDR. Results: The Brazilian version of the FTD-FRS seemed appropriate for use in this country. Preliminary results revealed greater levels of disability in bvFTD than in AD patients (bvFTD: 25% mild, 50% moderate and 25% severe; AD: 36.36% mild, 63.64% moderate. It appears that the CDR underrates disease severity in bvFTD since a relevant proportion of patients rated as having mild dementia (CDR=1.0 in fact had moderate or severe levels of disability according to the FTD-FRS. Conclusion: The Brazilian version of the FTD-FRS seems suitable to aid staging and determining disease progression.

Art and the brain: the influence of frontotemporal dementia on an accomplished artist.

Science.gov (United States)

Mell, Joshua Chang; Howard, Sara M; Miller, Bruce L

2003-05-27

A talented artist developed a progressive aphasia syndrome associated with frontotemporal dementia (FTD). As her disease progressed, language and executive skills declined, but her paintings became freer and more original. She demonstrates that artistic development can occur in the setting of language-dominant types of FTD. The study of artistic development in the setting of FTD suggests that language is not required for, and may even inhibit, certain types of visual creativity.

Structural and functional brain abnormalities place phenocopy frontotemporal dementia (FTD in the FTD spectrum

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Rebecca M.E. Steketee

2016-01-01

Conclusion: PhFTD and bvFTD show overlapping cortical structural abnormalities indicating a continuum of changes especially in the frontotemporal regions. Together with functional changes suggestive of a compensatory response to incipient pathology in the left prefrontal regions, these findings are the first to support a possible neuropathological etiology of phFTD and suggest that phFTD may be a neurodegenerative disease on the FTD spectrum.

[The neurochemistry and neuropharmacology of frontotemporal dementia].

Science.gov (United States)

Alonso-Navarro, H; Jabbour-Wadih, T; Ayuso-Peralta, L; Jiménez-Jiménez, F J

To review the neurochemical features and therapeutic options for frontotemporal dementia (FTD). The main neurochemical alterations in FTD are the serotoninergic and dopamine depletion. In contrast with Alzheimer's and diffuse Lewy bodies disease, there are not significant alterations of the cholinergic system. Cerebral perfusion and glucose metabolism studies usually show hypoperfusion or hypometabolism, with predominant involvement of temporal and frontal cortices. There have been described some alterations related with oxidative stress and apoptosis, although its pathogenetic role in FTD is not well known. Treatment of FTD is not well established, because there are only a few studies with some drugs. The most studied drugs are serotonin reuptake inhibitors, however, despite the well-known serotoninergic deficiency described in FTD, the results are not conclusive. The main neurochemical alterations of FTD are serotoninergic and dopaminergic deficiencies. The treatment is not well established, although it should be theoretically ideal to use drugs which modulate these neurotransmitter systems.

Microcystic Variant of Urothelial Carcinoma

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Anthony Kodzo-Grey Venyo

2013-01-01

Full Text Available Background. Microcystic variant of urothelial carcinoma is one of the new variants of urothelial carcinoma that was added to the WHO classification in 2004. Aims. To review the literature on microcystic variant of urothelial carcinoma. Methods. Various internet search engines were used to identify reported cases of the tumour. Results. Microscopic features of the tumour include: (i Conspicuous intracellular and intercellular lumina/microcysts encompassed by malignant urothelial or squamous cells. (ii The lumina are usually empty; may contain granular eosinophilic debris, mucin, or necrotic cells. (iii The cysts may be variable in size; round, or oval, up to 2 mm; lined by urothelium which are either flattened cells or low columnar cells however, they do not contain colonic epithelium or goblet cells; are infiltrative; invade the muscularis propria; mimic cystitis cystica and cystitis glandularis; occasionally exhibit neuroendocrine differentiation. (iv Elongated and irregular branching spaces are usually seen. About 17 cases of the tumour have been reported with only 2 patients who have survived. The tumour tends to be of high-grade and high-stage. There is no consensus opinion on the best option of treatment of the tumour. Conclusions. It would prove difficult at the moment to be dogmatic regarding its prognosis but it is a highly aggressive tumour. New cases of the tumour should be reported in order to document its biological behaviour.

Memantine in frontotemporal lobar degeneration: A multicenter, randomised, double-blind, placebo-controlled trial

Science.gov (United States)

Boxer, Adam L.; Knopman, David S.; Kaufer, Daniel I.; Grossman, Murray; Onyike, Chiadi; Graf-Radford, Neill; Mendez, Mario; Kerwin, Diana; Lerner, Alan; Wu, Chuang-Kuo; Koestler, Mary; Shapira, Jill; Sullivan, Kathryn; Klepac, Kristen; Lipowski, Kristine; Ullah, Jerin; Fields, Scott; Kramer, Joel H.; Merrilees, Jennifer; Neuhaus, John; Mesulam, M. Marsel; Miller, Bruce L.

2013-01-01

Background Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26 week open label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI). Methods We performed a randomized, parallel group, double blind, placebo controlled trial of 20 mg memantine taken orally daily for 26 weeks in FTD. Participants met Neary criteria for behavioral variant (bvFTD) or semantic dementia (SD) and had characteristic brain atrophy. Use of cholinesterase inhibitors was prohibited. The objective of the study was to determine whether memantine is an effective treatment for FTD. Individuals were randomized to memantine or matched placebo tablets in blocks of two and four. Primary endpoints were the change in total NPI score and Clinical Global Impression of Change (CGIC) scores after 26 weeks. Secondary outcomes included a neuropsychological battery, and other cognitive, global and activity of daily living measures. Clinicaltrials.gov identifier: NCT00545974 Findings 100 subjects were screened, 81 were randomized, 5 (6%) discontinued and 76 completed all visits. Enrollment numbers were lower than planned due to many subjects’ preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. 39 memantine and 42 placebo subjects entered the primary intent to treat analysis. There was no effect of memantine treatment on either the NPI (mean difference [MD] 2.2, 95%CI: −3.9, 8.3, p = 0.47) or CGIC (MD 0, 95%CI: −0.4, 0.4, p = 0.90) after 26 weeks of treatment. Memantine was generally well tolerated, however there were more frequent cognitive adverse events in the memantine group. Interpretation There was no benefit of memantine treatment in bvFTD or SD. These data do not support memantine use in FTD. Funding Forest Research Institute PMID:23290598

Common and unique gray matter correlates of episodic memory dysfunction in frontotemporal dementia and Alzheimer's disease.

Science.gov (United States)

Irish, Muireann; Piguet, Olivier; Hodges, John R; Hornberger, Michael

2014-04-01

Conflicting evidence exists regarding the integrity of episodic memory in the behavioral variant of frontotemporal dementia (bvFTD). Recent converging evidence suggests that episodic memory in progressive cases of bvFTD is compromised to the same extent as in Alzheimer's disease (AD). The underlying neural substrates of these episodic memory deficits, however, likely differ contingent on dementia type. In this study we sought to elucidate the neural substrates of episodic memory performance, across recall and recognition tasks, in both patient groups using voxel-based morphometry (VBM) analyses. We predicted that episodic memory dysfunction would be apparent in both patient groups but would relate to divergent patterns of neural atrophy specific to each dementia type. We assessed episodic memory, across verbal and visual domains, in 19 bvFTD, 18 AD patients, and 19 age- and education-matched controls. Behaviorally, patient groups were indistinguishable for immediate and delayed recall, across verbal and visual domains. Whole-brain VBM analyses revealed regions commonly implicated in episodic retrieval across groups, namely the right temporal pole, right frontal lobe, left paracingulate gyrus, and right anterior hippocampus. Divergent neural networks specific to each group were also identified. Whereas a widespread network including posterior regions such as the posterior cingulate cortex, parietal and occipital cortices was exclusively implicated in AD, the frontal and anterior temporal lobes underpinned the episodic memory deficits in bvFTD. Our results point to distinct neural changes underlying episodic memory decline specific to each dementia syndrome. Copyright © 2013 Wiley Periodicals, Inc.

TMEM106B, the risk gene for frontotemporal dementia, is regulated by the miRNA-132/212 cluster and affects progranulin pathways

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Chen-Plotkin, Alice S.; Unger, Travis L.; Gallagher, Michael D.; Bill, Emily; Kwong, Linda K.; Volpicelli-Daley, Laura; Busch, Johanna I.; Akle, Sebastian; Grossman, Murray; Van Deerlin, Vivianna; Trojanowski, John Q.; Lee, Virginia M.-Y.

2012-01-01

Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a fatal neurodegenerative disease with no available treatments. Mutations in the progranulin gene (GRN) causing impaired production or secretion of progranulin are a common Mendelian cause of FTLD-TDP; additionally, common variants at chromosome 7p21 in the uncharacterized gene TMEM106B were recently linked by genome-wide association to FTLD-TDP with and without GRN mutations. Here we show that TMEM106B is neuronally expressed in postmortem human brain tissue, and that expression levels are increased in FTLD-TDP brain. Furthermore, using an unbiased, microarray-based screen of over 800 microRNAs, we identify microRNA-132 as the top microRNA differentiating FTLD-TDP and control brains, with progranulin in late endo-lysosomes, and TMEM106B over-expression increases intracellular levels of progranulin. Thus, TMEM106B is an FTLD-TDP risk gene, with microRNA-132/212 depression as an event which can lead to aberrant over-expression of TMEM106B, which in turn alters progranulin pathways. Evidence for this pathogenic cascade includes the striking convergence of two independent, genomic-scale screens on a microRNA:mRNA regulatory pair. Our findings open novel directions for elucidating miRNA-based therapies in FTLD-TDP. PMID:22895706

Transgenerational epigenetic effects on animal behaviour.

Science.gov (United States)

Jensen, Per

2013-12-01

Over the last decade a shift in paradigm has occurred with respect to the interaction between environment and genes. It is now clear that animal genomes are regulated to a large extent as a result of input from environmental events and experiences, which cause short- and long-term modifications in epigenetic markings of DNA and histones. In this review, the evidence that such epigenetic modifications can affect the behaviour of animals is explored, and whether such acquired behaviour alterations can transfer across generation borders. First, the mechanisms by which experiences cause epigenetic modifications are examined. This includes, for example, methylation of cytosine in CpG positions and acetylation of histones, and studies showing that this can be modified by early experiences. Secondly, the evidence that specific modifications in the epigenome can be the cause of behaviour variation is reviewed. Thirdly, the extent to which this phenotypically active epigenetic variants can be inherited either through the germline or through reoccurring environmental conditions is examined. A particularly interesting observation is that epigenetic modifications are often linked to stress, and may possibly be mediated by steroid effects. Finally, the idea that transgenerationally stable epigenetic variants may serve as substrates for natural selection is explored, and it is speculated that they may even predispose for directed, non-random mutations. Copyright © 2013 Elsevier Ltd. All rights reserved.

Survival in the pre-senile dementia frontotemporal lobar degeneration with TDP-43 proteinopathy: effects of genetic, demographic and neuropathological variables

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Richard A. Armstrong

2016-06-01

Full Text Available Factors associated with survival were studied in 84 neuropathologically documented cases of the pre-senile dementia frontotemporal dementia lobar degeneration (FTLD with transactive response (TAR DNA-binding protein of 43 kDa (TDP-43 proteinopathy (FTLD-TDP. Kaplan-Meier survival analysis estimated mean survival as 7.9 years (range: 1-19 years, SD = 4.64. Familial and sporadic cases exhibited similar survival, including progranulin (GRN gene mutation cases. No significant differences in survival were associated with sex, disease onset, Braak disease stage, or disease subtype, but higher survival was associated with lower post-mortem brain weight. Survival was significantly reduced in cases with associated motor neuron disease (FTLD-MND but increased with Alzheimer’s disease (AD or hippocampal sclerosis (HS co-morbidity. Cox regression analysis suggested that reduced survival was associated with increased densities of neuronal cytoplasmic inclusions (NCI while increased survival was associated with greater densities of enlarged neurons (EN in the frontal and temporal lobes. The data suggest that: (1 survival in FTLD-TDP is more prolonged than typical in pre-senile dementia but shorter than some clinical subtypes such as the semantic variant of primary progressive aphasia (svPPA, (2 MND co-morbidity predicts poor survival, and (3 NCI may develop early and EN later in the disease. The data have implications for both neuropathological characterization and subtyping of FTLD-TDP.

Head to head comparison of [18F] AV-1451 and [18F] THK5351 for tau imaging in Alzheimer's disease and frontotemporal dementia

International Nuclear Information System (INIS)

Jang, Young Kyoung; Kim, Hee Jin; Jang, Hyemin; Lyoo, Chul Hyoung; Cho, Hanna; Park, Seongbeom; Oh, Seung Jun; Oh, Minyoung; Kim, Jae Seung; Ryu, Young Hoon; Choi, Jae Yong; Rabinovici, Gil D.; Moon, Seung Hwan; Lee, Jin San; Jagust, William J.; Na, Duk L.; Seo, Sang Won

2018-01-01

Tau accumulation is a core pathologic change in various neurodegenerative diseases including Alzheimer's disease and frontotemporal lobar degeneration-tau. Recently, tau positron emission tomography tracers such as [ 18 F] AV-1451 and [ 18 F] THK5351 have been developed to detect tau deposition in vivo. In the present study, we performed a head to head comparison of these two tracers in Alzheimer's disease and frontotemporal dementia cases and aimed to investigate which tracers are better suited to image tau in these disorders. A cross-sectional study was conducted using a hospital-based sample at a tertiary referral center. We recruited eight participants (two Alzheimer's disease, four frontotemporal dementia and two normal controls) who underwent magnetic resonance image, amyloid positron emission tomography with [ 18 F]-Florbetaben and tau positron emission tomography with both THK5351 and AV-1451. To measure regional AV1451 and THK5351 uptakes, we used the standardized uptake value ratios by dividing mean activity in target volume of interest by mean activity in the cerebellar hemispheric gray matter. Although THK5351 and AV-1451 uptakes were highly correlated, cortical uptake of AV-1451 was more striking in Alzheimer's disease, while cortical uptake of THK5351 was more prominent in frontotemporal dementia. THK5351 showed higher off-target binding than AV-1451 in the white matter, midbrain, thalamus, and basal ganglia. AV-1451 is more sensitive and specific to Alzheimer's disease type tau and shows lower off-target binding, while THK5351 may mirror non-specific neurodegeneration. (orig.)

Use of antidementia drugs in frontotemporal lobar degeneration.

Science.gov (United States)

López-Pousa, Secundino; Calvó-Perxas, Laia; Lejarreta, Saioa; Cullell, Marta; Meléndez, Rosa; Hernández, Erélido; Bisbe, Josep; Perkal, Héctor; Manzano, Anna; Roig, Anna Maria; Turró-Garriga, Oriol; Vilalta-Franch, Joan; Garre-Olmo, Josep

2012-06-01

Clinical evidence indicates that acetylcholinesterase inhibitors (AChEIs) are not efficacious to treat frontotemporal lobar degeneration (FTLD). The British Association for Psychopharmacology recommends avoiding the use of AChEI and memantine in patients with FTLD. Cross-sectional design using 1092 cases with Alzheimer's disease (AD) and 64 cases with FTLD registered by the Registry of Dementias of Girona. Bivariate analyses were performed, and binary logistic regressions were used to detect variables associated with antidementia drugs consumption. The AChEIs were consumed by 57.6% and 42.2% of the patients with AD and FTLD, respectively. Memantine was used by 17.2% and 10.9% of patients with AD and FTLD, respectively. Binary logistic regressions yielded no associations with antidementia drugs consumption. There is a discrepancy regarding clinical practice and the recommendations based upon clinical evidence. The increased central nervous system drug use detected in FTLD requires multicentric studies aiming at finding the best means to treat these patients.

Current Role for Biomarkers in Clinical Diagnosis of Alzheimer Disease and Frontotemporal Dementia.

Science.gov (United States)

Sheikh-Bahaei, Nasim; Sajjadi, Seyed Ahmad; Pierce, Aimee L

2017-11-14

Purpose of review Alzheimer's disease (AD) and frontotemporal dementia can often be diagnosed accurately with careful clinical history, cognitive testing, neurological examination, and structural brain MRI. However, there are certain circumstances wherein detection of specific biomarkers of neurodegeneration or underlying AD pathology will impact the clinical diagnosis or treatment plan. We will review the currently available biomarkers for AD and frontotemporal dementia (FTD) and discuss their clinical importance. Recent findings With the advent of 18 F-labeled tracers that bind amyloid plaques, amyloid PET is now clinically available for the detection of amyloid pathology and to aid in a biomarker-supported diagnosis of AD or mild cognitive impairment (MCI) due to AD. It is not yet possible to test for the specific FTD pathologies (tau or TDP-43); however, a diagnosis of FTD may be "imaging supported" based upon specific MRI or FDG-PET findings. Cerebrospinal fluid measures of amyloid-beta, total-tau, and phospho-tau are clinically available and allow detection of both of the cardinal pathologies of AD: amyloid and tau pathology. Summary It is appropriate to pursue biomarker testing in cases of MCI and dementia when there remains diagnostic uncertainty and the result will impact diagnosis or treatment. Practically speaking, due to the rising prevalence of amyloid positivity with advancing age, measurement of biomarkers in cases of MCI and dementia is most helpful in early-onset patients, patients with atypical clinical presentations, or when considering referral for AD clinical trials.

Techniques for Preservation of the Frontotemporal Branch of Facial Nerve during Orbitozygomatic Approaches

DEFF Research Database (Denmark)

Spiriev, Toma; Poulsgaard, Lars; Fugleholm, Kaare

2015-01-01

Background During orbitozygomatic (OZ) approaches, the frontotemporal branch (FTB) of the facial nerve is exposed to injury if proper measures are not taken. This article describes in detail the nuances of the two most common techniques (interfascial and subfascial dissection). Design The FTB...... of the facial nerve was dissected and followed in its tissue planes on fresh-frozen cadaver heads. The interfascial and subfascial dissections were performed, and every step was photographed and examined. Results The interfascial dissection is safe to be started from the most anterior part of the superior...

Genetics of frontotemporal lobar degeneration

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Aswathy P

2010-10-01

Full Text Available Frontotemporal lobar degeneration (FTLD is a highly heterogenous group of progressive neurodegenerative disorders characterized by atrophy of prefrontal and anterior temporal cortices. Recently, the research in the field of FTLD has gained increased attention due to the clinical, neuropathological, and genetic heterogeneity and has increased our understanding of the disease pathogenesis. FTLD is a genetically complex disorder. It has a strong genetic basis and 50% of patients show a positive family history for FTLD. Linkage studies have revealed seven chromosomal loci and a number of genes including MAPT, PGRN, VCP, and CHMB-2B are associated with the disease. Neuropathologically, FTLD is classified into tauopathies and ubiquitinopathies. The vast majority of FTLD cases are characterized by pathological accumulation of tau or TDP-43 positive inclusions, each as an outcome of mutations in MAPT or PGRN, respectively. Identification of novel proteins involved in the pathophysiology of the disease, such as progranulin and TDP-43, may prove to be excellent biomarkers of disease progression and thereby lead to the development of better therapeutic options through pharmacogenomics. However, much more dissections into the causative pathways are needed to get a full picture of the etiology. Over the past decade, advances in research on the genetics of FTLD have revealed many pathogenic mutations leading to different clinical manifestations of the disease. This review discusses the current concepts and recent advances in our understanding of the genetics of FTLD.

Fronto-parietal and fronto-temporal theta phase synchronization for visual and auditory-verbal working memory

OpenAIRE

Masahiro eKawasaki; Masahiro eKawasaki; Masahiro eKawasaki; Keiichi eKitajo; Keiichi eKitajo; Yoko eYamaguchi

2014-01-01

In humans, theta phase (4–8 Hz) synchronization observed on electroencephalography (EEG) plays an important role in the manipulation of mental representations during working memory (WM) tasks; fronto-temporal synchronization is involved in auditory-verbal WM tasks and fronto-parietal synchronization is involved in visual WM tasks. However, whether or not theta phase synchronization is able to select the to-be-manipulated modalities is uncertain. To address the issue, we recorded EEG data from...

Variants in the Dopamine-4-Receptor Gene Promoter Are Not Associated with Sensation Seeking in Skiers

OpenAIRE

Thomson, Cynthia J.; Rajala, Amelia K.; Carlson, Scott R.; Rupert, Jim L.

2014-01-01

Sensation seeking is a personality trait that has been associated with disinhibited behaviours including substance use and gambling, but also with high-risk sport practices including skydiving, paragliding, and downhill skiing. Twin studies have shown that sensation seeking is moderately heritable, and candidate genes encoding components involved in dopaminergic transmission have been investigated as contributing to this type of behaviour. To determine whether variants in the regulatory regio...

Gene Variants Associated with Antisocial Behaviour: A Latent Variable Approach

Science.gov (United States)

Bentley, Mary Jane; Lin, Haiqun; Fernandez, Thomas V.; Lee, Maria; Yrigollen, Carolyn M.; Pakstis, Andrew J.; Katsovich, Liliya; Olds, David L.; Grigorenko, Elena L.; Leckman, James F.

2013-01-01

Objective: The aim of this study was to determine if a latent variable approach might be useful in identifying shared variance across genetic risk alleles that is associated with antisocial behaviour at age 15 years. Methods: Using a conventional latent variable approach, we derived an antisocial phenotype in 328 adolescents utilizing data from a…

Progranulin in frontotemporal lobar degeneration and neuroinflammation

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Hutton Michael L

2007-02-01

Full Text Available Abstract Progranulin (PGRN is a pleiotropic protein that has gained the attention of the neuroscience community with recent discoveries of mutations in the gene for PGRN that cause frontotemporal lobar degeneration (FTLD. Pathogenic mutations in PGRN result in null alleles, and the disease is likely the result of haploinsufficiency. Little is known about the normal function of PGRN in the central nervous system apart from a role in brain development. It is expressed by microglia and neurons. In the periphery, PGRN is involved in wound repair and inflammation. High PGRN expression has been associated with more aggressive growth of various tumors. The properties of full length PGRN are distinct from those of proteolytically derived peptides, referred to as granulins (GRNs. While PGRN has trophic properties, GRNs are more akin to inflammatory mediators such as cytokines. Loss of the neurotrophic properties of PGRN may play a role in selective neuronal degeneration in FTLD, but neuroinflammation may also be important. Gene expression studies suggest that PGRN is up-regulated in a variety of neuroinflammatory conditions, and increased PGRN expression by microglia may play a pivotal role in the response to brain injury, neuroinflammation and neurodegeneration.

Polygenic scores for schizophrenia and educational attainment are associated with behavioural problems in early childhood in the general population

NARCIS (Netherlands)

Jansen, Philip R; Polderman, Tinca J C; Bolhuis, Koen; van der Ende, Jan; Jaddoe, Vincent W V; Verhulst, Frank C; White, Tonya; Posthuma, Danielle; Tiemeier, Henning

BACKGROUND: Genome-wide association studies in adults have identified numerous genetic variants related to psychiatric disorders and related traits, such as schizophrenia and educational attainment. However, the effects of these genetic variants on behaviour in the general population remain to be

Head to head comparison of [{sup 18}F] AV-1451 and [{sup 18}F] THK5351 for tau imaging in Alzheimer's disease and frontotemporal dementia

Energy Technology Data Exchange (ETDEWEB)

Jang, Young Kyoung; Kim, Hee Jin; Jang, Hyemin [Sungkyunkwan University School of Medicine, Department of Neurology, Samsung Medical Center, Seoul (Korea, Republic of); Neuroscience Center, Samsung Medical Center, Seoul (Korea, Republic of); Lyoo, Chul Hyoung; Cho, Hanna [Yonsei University College of Medicine, Department of Neurology, Gangnam Severance Hospital, Seoul (Korea, Republic of); Park, Seongbeom [Sungkyunkwan University School of Medicine, Department of Neurology, Samsung Medical Center, Seoul (Korea, Republic of); Oh, Seung Jun; Oh, Minyoung; Kim, Jae Seung [University of Ulsan College of Medicine, Department of Nuclear Medicine, Asan Medical Center, Seoul (Korea, Republic of); Ryu, Young Hoon; Choi, Jae Yong [Yonsei University College of Medicine, Department of Nuclear Medicine, Gangnam Severance Hospital, Seoul (Korea, Republic of); Rabinovici, Gil D. [University of California, San Francisco, Memory and Aging Center, San Francisco, CA (United States); University of California, Berkeley, Helen Wills Neuroscience Institute, Berkeley, CA (United States); Moon, Seung Hwan [Sungkyunkwan University School of Medicine, Department of Nuclear Medicine, Samsung Medical Center, Seoul (Korea, Republic of); Lee, Jin San [Kyung Hee University Hospital, Department of Neurology, Seoul (Korea, Republic of); Jagust, William J. [University of California, Berkeley, Helen Wills Neuroscience Institute, Berkeley, CA (United States); Lawrence Berkeley National Laboratory, Center of Functional Imaging, Berkeley, CA (United States); Na, Duk L. [Sungkyunkwan University School of Medicine, Department of Neurology, Samsung Medical Center, Seoul (Korea, Republic of); Neuroscience Center, Samsung Medical Center, Seoul (Korea, Republic of); Sungkyunkwan University, Department of Health Sciences and Technology, SAIHST, Seoul (Korea, Republic of); Seo, Sang Won [Sungkyunkwan University School of Medicine, Department of Neurology, Samsung Medical Center, Seoul (Korea, Republic of); Neuroscience Center, Samsung Medical Center, Seoul (Korea, Republic of); Sungkyunkwan University, Department of Health Sciences and Technology, SAIHST, Seoul (Korea, Republic of); Sungkyunkwan University, Department of Clinical Research Design and Evaluation, SAIHST, Seoul (Korea, Republic of)

2018-03-15

Tau accumulation is a core pathologic change in various neurodegenerative diseases including Alzheimer's disease and frontotemporal lobar degeneration-tau. Recently, tau positron emission tomography tracers such as [{sup 18}F] AV-1451 and [{sup 18}F] THK5351 have been developed to detect tau deposition in vivo. In the present study, we performed a head to head comparison of these two tracers in Alzheimer's disease and frontotemporal dementia cases and aimed to investigate which tracers are better suited to image tau in these disorders. A cross-sectional study was conducted using a hospital-based sample at a tertiary referral center. We recruited eight participants (two Alzheimer's disease, four frontotemporal dementia and two normal controls) who underwent magnetic resonance image, amyloid positron emission tomography with [{sup 18}F]-Florbetaben and tau positron emission tomography with both THK5351 and AV-1451. To measure regional AV1451 and THK5351 uptakes, we used the standardized uptake value ratios by dividing mean activity in target volume of interest by mean activity in the cerebellar hemispheric gray matter. Although THK5351 and AV-1451 uptakes were highly correlated, cortical uptake of AV-1451 was more striking in Alzheimer's disease, while cortical uptake of THK5351 was more prominent in frontotemporal dementia. THK5351 showed higher off-target binding than AV-1451 in the white matter, midbrain, thalamus, and basal ganglia. AV-1451 is more sensitive and specific to Alzheimer's disease type tau and shows lower off-target binding, while THK5351 may mirror non-specific neurodegeneration. (orig.)

Analyses of User Rationality and System Learnability: Performing Task Variants in User Tests

Science.gov (United States)

Law, Effie Lai-Chong; Blazic, Borka Jerman; Pipan, Matic

2007-01-01

No systematic empirical study on investigating the effects of performing task variants on user cognitive strategy and behaviour in usability tests and on learnability of the system being tested has been documented in the literature. The current use-inspired basic research work aims to identify the underlying cognitive mechanisms and the practical…

Telephone-Based Cognitive-Behavioral Screening for Frontotemporal Changes in Patients with Amyotrophic Lateral Sclerosis (ALS)

Science.gov (United States)

Christodoulou, Georgia; Gennings, Chris; Hupf, Jonathan; Factor-Litvak, Pam; Murphy, Jennifer; Goetz, Raymond R.; Mitsumoto, Hiroshi

2017-01-01

Objective To establish a valid and reliable battery of measures to evaluate frontotemporal dementia (FTD) in patients with ALS over the phone. Methods Thirty-one subjects were administered either in-person or telephone-based screening followed by the opposite mode of testing two weeks later, using a modified version of the UCSF Cognitive Screening Battery. Results Equivalence testing was performed for in-person and telephone-based tests. The standard ALS Cognitive Behavioral Screen (ALS-CBS) showed statistical equivalence at the 5% significance level when compared to a revised phone-version of the ALS-CBS. In addition, the Controlled Oral Word Association Test (COWAT) and Center for Neurologic Study-Lability Scale (CNS-LS) were also found to be equivalent at the 5% and 10% significance level respectively. Similarly, the Mini-Mental State Examination (MMSE) and the well-established Telephone Interview for Cognitive Status (TICS) were also statistically equivalent. Equivalence could not be claimed for the ALS-Frontal Behavioral Inventory (ALS-FBI) caregiver interview and the Written Verbal Fluency Index (WVFI). Conclusions Our study suggests that telephone-based versions of the ALS-CBS, COWAT, and CNS-LS may offer clinicians valid tools to detect frontotemporal changes in the ALS population. Development of telephone-based cognitive testing for ALS could become an integral resource for population-based research in the future. PMID:27121545

Telephone based cognitive-behavioral screening for frontotemporal changes in patients with amyotrophic lateral sclerosis (ALS).

Science.gov (United States)

Christodoulou, Georgia; Gennings, Chris; Hupf, Jonathan; Factor-Litvak, Pam; Murphy, Jennifer; Goetz, Raymond R; Mitsumoto, Hiroshi

Our objective was to establish a valid and reliable battery of measures to evaluate frontotemporal dementia (FTD) in patients with ALS over the telephone. Thirty-one subjects were administered either in-person or by telephone-based screening followed by the opposite mode of testing two weeks later, using a modified version of the UCSF Cognitive Screening Battery. Equivalence testing was performed for in-person and telephone based tests. The standard ALS Cognitive Behavioral Screen (ALS-CBS) showed statistical equivalence at the 5% significance level compared to a revised phone version of the ALS-CBS. In addition, the Controlled Oral Word Association Test (COWAT) and Center for Neurologic Study-Lability Scale (CNS-LS) were also found to be equivalent at the 5% and 10% significance level, respectively. Similarly, the Mini-Mental State Examination (MMSE) and the well-established Telephone Interview for Cognitive Status (TICS) were also statistically equivalent. Equivalence could not be claimed for the ALS-Frontal Behavioral Inventory (ALS-FBI) caregiver interview and the Written Verbal Fluency Index (WVFI). In conclusion, our study suggests that telephone-based versions of the ALS-CBS, COWAT, and CNS-LS may offer clinicians valid tools to detect frontotemporal changes in the ALS population. Development of telephone based cognitive testing for ALS could become an integral resource for population based research in the future.

Individual Music Therapy with Persons with Frontotemporal Dementia

DEFF Research Database (Denmark)

Ridder, Hanne Mette Ochsner

2007-01-01

It is possible to slow down the progression of Alzheimer's disease with pharmacological treatment. When this treatment is given to people with types of dementia that affect the frontal and temporal lobes (Frontotemporal Dementia) the results are discouraging. It is observed that the patients show...... is an integration of a relational music therapy approach and a more physiologically based arousal model, and is here illustrated in a case study that integrated both qualitative and quantitative data in a flexible research design1 ....... pronounced restlessness and mania. In this article we describe a nonpharmacological psychosocial approach, music therapy, and how it is possible to work with this method when constitutional, regulative, dialogical, and integrative aspects are included. The focus is on therapeutic singing where well......-known songs are applied in order to build up structure and stability and/or as means of arousal regulation. Songs with personal meaning make it possible to acknowledge the person's emotions, breaking the social isolation, and meeting the music therapy participant's psychosocial needs. The clinical approach...

Individual Music Therapy with Persons with Frontotemporal Dementia

DEFF Research Database (Denmark)

Ridder, Hanne Mette Ochsner; Aldridge, David

2005-01-01

It is possible to slow down the progression of Alzheimer’s disease with pharmacological treatment. When this treatment is given to people with types of dementia that affect the frontal and temporal lobes (Frontotemporal Dementia) the results are discouraging. It is observed that the patients show...... is an integration of a relational music therapy approach and a more physiologically based arousal model, and is here illustrated in a case study research that integrated both qualitative and quantitative data in a flexible research design....... pronounced restlessness and mania. In this article we describe a non-pharmacological psychosocial approach, music therapy, and how it is possible to work with this method when constitutional, regulative, dialogical, and integrative aspects are included. The focus is on therapeutic singing where well known...... songs are applied in order to build up structure and stability and/or as means of arousal regulation. Songs with personal meaning make it possible to acknowledge the person’s emotions, breaking the social isolation, and meeting the music therapy participant’s psychosocial needs. The clinical approach...

Fitness of isogenic colony morphology variants of Pseudomonas aeruginosa in murine airway infection.

Directory of Open Access Journals (Sweden)

Elza Rakhimova

Full Text Available Chronic lung infections with Pseudomonas aeruginosa are associated with the diversification of the persisting clone into niche specialists and morphotypes, a phenomenon called 'dissociative behaviour'. To explore the potential of P. aeruginosa to change its morphotype by single step loss-of-function mutagenesis, a signature-tagged mini-Tn5 plasposon library of the cystic fibrosis airway isolate TBCF10839 was screened for colony morphology variants under nine different conditions in vitro. Transposon insertion into 1% of the genome changed colony morphology into eight discernable morphotypes. Half of the 55 targets encode features of primary or secondary metabolism whereby quinolone production was frequently affected. In the other half the transposon had inserted into genes of the functional categories transport, regulation or motility/chemotaxis. To mimic dissociative behaviour of isogenic strains in lungs, pools of 25 colony morphology variants were tested for competitive fitness in an acute murine airway infection model. Six of the 55 mutants either grew better or worse in vivo than in vitro, respectively. Metabolic proficiency of the colony morphology variant was a key determinant for survival in murine airways. The most common morphotype of self-destructive autolysis did unexpectedly not impair fitness. Transposon insertions into homologous genes of strain PAO1 did not reproduce the TBCF10839 mutant morphotypes for 16 of 19 examined loci pointing to an important role of the genetic background on colony morphology. Depending on the chosen P. aeruginosa strain, functional genome scans will explore other areas of the evolutionary landscape. Based on our discordant findings of mutant phenotypes in P. aeruginosa strains PAO1, PA14 and TBCF10839, we conclude that the current focus on few reference strains may miss modes of niche adaptation and dissociative behaviour that are relevant for the microevolution of complex traits in the wild.

The unique predisposition to criminal violations in frontotemporal dementia.

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Mendez, Mario F

2010-01-01

Brain disorders can lead to criminal violations. Patients with frontotemporal dementia (FTD) are particularly prone to sociopathic behavior while retaining knowledge of their acts and of moral and conventional rules. This report describes four FTD patients who committed criminal violations in the presence of clear consciousness and sufficiently intact cognition. They understood the nature of their acts and the potential consequences, but did not feel sufficiently concerned to be deterred. FTD involves a unique pathologic combination affecting the ventromedial prefrontal cortex, with altered moral feelings, right anterior temporal loss of emotional empathy, and orbitofrontal changes with disinhibited, compulsive behavior. These case histories and the literature indicate that those with right temporal FTD retain the capacity to tell right from wrong but have the slow and insidious loss of the capacity for moral rationality. Patients with early FTD present a challenge to the criminal justice system to consider alterations in moral cognition before ascribing criminal responsibility.

SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis.

Science.gov (United States)

Le Ber, Isabelle; Camuzat, Agnès; Guerreiro, Rita; Bouya-Ahmed, Kawtar; Bras, Jose; Nicolas, Gael; Gabelle, Audrey; Didic, Mira; De Septenville, Anne; Millecamps, Stéphanie; Lenglet, Timothée; Latouche, Morwena; Kabashi, Edor; Campion, Dominique; Hannequin, Didier; Hardy, John; Brice, Alexis

2013-11-01

Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD. To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients. A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes. Primary care or referral center. An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS. Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes. We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations. Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD.

Accurate genotyping across variant classes and lengths using variant graphs

DEFF Research Database (Denmark)

Sibbesen, Jonas Andreas; Maretty, Lasse; Jensen, Jacob Malte

2018-01-01

of read k-mers to a graph representation of the reference and variants to efficiently perform unbiased, probabilistic genotyping across the variation spectrum. We demonstrate that BayesTyper generally provides superior variant sensitivity and genotyping accuracy relative to existing methods when used...... collecting a set of candidate variants across discovery methods, individuals and databases, and then realigning the reads to the variants and reference simultaneously. However, this realignment problem has proved computationally difficult. Here, we present a new method (BayesTyper) that uses exact alignment...... to integrate variants across discovery approaches and individuals. Finally, we demonstrate that including a ‘variation-prior’ database containing already known variants significantly improves sensitivity....

Variants in the dopamine-4-receptor gene promoter are not associated with sensation seeking in skiers.

Science.gov (United States)

Thomson, Cynthia J; Rajala, Amelia K; Carlson, Scott R; Rupert, Jim L

2014-01-01

Sensation seeking is a personality trait that has been associated with disinhibited behaviours including substance use and gambling, but also with high-risk sport practices including skydiving, paragliding, and downhill skiing. Twin studies have shown that sensation seeking is moderately heritable, and candidate genes encoding components involved in dopaminergic transmission have been investigated as contributing to this type of behaviour. To determine whether variants in the regulatory regions of the dopamine-4-receptor gene (DRD4) influenced sport-specific sensation seeking, we analyzed five polymorphisms (-1106T/C, -906T/C, -809G/A, -291C/T, 120-bp duplication) in the promoter region of the gene in a cohort of skiers and snowboarders (n = 599) that represented a broad range of sensation seeking behaviours. We grouped subjects by genotype at each of the five loci and compared impulsive sensation seeking and domain-specific (skiing) sensation seeking between groups. There were no significant associations between genotype(s) and general or domain-specific sensation seeking in the skiers and snowboarders, suggesting that while DRD4 has previously been implicated in sensation seeking, the promoter variants investigated in this study do not contribute to sensation seeking in this athlete population.

Dandy walker variant and bipolar I disorder with graphomania.

Science.gov (United States)

Can, Serdar Suleyman; Karakaş Uğurlu, Görkem; Cakmak, Selcen

2014-07-01

Cerebellum is known to play an important role in coordination and motor functions. In some resent studies it is also considered to be involved in modulation of mood, cognition and psychiatric disorders. Dandy Walker Malformation is a congenital malformation that is characterized by hypoplasia or aplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of the posterior fossa. When the volume of posterior fossa is normal, the malformation is called Dandy Walker Variant. Case is a 32 year old male with a 12 year history of Bipolar I Disorder presented with manic and depresive symptoms, including dysphoric and depressive affect, anhedonia, suicidal thoughts and behaviours, thoughts of fear about future, overtalkativeness and graphomania, increased energy, irregular sleep, loss of appetite, increased immersion in projects, irritability, agressive behavior, impulsivity. Cranial Magnetic Resonance Imaging was compatible to the morphological features of Dandy Walker Variant.

Cellulase variants

Science.gov (United States)

Blazej, Robert; Toriello, Nicholas; Emrich, Charles; Cohen, Richard N.; Koppel, Nitzan

2015-07-14

This invention provides novel variant cellulolytic enzymes having improved activity and/or stability. In certain embodiments the variant cellulotyic enzymes comprise a glycoside hydrolase with or comprising a substitution at one or more positions corresponding to one or more of residues F64, A226, and/or E246 in Thermobifida fusca Cel9A enzyme. In certain embodiments the glycoside hydrolase is a variant of a family 9 glycoside hydrolase. In certain embodiments the glycoside hydrolase is a variant of a theme B family 9 glycoside hydrolase.

Verbal creativity in semantic variant primary progressive aphasia.

Science.gov (United States)

Wu, Teresa Q; Miller, Zachary A; Adhimoolam, Babu; Zackey, Diana D; Khan, Baber K; Ketelle, Robin; Rankin, Katherine P; Miller, Bruce L

2015-02-01

Emergence of visual and musical creativity in the setting of neurologic disease has been reported in patients with semantic variant primary progressive aphasia (svPPA), also called semantic dementia (SD). It is hypothesized that loss of left anterior frontotemporal function facilitates activity of the right posterior hemispheric structures, leading to de novo creativity observed in visual artistic representation. We describe creativity in the verbal domain, for the first time, in three patients with svPPA. Clinical presentations are carefully described in three svPPA patients exhibiting verbal creativity, including neuropsychology, neurologic exam, and structural magnetic resonance imaging (MRI). Voxel-based morphometry (VBM) was performed to quantify brain atrophy patterns in these patients against age-matched healthy controls. All three patients displayed new-onset creative writing behavior and produced extensive original work during the course of disease. Patient A developed interest in wordplay and generated a large volume of poetry. Patient B became fascinated with rhyming and punning. Patient C wrote and published a lifestyle guidebook. An overlap of their structural MR scans showed uniform sparing in the lateral portions of the language-dominant temporal lobe (superior and middle gyri) and atrophy in the medial temporal cortex (amygdala, limbic cortex). New-onset creativity in svPPA may represent a paradoxical functional facilitation. A similar drive for production is found in visually artistic and verbally creative patients. Mirroring the imaging findings in visually artistic patients, verbal preoccupation and creativity may be associated with medial atrophy in the language-dominant temporal lobe, but sparing of lateral dominant temporal and non-dominant posterior cortices.

Assessment of socioemotional processes facilitates the distinction between frontotemporal lobar degeneration and Alzheimer's disease.

Science.gov (United States)

Narme, Pauline; Mouras, Harold; Roussel, Martine; Devendeville, Agnès; Godefroy, Olivier

2013-01-01

We explored the value of a battery of socioemotional tasks for differentiating between frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Patients with FTLD (n = 13) or AD (n = 13) and healthy controls (n = 26) underwent a neuropsychological assessment and the socioemotional battery (an empathy questionnaire, an emotion recognition task, and theory of mind tasks). Socioemotional processes were markedly impaired in FTLD but relatively unaffected in mild AD. The computed Socioemotional Index discriminated more accurately between FTLD from AD than behavioral and executive assessments did. Furthermore, impairments in socioemotional processes were correlated with indifference to others.

The study of fMRI in Alzheimer's disease, frontotemporal dementia and Lewy bodies dementia

International Nuclear Information System (INIS)

Zhang Bing; Xu Jun; Xu Yun; Zhu Bin

2010-01-01

Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) are the main type of neuro degenerative diseases, but the FTD and DLB are always confused with AD. Structural MRI, diffusion-weighted imaging and proton magnetic resonance spectroscopy have the potential to support the diagnosis of AD and the relative disease. Brain atrophy pattern, apparent diffusion coefficient and fractional anisotropy pattern, the distribution mode of N-acetylaspartate and myo-inositol in temporal lobe, hippocampus, parietal lobe, frontal lobe could help to differentiate AD from FTD, DLB and those patterns are in accordance with the pathological changes. (authors)

Somatic cancer variant curation and harmonization through consensus minimum variant level data

Directory of Open Access Journals (Sweden)

Deborah I. Ritter

2016-11-01

Full Text Available Abstract Background To truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG of the Clinical Genome Resource (ClinGen, in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD. MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVLD standards, and in a working partnership with ClinVar, we aim to streamline the somatic variant curation efforts in the community and reduce redundancy and time burden for the interpretation of cancer variants in clinical practice. Methods We developed MVLD through a consensus approach by i reviewing clinical actionability interpretations from institutions participating in the WG, ii conducting extensive literature search of clinical somatic interpretation schemas, and iii survey of cancer variant web portals. A forthcoming guideline on cancer variant interpretation, from the Association of Molecular Pathology (AMP, can be incorporated into MVLD. Results Along with harmonizing standardized terminology for allele interpretive and descriptive fields that are collected by many databases, the MVLD includes unique fields for cancer variants such as Biomarker Class, Therapeutic Context and Effect. In addition, MVLD includes recommendations for controlled semantics and ontologies. The Somatic WG is collaborating with ClinVar to evaluate MVLD use for somatic variant submissions. ClinVar is an open and centralized repository where sequencing laboratories can report summary-level variant data with clinical significance, and ClinVar accepts cancer variant data. Conclusions We expect the use of the MVLD to streamline clinical interpretation of cancer variants, enhance interoperability among multiple redundant curation efforts, and increase submission of

HOW TO DIFFERENTIATE FRONTOTEMPORAL FROMALZHEIMER’S DEMENTIA? RECENT DEVELOPMENTS INMOLECULAR GENETICS AND NEUROPATHOLOGY

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Rajko Liščić

2008-05-01

Full Text Available Frontotemporal dementia is a major cause of non-Alzheimer dementia (AD. Frontotemporal lobar degeneration (FTLD is used here as an umbrella term for both clinical andneuropathological entities starting before age of 65 years. FTLD differs clinically from ADbecause memory loss is rarely an early symptom. Instead, the dementia of FTLD is usuallydenoted by behavioral and language difficulties, although clinical and cognitive featuresof FTLD may overlap with AD. Aphasia may be prominent, either fluent or nonfluent.Clinical FTLD is associated with a variety of different neuropathological entities, whichshare common feature of preferential degeneration of the frontal and temporal lobes. Whereas, in the past, most attention focused on FTLD pathology associated with tau-positive inclusions and microtubule associated protein tau gene (MAPT mutations (tauopathies,there has recently been greater attention paid to non-tau, ubiquitin positive inclusions(FTLD-U or non-tauopathies. It is now recognized that FTLD-U is the most common pathology associated with clinical FTLD. Clinically, cases with FTLD-U may additionally presentwith or without motor neuron disease and parkinsonism. Majority of familial cases ofFTLD-U have mutations in the progranulin (PRGN gene. Some families of FTLD-U withPGRN mutation (hereditary dysphasic disinhibition dementia 1 and 2 are characterized,besides behavior and language difficulties, by additional memory loss and AD-type pathology. Recently, the ubiquitinated pathological protein in FTLD-U has been identified asTAR DNA binding protein (TDP 43 and found in an increasing number of neurodegenerative diseases, including AD. The overlap between FTLD-U and AD is important since asmany as 20 % of AD cases show some FTLD-U type TDP-43 pathology. Recent developmentshave helped to clarify the relationship between different types of FTLD and related conditions. Understanding and differentiating between FTLD and AD is very important for

CDKL5 variants

Science.gov (United States)

Kalscheuer, Vera M.; Hennig, Friederike; Leonard, Helen; Downs, Jenny; Clarke, Angus; Benke, Tim A.; Armstrong, Judith; Pineda, Mercedes; Bailey, Mark E.S.; Cobb, Stuart R.

2017-01-01

Objective: To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene. Methods: We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity. Results: The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants, we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also describe benign splicing and nonsense variants within these exons, suggesting that isoform hCDKL5_5 is likely to have little or no neurologic significance. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency. Conclusions: These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency. Together, these analyses support the view that the predominant brain isoform in humans (hCDKL5_1) is crucial for normal neurodevelopment and that the catalytic domain is the primary functional domain. PMID:29264392

Role of vaspin in human eating behaviour.

Science.gov (United States)

Breitfeld, Jana; Tönjes, Anke; Gast, Marie-Therese; Schleinitz, Dorit; Blüher, Matthias; Stumvoll, Michael; Kovacs, Peter; Böttcher, Yvonne

2013-01-01

The adipokine vaspin (visceral adipose tissue derived serine protease inhibitor, serpinA12) follows a meal-related diurnal variation in humans and intracerebroventricular vaspin administration leads to acutely reduced food intake in db/db mice. We therefore hypothesized that vaspin may play a role in human eating behaviour. We measured serum vaspin concentrations in 548 subjects from a self-contained population of Sorbs (Germany) who underwent detailed metabolic testing including eating behaviour assessments using the three-factor eating questionnaire. In addition, genetic variation within vaspin was assessed by genotyping 28 single nucleotide polymorphisms (SNPs) in all study subjects. Serum vaspin concentrations correlated positively with restraint, disinhibition and hunger (all P0.05). Independent of observed correlations, genetic variants in vaspin were associated with serum vaspin levels but showed no significant association with any of the eating behaviour phenotypes after accounting for multiple testing (P≥0.05 after adjusting for age, gender and BMI). Our data suggest that serum vaspin concentrations might modulate human eating behaviour, which does not seem to be affected by common genetic variation in vaspin.

Variants in the dopamine-4-receptor gene promoter are not associated with sensation seeking in skiers.

Directory of Open Access Journals (Sweden)

Cynthia J Thomson

Full Text Available Sensation seeking is a personality trait that has been associated with disinhibited behaviours including substance use and gambling, but also with high-risk sport practices including skydiving, paragliding, and downhill skiing. Twin studies have shown that sensation seeking is moderately heritable, and candidate genes encoding components involved in dopaminergic transmission have been investigated as contributing to this type of behaviour. To determine whether variants in the regulatory regions of the dopamine-4-receptor gene (DRD4 influenced sport-specific sensation seeking, we analyzed five polymorphisms (-1106T/C, -906T/C, -809G/A, -291C/T, 120-bp duplication in the promoter region of the gene in a cohort of skiers and snowboarders (n = 599 that represented a broad range of sensation seeking behaviours. We grouped subjects by genotype at each of the five loci and compared impulsive sensation seeking and domain-specific (skiing sensation seeking between groups. There were no significant associations between genotype(s and general or domain-specific sensation seeking in the skiers and snowboarders, suggesting that while DRD4 has previously been implicated in sensation seeking, the promoter variants investigated in this study do not contribute to sensation seeking in this athlete population.

Augmented Input Reveals Word Deafness in a Man with Frontotemporal Dementia

Directory of Open Access Journals (Sweden)

Chris Gibbons

2012-01-01

Full Text Available We describe a 57 year old, right handed, English speaking man initially diagnosed with progressive aphasia. Language assessment revealed inconsistent performance in key areas. Expressive language was reduced to a few short, perseverative phrases. Speech was severely apraxic. Primary modes of communication included gesture, pointing, gaze, physical touch and leading. Responses were 100% accurate when he was provided with written words, with random or inaccurate responses for strictly auditory/verbal input. When instructions to subsequent neuropsychological tests were written instead of spoken, performance improved markedly. A comprehensive audiology assessment revealed no hearing impairment. Neuroimaging was unremarkable. Neurobehavioral evaluation utilizing written input led to diagnoses of word deafness and frontotemporal dementia, resulting in very different management. We highlight the need for alternative modes of language input for assessment and treatment of patients with language comprehension symptoms.

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study

NARCIS (Netherlands)

E. Majounie (Elisa); A. Renton (Alan); K. Mok (Kin); E.G.P. Dopper (Elise); A. Waite (Adrian); S. Rollinson (Sara); A. Chiò (Adriano); G. Restagno (Gabriella); N. Nicolaou (Nayia); J. Simón-Sánchez (Javier); J.C. van Swieten (John); Y. Abramzon (Yevgeniya); J. Johnson (Janel); M. Sendtner (Michael); R. Pamphlett (Roger); R. Orrell (Richard); S. Mead (Simon); K.C. Sidle (Katie); H. Houlden (Henry); J.D. Rohrer (Jonathan Daniel); K.E. Morrison (Karen); H. Pall (Hardev); D. Talbot; O. Ansorge (Olaf); D.G. Hernandez (Dena); S. Arepalli (Sampath); M. Sabatelli (Mario); G. Mora (Gabriele); J.C. Corbo (Joseph); F. Giannini (Fabio); A. Calvo (Andrea); E. Englund (Elisabet); G. Borghero (Giuseppe); O.A.M. Floris; A. Remes (Anne); H. Laaksovirta (Hannu); L. McCluskey (Leo); J.Q. Trojanowski (John); V.M. Deerlin (Vivianna); G.D. Schellenberg (Gerard); M.A. Nalls (Michael); V.E. Drory (Vivian E); C.S. Lu (Chin-Song); T.-H. Yeh (Tu-Hsueh); H. Ishiura (Hiroyuki); Y. Takahashi (Yukari); S. Tsuji (Shoji); I. Le Ber (Isabelle); A. Brice; C. Drepper (Carsten); N. Williams (Nigel); J. Kirby (Janine); P.J. Shaw (Pamela); J. Hardy (John); P.J. Tienari (Pentti); P. Heutink (Peter); H. Morris (Huw); S. Pickering-Brown (Stuart); B.J. Traynor (Bryan)

2012-01-01

textabstractBackground: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods: We screened 4448 patients diagnosed with

Frontotemporal dementia linked to chromosome 3 (FTD-3)--current concepts and the detection of a previously unknown branch of the Danish FTD-3 family

DEFF Research Database (Denmark)

Lindquist, S.G.; Braedgaard, H.; Svenstrup, K.

2008-01-01

BACKGROUND: Among patients with onset of dementia below the age of 65 years, frontotemporal dementia (FTD) is the second most prevalent cause, secondary only to Alzheimer's disease. Recent advances in understanding the heterogeneous genetic background for different clinical and neuropathological ...

Is the emotion recognition deficit associated with frontotemporal dementia caused by selective inattention to diagnostic facial features?

Science.gov (United States)

Oliver, Lindsay D; Virani, Karim; Finger, Elizabeth C; Mitchell, Derek G V

2014-07-01

Frontotemporal dementia (FTD) is a debilitating neurodegenerative disorder characterized by severely impaired social and emotional behaviour, including emotion recognition deficits. Though fear recognition impairments seen in particular neurological and developmental disorders can be ameliorated by reallocating attention to critical facial features, the possibility that similar benefits can be conferred to patients with FTD has yet to be explored. In the current study, we examined the impact of presenting distinct regions of the face (whole face, eyes-only, and eyes-removed) on the ability to recognize expressions of anger, fear, disgust, and happiness in 24 patients with FTD and 24 healthy controls. A recognition deficit was demonstrated across emotions by patients with FTD relative to controls. Crucially, removal of diagnostic facial features resulted in an appropriate decline in performance for both groups; furthermore, patients with FTD demonstrated a lack of disproportionate improvement in emotion recognition accuracy as a result of isolating critical facial features relative to controls. Thus, unlike some neurological and developmental disorders featuring amygdala dysfunction, the emotion recognition deficit observed in FTD is not likely driven by selective inattention to critical facial features. Patients with FTD also mislabelled negative facial expressions as happy more often than controls, providing further evidence for abnormalities in the representation of positive affect in FTD. This work suggests that the emotional expression recognition deficit associated with FTD is unlikely to be rectified by adjusting selective attention to diagnostic features, as has proven useful in other select disorders. Copyright © 2014 Elsevier Ltd. All rights reserved.

Progranulin, a Glycoprotein Deficient in Frontotemporal Dementia, Is a Novel Substrate of Several Protein Disulfide Isomerase Family Proteins

OpenAIRE

Almeida, Sandra; Zhou, Lijuan; Gao, Fen-Biao

2011-01-01

The reduced production or activity of the cysteine-rich glycoprotein progranulin is responsible for about 20% of cases of familial frontotemporal dementia. However, little is known about the molecular mechanisms that govern the level and secretion of progranulin. Here we show that progranulin is expressed in mouse cortical neurons and more prominently in mouse microglia in culture and is abundant in the endoplasmic reticulum (ER) and Golgi. Using chemical crosslinking, immunoprecipitation, an...

[Reconciliating neurology and psychiatry: The prototypical case of frontotemporal dementia].

Science.gov (United States)

Lagarde, J; Sarazin, M

2017-10-01

Frontotemporal degeneration (FTD) in its behavioral variant (bvFTD) is probably one of the conditions that best illustrates the links between psychiatry and neurology. It is indeed admitted that between a third and half of patients with this condition, especially in early-onset forms, receive an initial diagnosis of psychiatric disorder (depression, schizophrenia, bipolar disorder) and are then referred to a psychiatric ward. BvFTD can thus be considered a neurological disorder with a psychiatric presentation. Among psychiatric symptoms reported in this disease, psychotic symptoms (hallucinations, delusions, especially of persecution), which have long been underestimated in bvFTD and are not part of the current diagnostic criteria, are present in about 20% of cases and may be inaugural. They are particularly common in the genetic forms related to a mutation in the C9orf72 gene (up to 50%), and to a lesser extent in the GRN gene (up to 25%). C9orf72 gene mutation is often associated with a family history of dementia or motor neuron disease but also of psychiatric disorders. It has also been described in sporadic presentation forms. Sometimes, the moderate degree of brain atrophy on MRI described in patients carrying this mutation may complicate the differential diagnosis with late-onset psychiatric diseases. In the present article, we underline the importance of considering that psychiatric - especially psychotic - symptoms are not rare in bvFTD, which should lead to a revision of the diagnostic criteria of this disease by taking greater account of this fact. We also propose a diagnostic chart, based on concerted evaluation by neurologists and psychiatrists for cases of atypical psychiatric symptoms (late-onset or pharmacoresistant troubles) leading to consider the possibility of a neurological disorder, in order to shed a new light on these difficult clinical situations. In the field of research, bvFTD may constitute a model to explore the neural basis of certain

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

NARCIS (Netherlands)

Majounie, E.; Renton, A.E.; Mok, K.; Dopper, E.G.P.; Waite, A.; Rollinson, S.; Chio, A.; Restagno, G.; Nicolaou, N.; Simon-Sanchez, J.; van Swieten, J.C.; Abramzon, Y.; Johnson, J.O.; Sendtner, M.; Pamphlett, R.; Orrell, R.W.; Mead, S.; Sidle, K.C.; Houlden, H.; Rohrer, J.D.; Morrison, K.E.; Pall, H.; Talbot, K.; Ansorge, O.; Hernandez, D.G.; Arepalli, S.; Sabatelli, M.; Mora, G.; Corbo, M.; Giannini, F.; Calvo, A.; Englund, E.; Borghero, G.; Foris, G.L.; Remes, A.M.; Laaksovirta, H.; McCluskey, L.; Trojanowski, J.Q.; Van Deerlin, V.M.; Schellenberg, G.D.; Nalls, M.A.; Drory, V.E.; Lu, C.S.; Yeh, T.H.; Ishiura, H.; Takahashi, Y.; Tsuji, S.; Le Ber, I.; Brice, A.; Drepper, C.; Williams, N.; Kirby, J.; Shaw, P.; Hardy, J.; Tienari, P.J.; Heutink, P.; Morris, H.R.; Pickering-Brown, S.; Traynor, B.J.

2012-01-01

Background: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods: We screened 4448 patients diagnosed with ALS (El

The ALS-FTD-Q: A new screening tool for behavioral disturbances in ALS

NARCIS (Netherlands)

Raaphorst, J.; Beeldman, E.; Schmand, B.; Berkhout, J.; Linssen, W.H.J.P.; Van den Berg, L.H.; Pijnenburg, Y.A.L.; Grupstra, H.F.; Weikamp, J.G.; Schelhaas, H.J.; Papma, J.M.; van Swieten, J.C.; de Visser, M.; de Haan, R.J.

2012-01-01

Objective: The assessment of behavioral disturbances in amyotrophic lateral sclerosis (ALS) is important because of the overlap with the behavioral variant of frontotemporal dementia (ALS-bvFTD). Motor symptoms and dysarthria are not taken into account in currently used behavioral questionnaires. We

The ALS-FTD-Q A new screening tool for behavioral disturbances in ALS

NARCIS (Netherlands)

Raaphorst, Joost; Beeldman, Emma; Schmand, Ben; Berkhout, Joris; Linssen, Wim H. J. P.; van den Berg, Leonard H.; Pijnenburg, Yolande A.; Grupstra, Hepke F.; Weikamp, Janneke G.; Schelhaas, H. Jurgen; Papma, Janne M.; van Swieten, John C.; de Visser, Marianne; de Haan, Rob J.

2012-01-01

Objective: The assessment of behavioral disturbances in amyotrophic lateral sclerosis (ALS) is important because of the overlap with the behavioral variant of frontotemporal dementia (ALS-bvFTD). Motor symptoms and dysarthria are not taken into account in currently used behavioral questionnaires. We

The ALS-FTD-Q: a new screening tool for behavioral disturbances in ALS

NARCIS (Netherlands)

Raaphorst, J.; Beeldman, E.; Schmand, B.A.; Berkhout, J.; Linssen, W.H.J.P.; Berg, L.H. van den; Pijnenburg, Y.A.; Grupstra, H.F.; Weikamp, J.G.; Schelhaas, H.J.; Papma, J.M.; van Swieten, J.C.; Visser, M. de; Haan, R.J. de

2012-01-01

OBJECTIVE: The assessment of behavioral disturbances in amyotrophic lateral sclerosis (ALS) is important because of the overlap with the behavioral variant of frontotemporal dementia (ALS-bvFTD). Motor symptoms and dysarthria are not taken into account in currently used behavioral questionnaires. We

Intact protein analysis of ubiquitin in cerebrospinal fluid by multiple reaction monitoring reveals differences in Alzheimer's disease and frontotemporal lobar degeneration.

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Oeckl, Patrick; Steinacker, Petra; von Arnim, Christine A F; Straub, Sarah; Nagl, Magdalena; Feneberg, Emily; Weishaupt, Jochen H; Ludolph, Albert C; Otto, Markus

2014-11-07

The impairment of the ubiquitin-proteasome system (UPS) is thought to be an early event in neurodegeneration, and monitoring UPS alterations might serve as a disease biomarker. Our aim was to establish an alternate method to antibody-based assays for the selective measurement of free monoubiquitin in cerebrospinal fluid (CSF). Free monoubiquitin was measured with liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MS/MS) in CSF of patients with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), behavioral variant of frontotemporal dementia (bvFTD), Creutzfeldt-Jakob disease (CJD), Parkinson's disease (PD), primary progressive aphasia (PPA), and progressive supranuclear palsy (PSP). The LC-MS/MS method showed excellent intra- and interassay precision (4.4-7.4% and 4.9-10.3%) and accuracy (100-107% and 100-106%). CSF ubiquitin concentration was increased compared with that of controls (33.0 ± 9.7 ng/mL) in AD (47.5 ± 13.1 ng/mL, p < 0.05) and CJD patients (171.5 ± 103.5 ng/mL, p < 0.001) but not in other neurodegenerative diseases. Receiver operating characteristic curve (ROC) analysis of AD vs control patients revealed an area under the curve (AUC) of 0.832, and the specificity and sensitivity were 75 and 75%, respectively. ROC analysis of AD and FTLD patients yielded an AUC of 0.776, and the specificity and sensitivity were 53 and 100%, respectively. In conclusion, our LC-MS/MS method may facilitate ubiquitin determination to a broader community and might help to discriminate AD, CJD, and FTLD patients.

A neurocomputational model of analogical reasoning and its breakdown in frontotemporal lobar degeneration.

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Morrison, Robert G; Krawczyk, Daniel C; Holyoak, Keith J; Hummel, John E; Chow, Tiffany W; Miller, Bruce L; Knowlton, Barbara J

2004-03-01

Analogy is important for learning and discovery and is considered a core component of intelligence. We present a computational account of analogical reasoning that is compatible with data we have collected from patients with cortical degeneration of either their frontal or anterior temporal cortices due to frontotemporal lobar degeneration (FTLD). These two patient groups showed different deficits in picture and verbal analogies: frontal lobe FTLD patients tended to make errors due to impairments in working memory and inhibitory abilities, whereas temporal lobe FTLD patients tended to make errors due to semantic memory loss. Using the "Learning and Inference with Schemas and Analogies" model, we provide a specific account of how such deficits may arise within neural networks supporting analogical problem solving.

A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype in two siblings: case report and literature review.

Science.gov (United States)

Hosaka, Takashi; Ishii, Kazuhiro; Miura, Takeshi; Mezaki, Naomi; Kasuga, Kensaku; Ikeuchi, Takeshi; Tamaoka, Akira

2017-09-15

Progranulin gene (GRN) mutations are major causes of frontotemporal lobar degeneration. To date, 68 pathogenic GRN mutations have been identified. However, very few of these mutations have been reported in Asians. Moreover, some GRN mutations manifest with familial phenotypic heterogeneity. Here, we present a novel GRN mutation resulting in frontotemporal lobar degeneration with a distinct clinical phenotype, and we review reports of GRN mutations associated with familial phenotypic heterogeneity. We describe the case of a 74-year-old woman with left frontotemporal lobe atrophy who presented with progressive anarthria and non-fluent aphasia. Her brother had been diagnosed with corticobasal syndrome (CBS) with right-hand limb-kinetic apraxia, aphasia, and a similar pattern of brain atrophy. Laboratory blood examinations did not reveal abnormalities that could have caused cognitive dysfunction. In the cerebrospinal fluid, cell counts and protein concentrations were within normal ranges, and concentrations of tau protein and phosphorylated tau protein were also normal. Since similar familial cases due to mutation of GRN and microtubule-associated protein tau gene (MAPT) were reported, we performed genetic analysis. No pathological mutations of MAPT were identified, but we identified a novel GRN frameshift mutation (c.1118_1119delCCinsG: p.Pro373ArgX37) that resulted in progranulin haploinsufficiency. This is the first report of a GRN mutation associated with familial phenotypic heterogeneity in Japan. Literature review of GRN mutations associated with familial phenotypic heterogeneity revealed no tendency of mutation sites. The role of progranulin has been reported in this and other neurodegenerative diseases, and the analysis of GRN mutations may lead to the discovery of a new therapeutic target.

A case of variant biochemical phenotype of Niemann-Pick disease type C accompanying savant syndrome.

Science.gov (United States)

Hamatani, Mio; Jingami, Naoto; Uemura, Kengo; Nakasone, Naoe; Kinoshita, Hisanori; Yamakado, Hodaka; Ninomiya, Haruaki; Takahashi, Ryosuke

2016-06-22

A 40-year-old man was referred to our hospital because of vertical supranuclear gaze palsy, frequent sudden loss of muscle tonus and ataxia for several years. He had a history of prolonged neonatal jaundice. He was given a diagnosis of autism in his childhood, followed by a diagnosis of schizophrenia in his teenage. He also developed a savant skill of calendar calculating. (123)I-IMP-SPECT showed decreased cerebral blood flow in the left frontotemporal lobe as often seen in savant syndrome. Although genetic analysis of NPC1 and NPC2 revealed no pathogenic mutation, filipin staining of cultured fibroblasts from his biopsied skin revealed a certain amount of intracellular cholesterol storage pattern, indicating a variant biochemical phenotype of Niemann-Pick disease type C (NPC). The diagnosis of adulthood onset NPC is difficult and challenging, especially for neurologists, because the symptoms and signs are not as clear as those in the classical childhood onset NPC and this subtype is not yet widely known. However, the diagnosis can be made by a combination of filipin staining of fibroblast and/or gene analysis. As a disease-specific therapy for NPC has been approved in Japan, the diagnosis of NPC is of significance.

[Transcultural aspects of suicidal behaviour].

Science.gov (United States)

Calliess, I T; Machleidt, W; Ziegenbein, M; Haltenhof, H

2007-11-01

Due to increasing immigration in Germany the German Mental Health Care System today has to deal in a growing number with the assessment of the level of psychic functioning and the capability of self control in patients of different ethnic origin. For clinicians this is a challenge, since suicidal behaviour in terms of its frequency, meaning, motives and manner is very much dependent on the cultural context in which it occurs. Moreover, the general attitude of an individual towards suicide is embedded in the culture of origin of the immigrant. Until now there has been only little systematic research on the influence of culture on suicidal behaviour. In this review the traditions of suicidal behaviour in different cultures in their religious and historical dimensions will be reflected. The historical and cultural roots of suicidal behaviour will be put in context to a categorization of the different variants of suicide, such as institutionalized suicide versus individualized suicide. Psychodynamic aspects of suicidal ideation will be highlighted in cross-cultural perspective with a distinction between a. the wish to die, b. the wish to kill and c. the wish to be killed. It will be shown that there can be differentiated between accepted and non-accepted suicide. With respect to epidemiology there will be discussed the impact of culture on the suicide rates across cultures. The influence of culture on the psychopathology of suicidal behaviour will be summed up systematically. These aspects are of high relevance for the understanding and assessment of suicidal crisis in immigrants, since the suicidal patient even today - although subconsciously - is influenced by the deep rooted traditions of suicidal behaviour in his culture of origin.

Music recognition in frontotemporal lobar degeneration and Alzheimer disease.

Science.gov (United States)

Johnson, Julene K; Chang, Chiung-Chih; Brambati, Simona M; Migliaccio, Raffaella; Gorno-Tempini, Maria Luisa; Miller, Bruce L; Janata, Petr

2011-06-01

To compare music recognition in patients with frontotemporal dementia, semantic dementia, Alzheimer disease, and controls and to evaluate the relationship between music recognition and brain volume. Recognition of familiar music depends on several levels of processing. There are few studies about how patients with dementia recognize familiar music. Subjects were administered tasks that assess pitch and melody discrimination, detection of pitch errors in familiar melodies, and naming of familiar melodies. There were no group differences on pitch and melody discrimination tasks. However, patients with semantic dementia had considerable difficulty naming familiar melodies and also scored the lowest when asked to identify pitch errors in the same melodies. Naming familiar melodies, but not other music tasks, was strongly related to measures of semantic memory. Voxel-based morphometry analysis of brain magnetic resonance imaging showed that difficulty in naming songs was associated with the bilateral temporal lobes and inferior frontal gyrus, whereas difficulty in identifying pitch errors in familiar melodies correlated with primarily the right temporal lobe. The results support a view that the anterior temporal lobes play a role in familiar melody recognition, and that musical functions are affected differentially across forms of dementia.

Music Recognition in Frontotemporal Lobar Degeneration and Alzheimer Disease

Science.gov (United States)

Johnson, Julene K; Chang, Chiung-Chih; Brambati, Simona M; Migliaccio, Raffaella; Gorno-Tempini, Maria Luisa; Miller, Bruce L; Janata, Petr

2013-01-01

Objective To compare music recognition in patients with frontotemporal dementia, semantic dementia, Alzheimer disease, and controls and to evaluate the relationship between music recognition and brain volume. Background Recognition of familiar music depends on several levels of processing. There are few studies about how patients with dementia recognize familiar music. Methods Subjects were administered tasks that assess pitch and melody discrimination, detection of pitch errors in familiar melodies, and naming of familiar melodies. Results There were no group differences on pitch and melody discrimination tasks. However, patients with semantic dementia had considerable difficulty naming familiar melodies and also scored the lowest when asked to identify pitch errors in the same melodies. Naming familiar melodies, but not other music tasks, was strongly related to measures of semantic memory. Voxel-based morphometry analysis of brain MRI showed that difficulty in naming songs was associated with the bilateral temporal lobes and inferior frontal gyrus, whereas difficulty in identifying pitch errors in familiar melodies correlated with primarily the right temporal lobe. Conclusions The results support a view that the anterior temporal lobes play a role in familiar melody recognition, and that musical functions are affected differentially across forms of dementia. PMID:21617528

The Use of Stem Cells to Model Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: From Basic Research to Regenerative Medicine

OpenAIRE

Hedges, Erin C.; Mehler, Vera J.; Nishimura, Agnes L.

2016-01-01

In recent years several genes have linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as a spectrum disease; however little is known about what triggers their onset. With the ability to generate patient specific stem cell lines from somatic cells, it is possible to model disease without the need to transfect cells with exogenous DNA. These pluripotent stem cells have opened new avenues for identification of disease phenotypes and their relation to specific molecular ...

Prion disease resembling frontotemporal dementia and parkinsonism linked to chromosome 17

Directory of Open Access Journals (Sweden)

Nitrini Ricardo

2001-01-01

Full Text Available OBJECTIVE: To compare the clinical features of a familial prion disease with those of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17. BACKGROUND: Prion diseases are not usually considered in the differential diagnosis of FTDP-17, since familial Creutzfeldt-Jakob disease (CJD, the most common inherited prion disease, often manifests as a rapidly progressive dementia. Conversely, FTDP-17 usually has an insidious onset in the fifth decade, with abnormal behavior and parkinsonian features. METHOD: We present the clinical features of 12 patients from a family with CJD associated with a point mutation at codon 183 of the prion protein gene. RESULTS: The mean age at onset was 44.0 ± 3.7; the duration of the symptoms until death ranged from two to nine years. Behavioral disturbances were the predominant presenting symptoms. Nine patients were first seen by psychiatrists. Eight patients manifested parkinsonian signs. CONCLUSION: These clinical features bear a considerable resemblance to those described in FTDP-17.

Validation of the Addenbrooke's Cognitive Examination III in frontotemporal dementia and Alzheimer's disease.

Science.gov (United States)

Hsieh, Sharpley; Schubert, Samantha; Hoon, Christopher; Mioshi, Eneida; Hodges, John R

2013-01-01

The aims of this study were to validate the newly developed version of the Addenbrooke's Cognitive Examination (ACE-III) against standardised neuropsychological tests and its predecessor (ACE-R) in early dementia. A total of 61 patients with dementia (frontotemporal dementia, FTD, n = 33, and Alzheimer's disease, AD, n = 28) and 25 controls were included in the study. ACE-III cognitive domains correlated significantly with standardised neuropsychological tests used in the assessment of attention, language, verbal memory and visuospatial function. The ACE-III also compared very favourably with its predecessor, the ACE-R, with similar levels of sensitivity and specificity. The results of this study provide objective validation of the ACE-III as a screening tool for cognitive deficits in FTD and AD. © 2013 S. Karger AG, Basel.

Presymptomatic generalized brain atrophy in frontotemporal dementia caused by CHMP2B mutation

DEFF Research Database (Denmark)

Rohrer, Jonathan D; Ahsan, R Laila; Isaacs, Adrian M

2009-01-01

mutation carriers with a control group of 7 mutation-negative family members. Volumetric MRI brain scans were performed on all subjects at two time points, and rates of volume change were compared between the two groups. RESULTS: We demonstrate that generalized atrophy occurs presymptomatically in CHMP2B...... gene mutation carriers. CONCLUSIONS: This finding suggests that mutations in CHMP2B have widespread effects throughout the brain, leading to a neuro-anatomical signature distinct from other diseases in the frontotemporal lobar degeneration spectrum........ There are no detailed studies of brain imaging in CHMP2B mutation-associated FTD. This study aimed to investigate whether there were early or presymptomatic changes in this group of patients. METHODS: Subjects comprised 16 members of a Danish family with CHMP2B mutation-associated FTD. Nine subjects were presymptomatic...

Conversion between Addenbrooke's Cognitive Examination III and Mini-Mental State Examination.

Science.gov (United States)

Matías-Guiu, Jordi A; Pytel, Vanesa; Cortés-Martínez, Ana; Valles-Salgado, María; Rognoni, Teresa; Moreno-Ramos, Teresa; Matías-Guiu, Jorge

2017-12-10

We aim to provide a conversion between Addenbrooke's Cognitive Examination III (ACE-III) and Mini-Mental State Examination (MMSE) scores, to predict the MMSE result based on ACE-III, thus avoiding the need for both tests, and improving their comparability. Equipercentile equating method was used to elaborate a conversion table using a group of 400 participants comprising healthy controls and Alzheimer's disease (AD) patients. Then, reliability was assessed in a group of 100 healthy controls and patients with AD, 52 with primary progressive aphasia and 22 with behavioral variant frontotemporal dementia. The conversion table between ACE-III and MMSE denoted a high reliability, with intra-class correlation coefficients of 0.940, 0.922, and 0.902 in the groups of healthy controls and AD, behavioral variant frontotemporal dementia, and primary progressive aphasia, respectively. Our conversion table between ACE-III and MMSE suggests that MMSE may be estimated based on the ACE-III score, which could be useful for clinical and research purposes.

A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies

DEFF Research Database (Denmark)

Lashley, Tammaryn; Rohrer, Jonathan D; Bandopadhyay, Rina

2011-01-01

Neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration are rare diseases characterized by ubiquitin-positive inclusions lacking transactive response DNA-binding protein-43 and tau. Recently, mutations in the fused in sarcoma gene have been shown to cause...... findings, as well as genetic and biochemical data in 14 fused in sarcoma proteinopathy cases. In this cohort, the age of onset was variable but included cases of young-onset disease. Patients with atypical frontotemporal lobar degeneration with ubiquitinated inclusions all presented with behavioural...... familial amyotrophic lateral sclerosis and fused in sarcoma-positive neuronal inclusions have subsequently been demonstrated in neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration with ubiquitinated inclusions. Here we provide clinical, imaging, morphological...

A targeted genotyping approach enhances identification of variants in taste receptor and appetite/reward genes of potential functional importance for obesity-related porcine traits

DEFF Research Database (Denmark)

Cirera, S.; Clop, A.; Jacobsen, M. J.

2018-01-01

Taste receptors (TASRs) and appetite and reward (AR) mechanisms influence eating behaviour, which in turn affects food intake and risk of obesity. In a previous study, we used next generation sequencing to identify potentially functional mutations in TASR and AR genes and found indications...... for genetic associations between identified variants and growth and fat deposition in a subgroup of animals (n = 38) from the UNIK resource pig population. This population was created for studying obesity and obesity-related diseases. In the present study we validated results from our previous study...... by investigating genetic associations between 24 selected single nucleotide variants in TASR and AR gene variants and 35 phenotypes describing obesity and metabolism in the entire UNIK population (n = 564). Fifteen variants showed significant association with specific obesity-related phenotypes after Bonferroni...

Induced pluripotent stem cells (iPSCs) derived from a patient with frontotemporal dementia caused by a R406W mutation in microtubule-associated protein tau (MAPT)

DEFF Research Database (Denmark)

Rasmussen, Mikkel A.; Hjermind, Lena E.; Hasholt, Lis F.

2016-01-01

Skin fibroblasts were obtained from a 59-year-old woman diagnosed with frontotemporal dementia. The disease is caused by a R406W mutation in microtubule-associated protein tau (MAPT). Induced pluripotent stem cells (iPSCs) were established by electroporation with episomal plasmids containing hOCT4...

A Novel MAPT Mutation, G55R, in a Frontotemporal Dementia Patient Leads to Altered Tau Function

Science.gov (United States)

Guzman, Elmer; Barczak, Anna; Chodakowska-Żebrowska, Małgorzata; Barcikowska, Maria; Feinstein, Stuart

2013-01-01

Over two dozen mutations in the gene encoding the microtubule associated protein tau cause a variety of neurodegenerative dementias known as tauopathies, including frontotemporal dementia (FTD), PSP, CBD and Pick's disease. The vast majority of these mutations map to the C-terminal region of tau possessing microtubule assembly and microtubule dynamics regulatory activities as well as the ability to promote pathological tau aggregation. Here, we describe a novel and non-conservative tau mutation (G55R) mapping to an alternatively spliced exon encoding part of the N-terminal region of the protein in a patient with the behavioral variant of FTD. Although less well understood than the C-terminal region of tau, the N-terminal region can influence both MT mediated effects as well as tau aggregation. The mutation changes an uncharged glycine to a basic arginine in the midst of a highly conserved and very acidic region. In vitro, 4-repeat G55R tau nucleates microtubule assembly more effectively than wild-type 4-repeat tau; surprisingly, this effect is tau isoform specific and is not observed in a 3-repeat G55R tau versus 3-repeat wild-type tau comparison. In contrast, the G55R mutation has no effect upon the abilities of tau to regulate MT growing and shortening dynamics or to aggregate. Additionally, the mutation has no effect upon kinesin translocation in a microtubule gliding assay. Together, (i) we have identified a novel tau mutation mapping to a mutation deficient region of the protein in a bvFTD patient, and (ii) the G55R mutation affects the ability of tau to nucleate microtubule assembly in vitro in a 4-repeat tau isoform specific manner. This altered capability could markedly affect in vivo microtubule function and neuronal cell biology. We consider G55R to be a candidate mutation for bvFTD since additional criteria required to establish causality are not yet available for assessment. PMID:24086739

The brain basis of musicophilia: evidence from frontotemporal lobar degeneration

Directory of Open Access Journals (Sweden)

Phillip David Fletcher

2013-06-01

Full Text Available Musicophilia, or abnormal craving for music, is a poorly understood phenomenon that has been associated in particular with focal degeneration of the temporal lobes. Here we addressed the brain basis of musicophilia using voxel-based morphometry (VBM on MR volumetric brain images in a retrospectively ascertained cohort of patients meeting clinical consensus criteria for frontotemporal lobar degeneration: of 37 cases ascertained, 12 had musicophilia and 25 did not exhibit the phenomenon. The syndrome of semantic dementia was relatively over-represented among the musicophilic subgroup. A VBM analysis revealed significantly increased regional grey matter volume in left posterior hippocampus in the musicophilic subgroup relative to the non-musicophilic group (p<0.05 corrected for regional comparisons; at a relaxed significance threshold (P<0.001 uncorrected across the brain volume musicophilia was associated with additional relative sparing of regional grey matter in other temporal lobe and prefrontal areas and atrophy of grey matter in posterior parietal and orbitofrontal areas. The present findings suggest a candidate brain substrate for musicophilia as a signature of distributed network damage that may reflect a shift of hedonic processing toward more abstract (non-social stimuli, with some specificity for particular neurodegenerative pathologies.

Investment behaviour in individual nontransferable quota systems

DEFF Research Database (Denmark)

Jensen, Frank; Andersen, Jesper Levring; Jensen, Carsten Lynge

2012-01-01

This article studies the investment behaviour of the Danish demersal fishery in the North Sea. For the study period, this fishery is regulated by variants of individual nontransferable quotas. It is shown that interest rates and capital stocks are primary determinants of investments. Another......, the variance of the estimated parameters is lower in the disaggregated models. This result arises because vessels in the disaggregated models are more homogeneous. Furthermore, investments in machinery, electronics and vessels are governed by one year lagged variables, while investment in gears is governed...

Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia.

Science.gov (United States)

Holler, Christopher J; Taylor, Georgia; McEachin, Zachary T; Deng, Qiudong; Watkins, William J; Hudson, Kathryn; Easley, Charles A; Hu, William T; Hales, Chadwick M; Rossoll, Wilfried; Bassell, Gary J; Kukar, Thomas

2016-06-24

Progranulin (PGRN) is a secreted growth factor important for neuronal survival and may do so, in part, by regulating lysosome homeostasis. Mutations in the PGRN gene (GRN) are a common cause of frontotemporal lobar degeneration (FTLD) and lead to disease through PGRN haploinsufficiency. Additionally, complete loss of PGRN in humans leads to neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Importantly, Grn-/- mouse models recapitulate pathogenic lysosomal features of NCL. Further, GRN variants that decrease PGRN expression increase the risk of developing Alzheimer's disease (AD) and Parkinson's disease (PD). Together these findings demonstrate that insufficient PGRN predisposes neurons to degeneration. Therefore, compounds that increase PGRN levels are potential therapeutics for multiple neurodegenerative diseases. Here, we performed a cell-based screen of a library of known autophagy-lysosome modulators and identified multiple novel activators of a human GRN promoter reporter including several common mTOR inhibitors and an mTOR-independent activator of autophagy, trehalose. Secondary cellular screens identified trehalose, a natural disaccharide, as the most promising lead compound because it increased endogenous PGRN in all cell lines tested and has multiple reported neuroprotective properties. Trehalose dose-dependently increased GRN mRNA as well as intracellular and secreted PGRN in both mouse and human cell lines and this effect was independent of the transcription factor EB (TFEB). Moreover, trehalose rescued PGRN deficiency in human fibroblasts and neurons derived from induced pluripotent stem cells (iPSCs) generated from GRN mutation carriers. Finally, oral administration of trehalose to Grn haploinsufficient mice significantly increased PGRN expression in the brain. This work reports several novel autophagy-lysosome modulators that enhance PGRN expression and identifies trehalose as a promising therapeutic for raising PGRN levels to treat

Orthorexic eating behaviour as a coping strategy in patients with anorexia nervosa.

Science.gov (United States)

Barthels, Friederike; Meyer, Frank; Huber, Thomas; Pietrowsky, Reinhard

2017-06-01

Orthorexia nervosa is defined as the fixation on health-conscious eating behaviour and has recently been discussed as a new variant of disordered eating. The aim of the present study was to analyse orthorexic eating behaviour in an inpatient treatment sample of female anorexics to investigate the relation between anorexic and orthorexic eating behaviour. Female anorexic patients with low (n = 29) and pronounced (n = 13) orthorexic eating behaviour as well as a matched control group composed of healthy females (n = 30) were compared with regard to several aspects of disordered eating, hypochondriacal traits, food consumption frequency and fulfilment of basic psychological needs in terms of eating. Orthorexic eating behaviour was assessed using the Düsseldorfer Orthorexie Skala. Fulfilment of basic psychological needs with respect to autonomy and competence is higher in anorexic individuals with pronounced orthorexic eating behaviour compared to patients with low orthorexic eating behaviour. Furthermore, patients with pronounced orthorexic eating behaviour state eating healthy food regardless of calorie content more often. No difference was found for hypochondriacal traits and eating disordered symptoms in general. Orthorexic eating behaviour enhances self-perception of eating behaviour as autonomous and competent, indicating that it might serve as a coping strategy in anorexic individuals. Further research is needed to investigate if this tendency in food selection strategy leads to positive effects in the long term.

Product Variant Master as a Means to Handle Variant Design

DEFF Research Database (Denmark)

Hildre, Hans Petter; Mortensen, Niels Henrik; Andreasen, Mogens Myrup

1996-01-01

be implemented in the CAD system I-DEAS. A precondition for high degree of computer support is identification of a product variant master from which new variants can be derived. This class platform defines how a product build up fit certain production methods and rules governing determination of modules...

Coexistência das síndromes de Capgras e Frégoli associadas à redução de volume frontotemporal e hiperintensidades em substância branca cerebral Coexistence of Capgras and Frégoli syndromes associated to frontotemporal volume reduction and cerebral white matter hyperintensities

Directory of Open Access Journals (Sweden)

Gizela Turkiewicz

2009-01-01

Full Text Available CONTEXTO: Transtornos delirantes de identificação são condições nas quais os pacientes identificam de maneira patologicamente equivocada pessoas, lugares, objetos ou eventos. Esses transtornos têm sido categorizados em quatro diferentes subtipos: Capgras, Frégoli, intermetamorfose e síndrome do duplo subjetivo. Tais síndromes podem estar presentes em diferentes transtornos psiquiátricos, como esquizofrenia e transtornos do humor, bem como em diferentes doenças neurológicas, como Alzheimer, Parkinson, lesões cerebrais traumáticas ou vasculares. OBJETIVOS: Descrever e discutir um caso de coexistência entre as síndromes de Capgras e Frégoli em uma paciente com esquizofrenia paranoide e com alterações cerebrais. MÉTODOS: Entrevista psiquiátrica e ressonância magnética de crânio. RESULTADOS: A paciente apresentava hiperintensidades periventriculares em aquisição flair e de substância branca subcortical concentradas principalmente na região frontotemporal direita, bem como perda do volume da região frontotemporal bilateral. DISCUSSÃO: As alterações descritas podem representar substrato orgânico das síndromes dos transtornos delirantes de identificação. Os delírios nas síndromes de Capgras e Frégoli podem ocorrer como resultado de uma desconexão têmporo-límbica-frontal direita, resultando em uma impossibilidade de associar memórias prévias a novas informações, levando consequentemente a alterações na capacidade de reconhecimento. Ademais, uma perda do volume de tais regiões cerebrais também pode desempenhar papel importante no desenvolvimento de tais síndromes delirantes de identificação.BACKGROUND: Delusional misidentification syndromes are conditions in which the patients pathologically misidentify people, places, objects or events. They have been categorized in four subtypes: Capgras, Frégoli, intermetamorphosis and subjective double syndromes. Such syndromes may be present in patients with

TREM2 mutations are rare in a French cohort of patients with frontotemporal dementia.

Science.gov (United States)

Lattante, Serena; Le Ber, Isabelle; Camuzat, Agnès; Dayan, Sarah; Godard, Chloé; Van Bortel, Inge; De Septenville, Anne; Ciura, Sorana; Brice, Alexis; Kabashi, Edor

2013-10-01

Homozygous mutations in TREM2 have been recently identified by exome sequencing in families presenting with frontotemporal dementia (FTD)-like phenotype. No study has evaluated the exact frequency of TREM2 mutations in cohorts of FTD patients so far. We sequenced TREM2 in 175 patients with pure FTD, mostly French, to test whether mutations could be implicated in the pathogenesis of the disease. No disease-causing mutation was identified in 175 individuals from the French cohort of FTD patients. We did not identify the polymorphism p.R47H (rs75932628), strongly associated with an increased risk of developing Alzheimer's disease. We conclude that TREM2 mutations are extremely rare in patients with pure FTD, although further investigation in larger populations is needed. Copyright © 2013 Elsevier Inc. All rights reserved.

The genetics of dementias. Part 1: Molecular basis of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17

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Anna Kowalska

2009-06-01

Full Text Available Frontotemporal dementia (FTD, characterized by neurodegeneration mainly in the frontal and temporal lobes, accounts for ca. 10–15�0of all dementias. In 1892 the Czech-German neuropsychiatrist Arnold Pick reported the first case of FTD in a 71-year-old patient suffering from progressive dementia, memory disturbances, and aphasia associated with frontal and temporal lobe atrophy and the presence of neuronal inclusions. Later the inclusions were named Pick bodies. The neuropathological hallmark of FTD is very differentiated. In contrast to Alzheimer’s disease (AD, there are neither senile plaques nor neurofibrillary tangles in the brains of FTD patients. Frontotemporal dementias are tauopathies, a group of disorders caused by aberrant metabolism of tau protein, a family of proteins associated with microtubules (MAPT: macrotubule-associated tau protein. In the nervous system the protein stabilizes microtubules in neuronal axons and is thus responsible for crucial processes in neuron metabolism, such as signal transduction, plasticity, and intracellular transport. In the human brain, six isoforms are produced from the MAPT gene (chromosome 17 q21.2 by alternative mRNA splicing. The isoforms differ in the number of amino acids in the protein chain, the presence of three (3R tau type or four (4R tau type domains responsible for binding to microtubules, and one or two inserts containing from 29 to 58 amino acids. The isoforms are modified posttranslationally by hyperphosphorylation, glycation, or oxidation, which can change the protein’s properties and disturb its normal function. Altered metabolism of tau protein changes its interactions with tubulin, leading to destabilization of the microtubule structure and initiating the generation of toxic tau aggregates. The first mutations in the MAPT gene responsible for frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17 were found in 1998. So far over 40 mutations in the MAPT

Induced pluripotent stem cells (iPSCs) derived from af pre-symptomatic carrier of a R406W mutation in microtubule-associated protein tau (MAPT) causing frontotemporal dementia

DEFF Research Database (Denmark)

Rasmussen, Mikkel A.; Hjermind, Lena Elisabeth; Hasholt, Lis Frydenreich

2016-01-01

Skin fibroblasts were obtained from a 28-year-old pre-symptomatic woman carrying a R406W mutation in microtubule-associated protein tau (MAPT), known to cause frontotemporal dementia. Induced pluripotent stem cell (iPSCs) were established by electroporation with episomal plasmids containing hOCT4...

Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology

DEFF Research Database (Denmark)

Clayton, Emma L.; Mizielinska, Sarah; Edgar, James R.

2015-01-01

Mutations in the charged multivesicular body protein 2B (CHMP2B) cause frontotemporal dementia (FTD). We report that mice which express FTD-causative mutant CHMP2B at physiological levels develop a novel lysosomal storage pathology characterised by large neuronal autofluorescent aggregates...... in human CHMP2B mutation brain than in neurodegenerative disease or age-matched control brains. These data suggest that lysosomal storage pathology is the major neuronal pathology in FTD caused by CHMP2B mutation. Recent evidence suggests that two other genes associated with FTD, GRN and TMEM106B...... are important for lysosomal function. Our identification of lysosomal storage pathology in FTD caused by CHMP2B mutation now provides evidence that endolysosomal dysfunction is a major degenerative pathway in FTD....

Hairy cell leukemia-variant

International Nuclear Information System (INIS)

Quadri, Mohammad I.; Al-Sheikh, Iman H.

2001-01-01

Hairy cell leukaemia variant is a very rare chronic lymphoproliferative disorder and is closely related to hairy cell leukemia. We hereby describe a case of hairy cell leukaemia variant for the first time in Saudi Arabia. An elderly Saudi man presented with pallor, massive splenomegaly, and moderate hepatomegaly. Hemoglobin was 7.7 g/dl, Platelets were 134 x109/l and white blood count was 140x10 9/l with 97% being abnormal lymphoid cells with cytoplasmic projections. The morphology, cytochemistry, and immunophenotype of the lymphoid cells were classical of hairy cell leukaemia variant. The bone marrow was easily aspirated and findings were consistent with hairy cell leukaemia variant. (author)

Healthy brain connectivity predicts atrophy progression in non-fluent variant of primary progressive aphasia.

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Mandelli, Maria Luisa; Vilaplana, Eduard; Brown, Jesse A; Hubbard, H Isabel; Binney, Richard J; Attygalle, Suneth; Santos-Santos, Miguel A; Miller, Zachary A; Pakvasa, Mikhail; Henry, Maya L; Rosen, Howard J; Henry, Roland G; Rabinovici, Gil D; Miller, Bruce L; Seeley, William W; Gorno-Tempini, Maria Luisa

2016-10-01

Neurodegeneration has been hypothesized to follow predetermined large-scale networks through the trans-synaptic spread of toxic proteins from a syndrome-specific epicentre. To date, no longitudinal neuroimaging study has tested this hypothesis in vivo in frontotemporal dementia spectrum disorders. The aim of this study was to demonstrate that longitudinal progression of atrophy in non-fluent/agrammatic variant primary progressive aphasia spreads over time from a syndrome-specific epicentre to additional regions, based on their connectivity to the epicentre in healthy control subjects. The syndrome-specific epicentre of the non-fluent/agrammatic variant of primary progressive aphasia was derived in a group of 10 mildly affected patients (clinical dementia rating equal to 0) using voxel-based morphometry. From this region, the inferior frontal gyrus (pars opercularis), we derived functional and structural connectivity maps in healthy controls (n = 30) using functional magnetic resonance imaging at rest and diffusion-weighted imaging tractography. Graph theory analysis was applied to derive functional network features. Atrophy progression was calculated using voxel-based morphometry longitudinal analysis on 34 non-fluent/agrammatic patients. Correlation analyses were performed to compare volume changes in patients with connectivity measures of the healthy functional and structural speech/language network. The default mode network was used as a control network. From the epicentre, the healthy functional connectivity network included the left supplementary motor area and the prefrontal, inferior parietal and temporal regions, which were connected through the aslant, superior longitudinal and arcuate fasciculi. Longitudinal grey and white matter changes were found in the left language-related regions and in the right inferior frontal gyrus. Functional connectivity strength in the healthy speech/language network, but not in the default network, correlated with

Induced pluripotent stem cells (iPSCs) derived from a symptomatic carrier of a S305I mutation in the microtubule-associated protein tau (MAPT)-gene causing frontotemporal dementia

DEFF Research Database (Denmark)

Nimsanor, Natakarn; Jørring, Ida; Rasmussen, Mikkel A.

2016-01-01

Frontotemporal dementia with parkinsonism linked to chromosome 17q21.2 (FTDP-17) is an autosomal-dominant neurodegenerative disorder. Mutations in the gene coding the microtubule-associated protein tau (MAPT) can cause FTDP-17 but the underlying mechanisms of the disease are still unknown. Induced...

Structural and Functional Characterization of a New Double Variant Haemoglobin (HbG-Philadelphia/Duarte α(2)β(2)).

Science.gov (United States)

Fais, Antonella; Casu, Mariano; Ruggerone, Paolo; Ceccarelli, Matteo; Porcu, Simona; Era, Benedetta; Anedda, Roberto; Sollaino, Maria Carla; Galanello, Renzo; Corda, Marcella

2011-01-01

WE REPORT THE FIRST CASE OF COSEGREGATION OF TWO HAEMOGLOBINS (HBS): HbG-Philadelphia [α68(E17)Asn → Lys] and HbDuarte [β62(E6)Ala → Pro]. The proband is a young patient heterozygous also for β°-thalassaemia. We detected exclusively two haemoglobin variants: HbDuarte and HbG-Philadelphia/Duarte. Functional study of the new double variant HbG-Philadelphia/Duarte exhibited an increase in oxygen affinity, with a slight decrease of cooperativity and Bohr effect. This functional behaviour is attributed to β62Ala → Pro instead of α68Asn → Lys substitution. Indeed, HbG-Philadelphia isolated in our laboratory from blood cells donor carrier for this variant is not affected by any functional modification, whereas purified Hb Duarte showed functional properties very similar to the double variant. NMR and MD simulation studies confirmed that the presence of Pro instead of Ala at the β62 position produces displacement of the E helix and modifications of the tertiary structure. The substitution α68(E17)Asn → Lys does not cause significant structural and dynamical modifications of the protein. A possible structure-based rational of substitution effects is suggested.

Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic

DEFF Research Database (Denmark)

Ahlborn, Lise B; Dandanell, Mette; Steffensen, Ane Y

2015-01-01

by functional analysis at the protein level. Results from a validated mini-gene splicing assay indicated that nine BRCA1 variants resulted in splicing aberrations leading to truncated transcripts and thus can be considered pathogenic (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5072C>T/p.Thr1691Ile, c......Pathogenic germline mutations in the BRCA1 gene predispose carriers to early onset breast and ovarian cancer. Clinical genetic screening of BRCA1 often reveals variants with uncertain clinical significance, complicating patient and family management. Therefore, functional examinations are urgently...... needed to classify whether these uncertain variants are pathogenic or benign. In this study, we investigated 14 BRCA1 variants by in silico splicing analysis and mini-gene splicing assay. All 14 alterations were missense variants located within the BRCT domain of BRCA1 and had previously been examined...

Genome-wide association study of response to cognitive–behavioural therapy in children with anxiety disorders

Science.gov (United States)

Coleman, Jonathan R. I.; Lester, Kathryn J.; Keers, Robert; Roberts, Susanna; Curtis, Charles; Arendt, Kristian; Bögels, Susan; Cooper, Peter; Creswell, Cathy; Dalgleish, Tim; Hartman, Catharina A.; Heiervang, Einar R.; Hötzel, Katrin; Hudson, Jennifer L.; In-Albon, Tina; Lavallee, Kristen; Lyneham, Heidi J.; Marin, Carla E.; Meiser-Stedman, Richard; Morris, Talia; Nauta, Maaike H.; Rapee, Ronald M.; Schneider, Silvia; Schneider, Sophie C.; Silverman, Wendy K.; Thastum, Mikael; Thirlwall, Kerstin; Waite, Polly; Wergeland, Gro Janne; Breen, Gerome; Eley, Thalia C.

2016-01-01

Background Anxiety disorders are common, and cognitive–behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent. Aims To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980). Method Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up. Results No variants passed a genome-wide significance threshold (P = 5 × 10−8) in either analysis. Four variants met criteria for suggestive significance (P<5 × 10−6) in association with response post-treatment, and three variants in the 6-month follow-up analysis. Conclusions This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts. PMID:26989097

Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia.

Science.gov (United States)

Bertolino, Alessandro; Fazio, Leonardo; Caforio, Grazia; Blasi, Giuseppe; Rampino, Antonio; Romano, Raffaella; Di Giorgio, Annabella; Taurisano, Paolo; Papp, Audrey; Pinsonneault, Julia; Wang, Danxin; Nardini, Marcello; Popolizio, Teresa; Sadee, Wolfgang

2009-02-01

Dopamine D2 receptor signalling is strongly implicated in the aetiology of schizophrenia. We have recently characterized the function of three DRD2 SNPs: rs12364283 in the promoter affecting total D2 mRNA expression; rs2283265 and rs1076560, respectively in introns 5 and 6, shifting mRNA splicing to two functionally distinct isoforms, the short form of D2 (D2S) and the long form (D2L). These two isoforms differentially contribute to dopamine signalling in prefrontal cortex and in striatum. We performed a case-control study to determine association of these variants and of their main haplotypes with several schizophrenia-related phenotypes. We demonstrate that the minor allele in the intronic variants is associated with reduced expression of %D2S of total mRNA in post-mortem prefrontal cortex, and with impaired working memory behavioural performance, both in patients and controls. However, the fMRI results show opposite effects in patients compared with controls: enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients. Moreover, the promoter variant is also associated with working memory activity in prefrontal cortex and striatum of patients, and less robustly with negative symptoms scores. Main haplotypes formed by the three DRD2 variants showed significant associations with these phenotypes consistent with those of the individual SNPs. Our results indicate that the three functional DRD2 variants modulate schizophrenia phenotypes possibly by modifying D2S/D2L ratios in the context of different total D2 density.

Reduced miR-659-3p levels correlate with progranulin increase in hypoxic conditions: implications for frontotemporal dementia.

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Paola ePiscopo

2016-05-01

Full Text Available Progranulin (PGRN is a secreted protein expressed ubiquitously throughout the body, including the brain, where it localizes in neurons and activated microglia. Loss-of-function mutations in the GRN gene are an important cause of familial Frontotemporal Lobar Degeneration (FTLD. PGRN has a neurotrophic and anti-inflammatory activity, and it is neuroprotective in several injury conditions, such as oxygen or glucose deprivation, oxidative injury, and hypoxic stress. Indeed, we have previously demonstrated that hypoxia induces the up-regulation of GRN transcripts. Several studies have shown microRNAs involvement in hypoxia. Moreover, in FTLD patients with a genetic variant of GRN (rs5848, the reinforcement of miR-659-3p binding site has been suggested to be a risk factor. Here, we report that miR-659-3p interacts directly with GRN 3’UTR as shown by luciferase assay in HeLa cells and ELISA and Western Blot analysis in HeLa and Kelly cells. Moreover, we demonstrate the physical binding between GRN mRNA and miR-659-3p employing a miRNA capture-affinity technology in SK-N-BE and Kelly cells. In order to study miRNAs involvement in hypoxia-mediated up-regulation of GRN, we evaluated miR-659-3p levels in SK-N-BE cells after 24h of hypoxic treatment, finding them inversely correlated to GRN transcripts. Furthermore, we analyzed an animal model of asphyxia, finding that GRN mRNA levels increased at post-natal day (pnd 1 and pnd 4 in rat cortices subjected to asphyxia in comparison to control rats and miR-659-3p decreased at pnd 4 just when GRN reached the highest levels. Our results demonstrate the interaction between miR-659-3p and GRN transcript and the involvement of miR-659-3p in GRN up-regulation mediated by hypoxic/ischemic insults.

Network degeneration and dysfunction in presymptomatic C9ORF72 expansion carriers

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Suzee E. Lee

2017-01-01

Full Text Available Hexanucleotide repeat expansions in C9ORF72 are the most common known genetic cause of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis. Previous work has shown that patients with behavioral variant frontotemporal dementia due to C9ORF72 show salience and sensorimotor network disruptions comparable to those seen in sporadic behavioral variant frontotemporal dementia, but it remains unknown how early in the lifespan these and other changes in brain structure and function arise. To gain insights into this question, we compared 15 presymptomatic carriers (age 43.7 ± 10.2 years, nine females to matched healthy controls. We used voxel-based morphometry to assess gray matter, diffusion tensor imaging to interrogate white matter tracts, and task-free functional MRI to probe the salience, sensorimotor, default mode, and medial pulvinar thalamus-seeded networks. We further used a retrospective chart review to ascertain psychiatric histories in carriers and their non-carrier family members. Carriers showed normal cognition and behavior despite gray matter volume and brain connectivity deficits that were apparent as early as the fourth decade of life. Gray matter volume deficits were topographically similar though less severe than those in patients with behavioral variant frontotemporal dementia due to C9ORF72, with major foci in cingulate, insula, thalamus, and striatum. Reduced white matter integrity was found in the corpus callosum, cingulum bundles, corticospinal tracts, uncinate fasciculi and inferior longitudinal fasciculi. Intrinsic connectivity deficits were detected in all four networks but most prominent in salience and medial pulvinar thalamus-seeded networks. Carrier and control groups showed comparable relationships between imaging metrics and age, suggesting that deficits emerge during early adulthood. Carriers and non-carrier family members had comparable lifetime histories of psychiatric symptoms. Taken

Exploring frontotemporal dementia through a case report: An emerging public health concern in disguise

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Nitin Khadilkar

2015-01-01

Full Text Available Dementia has been declared by the World Health Organization as a significant public health problem around the world. Frontotemporal dementia (FTD is a lesser known, yet the second most common type of dementia among older adults under the age of 65 years. Age of onset in FTD is around late fifties, which is not typical for a diagnosis of dementia. In dementia, it is common to see psychiatric symptoms such as hallucinations or delusions as initial presentations. However, FTD may mimic mood disorders. Unfortunately, there are no definitive treatments or ways to prevent FTD. Additionally, challenges such as an earlier age of onset, delay in diagnosis, and difficulties with placement in nursing homes may be encountered while treating FTD patients. Here, we explore FTD through the case of a 61-year-old Caucasian female who initially presented with suicidal ideations.

The Utility of the Addenbrooke's Cognitive Examination Version Three in Early-Onset Dementia.

Science.gov (United States)

Elamin, Marwa; Holloway, Guy; Bak, Thomas H; Pal, Suvankar

2016-01-01

Early-onset dementia (EOD) is defined as functionally relevant cognitive decline with age of onset at less than 65 years. The aim of this study was to investigate the utility of the recently validated third version of the Addenbrooke's Cognitive Examination (ACE-III) in predicting dementia diagnoses in EOD. ACE-III scores of EOD patients were compared to those of healthy controls (HC) and individuals with subjective memory impairment (SMI). The study included 71 EOD patients (Alzheimer's disease, n = 31; primary progressive aphasia, n = 11; behavioural-variant frontotemporal dementia, n = 18, and posterior cortical atrophy, n = 11); there were 28 HC and 15 individuals with SMI. At a cut-off score of 88/100, the ACE-III displayed high sensitivity and specificity in distinguishing EOD from HC (91.5 and 96.4%) and SMI (91.5 and 86.7%). The ACE-III is a reliable cognitive screening tool in EOD. © 2015 S. Karger AG, Basel.

Argentinian/Chilean validation of the Spanish-language version of Addenbrooke's Cognitive Examination III for diagnosing dementia.

Science.gov (United States)

Bruno, D; Slachevsky, A; Fiorentino, N; Rueda, D S; Bruno, G; Tagle, A R; Olavarria, L; Flores, P; Lillo, P; Roca, M; Torralva, T

2017-08-30

The Addenbrooke's Cognitive Examination III (ACE-III), an adaptation of the ACE cognitive screening test, has been demonstrated to have high sensitivity and specificity in detecting cognitive impairment in patients with dementia and other neurological and psychiatric disorders. Although the Spanish-language version of the ACE-III has already been validated in Spain, it is yet to be validated in Latin America. The aim of this study was to validate the ACE-III test in an Argentinean and Chilean population. ACE-III was administered to 70 patients with Alzheimer disease, 31 patients with behavioural variant frontotemporal dementia, and a control group of 139 healthy volunteers. Participants were recruited at centres in both countries. The Spanish-language version of ACE-III was found to have good internal consistency (Cronbach's alpha=0.87). We found significant differences in total ACE-III scores between patients with Alzheimer disease and controls (pcognitive dysfunction in patients with dementia. Copyright © 2017. Publicado por Elsevier España, S.L.U.

Frontotemporal Dysfunction in Amyotrophic Lateral Sclerosis: A Discriminant Function Analysis.

Science.gov (United States)

Nidos, Andreas; Kasselimis, Dimitrios S; Simos, Panagiotis G; Rentzos, Michael; Alexakis, Theodoros; Zalonis, Ioannis; Zouvelou, Vassiliki; Potagas, Constantin; Evdokimidis, Ioannis; Woolley, Susan C

2016-01-01

There is growing evidence for extramotor dysfunction (EMd) in amyotrophic lateral sclerosis (ALS), with a reported prevalence of up to 52%. In the present study, we explore the clinical utility of a brief neuropsychological battery for the investigation of cognitive, behavioral, and language deficits in patients with ALS. Thirty-four consecutive ALS patients aged 44-89 years were tested with a brief neuropsychological battery, including executive, behavioral, and language measures. Patients were initially classified as EMd or non-EMd based on their scores on the frontal assessment battery (FAB). Between-group comparisons revealed significant differences in all measures (p < 0.01). Discriminant analysis resulted in a single canonical function, with all tests serving as significant predictors. This function agreed with the FAB in 13 of 17 patients screened as EMd and identified extramotor deficits in 2 additional patients. Overall sensitivity and specificity estimates against FAB were 88.2%. We stress the importance of discriminant function analysis in clinical neuropsychological assessment and argue that the proposed neuropsychological battery may be of clinical value, especially when the option of extensive and comprehensive neuropsychological testing is limited. The psychometric validity of an ALS-frontotemporal dementia diagnosis using neuropsychological tests is also discussed. © 2015 S. Karger AG, Basel.

A rabies virus vampire bat variant shows increased neuroinvasiveness in mice when compared to a carnivore variant.

Science.gov (United States)

Mesquita, Leonardo Pereira; Gamon, Thais Helena Martins; Cuevas, Silvia Elena Campusano; Asano, Karen Miyuki; Fahl, Willian de Oliveira; Iamamoto, Keila; Scheffer, Karin Correa; Achkar, Samira Maria; Zanatto, Dennis Albert; Mori, Cláudia Madalena Cabrera; Maiorka, Paulo César; Mori, Enio

2017-12-01

Rabies is one of the most important zoonotic diseases and is caused by several rabies virus (RABV) variants. These variants can exhibit differences in neurovirulence, and few studies have attempted to evaluate the neuroinvasiveness of variants derived from vampire bats and wild carnivores. The aim of this study was to evaluate the neuropathogenesis of infection with two Brazilian RABV street variants (variant 3 and crab-eating fox) in mice. BALB/c mice were inoculated with RABV through the footpad, with the 50% mouse lethal dose (LD 50 ) determined by intracranial inoculation. The morbidity of rabies in mice infected with variant 3 and the crab-eating fox strain was 100% and 50%, respectively, with an incubation period of 7 and 6 days post-inoculation (dpi), respectively. The clinical disease in mice was similar with both strains, and it was characterized initially by weight loss, ruffled fur, hunched posture, and hind limb paralysis progressing to quadriplegia and recumbency at 9 to 12 dpi. Histological lesions within the central nervous system (CNS) characterized by nonsuppurative encephalomyelitis with neuronal degeneration and necrosis were observed in mice infected with variant 3 and those infected with the crab-eating fox variant. However, lesions and the presence of RABV antigen, were more widespread within the CNS of variant-3-infected mice, whereas in crab-eating fox-variant-infected mice, RABV antigens were more restricted to caudal areas of the CNS, such as the spinal cord and brainstem. In conclusion, the results shown here demonstrate that the RABV vampire bat strain (variant 3) has a higher potential for neuroinvasiveness than the carnivore variant.

Homozygous TREM2 mutation in a family with atypical frontotemporal dementia.

Science.gov (United States)

Le Ber, Isabelle; De Septenville, Anne; Guerreiro, Rita; Bras, José; Camuzat, Agnès; Caroppo, Paola; Lattante, Serena; Couarch, Philippe; Kabashi, Edor; Bouya-Ahmed, Kawtar; Dubois, Bruno; Brice, Alexis

2014-10-01

TREM2 mutations were first identified in Nasu-Hakola disease, a rare autosomal recessive disease characterized by recurrent fractures because of bone cysts and presenile dementia. Recently, homozygous and compound heterozygous TREM2 mutations were identified in rare families with frontotemporal lobar degeneration (FTLD) but without bone involvement. We identified a p.Thr66Met heterozygous mutation in a new consanguineous Italian family. Two sibs had early onset autosomal recessive FTLD without severe bone disorders. Atypical signs were present in this family: early parietal and hippocampus involvement, parkinsonism, epilepsy, and corpus callosum thickness on brain magnetic resonance imaging. This study further demonstrates the implication of TREM2 mutations in FTLD phenotypes. It illustrates the variability of bone phenotype and underlines the frequency of atypical signs in TREM2 carriers. This and previous studies evidence that TREM2 mutation screening should be limited to autosomal recessive FTLD with atypical phenotypes characterized by: (1) a very young age at onset (20-50 years); (2) early parietal and hippocampal deficits; (3) the presence of seizures and parkinsonism; (4) suggestive extensive white matter lesions and corpus callosum thickness on brain magnetic resonance imaging. Copyright © 2014 Elsevier Inc. All rights reserved.

Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia

DEFF Research Database (Denmark)

Rostgaard, Nina; Waldemar, Gunhild; Nielsen, Jørgen Erik

2015-01-01

As dementia is a fast-growing health care problem, it is becoming an increasingly urgent need to provide an early diagnosis in order to offer patients the best medical treatment and care. Validated biomarkers which reflect the pathology and disease progression are essential for diagnosis and are ......As dementia is a fast-growing health care problem, it is becoming an increasingly urgent need to provide an early diagnosis in order to offer patients the best medical treatment and care. Validated biomarkers which reflect the pathology and disease progression are essential for diagnosis...... and are important when developing new therapies. Today, the core protein biomarkers amyloid-β42, total tau and phosphorylated tau in the cerebrospinal fluid (CSF) are used to diagnose Alzheimer's disease (AD), because these biomarkers have shown to reflect the underlying amyloid and tau pathology. However......, the biomarkers have proved insufficient predictors of dementias with a different pathology, e.g. frontotemporal dementia (FTD); furthermore, the biomarkers are not useful for early AD diagnosis. Familial dementias with a known disease-causing mutation can be extremely valuable to study; yet the biomarker...

De novo FBXO11 mutations are associated with intellectual disability and behavioural anomalies.

Science.gov (United States)

Fritzen, Daniel; Kuechler, Alma; Grimmel, Mona; Becker, Jessica; Peters, Sophia; Sturm, Marc; Hundertmark, Hela; Schmidt, Axel; Kreiß, Martina; Strom, Tim M; Wieczorek, Dagmar; Haack, Tobias B; Beck-Wödl, Stefanie; Cremer, Kirsten; Engels, Hartmut

2018-05-01

Intellectual disability (ID) has an estimated prevalence of 1.5-2%. In most affected individuals, its genetic basis remains unclear. Whole exome sequencing (WES) studies have identified a multitude of novel causative gene defects and have shown that a large proportion of sporadic ID cases results from de novo mutations. Here, we present two unrelated individuals with similar clinical features and deleterious de novo variants in FBXO11 detected by WES. Individual 1, a 14-year-old boy, has mild ID as well as mild microcephaly, corrected cleft lip and alveolus, hyperkinetic disorder, mild brain atrophy and minor facial dysmorphism. WES detected a heterozygous de novo 1 bp insertion in the splice donor site of exon 3. Individual 2, a 3-year-old boy, showed ID and pre- and postnatal growth retardation, postnatal mild microcephaly, hyperkinetic and restless behaviour, as well as mild dysmorphism. WES detected a heterozygous de novo frameshift mutation. While ten individuals with ID and de novo variants in FBXO11 have been reported as part of larger studies, only one of the reports has some additional clinical data. Interestingly, the latter individual carries the identical mutation as our individual 2 and also displays ID, intrauterine growth retardation, microcephaly, behavioural anomalies, and dysmorphisms. Thus, we confirm deleterious de novo mutations in FBXO11 as a cause of ID and start the delineation of the associated clinical picture which may also comprise postnatal microcephaly or borderline small head size and behavioural anomalies.

Variants of cellobiohydrolases

Energy Technology Data Exchange (ETDEWEB)

Bott, Richard R.; Foukaraki, Maria; Hommes, Ronaldus Wilhelmus; Kaper, Thijs; Kelemen, Bradley R.; Kralj, Slavko; Nikolaev, Igor; Sandgren, Mats; Van Lieshout, Johannes Franciscus Thomas; Van Stigt Thans, Sander

2018-04-10

Disclosed are a number of homologs and variants of Hypocrea jecorina Ce17A (formerly Trichoderma reesei cellobiohydrolase I or CBH1), nucleic acids encoding the same and methods for producing the same. The homologs and variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted and/or deleted.

Effectiveness of Electroconvulsive Therapy for Depression and Cotard’s Syndrome in a Patient with Frontotemporal Lobe Dementia

Directory of Open Access Journals (Sweden)

Toshiyuki Kobayashi

2012-01-01

Full Text Available In the field of psychogeriatrics, the differential diagnosis of depression and dementia, as well as the treatment of depression and comorbid dementia, is an important issue. In this paper, the authors present the case of a 72-year-old woman with Cotard’s syndrome and frontotemporal dementia (FTD who was admitted to a psychiatric hospital with delusions of negation accompanied by depressive symptoms. Pharmacotherapy over a 2-year hospitalization was unsuccessful, and she was subsequently transferred to our university hospital. A total of 18 sessions of electroconvulsive therapy released her from psychomotor inhibition, appetite loss, and Cotard’s delusions. The indication for electroconvulsive therapy in patients with dementia is discussed.

Perception of emotion in frontotemporal dementia and Alzheimer disease.

Science.gov (United States)

Lavenu, I; Pasquier, F; Lebert, F; Petit, H; Van der Linden, M

1999-01-01

Frontotemporal dementia (FTD) is the second cause of degenerative dementia. Behavioral changes occur before the cognitive decline and remain the major feature. A poor perception of emotion could account for some behavioral symptoms. The aim of this study was to assess the perception of emotion in patients with FTD and to compare it with that of patients with Alzheimer disease (AD). Fifty subjects performed the tests: 20 patients with probable AD, 18 patients with FTD, and 12 matched controls. The two patient groups did not differ in age, sex, severity of dementia, duration of the disease, and language tests. Subjects had to recognize and point out the name of one of seven basic emotions (anger, disgust, happiness, fear, sadness, surprise, and contempt) on a set of 28 faces presented on slides. The three groups were equally able to distinguish a face displaying affect from one not displaying affect. Naming of emotion was worse in patients with FTD than in patients with AD (correct answers 46% vs. 62%; p = 0.0006) who did not differ significantly from controls (72%). Anger, sadness, and disgust were less recognized in FTD than in AD patients who did not differ from controls, whereas fear and contempt were poorly recognized in both groups of patients compared with controls. These findings argue for different neural substrates underlying the recognition of various basic emotions. Behavioral disorders in FTD may be partly due to an impaired interpretation of the emotional environment.

Neuropsychological differences between frontotemporal lobar degeneration and Alzheimer's disease

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Claudia Sellitto Porto

Full Text Available Abstract Memory impairment is the main clinical feature in Alzheimer disease (AD, whereas in frontotemporal lobar degeneration (FTLD behavioral and language disorders predominate. Objectives: To investigate possible differences between the neuropsychological performance in FTLD and AD. Methods: Fifty-six AD patients (mean age=72.98±7.43; mean schooling=9.62±4.68; 35 women and 21 men, 17 FTLD patients (mean age=67.64±7.93; mean schooling=12.12±4.77; 9 women and 8 men, and 60 controls (mean age=68.90±7.48; mean schooling=10.72±4.74; 42 women and 18 men were submitted to a Dementia Rating Scale (DRS and a comprehensive neuropsychological evaluation composed of tasks assessing attention, visuoperceptual abilities, constructive abilities, executive functions, memory and language. Results: DRS total score and subscales were not able to differentiate FTLD from AD patients. However, FTLD and AD patients showed statistically significant differences in performance in tests of verbal (Logical Memory, Rey Auditory Verbal Learning Test and visual (Visual Reproduction, recall of the Rey Complex Figure episodic memory, verbal immediate memory (Logical Memory, attention with interference (Trail Making Test - Part B, verbal fluency (semantic and phonemic and concept formation (WCST. Conclusion: Contrary to expectations, only a few tasks executive function tasks (Trail Making Test - Part B, F.A.S. and WCST and two memory tests (verbal and visual episodic memory tests were able to differentiate between FTLD and AD patients.

Transcranial magnetic stimulation distinguishes Alzheimer disease from frontotemporal dementia.

Science.gov (United States)

Benussi, Alberto; Di Lorenzo, Francesco; Dell'Era, Valentina; Cosseddu, Maura; Alberici, Antonella; Caratozzolo, Salvatore; Cotelli, Maria Sofia; Micheli, Anna; Rozzini, Luca; Depari, Alessandro; Flammini, Alessandra; Ponzo, Viviana; Martorana, Alessandro; Caltagirone, Carlo; Padovani, Alessandro; Koch, Giacomo; Borroni, Barbara

2017-08-15

To determine whether a transcranial magnetic stimulation (TMS) multiparadigm approach can be used to distinguish Alzheimer disease (AD) from frontotemporal dementia (FTD). Paired-pulse TMS was used to investigate short-interval intracortical inhibition (SICI) and facilitation (ICF), long-interval intracortical inhibition, and short-latency afferent inhibition (SAI) to measure the activity of different intracortical circuits in patients with AD, patients with FTD, and healthy controls (HC). The primary outcome measures were sensitivity and specificity of TMS measures, derived from receiver operating curve analysis. A total of 175 participants met the inclusion criteria. We diagnosed 79 patients with AD, 64 patients with FTD, and 32 HC. We found that while patients with AD are characterized by a specific impairment of SAI, FTD shows a remarkable dysfunction of SICI-ICF intracortical circuits. With the use of the best indexes, TMS differentiated FTD from AD with a sensitivity of 91.8% and specificity of 88.6%, AD from HC with a sensitivity of 84.8% and specificity of 90.6%, and FTD from HC with a sensitivity of 90.2% and specificity of 78.1%. These results were confirmed in patients with mild disease. TMS is a noninvasive procedure that reliably distinguishes AD from FTD and HC and, if these findings are replicated in larger studies, could represent a useful additional diagnostic tool for clinical practice. This study provides Class III evidence that TMS measures can distinguish patients with AD from those with FTD. © 2017 American Academy of Neurology.

FTO gene variant modulates the neural correlates of visual food perception.

Science.gov (United States)

Kühn, Anne B; Feis, Delia-Lisa; Schilbach, Leonhard; Kracht, Lutz; Hess, Martin E; Mauer, Jan; Brüning, Jens C; Tittgemeyer, Marc

2016-03-01

Variations in the fat mass and obesity associated (FTO) gene are currently the strongest known genetic factor predisposing humans to non-monogenic obesity. Recent experiments have linked these variants to a broad spectrum of behavioural alterations, including food choice and substance abuse. Yet, the underlying neurobiological mechanisms by which these genetic variations influence body weight remain elusive. Here, we explore the brain structural substrate of the obesity-predisposing rs9939609 T/A variant of the FTO gene in non-obese subjects by means of multivariate classification and use fMRI to investigate genotype-specific differences in neural food-cue reactivity by analysing correlates of a visual food perception task. Our findings demonstrate that MRI-derived measures of morphology along middle and posterior fusiform gyrus (FFG) are highly predictive for FTO at-risk allele carriers, who also show enhanced neural responses elicited by food cues in the same posterior FFG area. In brief, these findings provide first-time evidence for FTO-specific differences in both brain structure and function already in non-obese individuals, thereby contributing to a mechanistic understanding of why FTO is a predisposing factor for obesity. Copyright © 2015 Elsevier Inc. All rights reserved.

Automatic MRI Quantifying Methods in Behavioral-Variant Frontotemporal Dementia Diagnosis

DEFF Research Database (Denmark)

Cajanus, Antti; Hall, Anette; Koikkalainen, Juha

2018-01-01

genetic status in the differentiation sensitivity. Methods: The MRI scans of 50 patients with bvFTD (17 C9ORF72 expansion carriers) were analyzed using 6 quantification methods as follows: voxel-based morphometry (VBM), tensor-based morphometry, volumetry (VOL), manifold learning, grading, and white...

Sympatric song variant in mountain chickadees Poecile gambeli does not reduce aggression from black-capped chickadees Poecile atricapillus

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Snell Cara L.

2016-06-01

Full Text Available When habitats overlap and species compete for resources, negative interactions frequently occur. Character displacement in the form of behavioural, social or morphological divergences between closely related species can act to reduce negative interactions and often arise in regions of geographic overlap. Mountain chickadees Poecile gambeli have an altered song structure in regions of geographic overlap with the behaviourally dominant black-capped chickadee Poecile atricapillus. Similar to European and Asian tits, altered song in mountain chickadees may decrease aggression from black-capped chickadees. To test this hypothesis, we conducted a playback study in Prince George, BC, Canada, to examine how black-capped chickadees responded to the songs of mountain chickadees recorded in regions where the two species were either sympatric or allopatric. We used principal component analysis (PCA to collapse behavioural response variables into a single ‘approach’ variable and a single ‘vocalisation’ variable. We then used mixed-model analysis to determine whether there was a difference in approach or vocalisation response to the two types of mountain chickadee songs (allopatric songs and variant sympatric songs. Black-capped chickadees responded with equal intensity to both types of mountain chickadee songs, suggesting that the variant mountain chickadee songs from regions of sympatry with black-capped chickadees do not reduce heterospecific aggression. To our knowledge, this is the only instance of a character shift unassociated with reduced aggression in the family Paridae and raises interesting questions about the selective pressures leading to the evolution of this song divergence.

Variants of Moreau's sweeping process

International Nuclear Information System (INIS)

Siddiqi, A.H.; Manchanda, P.

2001-07-01

In this paper we prove the existence and uniqueness of two variants of Moreau's sweeping process -u'(t) is an element of Nc (t) (u(t)), where in one variant we replace u(t) by u'(t) in the right-hand side of the inclusion and in the second variant u'(t) and u(t) are respectively replaced by u''(t) and u'(t). (author)

Characterization of form variants of Xenorhabdus luminescens.

Science.gov (United States)

Gerritsen, L J; de Raay, G; Smits, P H

1992-01-01

From Xenorhabdus luminescens XE-87.3 four variants were isolated. One, which produced a red pigment and antibiotics, was luminescent, and could take up dye from culture media, was considered the primary form (XE-red). A pink-pigmented variant (XE-pink) differed from the primary form only in pigmentation and uptake of dye. Of the two other variants, one produced a yellow pigment and fewer antibiotics (XE-yellow), while the other did not produce a pigment or antibiotics (XE-white). Both were less luminescent, did not take up dye, and had small cell and colony sizes. These two variants were very unstable and shifted to the primary form after 3 to 5 days. It was not possible to separate the primary form and the white variant completely; subcultures of one colony always contained a few colonies of the other variant. The white variant was also found in several other X. luminescens strains. DNA fingerprints showed that all four variants are genetically identical and are therefore derivatives of the same parent. Protein patterns revealed a few differences among the four variants. None of the variants could be considered the secondary form. The pathogenicity of the variants decreased in the following order: XE-red, XE-pink, XE-yellow, and XE-white. The mechanism and function of this variability are discussed. Images PMID:1622273

Extended behavioural device modelling and circuit simulation with Qucs-S

Science.gov (United States)

Brinson, M. E.; Kuznetsov, V.

2018-03-01

Current trends in circuit simulation suggest a growing interest in open source software that allows access to more than one simulation engine while simultaneously supporting schematic drawing tools, behavioural Verilog-A and XSPICE component modelling, and output data post-processing. This article introduces a number of new features recently implemented in the 'Quite universal circuit simulator - SPICE variant' (Qucs-S), including structure and fundamental schematic capture algorithms, at the same time highlighting their use in behavioural semiconductor device modelling. Particular importance is placed on the interaction between Qucs-S schematics, equation-defined devices, SPICE B behavioural sources and hardware description language (HDL) scripts. The multi-simulator version of Qucs is a freely available tool that offers extended modelling and simulation features compared to those provided by legacy circuit simulators. The performance of a number of Qucs-S modelling extensions are demonstrated with a GaN HEMT compact device model and data obtained from tests using the Qucs-S/Ngspice/Xyce ©/SPICE OPUS multi-engine circuit simulator.

Urinary incontinence and its functional anatomy in frontotemporal lobar degenerations

International Nuclear Information System (INIS)

Perneczky, Robert; Diehl-Schmid, Janine; Foerstl, Hans; Kurz, Alexander; Drzezga, Alexander; May, Florian

2008-01-01

The frontal lobes play a crucial role in micturition control. However, no reports exist on the functional role of distinct frontal brain regions in urinary incontinence (UIC) in patients with a neurodegenerative damage of the frontal lobe. The aim of the present study was therefore to explore if functional brain lesions were associated with UIC in patients suffering from frontotemporal lobar degenerations (FTLD). Forty-four patients, including eight incontinent subjects, underwent cranial positron emission tomography scanning with 18 F-fluoro-2-deoxy-glucose ( 18 F-FDG PET) to assess the relative metabolic rate of glucose (rCMRglc). Group comparisons of rCMRglc were conducted in SPM2 to identify brain regions where the group of incontinent patients (FTLD+UIC) had significant alterations compared with the group without UIC (FTLD-UIC). At the stringent statistical threshold of p < 0.05, corrected for multiple comparisons according to the family-wise error rate, the statistical analysis revealed two significant right-hemispheric hypometabolic clusters located in the premotor/anterior cingulate cortex and the putamen/claustrum/insula. No hypermetabolic regions were found. The present study is the first to provide evidence for brain functional alterations involved in the occurrence of UIC in FTLD. These results provide an important piece of evidence to the understanding of a particularly distressing autonomic nervous system symptom of dementia. (orig.)

Urinary incontinence and its functional anatomy in frontotemporal lobar degenerations

Energy Technology Data Exchange (ETDEWEB)

Perneczky, Robert [Technical University Munich Medical School, Department of Psychiatry and Psychotherapy, Munich (Germany); Technische Universitaet Muenchen, Klinik und Poliklinik fuer Psychiatrie und Psychotherapie, Muenchen (Germany); Diehl-Schmid, Janine; Foerstl, Hans; Kurz, Alexander [Technical University Munich Medical School, Department of Psychiatry and Psychotherapy, Munich (Germany); Drzezga, Alexander [Technical University Munich Medical School, Department of Nuclear Medicine, Munich (Germany); May, Florian [Technical University Munich Medical School, Department of Urology, Munich (Germany)

2008-03-15

The frontal lobes play a crucial role in micturition control. However, no reports exist on the functional role of distinct frontal brain regions in urinary incontinence (UIC) in patients with a neurodegenerative damage of the frontal lobe. The aim of the present study was therefore to explore if functional brain lesions were associated with UIC in patients suffering from frontotemporal lobar degenerations (FTLD). Forty-four patients, including eight incontinent subjects, underwent cranial positron emission tomography scanning with {sup 18}F-fluoro-2-deoxy-glucose ({sup 18}F-FDG PET) to assess the relative metabolic rate of glucose (rCMRglc). Group comparisons of rCMRglc were conducted in SPM2 to identify brain regions where the group of incontinent patients (FTLD+UIC) had significant alterations compared with the group without UIC (FTLD-UIC). At the stringent statistical threshold of p < 0.05, corrected for multiple comparisons according to the family-wise error rate, the statistical analysis revealed two significant right-hemispheric hypometabolic clusters located in the premotor/anterior cingulate cortex and the putamen/claustrum/insula. No hypermetabolic regions were found. The present study is the first to provide evidence for brain functional alterations involved in the occurrence of UIC in FTLD. These results provide an important piece of evidence to the understanding of a particularly distressing autonomic nervous system symptom of dementia. (orig.)

Random Plant Viral Variants Attain Temporal Advantages During Systemic Infections and in Turn Resist other Variants of the Same Virus.

Science.gov (United States)

Zhang, Xiao-Feng; Guo, Jiangbo; Zhang, Xiuchun; Meulia, Tea; Paul, Pierce; Madden, Laurence V; Li, Dawei; Qu, Feng

2015-10-20

Infection of plants with viruses containing multiple variants frequently leads to dominance by a few random variants in the systemically infected leaves (SLs), for which a plausible explanation is lacking. We show here that SL dominance by a given viral variant is adequately explained by its fortuitous lead in systemic spread, coupled with its resistance to superinfection by other variants. We analyzed the fate of a multi-variant turnip crinkle virus (TCV) population in Arabidopsis and N. benthamiana plants. Both wild-type and RNA silencing-defective plants displayed a similar pattern of random dominance by a few variant genotypes, thus discounting a prominent role for RNA silencing. When introduced to plants sequentially as two subpopulations, a twelve-hour head-start was sufficient for the first set to dominate. Finally, SLs of TCV-infected plants became highly resistant to secondary invasions of another TCV variant. We propose that random distribution of variant foci on inoculated leaves allows different variants to lead systemic movement in different plants. The leading variants then colonize large areas of SLs, and resist the superinfection of lagging variants in the same areas. In conclusion, superinfection resistance is the primary driver of random enrichment of viral variants in systemically infected plants.

Joint assessment of white matter integrity, cortical and subcortical atrophy to distinguish AD from behavioral variant FTD: A two-center study

Directory of Open Access Journals (Sweden)

Christiane Möller

2015-01-01

Full Text Available We investigated the ability of cortical and subcortical gray matter (GM atrophy in combination with white matter (WM integrity to distinguish behavioral variant frontotemporal dementia (bvFTD from Alzheimer's disease (AD and from controls using voxel-based morphometry, subcortical structure segmentation, and tract-based spatial statistics. To determine which combination of MR markers differentiated the three groups with the highest accuracy, we conducted discriminant function analyses. Adjusted for age, sex and center, both types of dementia had more GM atrophy, lower fractional anisotropy (FA and higher mean (MD, axial (L1 and radial diffusivity (L23 values than controls. BvFTD patients had more GM atrophy in orbitofrontal and inferior frontal areas than AD patients. In addition, caudate nucleus and nucleus accumbens were smaller in bvFTD than in AD. FA values were lower; MD, L1 and L23 values were higher, especially in frontal areas of the brain for bvFTD compared to AD patients. The combination of cortical GM, hippocampal volume and WM integrity measurements, classified 97–100% of controls, 81–100% of AD and 67–75% of bvFTD patients correctly. Our results suggest that WM integrity measures add complementary information to measures of GM atrophy, thereby improving the classification between AD and bvFTD.

Semantic prioritization of novel causative genomic variants

KAUST Repository

Boudellioua, Imene

2017-04-17

Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

Semantic prioritization of novel causative genomic variants

KAUST Repository

Boudellioua, Imene; Mohamad Razali, Rozaimi; Kulmanov, Maxat; Hashish, Yasmeen; Bajic, Vladimir B.; Goncalves-Serra, Eva; Schoenmakers, Nadia; Gkoutos, Georgios V.; Schofield, Paul N.; Hoehndorf, Robert

2017-01-01

Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

Longitudinal characterization of two siblings with frontotemporal dementia and parkinsonism linked to chromosome 17 associated with the S305N tau mutation.

Science.gov (United States)

Boeve, Bradley F; Tremont-Lukats, Ivo W; Waclawik, Andrew J; Murrell, Jill R; Hermann, Bruce; Jack, Clifford R; Shiung, Maria M; Smith, Glenn E; Nair, Anil R; Lindor, Noralane; Koppikar, Vinaya; Ghetti, Bernardino

2005-04-01

The background to this study began with the reporting of two Japanese kindreds with the S305N tau mutation. Although the pathological findings in the autopsied cases were well characterized, only limited ante-mortem data were presented. In this study, longitudinal characterization was carried out in two siblings of European ancestry found to have frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) through comprehensive neurobehavioural examinations and other scales at approximate 6-month intervals. Scales included the Mini-Mental State Examination, Short Test of Mental Status, modified motor subtest of the Unified Parkinson's Disease Rating Scale, detailed neuropsychological testing, and the Neuropsychiatric Inventory. Changes in whole-brain volume and ventricular volume were measured from serial MRI studies. All members of the kindred underwent molecular genetic analyses to elucidate the mechanism of inheritance. The missense mutation in tau, S305N, was detected in the proband (onset age 30), who has undergone serial evaluations for almost 4 years. Her older sister (onset age 36) was subsequently found to have the same mutation, and has undergone serial evaluations for 2 years. This mutation is absent in both parents and the only other sibling, and non-paternity was excluded by additional analyses. The siblings have exhibited cognitive and behavioural features typical of FTDP-17, which have proved challenging to manage despite aggressive pharmacological and behavioural therapies. The proband's sister has demonstrated an atypical profile of impairment on neuropsychological testing. Both siblings have developed striking atrophy of the anterior part of temporal lobes and moderate atrophy of the dorsolateral and orbitofrontal cortical regions, which in both cases is relatively symmetrical. The annualized changes in whole-brain volume and ventricular volume, respectively, were -35.2 ml/year (3.23% decrease per year) and +20.75 ml/year (16

Cognitive control during audiovisual working memory engages frontotemporal theta-band interactions.

Science.gov (United States)

Daume, Jonathan; Graetz, Sebastian; Gruber, Thomas; Engel, Andreas K; Friese, Uwe

2017-10-03

Working memory (WM) maintenance of sensory information has been associated with enhanced cross-frequency coupling between the phase of low frequencies and the amplitude of high frequencies, particularly in medial temporal lobe (MTL) regions. It has been suggested that these WM maintenance processes are controlled by areas of the prefrontal cortex (PFC) via frontotemporal phase synchronisation in low frequency bands. Here, we investigated whether enhanced cognitive control during audiovisual WM as compared to visual WM alone is associated with increased low-frequency phase synchronisation between sensory areas maintaining WM content and areas from PFC. Using magnetoencephalography, we recorded neural oscillatory activity from healthy human participants engaged in an audiovisual delayed-match-to-sample task. We observed that regions from MTL, which showed enhanced theta-beta phase-amplitude coupling (PAC) during the WM delay window, exhibited stronger phase synchronisation within the theta-band (4-7 Hz) to areas from lateral PFC during audiovisual WM as compared to visual WM alone. Moreover, MTL areas also showed enhanced phase synchronisation to temporooccipital areas in the beta-band (20-32 Hz). Our results provide further evidence that a combination of long-range phase synchronisation and local PAC might constitute a mechanism for neuronal communication between distant brain regions and across frequencies during WM maintenance.

Empirical study of self-configuring genetic programming algorithm performance and behaviour

International Nuclear Information System (INIS)

KrasnoyarskiyRabochiy prospect, Krasnoyarsk, 660014 (Russian Federation))" data-affiliation=" (Siberian State Aerospace University named after Academician M.F. Reshetnev 31 KrasnoyarskiyRabochiy prospect, Krasnoyarsk, 660014 (Russian Federation))" >Semenkin, E; KrasnoyarskiyRabochiy prospect, Krasnoyarsk, 660014 (Russian Federation))" data-affiliation=" (Siberian State Aerospace University named after Academician M.F. Reshetnev 31 KrasnoyarskiyRabochiy prospect, Krasnoyarsk, 660014 (Russian Federation))" >Semenkina, M

2015-01-01

The behaviour of the self-configuring genetic programming algorithm with a modified uniform crossover operator that implements a selective pressure on the recombination stage, is studied over symbolic programming problems. The operator's probabilistic rates interplay is studied and the role of operator variants on algorithm performance is investigated. Algorithm modifications based on the results of investigations are suggested. The performance improvement of the algorithm is demonstrated by the comparative analysis of suggested algorithms on the benchmark and real world problems

Swine Influenza/Variant Influenza Viruses

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... Address What's this? Submit What's this? Submit Button Influenza Types Seasonal Avian Swine Variant Pandemic Other Information on Swine Influenza/Variant Influenza Virus Language: English (US) Español Recommend ...

Frontotemporal Lobe Degeneration as Origin of Scans Without Evidence of Dopaminergic Deficit

Directory of Open Access Journals (Sweden)

Manuel Menéndez-González

2018-05-01

Full Text Available The term scans without evidence of dopaminergic deficit (SWEDD can be associated with any patient diagnosed at first with Parkinson’s disease but with a negative dopamine transporter-single photon emission computed tomography (DaTSPECT, which does not confirm the presynaptic dopaminergic deficiency. Therefore, an alternative diagnosis should be sought to support parkinsonism as a clinical diagnosis. Parkinsonism is a well-known manifestation of frontotemporal lobar degeneration (FTLD, particularly frequent in those with positive DaTSPECT. Here, we reinforce previous observations that parkinsonism can be present in FTLD patients with negative DaTSPECT and therefore, FTLD may account for a percentage of patients with SWEDD. We gather the clinical observations supporting this hypothesis and describe a case report illustrating this idea. Studies suggest the result of DaTSPECT in FTLD may depend on the neuropathology and clinical subtype. However, most studies do not provide a clinical description of the clinical subtype or pathological features making the association between subtypes of FTLD and DaTSPECT results impossible at the moment. Further studies correlating clinical, neuropsychological, neuroimaging, genetic, and pathology findings are needed to better understand parkinsonism in FTLD.

Beta-glucosidase variants and polynucleotides encoding same

Science.gov (United States)

Wogulis, Mark; Harris, Paul; Osborn, David

2017-06-27

The present invention relates to beta-glucosidase variants, e.g. beta-glucosidase variants of a parent Family GH3A beta-glucosidase from Aspergillus fumigatus. The present invention also relates to polynucleotides encoding the beta-glucosidase variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the beta-glucosidase variants.

In vivo amyloid imaging with PET in frontotemporal dementia

International Nuclear Information System (INIS)

Engler, Henry; Santillo, Alexander F.; Lindau, Maria; Lannfelt, Lars; Kilander, Lena; Wang, Shu Xia; Savitcheva, Irina; Nordberg, Agneta; Laangstroem, Bengt

2008-01-01

N-methyl[11C]2-(4'methylaminophenyl)-6-hydroxy-benzothiazole (PIB) is a positron emission tomography (PET) tracer with amyloid binding properties which allows in vivo measurement of cerebral amyloid load in Alzheimer's disease (AD). Frontotemporal dementia (FTD) is a syndrome that can be clinically difficult to distinguish from AD, but in FTD amyloid deposition is not a characteristic pathological finding. The aim of this study is to investigate PIB retention in FTD. Ten patients with the diagnosis of FTD participated. The diagnosis was based on clinical and neuropsychological examination, computed tomography or magnetic resonance imaging scan, and PET with 18Fluoro-2-deoxy-d-glucose (FDG). The PIB retention, measured in regions of interest, was normalised to a reference region (cerebellum). The results were compared with PIB retention data previously obtained from 17 AD patients with positive PIB retention and eight healthy controls (HC) with negative PIB retention. Statistical analysis was performed with a students t-test with significance level set to 0.00625 after Bonferroni correction. Eight FTD patients showed significantly lower PIB retention compared to AD in frontal (p < 0.0001), parietal (p < 0.0001), temporal (p = 0.0001), and occipital (p = 0.0003) cortices as well as in putamina (p < 0.0001). The PIB uptake in these FTD patients did not differ significantly from the HC in any region. However, two of the 10 FTD patients showed PIB retention similar to AD patients. The majority of FTD patients displayed no PIB retention. Thus, PIB could potentially aid in differentiating between FTD and AD. (orig.)

In vivo amyloid imaging with PET in frontotemporal dementia

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Engler, Henry [Uruguay University Hospital of Clinics and Faculty of Science, Department of Nuclear Medicine, Montevideo (Uruguay); Uppsala University Hospital, Department of Nuclear Medicine, Uppsala (Sweden); Uppsala University, Department of Medical Sciences, Uppsala (Sweden); GE Healthcare, Uppsala Imanet, Uppsala (Sweden); Santillo, Alexander F.; Lindau, Maria; Lannfelt, Lars; Kilander, Lena [Uppsala University, Department of Public Health and Caring Sciences/Geriatrics, Uppsala (Sweden); Wang, Shu Xia [Guangdong Provincial People' s Hospital, Weilun PET Centre, Guangzhou (China); Savitcheva, Irina [Uppsala University Hospital, Department of Nuclear Medicine, Uppsala (Sweden); Nordberg, Agneta [Karolinska Institute, Division of Molecular Neuropharmacology, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden); Laangstroem, Bengt [GE Healthcare, Uppsala Imanet, Uppsala (Sweden); Uppsala University, Departments of Biochemistry and Organic Chemistry, Uppsala (Sweden)

2008-01-15

N-methyl[11C]2-(4'methylaminophenyl)-6-hydroxy-benzothiazole (PIB) is a positron emission tomography (PET) tracer with amyloid binding properties which allows in vivo measurement of cerebral amyloid load in Alzheimer's disease (AD). Frontotemporal dementia (FTD) is a syndrome that can be clinically difficult to distinguish from AD, but in FTD amyloid deposition is not a characteristic pathological finding. The aim of this study is to investigate PIB retention in FTD. Ten patients with the diagnosis of FTD participated. The diagnosis was based on clinical and neuropsychological examination, computed tomography or magnetic resonance imaging scan, and PET with 18Fluoro-2-deoxy-d-glucose (FDG). The PIB retention, measured in regions of interest, was normalised to a reference region (cerebellum). The results were compared with PIB retention data previously obtained from 17 AD patients with positive PIB retention and eight healthy controls (HC) with negative PIB retention. Statistical analysis was performed with a students t-test with significance level set to 0.00625 after Bonferroni correction. Eight FTD patients showed significantly lower PIB retention compared to AD in frontal (p < 0.0001), parietal (p < 0.0001), temporal (p = 0.0001), and occipital (p = 0.0003) cortices as well as in putamina (p < 0.0001). The PIB uptake in these FTD patients did not differ significantly from the HC in any region. However, two of the 10 FTD patients showed PIB retention similar to AD patients. The majority of FTD patients displayed no PIB retention. Thus, PIB could potentially aid in differentiating between FTD and AD. (orig.)

Weighted Protein Interaction Network Analysis of Frontotemporal Dementia.

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Ferrari, Raffaele; Lovering, Ruth C; Hardy, John; Lewis, Patrick A; Manzoni, Claudia

2017-02-03

The genetic analysis of complex disorders has undoubtedly led to the identification of a wealth of associations between genes and specific traits. However, moving from genetics to biochemistry one gene at a time has, to date, rather proved inefficient and under-powered to comprehensively explain the molecular basis of phenotypes. Here we present a novel approach, weighted protein-protein interaction network analysis (W-PPI-NA), to highlight key functional players within relevant biological processes associated with a given trait. This is exemplified in the current study by applying W-PPI-NA to frontotemporal dementia (FTD): We first built the state of the art FTD protein network (FTD-PN) and then analyzed both its topological and functional features. The FTD-PN resulted from the sum of the individual interactomes built around FTD-spectrum genes, leading to a total of 4198 nodes. Twenty nine of 4198 nodes, called inter-interactome hubs (IIHs), represented those interactors able to bridge over 60% of the individual interactomes. Functional annotation analysis not only reiterated and reinforced previous findings from single genes and gene-coexpression analyses but also indicated a number of novel potential disease related mechanisms, including DNA damage response, gene expression regulation, and cell waste disposal and potential biomarkers or therapeutic targets including EP300. These processes and targets likely represent the functional core impacted in FTD, reflecting the underlying genetic architecture contributing to disease. The approach presented in this study can be applied to other complex traits for which risk-causative genes are known as it provides a promising tool for setting the foundations for collating genomics and wet laboratory data in a bidirectional manner. This is and will be critical to accelerate molecular target prioritization and drug discovery.

Congenital anomalies and normal skeletal variants

International Nuclear Information System (INIS)

Guebert, G.M.; Yochum, T.R.; Rowe, L.J.

1987-01-01

Congenital anomalies and normal skeletal variants are a common occurrence in clinical practice. In this chapter a large number of skeletal anomalies of the spine and pelvis are reviewed. Some of the more common skeletal anomalies of the extremities are also presented. The second section of this chapter deals with normal skeletal variants. Some of these variants may simulate certain disease processes. In some instances there are no clear-cut distinctions between skeletal variants and anomalies; therefore, there may be some overlap of material. The congenital anomalies are presented initially with accompanying text, photos, and references, beginning with the skull and proceeding caudally through the spine to then include the pelvis and extremities. The normal skeletal variants section is presented in an anatomical atlas format without text or references

Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

Directory of Open Access Journals (Sweden)

Mengmeng Du

Full Text Available Genome-wide association studies (GWAS have identified many common single nucleotide polymorphisms (SNPs associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs. We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33. We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s.

A targeted genotyping approach enhances identification of variants in taste receptor and appetite/reward genes of potential functional importance for obesity-related porcine traits.

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Cirera, S; Clop, A; Jacobsen, M J; Guerin, M; Lesnik, P; Jørgensen, C B; Fredholm, M; Karlskov-Mortensen, P

2018-04-01

Taste receptors (TASRs) and appetite and reward (AR) mechanisms influence eating behaviour, which in turn affects food intake and risk of obesity. In a previous study, we used next generation sequencing to identify potentially functional mutations in TASR and AR genes and found indications for genetic associations between identified variants and growth and fat deposition in a subgroup of animals (n = 38) from the UNIK resource pig population. This population was created for studying obesity and obesity-related diseases. In the present study we validated results from our previous study by investigating genetic associations between 24 selected single nucleotide variants in TASR and AR gene variants and 35 phenotypes describing obesity and metabolism in the entire UNIK population (n = 564). Fifteen variants showed significant association with specific obesity-related phenotypes after Bonferroni correction. Six of the 15 genes, namely SIM1, FOS, TAS2R4, TAS2R9, MCHR2 and LEPR, showed good correlation between known biological function and associated phenotype. We verified a genetic association between potentially functional variants in TASR/AR genes and growth/obesity and conclude that the combination of identification of potentially functional variants by next generation sequencing followed by targeted genotyping and association studies is a powerful and cost-effective approach for increasing the power of genetic association studies. © 2018 Stichting International Foundation for Animal Genetics.

Progranulin mutation causes frontotemporal dementia in the Swedish Karolinska family.

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Chiang, Huei-Hsin; Rosvall, Lina; Brohede, Jesper; Axelman, Karin; Björk, Behnosh F; Nennesmo, Inger; Robins, Tiina; Graff, Caroline

2008-11-01

Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by cognitive impairment, language dysfunction, and/or changes in personality. Recently it has been shown that progranulin (GRN) mutations can cause FTD as well as other neurodegenerative phenotypes. DNA from 30 family members, of whom seven were diagnosed with FTD, in the Karolinska family was available for GRN sequencing. Fibroblast cell mRNA from one affected family member and six control individuals was available for relative quantitative real-time polymerase chain reaction to investigate the effect of the mutation. Furthermore, the cDNA of an affected individual was sequenced. Clinical and neuropathologic findings of a previously undescribed family branch are presented. A frameshift mutation in GRN (g.102delC) was detected in all affected family members and absent in four unaffected family members older than 70 years. Real-time polymerase chain reaction data showed an approximately 50% reduction of GRN fibroblast mRNA in an affected individual. The mutated mRNA transcripts were undetectable by cDNA sequencing. Segregation and RNA analyses showed that the g.102delC mutation, previously reported, causes FTD in the Karolinska family. Our findings add further support to the significance of GRN in FTD etiology and the presence of modifying genes, which emphasize the need for further studies into the mechanisms of clinical heterogeneity. However, the results already call for attention to the complexity of predictive genetic testing of GRN mutations.

Annotating pathogenic non-coding variants in genic regions.

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Gelfman, Sahar; Wang, Quanli; McSweeney, K Melodi; Ren, Zhong; La Carpia, Francesca; Halvorsen, Matt; Schoch, Kelly; Ratzon, Fanni; Heinzen, Erin L; Boland, Michael J; Petrovski, Slavé; Goldstein, David B

2017-08-09

Identifying the underlying causes of disease requires accurate interpretation of genetic variants. Current methods ineffectively capture pathogenic non-coding variants in genic regions, resulting in overlooking synonymous and intronic variants when searching for disease risk. Here we present the Transcript-inferred Pathogenicity (TraP) score, which uses sequence context alterations to reliably identify non-coding variation that causes disease. High TraP scores single out extremely rare variants with lower minor allele frequencies than missense variants. TraP accurately distinguishes known pathogenic and benign variants in synonymous (AUC = 0.88) and intronic (AUC = 0.83) public datasets, dismissing benign variants with exceptionally high specificity. TraP analysis of 843 exomes from epilepsy family trios identifies synonymous variants in known epilepsy genes, thus pinpointing risk factors of disease from non-coding sequence data. TraP outperforms leading methods in identifying non-coding variants that are pathogenic and is therefore a valuable tool for use in gene discovery and the interpretation of personal genomes.While non-coding synonymous and intronic variants are often not under strong selective constraint, they can be pathogenic through affecting splicing or transcription. Here, the authors develop a score that uses sequence context alterations to predict pathogenicity of synonymous and non-coding genetic variants, and provide a web server of pre-computed scores.

Histone variants and lipid metabolism

NARCIS (Netherlands)

Borghesan, Michela; Mazzoccoli, Gianluigi; Sheedfar, Fareeba; Oben, Jude; Pazienza, Valerio; Vinciguerra, Manlio

2014-01-01

Within nucleosomes, canonical histones package the genome, but they can be opportunely replaced with histone variants. The incorporation of histone variants into the nucleosome is a chief cellular strategy to regulate transcription and cellular metabolism. In pathological terms, cellular steatosis

Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging.

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Ghetti, B; Oblak, A L; Boeve, B F; Johnson, K A; Dickerson, B C; Goedert, M

2015-02-01

Hereditary frontotemporal dementia associated with mutations in the microtubule-associated protein tau gene (MAPT) is a protean disorder. Three neuropathologic subtypes can be recognized, based on the presence of inclusions made of tau isoforms with three and four repeats, predominantly three repeats and mostly four repeats. This is relevant for establishing a correlation between structural magnetic resonance imaging and positron emission tomography using tracers specific for aggregated tau. Longitudinal studies will be essential to determine the evolution of anatomical alterations from the asymptomatic stage to the various phases of disease following the onset of symptoms. © 2014 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.

CLEVER: Clique-Enumerating Variant Finder

NARCIS (Netherlands)

Marschall, T.; Costa, I.; Canzar, S.; bauer, m; Klau, G.W.; Schliep, A.; Schönhuth, A.

2012-01-01

Motivation: Next-generation sequencing techniques have facilitated a large-scale analysis of human genetic variation. Despite the advances in sequencing speed, the computational discovery of structural variants is not yet standard. It is likely that many variants have remained undiscovered in most

The curation of genetic variants: difficulties and possible solutions.

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Pandey, Kapil Raj; Maden, Narendra; Poudel, Barsha; Pradhananga, Sailendra; Sharma, Amit Kumar

2012-12-01

The curation of genetic variants from biomedical articles is required for various clinical and research purposes. Nowadays, establishment of variant databases that include overall information about variants is becoming quite popular. These databases have immense utility, serving as a user-friendly information storehouse of variants for information seekers. While manual curation is the gold standard method for curation of variants, it can turn out to be time-consuming on a large scale thus necessitating the need for automation. Curation of variants described in biomedical literature may not be straightforward mainly due to various nomenclature and expression issues. Though current trends in paper writing on variants is inclined to the standard nomenclature such that variants can easily be retrieved, we have a massive store of variants in the literature that are present as non-standard names and the online search engines that are predominantly used may not be capable of finding them. For effective curation of variants, knowledge about the overall process of curation, nature and types of difficulties in curation, and ways to tackle the difficulties during the task are crucial. Only by effective curation, can variants be correctly interpreted. This paper presents the process and difficulties of curation of genetic variants with possible solutions and suggestions from our work experience in the field including literature support. The paper also highlights aspects of interpretation of genetic variants and the importance of writing papers on variants following standard and retrievable methods. Copyright © 2012. Published by Elsevier Ltd.

Word Variant Identification in Old French

Directory of Open Access Journals (Sweden)

Peter Willett

1997-01-01

Full Text Available Increasing numbers of historical texts are available in machine-readable form, which retain the original spelling, which can be very different from the modern-day equivalents due to the natural evolution of a language, and because the concept of standardisation in spelling is comparatively modern. Among medieval vernacular writers, the same word could be spelled in different ways and the same author (or scribe might even use several alternative spellings in the same passage. Thus, we do not know,a priori, how many variant forms of a particular word there are in such texts, let alone what these variants might be. Searching on the modern equivalent, or even the commonest historical variant, of a particular word may thus fail to retrieve an appreciable number of occurrences unless the searcher already has an extensive knowledge of the language of the documents. Moreover, even specialist scholars may be unaware of some idiosyncratic variants. Here, we consider the use of computer methods to retrieve variant historical spellings.

TREM2 Variants in Alzheimer's Disease

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Guerreiro, Rita; Wojtas, Aleksandra; Bras, Jose; Carrasquillo, Minerva; Rogaeva, Ekaterina; Majounie, Elisa; Cruchaga, Carlos; Sassi, Celeste; Kauwe, John S.K.; Younkin, Steven; Hazrati, Lilinaz; Collinge, John; Pocock, Jennifer; Lashley, Tammaryn; Williams, Julie; Lambert, Jean-Charles; Amouyel, Philippe; Goate, Alison; Rademakers, Rosa; Morgan, Kevin; Powell, John; St. George-Hyslop, Peter; Singleton, Andrew; Hardy, John

2013-01-01

BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.) PMID:23150934

Longitudinal Alterations of Frontoparietal and Frontotemporal Networks Predict Future Creative Cognitive Ability.

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Chen, Qunlin; Beaty, Roger E; Wei, Dongtao; Yang, Junyi; Sun, Jiangzhou; Liu, Wei; Yang, Wenjing; Zhang, Qinglin; Qiu, Jiang

2018-01-01

Creative cognition is important to academic performance and career success during late adolescence and adulthood. However, there is a lack of longitudinal data on whether brain structural development could predict improvements in creative thinking, and how such changes interact with other cognitive abilities to support creative performance. Here we examined longitudinal alterations of brain structure and their relation to creative cognitive ability in a sample of 159 healthy young adults who were scanned using magnetic resonance imaging 2-3 times over the course of 3 years. The most robust predictor of future creative ability was the right dorsolateral prefrontal cortex (DLPFC), which in conjunction with baseline creative capacity showed a 31% prediction rate. Longitudinal analysis revealed that slower decreases in gray matter density within left frontoparietal and right frontotemporal clusters predicted enhanced creative ability. Moreoever, the relationship between longitudinal alterations within frontal-related clusters and improved creative ability was moderated by the right DLPFC and working memory ability. We conclude that continuous goal-directed planning and accumulated knowledge are implemented in the right DLPFC and temporal areas, respectively, which in turn support longitudinal gains in creative cognitive ability. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice.

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Filiano, Anthony J; Martens, Lauren Herl; Young, Allen H; Warmus, Brian A; Zhou, Ping; Diaz-Ramirez, Grisell; Jiao, Jian; Zhang, Zhijun; Huang, Eric J; Gao, Fen-Biao; Farese, Robert V; Roberson, Erik D

2013-03-20

Frontotemporal dementia (FTD) is a neurodegenerative disease with hallmark deficits in social and emotional function. Heterozygous loss-of-function mutations in GRN, the progranulin gene, are a common genetic cause of the disorder, but the mechanisms by which progranulin haploinsufficiency causes neuronal dysfunction in FTD are unclear. Homozygous progranulin knock-out (Grn(-/-)) mice have been studied as a model of this disorder and show behavioral deficits and a neuroinflammatory phenotype with robust microglial activation. However, homozygous GRN mutations causing complete progranulin deficiency were recently shown to cause a different neurological disorder, neuronal ceroid lipofuscinosis, suggesting that the total absence of progranulin may have effects distinct from those of haploinsufficiency. Here, we studied progranulin heterozygous (Grn(+/-)) mice, which model progranulin haploinsufficiency. We found that Grn(+/-) mice developed age-dependent social and emotional deficits potentially relevant to FTD. However, unlike Grn(-/-) mice, behavioral deficits in Grn(+/-) mice occurred in the absence of gliosis or increased expression of tumor necrosis factor-α. Instead, we found neuronal abnormalities in the amygdala, an area of selective vulnerability in FTD, in Grn(+/-) mice. Our findings indicate that FTD-related deficits resulting from progranulin haploinsufficiency can develop in the absence of detectable gliosis and neuroinflammation, thereby dissociating microglial activation from functional deficits and suggesting an important effect of progranulin deficiency on neurons.

Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases

Science.gov (United States)

Coppola, Giovanni; Chinnathambi, Subashchandrabose; Lee, Jason JiYong; Dombroski, Beth A.; Baker, Matt C.; Soto-Ortolaza, Alexandra I.; Lee, Suzee E.; Klein, Eric; Huang, Alden Y.; Sears, Renee; Lane, Jessica R.; Karydas, Anna M.; Kenet, Robert O.; Biernat, Jacek; Wang, Li-San; Cotman, Carl W.; DeCarli, Charles S.; Levey, Allan I.; Ringman, John M.; Mendez, Mario F.; Chui, Helena C.; Le Ber, Isabelle; Brice, Alexis; Lupton, Michelle K.; Preza, Elisavet; Lovestone, Simon; Powell, John; Graff-Radford, Neill; Petersen, Ronald C.; Boeve, Bradley F.; Lippa, Carol F.; Bigio, Eileen H.; Mackenzie, Ian; Finger, Elizabeth; Kertesz, Andrew; Caselli, Richard J.; Gearing, Marla; Juncos, Jorge L.; Ghetti, Bernardino; Spina, Salvatore; Bordelon, Yvette M.; Tourtellotte, Wallace W.; Frosch, Matthew P.; Vonsattel, Jean Paul G.; Zarow, Chris; Beach, Thomas G.; Albin, Roger L.; Lieberman, Andrew P.; Lee, Virginia M.; Trojanowski, John Q.; Van Deerlin, Vivianna M.; Bird, Thomas D.; Galasko, Douglas R.; Masliah, Eliezer; White, Charles L.; Troncoso, Juan C.; Hannequin, Didier; Boxer, Adam L.; Geschwind, Michael D.; Kumar, Satish; Mandelkow, Eva-Maria; Wszolek, Zbigniew K.; Uitti, Ryan J.; Dickson, Dennis W.; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Ross, Owen A.; Rademakers, Rosa; Schellenberg, Gerard D.; Miller, Bruce L.; Mandelkow, Eckhard; Geschwind, Daniel H.

2012-01-01

Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6–5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3–4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated. PMID:22556362

Performance of patients with frontotemporal lobar degeneration on artistic tasks: A pilot study.

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Anauate, Maria Cristina; Bahia, Valéria Santoro; Nitrini, Ricardo; Radanovic, Marcia

2014-01-01

Several studies have addressed visuospatial and executive skills in artistic activities in Frontotemporal Lobar Degeneration (FTLD) and Alzheimer's disease (AD). To investigate the performance of FTLD patients compared to controls on two artistic tasks. Four FTLD patients with mean age of 57 (8.7) years and schooling of 12.2 (4.5) years plus 10 controls with mean age of 62.9 (8.6) years and schooling of 12.3 (4.6) years, were assessed using the Lowenstein Occupational Therapy Cognitive Assessment (LOTCA) and by a three-stage artistic protocol including visual observation, copying and collage, based on a Sisley painting. FTLD patients had lower scores than controls on Visuospatial Perception, Copy, Collage, Examiner's Observation, and Total, showing distinct patterns of performance according to FTLD sub-type: semantic PPA, nonfluent PPA and bvFTD. FTLD patients presented impairment in the visuospatial and executive skills required to perform artistic tasks. We demonstrated that the application of the instrument as a complimentary method for assessing cognitive skills in this group of patients is possible. Further studies addressing larger and more homogeneous samples of FTLD patients as well as other dementias are warranted.

Validation of the Spanish Version of the Addenbrooke's Cognitive Examination-Revised (ACE-R).

Science.gov (United States)

Torralva, T; Roca, M; Gleichgerrcht, E; Bonifacio, A; Raimondi, C; Manes, F

2011-01-01

The Addenbrooke's Cognitive Examination Revised (ACE-R) is an improved version of the earlier brief screening test which has been validated in English with high sensitivity and specificity to detect cognitive dysfunction. The aim of this study was to validate the Spanish version of the ACE-R in an Argentine population. A group of patients with Alzheimer Disease (AD) and patients with behavioural variant Frontotemporal Dementia (bvFTD) paired by age, sex, and years of education with healthy controls were assessed using the ACE-R. Stage of dementia was measured with the Clinical Dementia Rating Scale (CDR). The English version of the ACE-R was first translated into Spanish and then back-translated into English by two blind independent experts. Internal reliability was very good (Cronbach's alpha=0.89). Concurrent validity, determined by the correlation between total ACE-R and CDR was significant (Pcognitive impairment and has shown to discriminate between bvFTD and AD. Copyright © 2010 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Development of an MRI rating scale for multiple brain regions: comparison with volumetrics and with voxel-based morphometry

International Nuclear Information System (INIS)

Davies, R.R.; Williams, Guy B.; Scahill, Victoria L.; Graham, Kim S.; Graham, Andrew; Hodges, John R.

2009-01-01

We aimed to devise a rating method for key frontal and temporal brain regions validated against quantitative volumetric methods and applicable to a range of dementia syndromes. Four standardised coronal MR images from 36 subjects encompassing controls and cases with Alzheimer's disease (AD) and frontotemporal dementia (FTD) were used. After initial pilot studies, 15 regions produced good intra- and inter-rater reliability. We then validated the ratings against manual volumetry and voxel-based morphometry (VBM) and compared ratings across the subject groups. Validation against both manual volumetry (for both frontal and temporal lobes), and against whole brain VBM, showed good correlation with visual ratings for the majority of the brain regions. Comparison of rating scores across disease groups showed involvement of the anterior fusiform gyrus, anterior hippocampus and temporal pole in semantic dementia, while anterior cingulate and orbitofrontal regions were involved in behavioural variant FTD. This simple visual rating can be used as an alternative to highly technical methods of quantification, and may be superior when dealing with single cases or small groups. (orig.)

Development of an MRI rating scale for multiple brain regions: comparison with volumetrics and with voxel-based morphometry

Energy Technology Data Exchange (ETDEWEB)

Davies, R.R.; Williams, Guy B. [University of Cambridge, Department of Clinical Neurosciences, Cambridge (United Kingdom); Scahill, Victoria L.; Graham, Kim S. [Cardiff University, MRC Cognition and Brain Sciences Unit, Cambridge and Wales Institute of Cognitive Neuroscience, School of Psychology, Cardiff (United Kingdom); Graham, Andrew [University of Cambridge, Department of Clinical Neurosciences, Cambridge (United Kingdom); Cardiff University, MRC Cognition and Brain Sciences Unit, Cambridge and Wales Institute of Cognitive Neuroscience, School of Psychology, Cardiff (United Kingdom); Hodges, John R. [University of Cambridge, Department of Clinical Neurosciences, Cambridge (United Kingdom); Cardiff University, MRC Cognition and Brain Sciences Unit, Cambridge and Wales Institute of Cognitive Neuroscience, School of Psychology, Cardiff (United Kingdom); Prince of Wales Medical Research Institute, Cognitive Neurology, Sydney, NSW (Australia)

2009-08-15

We aimed to devise a rating method for key frontal and temporal brain regions validated against quantitative volumetric methods and applicable to a range of dementia syndromes. Four standardised coronal MR images from 36 subjects encompassing controls and cases with Alzheimer's disease (AD) and frontotemporal dementia (FTD) were used. After initial pilot studies, 15 regions produced good intra- and inter-rater reliability. We then validated the ratings against manual volumetry and voxel-based morphometry (VBM) and compared ratings across the subject groups. Validation against both manual volumetry (for both frontal and temporal lobes), and against whole brain VBM, showed good correlation with visual ratings for the majority of the brain regions. Comparison of rating scores across disease groups showed involvement of the anterior fusiform gyrus, anterior hippocampus and temporal pole in semantic dementia, while anterior cingulate and orbitofrontal regions were involved in behavioural variant FTD. This simple visual rating can be used as an alternative to highly technical methods of quantification, and may be superior when dealing with single cases or small groups. (orig.)

Researches of WWER fuel rods behaviour under RIA accident conditions

International Nuclear Information System (INIS)

Nechaeva, O.; Medvedev, A.; Novikov, V.; Salatov, A.

2003-01-01

Unirradiated fuel rod and refabricated fuel rod tests in the BIGR as well as acceptance criteria proving absence of fragmentation and the settlement modeling of refabricated fuel rods thermomechanical behavior in the BIGR-tests using RAPTA-5 code are discussed in this paper. The behaviour of WWER type simulators with E110 and E635 cladding was researched at the BIGR reactor under power pulse conditions simulating reactivity initiated accident. The results of the tests in four variants of experimental conditions are submitted. The behaviour of 12 WWER type refabricated fuel rods was researched in the BIGR reactor under power pulse conditions simulating reactivity initiated accident: burnup 48 and 60 MWd/kgU, pulse width 3 ms, peak fuel enthalpy 115-190 cal/g. The program of future tests in the research reactor MIR with high burnup fuel rod (up to 70 MWd/kgU) under conditions simulating design RIA in WWER-1000 is presented

Memory Test Performance on Analogous Verbal and Nonverbal Memory Tests in Patients with Frontotemporal Dementia and Alzheimer's Disease.

Science.gov (United States)

Baldock, Deanna; Miller, Justin B; Leger, Gabriel C; Banks, Sarah Jane

2016-01-01

Patients with frontotemporal dementia (FTD) typically have initial deficits in language or changes in personality, while the defining characteristic of Alzheimer's disease (AD) is memory impairment. Neuropsychological findings in the two diseases tend to differ, but can be confounded by verbal impairment in FTD impacting performance on memory tests in these patients. Twenty-seven patients with FTD and 102 patients with AD underwent a neuropsychological assessment before diagnosis. By utilizing analogous versions of a verbal and nonverbal memory test, we demonstrated differences in these two modalities between AD and FTD. Better differentiation between AD and FTD is found in a nonverbal memory test, possibly because it eliminates the confounding variable of language deficits found in patients with FTD. These results highlight the importance of nonverbal learning tests with multiple learning trials in diagnostic testing.

Problems of Face Recognition in Patients with Behavioral Variant Frontotemporal Dementia

OpenAIRE

Chandra, Sadanandavalli Retnaswami; Patwardhan, Ketaki; Pai, Anupama Ramakanth

2017-01-01

Introduction: Faces are very special as they are most essential for social cognition in humans. It is partly understood that face processing in its abstractness involves several extra striate areas. One of the most important causes for caregiver suffering in patients with anterior dementia is lack of empathy. This apart from being a behavioral disorder could be also due to failure to categorize the emotions of the people around them. Patients and Methods: Inlusion criteria: DSM IV for Bv FTD ...

Problems of Face Recognition in Patients with Behavioral Variant Frontotemporal Dementia.

Science.gov (United States)

Chandra, Sadanandavalli Retnaswami; Patwardhan, Ketaki; Pai, Anupama Ramakanth

2017-01-01

Faces are very special as they are most essential for social cognition in humans. It is partly understood that face processing in its abstractness involves several extra striate areas. One of the most important causes for caregiver suffering in patients with anterior dementia is lack of empathy. This apart from being a behavioral disorder could be also due to failure to categorize the emotions of the people around them. Inlusion criteria: DSM IV for Bv FTD Tested for prosopagnosia - familiar faces, famous face, smiling face, crying face and reflected face using a simple picture card (figure 1). Advanced illness and mixed causes. 46 patients (15 females, 31 males) 24 had defective face recognition. (mean age 51.5),10/15 females (70%) and 14/31males(47. Familiar face recognition defect was found in 6/10 females and 6/14 males. Total- 40%(6/15) females and 19.35%(6/31)males with FTD had familiar face recognition. Famous Face: 9/10 females and 7/14 males. Total- 60% (9/15) females with FTD had famous face recognition defect as against 22.6%(7/31) males with FTD Smiling face defects in 8/10 female and no males. Total- 53.33% (8/15) females. Crying face recognition defect in 3/10 female and 2 /14 males. Total- 20%(3/15) females and 6.5%(2/31) males. Reflected face recognition defect in 4 females. Famous face recognition and positive emotion recognition defect in 80%, only 20% comprehend positive emotions, Face recognition defects are found in only 45% of males and more common in females. Face recognition is more affected in females with FTD There is differential involvement of different aspects of the face recognition could be one of the important factor underlying decline in the emotional and social behavior of these patients. Understanding these pathological processes will give more insight regarding patient behavior.

Combined analyses of 20 common obesity susceptibility variants

DEFF Research Database (Denmark)

Sandholt, Camilla Helene; Sparsø, Thomas; Grarup, Niels

2010-01-01

Genome-wide association studies and linkage studies have identified 20 validated genetic variants associated with obesity and/or related phenotypes. The variants are common, and they individually exhibit small-to-modest effect sizes.......Genome-wide association studies and linkage studies have identified 20 validated genetic variants associated with obesity and/or related phenotypes. The variants are common, and they individually exhibit small-to-modest effect sizes....

Status report on experiments and modelling of the cleavage fracture behaviour of F82Hmod using local fracture grid. Task TTMS-005

International Nuclear Information System (INIS)

Riesch-Oppermann, H.; Walter, M.

2001-09-01

Within the European Fusion Technology Programme framework, a fracture mechanics description of the material behaviour in the ductile to brittle transition-regime is developed using local fracture criteria. Based on experimental results using axisymmetrically notched and pre-cracked specimens together with a numerical stress analysis at fracture load, a statistical evaluation of cleavage fracture parameters can be performed along the lines described in various code schemes such as the British Energy R6-Code or the ESIS P6 procedure. The report contains results of the experimental characterization of the deformation and fracture behaviour of the fusion candidate RAFM steel variant F82Hmod, details and background of the numerical procedure for cleavage fracture parameter determination as well as additional statistical inference methods for transferability analysis. Fractographic results give important information about fracture mode and fracture origin sites and their location. Numerical prediction of fracture origin distribution is an important tool for transferability assessment. Future issues comprise constraint effect and ductile damage as well as incorporation of irradiation effects, which are topically addressed. The methodology developed and described in the present report will be applied to characterize material behaviour of future RAFM variants as the EUROFER 97, for which analysis is currently under way. (orig.)

Variant Review with the Integrative Genomics Viewer.

Science.gov (United States)

Robinson, James T; Thorvaldsdóttir, Helga; Wenger, Aaron M; Zehir, Ahmet; Mesirov, Jill P

2017-11-01

Manual review of aligned reads for confirmation and interpretation of variant calls is an important step in many variant calling pipelines for next-generation sequencing (NGS) data. Visual inspection can greatly increase the confidence in calls, reduce the risk of false positives, and help characterize complex events. The Integrative Genomics Viewer (IGV) was one of the first tools to provide NGS data visualization, and it currently provides a rich set of tools for inspection, validation, and interpretation of NGS datasets, as well as other types of genomic data. Here, we present a short overview of IGV's variant review features for both single-nucleotide variants and structural variants, with examples from both cancer and germline datasets. IGV is freely available at https://www.igv.org Cancer Res; 77(21); e31-34. ©2017 AACR . ©2017 American Association for Cancer Research.

Secretory leukocyte protease inhibitor protein regulates the penetrance of frontotemporal lobar degeneration in progranulin mutation carriers.

Science.gov (United States)

Ghidoni, Roberta; Flocco, Rosa; Paterlini, Anna; Glionna, Michela; Caruana, Loredana; Tonoli, Elisa; Binetti, Giuliano; Benussi, Luisa

2014-01-01

The discovery that mutations in the gene encoding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases leading to dementia has brought renewed interest in progranulin and its functions in the central nervous system. Full length progranulin is preserved from cleavage by secretory leukocyte protease inhibitor (SLPI), one of the smallest serine protease inhibitor circulating in plasma. Herein, we investigated the relationship between circulating SLPI and progranulin in affected and unaffected subjects belonging to 26 Italian pedigrees carrying GRN null mutations. In GRN null mutation carriers, we demonstrated: i) an increase of circulating SLPI levels in affected subjects; ii) an age-related upregulation of the serine-protease inhibitor in response to lifetime progranulin shortage; and iii) a delay in the age of onset in subjects with the highest SLPI protein levels. The study of SLPI and its relation to progranulin suggests the existence of unexpected molecular players in progranulin-associated neurodegeneration.

TMEM106B and ApoE polymorphisms in CHMP2B-mediated frontotemporal dementia (FTD-3)

DEFF Research Database (Denmark)

Rostgaard, Nina; Roos, Peter; Budtz-Jørgensen, Esben

2017-01-01

(ApoE) in FTD is uncertain, though an established risk factor in Alzheimer's disease. In a unique Danish family, inherited FTD is caused by a mutation in the CHMP2B gene located on chromosome 3 (FTD-3). In this family, both risk factors TMEM106B and ApoE were analyzed and correlated to age at onset......Single-nucleotide polymorphisms in the TMEM106B gene have been identified as a risk factor in frontotemporal dementia (FTD). The major allele of SNP rs3173615 is a risk factor in sporadic FTD, whereas the minor allele seems protective in GRN- and C9orf72-mediated FTD. The role of apolipoprotein E...... factor with later AAO and AAI, whereas ε2 seemed to aggravate the disease with earlier AAO and AAD. These results indicate ApoE ε2 as a risk factor in FTD-3 and suggest a protective role of ε4....

Germline Variants of Prostate Cancer in Japanese Families.

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Takahide Hayano

Full Text Available Prostate cancer (PC is the second most common cancer in men. Family history is the major risk factor for PC. Only two susceptibility genes were identified in PC, BRCA2 and HOXB13. A comprehensive search of germline variants for patients with PC has not been reported in Japanese families. In this study, we conducted exome sequencing followed by Sanger sequencing to explore responsible germline variants in 140 Japanese patients with PC from 66 families. In addition to known susceptibility genes, BRCA2 and HOXB13, we identified TRRAP variants in a mutually exclusive manner in seven large PC families (three or four patients per family. We also found shared variants of BRCA2, HOXB13, and TRRAP from 59 additional small PC families (two patients per family. We identified two deleterious HOXB13 variants (F127C and G132E. Further exploration of the shared variants in rest of the families revealed deleterious variants of the so-called cancer genes (ATP1A1, BRIP1, FANCA, FGFR3, FLT3, HOXD11, MUTYH, PDGFRA, SMARCA4, and TCF3. The germline variant profile provides a new insight to clarify the genetic etiology and heterogeneity of PC among Japanese men.

Detecting rare variants in case-parents association studies.

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Kuang-Fu Cheng

Full Text Available Despite the success of genome-wide association studies (GWASs in detecting common variants (minor allele frequency ≥0.05 many suggested that rare variants also contribute to the genetic architecture of diseases. Recently, researchers demonstrated that rare variants can show a strong stratification which may not be corrected by using existing methods. In this paper, we focus on a case-parents study and consider methods for testing group-wise association between multiple rare (and common variants in a gene region and a disease. All tests depend on the numbers of transmitted mutant alleles from parents to their diseased children across variants and hence they are robust to the effect of population stratification. We use extensive simulation studies to compare the performance of four competing tests: the largest single-variant transmission disequilibrium test (TDT, multivariable test, combined TDT, and a likelihood ratio test based on a random-effects model. We find that the likelihood ratio test is most powerful in a wide range of settings and there is no negative impact to its power performance when common variants are also included in the analysis. If deleterious and protective variants are simultaneously analyzed, the likelihood ratio test was generally insensitive to the effect directionality, unless the effects are extremely inconsistent in one direction.

Differential susceptibility to maternal expressed emotion in children with ADHD and their siblings? Investigating plasticity genes, prosocial and antisocial behaviour.

Science.gov (United States)

Richards, Jennifer S; Hartman, Catharina A; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Arias Vásquez, Alejandro; Buitelaar, Jan K

2015-02-01

The differential susceptibility theory states that children differ in their susceptibility towards environmental experiences, partially due to plasticity genes. Individuals carrying specific variants in such genes will be more disadvantaged in negative but, conversely, more advantaged in positive environments. Understanding gene-environment interactions may help unravel the causal mechanisms involved in multifactorial psychiatric disorders such as Attention-Deficit/Hyperactivity Disorder (ADHD). The differential susceptibility theory was examined by investigating the presence of interaction effects between maternal expressed emotion (EE; warmth and criticism) and the solitary and combined effects of plasticity genes (DAT1, DRD4, 5-HTT) on prosocial and antisocial behaviour (measured with parent- and self-reports) in children with ADHD and their siblings (N = 366, M = 17.11 years, 74.9% male). Maternal warmth was positively associated with prosocial behaviour and negatively with antisocial behaviour, while maternal criticism was positively associated with antisocial behaviour and negatively with prosocial behaviour. No evidence of differential susceptibility was found. The current study found no evidence for differential susceptibility based on the selected plasticity genes, in spite of strong EE-behaviour associations. It is likely that additional factors play a role in the complex relationship between genes, environment and behaviour.

Variants of glycoside hydrolases

Science.gov (United States)

Teter, Sarah [Davis, CA; Ward, Connie [Hamilton, MT; Cherry, Joel [Davis, CA; Jones, Aubrey [Davis, CA; Harris, Paul [Carnation, WA; Yi, Jung [Sacramento, CA

2011-04-26

The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

Local binary patterns new variants and applications

CERN Document Server

Jain, Lakhmi; Nanni, Loris; Lumini, Alessandra

2014-01-01

This book introduces Local Binary Patterns (LBP), arguably one of the most powerful texture descriptors, and LBP variants. This volume provides the latest reviews of the literature and a presentation of some of the best LBP variants by researchers at the forefront of textual analysis research and research on LBP descriptors and variants. The value of LBP variants is illustrated with reported experiments using many databases representing a diversity of computer vision applications in medicine, biometrics, and other areas. There is also a chapter that provides an excellent theoretical foundation for texture analysis and LBP in particular. A special section focuses on LBP and LBP variants in the area of face recognition, including thermal face recognition. This book will be of value to anyone already in the field as well as to those interested in learning more about this powerful family of texture descriptors.

Variant Creutzfeldt-Jakob Disease (vCJD)

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... Form Controls Cancel Submit Search the CDC Variant Creutzfeldt-Jakob Disease (vCJD) Note: Javascript is disabled or is not ... gov . Recommend on Facebook Tweet Share Compartir Variant Creutzfeldt-Jakob disease (vCJD) is a prion disease that was first ...

Population structure analysis using rare and common functional variants

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Ding Lili

2011-11-01

Full Text Available Abstract Next-generation sequencing technologies now make it possible to genotype and measure hundreds of thousands of rare genetic variations in individuals across the genome. Characterization of high-density genetic variation facilitates control of population genetic structure on a finer scale before large-scale genotyping in disease genetics studies. Population structure is a well-known, prevalent, and important factor in common variant genetic studies, but its relevance in rare variants is unclear. We perform an extensive population structure analysis using common and rare functional variants from the Genetic Analysis Workshop 17 mini-exome sequence. The analysis based on common functional variants required 388 principal components to account for 90% of the variation in population structure. However, an analysis based on rare variants required 532 significant principal components to account for similar levels of variation. Using rare variants, we detected fine-scale substructure beyond the population structure identified using common functional variants. Our results show that the level of population structure embedded in rare variant data is different from the level embedded in common variant data and that correcting for population structure is only as good as the level one wishes to correct.

Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects

Science.gov (United States)

Almeida, Sandra; Zhang, Zhijun; Coppola, Giovanni; Mao, Wenjie; Futai, Kensuke; Karydas, Anna; Geschwind, Michael D.; Tartaglia, M. Carmela; Gao, Fuying; Gianni, Davide; Sena-Esteves, Miguel; Geschwind, Daniel H.; Miller, Bruce L.; Farese, Robert V.; Gao, Fen-Biao

2012-01-01

SUMMARY The pathogenic mechanisms of frontotemporal dementia (FTD) remain poorly understood. Here we generated multiple induced pluripotent stem cell (iPSC) lines from a control subject, a patient with sporadic FTD, and an FTD patient with a novel GRN mutation (PGRN S116X). In neurons and microglia differentiated from PGRN S116X iPSCs, the levels of intracellular and secreted progranulin were reduced, establishing patient-specific cellular models of progranulin haploinsufficiency. Through a systematic screen of inducers of cellular stress, we found that PGRN S116X neurons, but not sporadic FTD neurons, exhibited increased sensitivity to staurosporine and other kinase inhibitors. Moreover, the serine/threonine kinase S6K2, a component of the PI3K and MAPK pathways, was specifically downregulated in PGRN S116X neurons. Both increased sensitivity to kinase inhibitors and reduced S6K2 were rescued by progranulin expression. Our findings identify cell-autonomous, reversible defects in patient neurons with progranulin deficiency and provide a new model for studying progranulin-dependent pathogenic mechanisms and testing potential therapies. PMID:23063362

Reduced frequency of T lymphocytes expressing CTLA-4 in frontotemporal dementia compared to Alzheimer's disease.

Science.gov (United States)

Santos, Rodrigo Ribeiro; Torres, Karen C; Lima, Giselle S; Fiamoncini, Carolina M; Mapa, Filipe C; Pereira, Patricia A; Rezende, Vitor B; Martins, Luiza C; Bicalho, Maria A; Moraes, Edgar N; Reis, Helton J; Teixeira, Antonio L; Romano-Silva, Marco A

2014-01-03

Studies suggest that inflammation is involved in the neurodegenerative cascade of dementias. Immunological mechanisms may be part of the pathophysiological process in frontotemporal dementia (FTD), but up till now only vague evidence of such mechanisms has been presented. The B7- CD28/CTLA-4 pathway is an important immunological signaling pathway involved in modulation of T cell activation. The aim of this study was to compare the expression of molecules associated with co-stimulatory signaling in peripheral blood mononuclear cells (PBMC) of FTD to Alzheimer disease (AD) and control groups. Our results confirm the previous demonstrated increased expression of CD80 in CD14+ Alzheimer patients T cells but show, for the first time, a reduction in the expression of CTLA-4 in CD4+ FTD cells. As CTLA-4 is the most potent negative regulators of T-cell activation we speculated that peripheral T lymphocytes in FTD are more activated and this could be involved in the neurodegeneration observed in this dementia. © 2013 Elsevier Inc. All rights reserved.

Dissociation of Frontotemporal Dementia–Related Deficits and Neuroinflammation in Progranulin Haploinsufficient Mice

Science.gov (United States)

Filiano, Anthony J.; Martens, Lauren Herl; Young, Allen H.; Warmus, Brian A.; Zhou, Ping; Diaz-Ramirez, Grisell; Jiao, Jian; Zhang, Zhijun; Huang, Eric J.; Gao, Fen-Biao; Farese, Robert V.; Roberson, Erik D.

2013-01-01

Frontotemporal dementia (FTD) is a neurodegenerative disease with hallmark deficits in social and emotional function. Heterozygous loss-of-function mutations in GRN, the progranulin gene, are a common genetic cause of the disorder, but the mechanisms by which progranulin haploinsufficiency causes neuronal dysfunction in FTD are unclear. Homozygous progranulin knockout (Grn−/−) mice have been studied as a model of this disorder and show behavioral deficits and a neuroinflammatory phenotype with robust microglial activation. However, homozygous GRN mutations causing complete progranulin deficiency were recently shown to cause a different neurological disorder, neuronal ceroid lipofuscinosis, suggesting that the total absence of progranulin may have effects distinct from those of haploinsufficiency. Here, we studied progranulin heterozygous (Grn+/−) mice, which model progranulin haploinsufficiency. We found that Grn+/− mice developed age-dependent social and emotional deficits potentially relevant to FTD. However, unlike Grn−/− mice, behavioral deficits in Grn+/− mice occurred in the absence of gliosis or increased expression of tumor necrosis factor–α. Instead, we found neuronal abnormalities in the amygdala, an area of selective vulnerability in FTD, in Grn+/− mice. Our findings indicate that FTD-related deficits due to progranulin haploinsufficiency can develop in the absence of detectable gliosis and neuroinflammation, thereby dissociating microglial activation from functional deficits and suggesting an important effect of progranulin deficiency on neurons. PMID:23516300

Progranulin, a glycoprotein deficient in frontotemporal dementia, is a novel substrate of several protein disulfide isomerase family proteins.

Directory of Open Access Journals (Sweden)

Sandra Almeida

Full Text Available The reduced production or activity of the cysteine-rich glycoprotein progranulin is responsible for about 20% of cases of familial frontotemporal dementia. However, little is known about the molecular mechanisms that govern the level and secretion of progranulin. Here we show that progranulin is expressed in mouse cortical neurons and more prominently in mouse microglia in culture and is abundant in the endoplasmic reticulum (ER and Golgi. Using chemical crosslinking, immunoprecipitation, and mass spectrometry, we found that progranulin is bound to a network of ER Ca(2+-binding chaperones including BiP, calreticulin, GRP94, and four members of the protein disulfide isomerase (PDI family. Loss of ERp57 inhibits progranulin secretion. Thus, progranulin is a novel substrate of several PDI family proteins and modulation of the ER chaperone network may be a therapeutic target for controlling progranulin secretion.

Memory Test Performance on Analogous Verbal and Nonverbal Memory Tests in Patients with Frontotemporal Dementia and Alzheimer's Disease

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Deanna Baldock

2016-01-01

Full Text Available Background: Patients with frontotemporal dementia (FTD typically have initial deficits in language or changes in personality, while the defining characteristic of Alzheimer's disease (AD is memory impairment. Neuropsychological findings in the two diseases tend to differ, but can be confounded by verbal impairment in FTD impacting performance on memory tests in these patients. Methods: Twenty-seven patients with FTD and 102 patients with AD underwent a neuropsychological assessment before diagnosis. By utilizing analogous versions of a verbal and nonverbal memory test, we demonstrated differences in these two modalities between AD and FTD. Discussion: Better differentiation between AD and FTD is found in a nonverbal memory test, possibly because it eliminates the confounding variable of language deficits found in patients with FTD. These results highlight the importance of nonverbal learning tests with multiple learning trials in diagnostic testing.

Three-dimensional spatial analysis of missense variants in RTEL1 identifies pathogenic variants in patients with Familial Interstitial Pneumonia.

Science.gov (United States)

Sivley, R Michael; Sheehan, Jonathan H; Kropski, Jonathan A; Cogan, Joy; Blackwell, Timothy S; Phillips, John A; Bush, William S; Meiler, Jens; Capra, John A

2018-01-23

Next-generation sequencing of individuals with genetic diseases often detects candidate rare variants in numerous genes, but determining which are causal remains challenging. We hypothesized that the spatial distribution of missense variants in protein structures contains information about function and pathogenicity that can help prioritize variants of unknown significance (VUS) and elucidate the structural mechanisms leading to disease. To illustrate this approach in a clinical application, we analyzed 13 candidate missense variants in regulator of telomere elongation helicase 1 (RTEL1) identified in patients with Familial Interstitial Pneumonia (FIP). We curated pathogenic and neutral RTEL1 variants from the literature and public databases. We then used homology modeling to construct a 3D structural model of RTEL1 and mapped known variants into this structure. We next developed a pathogenicity prediction algorithm based on proximity to known disease causing and neutral variants and evaluated its performance with leave-one-out cross-validation. We further validated our predictions with segregation analyses, telomere lengths, and mutagenesis data from the homologous XPD protein. Our algorithm for classifying RTEL1 VUS based on spatial proximity to pathogenic and neutral variation accurately distinguished 7 known pathogenic from 29 neutral variants (ROC AUC = 0.85) in the N-terminal domains of RTEL1. Pathogenic proximity scores were also significantly correlated with effects on ATPase activity (Pearson r = -0.65, p = 0.0004) in XPD, a related helicase. Applying the algorithm to 13 VUS identified from sequencing of RTEL1 from patients predicted five out of six disease-segregating VUS to be pathogenic. We provide structural hypotheses regarding how these mutations may disrupt RTEL1 ATPase and helicase function. Spatial analysis of missense variation accurately classified candidate VUS in RTEL1 and suggests how such variants cause disease. Incorporating

Cerebrospinal fluid neurofilament light concentration in motor neuron disease and frontotemporal dementia predicts survival.

Science.gov (United States)

Skillbäck, Tobias; Mattsson, Niklas; Blennow, Kaj; Zetterberg, Henrik

2017-08-01

To aid diagnostics, patient stratification and studies seeking to find treatments for the related diseases motor neuron disease (MND) and frontotemporal dementia (FTD), there is a need to establish a way to assess disease severity and the amount of ongoing neurodegeneration. Previous studies have suggested that cerebrospinal fluid (CSF) neurofilament light (NFL) may serve this purpose. We cross-referenced the Swedish mortality registry with the laboratory database at Sahlgrenska University Hospital to produce a dataset of CSF NFL concentrations and mortality information for 715 MND patients, 87 FTD patients, and 107 healthy controls. Biomarker concentrations were analysed in relation to recorded cause of death and time of death. MND patients had significantly higher CSF NFL concentrations than FTD patients. Both groups had significantly higher concentrations than the healthy controls (mean 709% increase in MND and 307% increase in FTD). Higher concentrations of CSF NFL were associated with shorter survival in both MND and FTD. The results of this study strengthen the notion of CSF NFL as a useful tool for determining disease intensity in MND and FTD patients. Further studies in patient cohorts with clinically subtyped and genetically classified diagnoses are needed.

Distinct perfusion patterns in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies

International Nuclear Information System (INIS)

Binnewijzend, Maja A.A.; Wattjes, Mike P.; Berckel, Bart N.M. van; Barkhof, Frederik; Kuijer, Joost P.A.; Flier, Wiesje M. van der; Benedictus, Marije R.; Moeller, Christiane M.; Pijnenburg, Yolande A.L.; Lemstra, Afina W.; Prins, Niels D.; Scheltens, Philip

2014-01-01

To compare pseudo-continuous arterial spin-labelled (PCASL) magnetic resonance imaging (MRI) measured quantitative cerebral blood flow (CBF) of patients with frontotemporal dementia (FTD), dementia with Lewy Bodies (DLB), Alzheimer's disease (AD) and controls, in a region of interest (ROI) and voxel-wise fashion. We analysed whole-brain 3D fast-spin-echo PCASL images of 20 FTD patients, 14 DLB patients, 48 AD patients and 50 controls from the Amsterdam Dementia Cohort. Regional CBF patterns were compared using analyses of variance for repeated measures. Permutation tests were used for voxel-wise comparisons. Analyses were performed using uncorrected and partial volume corrected (PVC) maps. All analyses were corrected for age and sex. There was an interaction between diagnosis and region (p < 0.001), implying differences in regional CBF changes between diagnostic groups. In AD patients, CBF was decreased in all supratentorial regions, most prominently so in the posterior regions. DLB patients showed lowest CBF values throughout the brain, but temporal CBF was preserved. Supratentorial PVC cortical CBF values were lowest in the frontal lobes in FTD patients, and in the temporal lobes in AD patients. Patients with AD, FTD and DLB display distinct patterns of quantitative regional CBF changes. 3D-PCASL may provide additional value in the workup of dementia patients. (orig.)

Data-variant kernel analysis

CERN Document Server

Motai, Yuichi

2015-01-01

Describes and discusses the variants of kernel analysis methods for data types that have been intensely studied in recent years This book covers kernel analysis topics ranging from the fundamental theory of kernel functions to its applications. The book surveys the current status, popular trends, and developments in kernel analysis studies. The author discusses multiple kernel learning algorithms and how to choose the appropriate kernels during the learning phase. Data-Variant Kernel Analysis is a new pattern analysis framework for different types of data configurations. The chapters include

Functional communication ability in frontotemporal lobar degeneration and Alzheimer's disease

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Isabel Albuquerque M. de Carvalho

Full Text Available Abstract Functional communication is crucial for independent and efficient communicative behavior in response to every day activities. In the course of dementia progression, cognitive losses may impair these abilities. For this reason, functional communication assessment should be part of a formal assessment to quantify and qualify the impact of deficiency on patients' lives. Objective: To compare functional communication abilities in fronto-temporal lobar degeneration (FLTD and Alzheimer's disease (AD. Methods: Six AD patients (mean age: 82.50±2.66 years; mean education: 5.67±3.61 years, and eight FTLD patients (mean age: 57.13±9.63 years; mean education: 10.86±6.91 years had their close relatives answer the Functional Assessment of Communication Skills for Adults (Asha-facs . Statistical analyses correlated the performance on each of the Asha-facs domains (social communication, communication of basic needs; reading, writing, number concept and daily planning between both groups. Results: Analyses showed that functional communication was similar for AD and FTLD patients. Only two items had statistical difference, namely 'Comprehension of inference' (AD 6.7±1.33; FTLD 2.43±2.30, p=0.017 and 'capacity to make basic money transactions' (AD 2.17±2.04; FTLD 4.00±0.90, p=0.044. Comparison among the four domains' mean scores revealed no significant difference. Conclusion: The Asha-facs is a useful instrument to characterize functional communication abilities in both FTLD and AD. Nevertheless, the analysis presented for this sample showed that the Asha-facs could not discriminate which aspects of the FTLD and AD differed.

Combinations of Genetic Variants Occurring Exclusively in Patients

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Erling Mellerup

Full Text Available In studies of polygenic disorders, scanning the genetic variants can be used to identify variant combinations. Combinations that are exclusively found in patients can be separated from those combinations occurring in control persons. Statistical analyses can be performed to determine whether the combinations that occur exclusively among patients are significantly associated with the investigated disorder. This research strategy has been applied in materials from various polygenic disorders, identifying clusters of patient-specific genetic variant combinations that are significant associated with the investigated disorders. Combinations from these clusters are found in the genomes of up to 55% of investigated patients, and are not present in the genomes of any control persons. Keywords: Genetic variants, Polygenic disorder, Combinations of genetic variants, Patient-specific combinations

Rates of Amyloid Imaging Positivity in Patients With Primary Progressive Aphasia

Science.gov (United States)

Santos-Santos, Miguel A.; Rabinovici, Gil D.; Iaccarino, Leonardo; Ayakta, Nagehan; Tammewar, Gautam; Lobach, Iryna; Henry, Maya L.; Hubbard, Isabel; Mandelli, Maria Luisa; Spinelli, Edoardo; Miller, Zachary A.; Pressman, Peter S.; O’Neil, James P.; Ghosh, Pia; Lazaris, Andreas; Meyer, Marita; Watson, Christa; Yoon, Soo Jin; Rosen, Howard J.; Grinberg, Lea; Seeley, William W.; Miller, Bruce L.; Jagust, William J.; Gorno-Tempini, Maria Luisa

2018-01-01

with available autopsy data (2 of 4 and 2 of 3, respectively) all had a primary frontotemporal lobar degeneration and secondary Alzheimer disease pathologic diagnoses, whereas autopsy of 2 patients with amyloid PET–positive logopenic variant PPA confirmed Alzheimer disease. One mixed PPA patient with a negative amyloid PET scan had Pick disease at autopsy. CONCLUSIONS AND RELEVANCE Primary progressive aphasia variant diagnosis according to the current classification scheme is associated with Alzheimer disease biomarker status, with the logopenic variant being associated with carbon 11–labeled Pittsburgh Compound-B positivity in more than 95% of cases. Furthermore, in the presence of a clinical syndrome highly predictive of frontotemporal lobar degeneration pathology, biomarker positivity for Alzheimer disease may be associated more with mixed pathology rather than primary Alzheimer disease. PMID:29309493

The unexpected co-occurrence of GRN and MAPT p.A152T in Basque families: Clinical and pathological characteristics.

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Fermin Moreno

Full Text Available The co-occurrence of the c.709-1G>A GRN mutation and the p.A152T MAPT variant has been identified in 18 Basque families affected by frontotemporal dementia (FTD. We aimed to investigate the influence of the p.A152T MAPT variant on the clinical and neuropathological features of these Basque GRN families.We compared clinical characteristics of 14 patients who carried the c.709-1G>A GRN mutation (GRN+/A152T- with 21 patients who carried both the c.709-1G>A GRN mutation and the p.A152T MAPT variant (GRN+/A152T+. Neuropsychological data (n = 17 and plasma progranulin levels (n = 23 were compared between groups, and 7 subjects underwent neuropathological studies. We genotyped six short tandem repeat markers in the two largest families. By the analysis of linkage disequilibrium decay in the haplotype block we estimated the time when the first ancestor to carry both genetic variants emerged. GRN+/A152T+ and GRN+/A152T- patients shared similar clinical and neuropsychological features and plasma progranulin levels. All were diagnosed with an FTD disorder, including behavioral variant FTD or non fluent / agrammatic variant primary progressive aphasia, and shared a similar pattern of neuropsychological deficits, predominantly in executive function, memory, and language. All seven participants with available brain autopsies (6 GRN+/A152T+, 1 GRN+/A152T- showed frontotemporal lobar degeneration with TDP-43 inclusions (type A classification, which is characteristic of GRN carriers. Additionally, all seven showed mild to moderate tau inclusion burden: five cases lacked β-amyloid pathology and two cases had Alzheimer's pathology. The co-occurrence of both genes within one individual is recent, with the birth of the first GRN+/A152T+ individual estimated to be within the last 50 generations (95% probability.In our sample, the p.A152T MAPT variant does not appear to show a discernible influence on the clinical phenotype of GRN carriers. Whether p.A152T confers a

Determination of uranium by luminescent method (tablet variant)

International Nuclear Information System (INIS)

Sergeev, A.N.; Yufa, B.Ya.

1985-01-01

A new tablet variant of luminescent determination of uranium in rocks is developed. The analytical process includes the following operations: sample decomposition, uranium separation from luminescence quencher impurities, preparation of luminescent sample (tablet), photometry of the tablet. The method has two variants developed: the first one is characterized by a more hard decomposition, sample mass being 0.2 g; the second variant has a better detection limit (5x10 -6 %), the sample mass being 0.2-1 g. Procedures of the sample preparation for both variants of analysis are described

NMNAT1 variants cause cone and cone-rod dystrophy.

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Nash, Benjamin M; Symes, Richard; Goel, Himanshu; Dinger, Marcel E; Bennetts, Bruce; Grigg, John R; Jamieson, Robyn V

2018-03-01

Cone and cone-rod dystrophies (CD and CRD, respectively) are degenerative retinal diseases that predominantly affect the cone photoreceptors. The underlying disease gene is not known in approximately 75% of autosomal recessive cases. Variants in NMNAT1 cause a severe, early-onset retinal dystrophy called Leber congenital amaurosis (LCA). We report two patients where clinical phenotyping indicated diagnoses of CD and CRD, respectively. NMNAT1 variants were identified, with Case 1 showing an extremely rare homozygous variant c.[271G > A] p.(Glu91Lys) and Case 2 compound heterozygous variants c.[53 A > G];[769G > A] p.(Asn18Ser);(Glu257Lys). The detailed variant analysis, in combination with the observation of an associated macular atrophy phenotype, indicated that these variants were disease-causing. This report demonstrates that the variants in NMNAT1 may cause CD or CRD associated with macular atrophy. Genetic investigations of the patients with CD or CRD should include NMNAT1 in the genes examined.

Sedentary behaviours and obesity in adults: the Cardiovascular Risk in Young Finns Study

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Heinonen, I; Helajärvi, H; Pahkala, K; Heinonen, O J; Hirvensalo, M; Pälve, K; Tammelin, T; Yang, X; Juonala, M; Mikkilä, V; Kähönen, M; Lehtimäki, T; Viikari, J; Raitakari, O T

2013-01-01

Objective Sedentary behaviour may contribute to the development of obesity. We investigated the relations between different types of sedentary behaviour and adiposity markers in a well-characterised adult population after controlling for a wide range of potential confounders. Design Cross-sectional study. Setting The Cardiovascular Risk in Young Finns Multicenter Study. Participants Sedentary time (TV viewing, computer time, reading, music/radio listening and other relaxation) was assessed with a questionnaire for 1084 women and 909 men aged 30–45 years. Other study variables included occupational and leisure-time physical activity, sleep duration, socioeconomic status, smoking, alcohol consumption, energy intake, adherence to the recommended diet, multiple individual food items, age and genetic variants associated with body mass index (BMI). Primary outcome measures BMI in kg/m2 and waist circumference (WC in cm). Results Of the different sedentary behaviour types, TV viewing was most consistently related to higher BMI and WC, both in men and women. One additional daily TV hour was associated with a 1.81±0.44 cm larger WC in women and 2 cm±0.44 cm in men (both psedentary behaviour remained associated with adiposity indices only in women. Conclusions Out of the different types of sedentary behaviour, TV viewing was most consistently associated with adiposity markers in adults. Partial dilution of these associations after adjustments for covariates suggests that the obesogenic effects of TV viewing are partly mediated by other lifestyle factors. PMID:23794543

Interpersonal traits change as a function of disease type and severity in degenerative brain diseases.

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Sollberger, Marc; Neuhaus, John; Ketelle, Robin; Stanley, Christine M; Beckman, Victoria; Growdon, Matthew; Jang, Jung; Miller, Bruce L; Rankin, Katherine P

2011-07-01

Different degenerative brain diseases result in distinct personality changes as a result of divergent patterns of brain damage; however, little is known about the natural history of these personality changes throughout the course of each disease. To investigate how interpersonal traits change as a function of degenerative brain disease type and severity. Using the Interpersonal Adjective Scales, informant ratings of retrospective premorbid and current scores for dominance, extraversion, warmth and ingenuousness were collected annually for 1 to 4 years on 188 patients (67 behavioural variant frontotemporal dementia (bvFTD), 40 semantic dementia (SemD), 81 Alzheimer's disease (AD)) and 65 older healthy controls. Using random coefficient models, interpersonal behaviour scores at very mild, mild or moderate-to-severe disease stages were compared within and between patient groups. Group-level changes from premorbid personality occurred as a function of disease type and severity, and were apparent even at a very mild disease stage (Clinical Dementia Rating=0.5) for all three diseases. Decreases in interpersonal traits were associated with emotional affiliation (ie, extraversion, warmth and ingenuousness) and more rigid interpersonal behaviour differentiated bvFTD and SemD patients from AD patients. Specific changes in affiliative interpersonal traits differentiate degenerative brain diseases even at a very mild disease stage, and patterns of personality change differ across bvFTD, SemD and AD with advancing disease. This study describes the typical progression of change of interpersonal traits in each disease, improving the ability of clinicians and caregivers to predict and plan for symptom progression.

Bayesian detection of causal rare variants under posterior consistency.

KAUST Repository

Liang, Faming

2013-07-26

Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD), to tackle this problem. The new method simultaneously addresses two issues: (i) (Global association test) Are there any of the variants associated with the disease, and (ii) (Causal variant detection) Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI) Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

Bayesian detection of causal rare variants under posterior consistency.

Directory of Open Access Journals (Sweden)

Faming Liang

Full Text Available Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD, to tackle this problem. The new method simultaneously addresses two issues: (i (Global association test Are there any of the variants associated with the disease, and (ii (Causal variant detection Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

Bayesian detection of causal rare variants under posterior consistency.

KAUST Repository

Liang, Faming; Xiong, Momiao

2013-01-01

Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD), to tackle this problem. The new method simultaneously addresses two issues: (i) (Global association test) Are there any of the variants associated with the disease, and (ii) (Causal variant detection) Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI) Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

Amino acid changes in disease-associated variants differ radically from variants observed in the 1000 genomes project dataset.

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Tjaart A P de Beer

Full Text Available The 1000 Genomes Project data provides a natural background dataset for amino acid germline mutations in humans. Since the direction of mutation is known, the amino acid exchange matrix generated from the observed nucleotide variants is asymmetric and the mutabilities of the different amino acids are very different. These differences predominantly reflect preferences for nucleotide mutations in the DNA (especially the high mutation rate of the CpG dinucleotide, which makes arginine mutability very much higher than other amino acids rather than selection imposed by protein structure constraints, although there is evidence for the latter as well. The variants occur predominantly on the surface of proteins (82%, with a slight preference for sites which are more exposed and less well conserved than random. Mutations to functional residues occur about half as often as expected by chance. The disease-associated amino acid variant distributions in OMIM are radically different from those expected on the basis of the 1000 Genomes dataset. The disease-associated variants preferentially occur in more conserved sites, compared to 1000 Genomes mutations. Many of the amino acid exchange profiles appear to exhibit an anti-correlation, with common exchanges in one dataset being rare in the other. Disease-associated variants exhibit more extreme differences in amino acid size and hydrophobicity. More modelling of the mutational processes at the nucleotide level is needed, but these observations should contribute to an improved prediction of the effects of specific variants in humans.

Electrophoretic variants of blood proteins in japanese, 5

International Nuclear Information System (INIS)

Fujita, Mikio; Satoh, Chiyoko; Asakawa, Jun-ichi; Nagahata, Yuko; Tanaka, Yoshiko; Hazama, Ryuji; Goriki, Kazuaki.

1985-08-01

The plasma ceruloplasmin (CP) of 22,367 children of atomic bomb survivors in Hiroshima and Nagasaki was examined for variants by electrophoresis. The sample was composed of 14,964 unrelated children and 7,403 siblings of the unrelated persons. A total of seven types of electrophoretic variants were detected; four migrating anodally and three cathodally to the normal B band. We have reported two of these variants, CP A sub(NG1) and CP C sub(NG1), previously but the other five, CP A sub(NG2), CP A sub(HR1), CP A sub(HR2), CP C sub(HR1), and CP C sub(HR2), are newly identified. The allelic frequency of CP*CNG1 was 0.00916, so that the variant is considered to be a polymorphic allele. Homozygosity for the CP*CNG1 allele was detected in five individuals. This is the first report of a homozygous phenotype for a CP variant in a Japanese population. Family study of the new five variants all demonstrated patterns of codominant inheritance. (author)

A review of game-theoretic models of road user behaviour.

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Elvik, Rune

2014-01-01

This paper reviews game-theoretic models that have been developed to explain road user behaviour in situations where road users interact with each other. The paper includes the following game-theoretic models: 1.A general model of the interaction between road users and their possible reaction to measures improving safety (behavioural adaptation).2.Choice of vehicle size as a Prisoners’ dilemma game.3.Speed choice as a co-ordination game.4.Speed compliance as a game between drivers and the police.5.Merging into traffic from an acceleration lane as a mixed-strategy game.6.Choice of level of attention in following situations as an evolutionary game.7.Choice of departure time to avoid congestion as variant of a Prisoners’ dilemma game.8.Interaction between cyclists crossing the road and car drivers.9.Dipping headlights at night well ahead of the point when glare becomes noticeable.10.Choice of evasive action in a situation when cars are on collision course. The models reviewed are different in many respects, but a common feature of the models is that they can explain how informal norms of behaviour can develop among road users and be sustained even if these informal norms violate the formal regulations of the traffic code. Game-theoretic models are not applicable to every conceivable interaction between road users or to situations in which road users choose behaviour without interacting with other road users. Nevertheless, it is likely that game-theoretic models can be applied more widely than they have been until now. Copyright © 2013 Elsevier Ltd. All rights reserved.

Why do patients with neurodegenerative frontal syndrome fail to answer: 'In what way are an orange and a banana alike?'.

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Lagarde, Julien; Valabrègue, Romain; Corvol, Jean-Christophe; Garcin, Béatrice; Volle, Emmanuelle; Le Ber, Isabelle; Vidailhet, Marie; Dubois, Bruno; Levy, Richard

2015-02-01

Concept formation is the ability to create an abstract link between dissimilar objects or thoughts and is crucial for abstract and creative thinking. This process is related to the integrity of the prefrontal cortex, given the altered performances reported in patients with frontal damage, particularly those suffering from the behavioural variant of frontotemporal dementia. However, the cognitive mechanisms and neural bases of verbal concept formation are not clearly understood. The present study was aimed at addressing the following unresolved issues regarding concept formation in the field of neurology and cognitive neuroscience: (i) Are alterations in concept formation specific to frontotemporal dementia or are they also present in other cortical neurodegenerative disorders such as Alzheimer's disease? (ii) Is impaired performance in concept formation due to cortical lesions specific to frontotemporal dementia or to a cortico-subcortical frontal syndrome? and (iii) What are the cognitive mechanisms and neural bases underlying concept formation? To address these questions, we designed the Verbal Concept Formation Task, an experimental paradigm based on the similarities test. Patients presenting with severe frontal dysfunction (frontotemporal dementia, n = 18, and the Richardson form of progressive supranuclear palsy, n = 21) or with medial temporal pathology (amnestic mild cognitive impairment or Alzheimer's disease, n = 14) and healthy participants (n = 18) were given the Verbal Concept Formation Task and a large battery of neuropsychological tests. In addition, all participants underwent 3D T1-weighted MRI to analyse grey matter volume using voxel-based morphometry. Frontal patients were significantly impaired on the Verbal Concept Formation Task as compared to non-frontal participants (P = 0.00001). Global performance score was positively correlated with scores in cognitive tasks assessing executive functions and with grey matter volume in several areas, mostly

The role of the innate immune system in Alzheimer's disease and frontotemporal lobar degeneration: an eye on microglia.

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Ridolfi, Elisa; Barone, Cinzia; Scarpini, Elio; Galimberti, Daniela

2013-01-01

In the last few years, genetic and biomolecular mechanisms at the basis of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) have been unraveled. A key role is played by microglia, which represent the immune effector cells in the central nervous system (CNS). They are extremely sensitive to the environmental changes in the brain and are activated in response to several pathologic events within the CNS, including altered neuronal function, infection, injury, and inflammation. While short-term microglial activity has generally a neuroprotective role, chronic activation has been implicated in the pathogenesis of neurodegenerative disorders, including AD and FTLD. In this framework, the purpose of this review is to give an overview of clinical features, genetics, and novel discoveries on biomolecular pathogenic mechanisms at the basis of these two neurodegenerative diseases and to outline current evidence regarding the role played by activated microglia in their pathogenesis.

Family caregivers of individuals with frontotemporal dementia: examining the relationship between coping and caregiver physical and mental health.

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Wong, Cindy C; Wallhagen, Margaret I

2014-01-01

To identify strategies to assist family caregivers of individuals with frontotemporal dementia (FTD) in dealing with their caregiving demands, nurses must understand these family members' unique needs and how they currently deal with their demands. The purpose of this study was to examine the relationship between coping and caregiver physical and mental health among FTD family caregivers. Participants were primary caregivers of individuals with FTD (with behavioral symptoms) living at home (N = 61). A small positive association was noted between problem-focused coping and caregiver physical health (r = 0.29, p caregiver mental health (r = 0.21, p = 0.10). However, multiple regression analysis showed that emotion-focused coping (β = 0.46, p caregiver mental health and explained approximately 14% of its variance. These findings support the potential value of emotion-focused coping strategies when dealing with behavioral symptoms manifested by individuals with FTD. Copyright 2014, SLACK Incorporated.

Association analysis identifies ZNF750 regulatory variants in psoriasis

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Birnbaum Ramon Y

2011-12-01

Full Text Available Abstract Background Mutations in the ZNF750 promoter and coding regions have been previously associated with Mendelian forms of psoriasis and psoriasiform dermatitis. ZNF750 encodes a putative zinc finger transcription factor that is highly expressed in keratinocytes and represents a candidate psoriasis gene. Methods We examined whether ZNF750 variants were associated with psoriasis in a large case-control population. We sequenced the promoter and exon regions of ZNF750 in 716 Caucasian psoriasis cases and 397 Caucasian controls. Results We identified a total of 47 variants, including 38 rare variants of which 35 were novel. Association testing identified two ZNF750 haplotypes associated with psoriasis (p ZNF750 promoter and 5' UTR variants displayed a 35-55% reduction of ZNF750 promoter activity, consistent with the promoter activity reduction seen in a Mendelian psoriasis family with a ZNF750 promoter variant. However, the rare promoter and 5' UTR variants identified in this study did not strictly segregate with the psoriasis phenotype within families. Conclusions Two haplotypes of ZNF750 and rare 5' regulatory variants of ZNF750 were found to be associated with psoriasis. These rare 5' regulatory variants, though not causal, might serve as a genetic modifier of psoriasis.

[Clinico-pathogenetic variants of chronic gastritis].

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Chernin, V V; Dzhulaĭ, G S

2004-01-01

To evaluate specific features of the course of chronic gastritis (CG), morphofunctional condition of gastric mucosa, vegetative regulation, adrenergic and cholinergic shifts, histamine metabolism and effects of exogenic and endogenic risk factors in CG patients; to study clinicopathogenetic variants of CG. A total of 311 CG patients aged from 16 to 72 years were studied. They were divided into three groups by their gastric mucosa condition. The control group consisted of 30 healthy donors. The following parameters were studied: visual and histological condition of gastric mucosa, total acidity, the levels of free hydrochloric acid, pepsin, bioelectric gastric activity, general autonomic tonicity, cholinesterase activity. Three clinicopathogenetic variants of the disease have been identified. Variant 1 was characterized by a recurrent course, subjective manifestation of the disease only in exacerbation, surface (primarily antral) mucosal affection, normal or enhanced secretory and motor functions of the stomach, adequate reaction of acid production to caffeine and histamine stimulation, parasympathicotonia, absolute hyperhistaminemia, relative hypoacetylcholinemia, subnormal urinary excretion of adrenalin. Variant 2 manifested with rare recurrences, longer and more severe exacerbations, frequent spontaneous and provoked aggravations, moderate focal atrophy of the mucosa, secretory insufficiency with adequate reaction to histamine and minor to caffeine stimuli, hypomotor gastric dyskinesia, vegetative eutonia, normohistaminemia, absolute hypoacetylcholinemia, subnormal urinary excretion of noradrenaline. Variant 3 runs without definite remissions and exacerbations, with continuous abdominal pain and dyspepsia, frequent spontaneous aggravations, marked extended mucosal atrophy with secretory insufficiency up to achlorhydria, no stimulation of acid production in response to caffeine and histamine, gastric hypomotility, sympathicotonia, absolute hypohistaminemia

FTLD-TDP with motor neuron disease, visuospatial impairment and a progressive supranuclear palsy-like syndrome: broadening the clinical phenotype of TDP-43 proteinopathies. A report of three cases

Directory of Open Access Journals (Sweden)

Holmerová Iva

2011-05-01

Full Text Available Abstract Background Frontotemporal lobar degeneration with ubiquitin and TDP-43 positive neuronal inclusions represents a novel entity (FTLD-TDP that may be associated with motor neuron disease (FTLD-MND; involvement of extrapyramidal and other systems has also been reported. Case presentation We present three cases with similar clinical symptoms, including Parkinsonism, supranuclear gaze palsy, visuospatial impairment and a behavioral variant of frontotemporal dementia, associated with either clinically possible or definite MND. Neuropathological examination revealed hallmarks of FTLD-TDP with major involvement of subcortical and, in particular, mesencephalic structures. These cases differed in onset and progression of clinical manifestations as well as distribution of histopathological changes in the brain and spinal cord. Two cases were sporadic, whereas the third case had a pathological variation in the progranulin gene 102 delC. Conclusions Association of a "progressive supranuclear palsy-like" syndrome with marked visuospatial impairment, motor neuron disease and early behavioral disturbances may represent a clinically distinct phenotype of FTLD-TDP. Our observations further support the concept that TDP-43 proteinopathies represent a spectrum of disorders, where preferential localization of pathogenetic inclusions and neuronal cell loss defines clinical phenotypes ranging from frontotemporal dementia with or without motor neuron disease, to corticobasal syndrome and to a progressive supranuclear palsy-like syndrome.

Analysis of the energy development variants

International Nuclear Information System (INIS)

Tsvetanov, P.

1990-01-01

Analysis of the variants of energy development is made as the third stage of a procedure of energy-economy interrelations dynamics study, the other two stages being the scenarios description and the formulation of the variants. This stage includes a research on the dimensions and the dynamics of the resources demands, the general features and the trends of the national energy development. There is a presentation of a comparative analysis of the variants in terms of economic indices and energy values, computed by the model IMPACT-B. A resource evaluation of the development variants is given in terms of investments, requirements (direct, indirect and total) and limited national resources demands of the energy system. The trends of the national energy development discussed are: trends characterizing the changes in the structure of the energy consumption, resulting from changes in the economy; trends of the energy system impact on the productivity of labor; general trends of the proportionality in the industrial, the household and services sector development. 16 refs., 16 figs., 4 tabs. (R.Ts.)

Detecting very low allele fraction variants using targeted DNA sequencing and a novel molecular barcode-aware variant caller.

Science.gov (United States)

Xu, Chang; Nezami Ranjbar, Mohammad R; Wu, Zhong; DiCarlo, John; Wang, Yexun

2017-01-03

Detection of DNA mutations at very low allele fractions with high accuracy will significantly improve the effectiveness of precision medicine for cancer patients. To achieve this goal through next generation sequencing, researchers need a detection method that 1) captures rare mutation-containing DNA fragments efficiently in the mix of abundant wild-type DNA; 2) sequences the DNA library extensively to deep coverage; and 3) distinguishes low level true variants from amplification and sequencing errors with high accuracy. Targeted enrichment using PCR primers provides researchers with a convenient way to achieve deep sequencing for a small, yet most relevant region using benchtop sequencers. Molecular barcoding (or indexing) provides a unique solution for reducing sequencing artifacts analytically. Although different molecular barcoding schemes have been reported in recent literature, most variant calling has been done on limited targets, using simple custom scripts. The analytical performance of barcode-aware variant calling can be significantly improved by incorporating advanced statistical models. We present here a highly efficient, simple and scalable enrichment protocol that integrates molecular barcodes in multiplex PCR amplification. In addition, we developed smCounter, an open source, generic, barcode-aware variant caller based on a Bayesian probabilistic model. smCounter was optimized and benchmarked on two independent read sets with SNVs and indels at 5 and 1% allele fractions. Variants were called with very good sensitivity and specificity within coding regions. We demonstrated that we can accurately detect somatic mutations with allele fractions as low as 1% in coding regions using our enrichment protocol and variant caller.

On the properties of a variant of the Riccati system of equations

International Nuclear Information System (INIS)

Sarkar, Amartya; Guha, Partha; Bhattacharjee, J K; Mallik, A K; Ghose-Choudhury, Anindya; Leach, P G L

2012-01-01

A variant of the generalized Riccati system of equations is considered. It is shown that for α = 2n + 3 the system admits a bilagrangian description and the dynamics has a node at the origin, whereas for α much smaller than a critical value the dynamics is periodic, the origin being a centre. It is found that the solution changes from being periodic to aperiodic at a critical point, α c = 2√(2(n+1)), which is independent of the initial conditions. This behaviour is explained by finding a scaling argument via which the phase trajectories corresponding to different initial conditions collapse onto a single universal orbit. Numerical evidence for the transition is shown. Further, using a perturbative renormalization group argument, it is conjectured that the oscillator exhibits isochronous oscillations. The correctness of the conjecture is established numerically. (paper)

The established and emerging roles of astrocytes and microglia in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

Directory of Open Access Journals (Sweden)

Rowan Andrew Warren Radford

2015-10-01

Full Text Available Amyotrophic lateral sclerosis (ALS and Frontotemporal Dementia (FTD are two progressive, fatal neurodegenerative syndromes with considerable clinical, genetic and pathological overlap. Clinical symptoms of FTD can be seen in ALS patients and vice versa, recent genetic discoveries conclusive link the two diseases, and several common molecular players have been identified (TDP-43, FUS, C9ORF72.The definitive aetiologies of ALS and FTD are currently unknown and both disorders lack a cure. Glia, specifically astrocytes and microglia are heavily implicated in the onset and progression of neurodegeneration witnessed in ALS and FTD. In this review, we summarise the current understanding of the role of microglia and astrocytes involved in ALS and FTD, highlighting their recent implications in neuroinflammation, alterations in waste clearance involving phagocytosis and the newly described glymphatic system, and vascular abnormalities. Elucidating the precise mechanisms of how astrocytes and microglia are involved in ALS and FTD will be crucial in characterising these two disorders and may represent more effective interventions for disease progression and treatment options in the future.

The established and emerging roles of astrocytes and microglia in amyotrophic lateral sclerosis and frontotemporal dementia.

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Radford, Rowan A; Morsch, Marco; Rayner, Stephanie L; Cole, Nicholas J; Pountney, Dean L; Chung, Roger S

2015-01-01

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two progressive, fatal neurodegenerative syndromes with considerable clinical, genetic and pathological overlap. Clinical symptoms of FTD can be seen in ALS patients and vice versa. Recent genetic discoveries conclusively link the two diseases, and several common molecular players have been identified (TDP-43, FUS, C9ORF72). The definitive etiologies of ALS and FTD are currently unknown and both disorders lack a cure. Glia, specifically astrocytes and microglia are heavily implicated in the onset and progression of neurodegeneration witnessed in ALS and FTD. In this review, we summarize the current understanding of the role of microglia and astrocytes involved in ALS and FTD, highlighting their recent implications in neuroinflammation, alterations in waste clearance involving phagocytosis and the newly described glymphatic system, and vascular abnormalities. Elucidating the precise mechanisms of how astrocytes and microglia are involved in ALS and FTD will be crucial in characterizing these two disorders and may represent more effective interventions for disease progression and treatment options in the future.

Identifying structural variants using linked-read sequencing data.

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Elyanow, Rebecca; Wu, Hsin-Ta; Raphael, Benjamin J

2017-11-03

Structural variation, including large deletions, duplications, inversions, translocations, and other rearrangements, is common in human and cancer genomes. A number of methods have been developed to identify structural variants from Illumina short-read sequencing data. However, reliable identification of structural variants remains challenging because many variants have breakpoints in repetitive regions of the genome and thus are difficult to identify with short reads. The recently developed linked-read sequencing technology from 10X Genomics combines a novel barcoding strategy with Illumina sequencing. This technology labels all reads that originate from a small number (~5-10) DNA molecules ~50Kbp in length with the same molecular barcode. These barcoded reads contain long-range sequence information that is advantageous for identification of structural variants. We present Novel Adjacency Identification with Barcoded Reads (NAIBR), an algorithm to identify structural variants in linked-read sequencing data. NAIBR predicts novel adjacencies in a individual genome resulting from structural variants using a probabilistic model that combines multiple signals in barcoded reads. We show that NAIBR outperforms several existing methods for structural variant identification - including two recent methods that also analyze linked-reads - on simulated sequencing data and 10X whole-genome sequencing data from the NA12878 human genome and the HCC1954 breast cancer cell line. Several of the novel somatic structural variants identified in HCC1954 overlap known cancer genes. Software is available at compbio.cs.brown.edu/software. braphael@princeton.edu. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Amygdala TDP-43 Pathology in Frontotemporal Lobar Degeneration and Motor Neuron Disease.

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Takeda, Takahiro; Seilhean, Danielle; Le Ber, Isabelle; Millecamps, Stéphanie; Sazdovitch, Véronique; Kitagawa, Kazuo; Uchihara, Toshiki; Duyckaerts, Charles

2017-09-01

TDP-43-positive inclusions are present in the amygdala in frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND) including amyotrophic lateral sclerosis. Behavioral abnormalities, one of the chief symptoms of FTLD, could be, at least partly, related to amygdala pathology. We examined TDP-43 inclusions in the amygdala of patients with sporadic FTLD/MND (sFTLD/MND), FTLD/MND with mutation of the C9ORF72 (FTLD/MND-C9) and FTLD with mutation of the progranulin (FTLD-GRN). TDP-43 inclusions were common in each one of these subtypes, which can otherwise be distinguished on topographical and genetic grounds. Conventional and immunological stainings were performed and we quantified the numerical density of inclusions on a regional basis. TDP-43 inclusions in amygdala could be seen in 10 out of 26 sFTLD/MND cases, 5 out of 9 FTLD/MND-C9 cases, and all 4 FTLD-GRN cases. Their numerical density was lower in FTLD/MND-C9 than in sFTLD/MND and FTLD-GRN. TDP-43 inclusions were more numerous in the ventral region of the basolateral nucleus group in all subtypes. This contrast was apparent in sporadic and C9-mutated FTLD/MND, while it was less evident in FTLD-GRN. Such differences in subregional involvement of amygdala may be related to the region-specific neuronal connections that are differentially affected in FTLD/MND and FTLD-GRN. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

In 17q21.31 microdeletion syndrome, hypersocial behaviour may be part of the neuropsychological phenotype

NARCIS (Netherlands)

Egger, J.I.M.; Wingbermühle, P.A.M.; Dijkman, M.W.; Verhoeven, W.M.A.

2013-01-01

Objective: The 17q21.31 microdeletion encompasses among others the microtubule associated protein tau (MAPT) gene that is highly expressed in the brain and is involved in several neurodegenerative disorders such as fronto-temporal dementias and progressive supranuclear palsy. It can be postulated

Progranulin Gene Therapy Improves Lysosomal Dysfunction and Microglial Pathology Associated with Frontotemporal Dementia and Neuronal Ceroid Lipofuscinosis.

Science.gov (United States)

Arrant, Andrew E; Onyilo, Vincent C; Unger, Daniel E; Roberson, Erik D

2018-02-28

Loss-of-function mutations in progranulin, a lysosomal glycoprotein, cause neurodegenerative disease. Progranulin haploinsufficiency causes frontotemporal dementia (FTD) and complete progranulin deficiency causes CLN11 neuronal ceroid lipofuscinosis (NCL). Progranulin replacement is a rational therapeutic strategy for these disorders, but there are critical unresolved mechanistic questions about a progranulin gene therapy approach, including its potential to reverse existing pathology. Here, we address these issues using an AAV vector (AAV- Grn ) to deliver progranulin in Grn -/- mice (both male and female), which model aspects of NCL and FTD pathology, developing lysosomal dysfunction, lipofuscinosis, and microgliosis. We first tested whether AAV- Grn could improve preexisting pathology. Even with treatment after onset of pathology, AAV- Grn reduced lipofuscinosis in several brain regions of Grn -/- mice. AAV- Grn also reduced microgliosis in brain regions distant from the injection site. AAV-expressed progranulin was only detected in neurons, not in microglia, indicating that the microglial activation in progranulin deficiency can be improved by targeting neurons and thus may be driven at least in part by neuronal dysfunction. Even areas with sparse transduction and almost undetectable progranulin showed improvement, indicating that low-level replacement may be sufficiently effective. The beneficial effects of AAV- Grn did not require progranulin binding to sortilin. Finally, we tested whether AAV- Grn improved lysosomal function. AAV-derived progranulin was delivered to the lysosome, ameliorated the accumulation of LAMP-1 in Grn -/- mice, and corrected abnormal cathepsin D activity. These data shed light on progranulin biology and support progranulin-boosting therapies for NCL and FTD due to GRN mutations. SIGNIFICANCE STATEMENT Heterozygous loss-of-function progranulin ( GRN ) mutations cause frontotemporal dementia (FTD) and homozygous mutations cause neuronal

Persistent trigeminal artery/persistent trigeminal artery variant and coexisting variants of the head and neck vessels diagnosed using 3 T MRA

International Nuclear Information System (INIS)

Bai, M.; Guo, Q.; Li, S.

2013-01-01

Aim: To report the prevalence and characteristic features of persistent trigeminal artery (PTA), PTA variant (PTAV), and other variants of the head and neck vessels, identified using magnetic resonance angiography (MRA). Materials and methods: The three-dimensional (3D) time of flight (TOF) MRA and 3D contrast-enhanced (CE) MRA images of 6095 consecutive patients who underwent 3 T MRA at Liaocheng People's Hospital from 1 September 2008 through 31 May 2012 were retrospectively reviewed and analysed. Thirty-two patients were excluded because of suboptimal image quality or internal carotid artery (ICA) occlusion. Results: The prevalence of both PTA and PTAV was 0.63% (PTA, 26 cases; PTAV, 12 cases). The prevalence of coexisting variants of the head and neck vessels in cases of PTA/PTAV was 52.6% (20 of 38 cases). The vascular variants that coexisted with cases of PTA/PTAV were as follows: the intracranial arteries varied in 10 cases, the origin of the supra-aortic arteries varied in nine cases, the vertebral artery (VA) varied in 14 cases, and six cases displayed fenestrations. Fifteen of the 20 cases contained more than two types of variants. Conclusion: The prevalence of both PTA and PTAV was 0.63%. Although PTA and PTAV are rare vascular variants, they frequently coexist with other variants of the head and neck vessels. Multiple vascular variations can coexist in a single patient. Recognizing PTA, PTAV, and other variants of the head and neck vessels is crucial when planning a neuroradiological intervention or surgery. Recognizing the medial PTA is very important in clinical practice when performing trans-sphenoidal surgery on the pituitary as failure to do so could result in massive haemorrhage

Developing consistent pronunciation models for phonemic variants

CSIR Research Space (South Africa)

Davel, M

2006-09-01

Full Text Available Pronunciation lexicons often contain pronunciation variants. This can create two problems: It can be difficult to define these variants in an internally consistent way and it can also be difficult to extract generalised grapheme-to-phoneme rule sets...

Comparison of the BioRad Variant and Primus Ultra2 high-pressure liquid chromatography (HPLC) instruments for the detection of variant hemoglobins.

Science.gov (United States)

Gosselin, R C; Carlin, A C; Dwyre, D M

2011-04-01

Hemoglobin variants are a result of genetic changes resulting in abnormal or dys-synchronous hemoglobin chain production (thalassemia) or the generation of hemoglobin chain variants such as hemoglobin S. Automated high-pressure liquid chromatography (HPLC) systems have become the method of choice for the evaluation of patients suspected with hemoglobinopathies. In this study, we evaluated the performance of two HPLC methods used in the detection of common hemoglobin variants: Variant and Ultra2. There were 377 samples tested, 26% (99/377) with HbS, 8.5% (32/377) with HbC, 20.7% (78/377) with other hemoglobin variant or thalassemia, and 2.9% with increased hemoglobin A(1) c. The interpretations of each chromatograph were compared. There were no differences noted for hemoglobins A(0), S, or C. There were significant differences between HPLC methods for hemoglobins F, A(2), and A(1) c. However, there was good concordance between normal and abnormal interpretations (97.9% and 96.2%, respectively). Both Variant and Ultra2 HPLC methods were able to detect most common hemoglobin variants. There was better discrimination for fast hemoglobins, between hemoglobins E and A(2), and between hemoglobins S and F using the Ultra2 HPLC method. © 2010 Blackwell Publishing Ltd.

Frontotemporal lobar degeneration: old knowledge and new insight into the pathogenetic mechanisms of tau mutations

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Giacomina eRossi

2015-10-01

Full Text Available Frontotemporal lobar degeneration is a group of heterogeneous neurodegenerative diseases which includes tauopathies. In the central nervous system tau is the major microtubule-associated protein of neurons, promoting assembly and stabilization of microtubules required for morphogenesis and axonal transport. Primary tauopathies are characterized by deposition of abnormal fibrils of tau in neuronal and glial cells, leading to neuronal death, brain atrophy and eventually dementia.In genetic tauopathies mutations of tau gene impair the ability of tau to bind to microtubules, alter the normal ratio among tau isoforms and favour fibril formation.Recently, additional functions have been ascribed to tau and different pathogenetic mechanisms are then emerging. In fact, a role of tau in DNA protection and genome stability has been reported and chromosome aberrations have been found associated with tau mutations. Furthermore, newly structurally and functionally characterized mutations have suggested novel pathological features, such as a tendency to form oligomeric rather than fibrillar aggregates. Tau mutations affecting axonal transport and plasma membrane interaction have also been described.In this paper, we will review the pathogenetic mechanisms underlying tau mutations, focusing in particular on the less common aspects, so far poorly investigated.

Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects

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Sandra Almeida

2012-10-01

Full Text Available The pathogenic mechanisms of frontotemporal dementia (FTD remain poorly understood. Here we generated multiple induced pluripotent stem cell lines from a control subject, a patient with sporadic FTD, and an FTD patient with a novel heterozygous GRN mutation (progranulin [PGRN] S116X. In neurons and microglia differentiated from PGRN S116X induced pluripotent stem cells, the levels of intracellular and secreted PGRN were reduced, establishing patient-specific cellular models of PGRN haploinsufficiency. Through a systematic screen of inducers of cellular stress, we found that PGRN S116X neurons, but not sporadic FTD neurons, exhibited increased sensitivity to staurosporine and other kinase inhibitors. Moreover, the serine/threonine kinase S6K2, a component of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, was specifically downregulated in PGRN S116X neurons. Both increased sensitivity to kinase inhibitors and reduced S6K2 were rescued by PGRN expression. Our findings identify cell-autonomous, reversible defects in patient neurons with PGRN deficiency, and provide a compelling model for studying PGRN-dependent pathogenic mechanisms and testing potential therapies.

Faulty Suppression of Irrelevant Material in Patients with Thought Disorder Linked to Attenuated Frontotemporal Activation

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S. M. Arcuri

2012-01-01

Full Text Available Formal thought disorder is a feature schizophrenia that manifests as disorganized, incoherent speech, and is associated with a poor clinical outcome. The neurocognitive basis of this symptom is unclear but it is thought to involve an impairment in semantic processing classically described as a loosening of meaningful associations. Using a paradigm derived from the n400 event-related, potential, we examined the extent to which regional activation during semantic processing is altered in schizophrenic patients with formal thought disorder. Ten healthy control and 18 schizophrenic participants (9 with and 9 without formal thought disorder performed a semantic decision sentence task during an event-related functional magnetic resonance imaging experiment. We employed analysis of variance to estimate the main effects of semantic congruency and groups on activation and specific effects of formal thought disorder were addressed using post-hoc comparisons. We found that the frontotemporal network, normally engaged by a semantic decision task, was underactivated in schizophrenia, particularly in patients with FTD. This network is implicated in the inhibition of automatically primed stimuli and impairment of its function interferes with language processing and contributes to the production of incoherent speech.

Variants of PLCXD3 are not associated with variant or sporadic Creutzfeldt-Jakob disease in a large international study.

Science.gov (United States)

Balendra, Rubika; Uphill, James; Collinson, Claire; Druyeh, Ronald; Adamson, Gary; Hummerich, Holger; Zerr, Inga; Gambetti, Pierluigi; Collinge, John; Mead, Simon

2016-04-07

Human prion diseases are relentlessly progressive neurodegenerative disorders which include sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD). Aside from variants of the prion protein gene (PRNP) replicated association at genome-wide levels of significance has proven elusive. A recent association study identified variants in or near to the PLCXD3 gene locus as strong disease risk factors in multiple human prion diseases. This study claimed the first non-PRNP locus to be highly significantly associated with prion disease in genomic studies. A sub-study of a genome-wide association study with imputation aiming to replicate the finding at PLCXD3 including 129 vCJD and 2500 sCJD samples. Whole exome sequencing to identify rare coding variants of PLCXD3. Imputation of relevant polymorphisms was accurate based on wet genotyping of a sample. We found no supportive evidence that PLCXD3 variants are associated with disease. The marked discordance in vCJD genotype frequencies between studies, despite extensive overlap in vCJD cases, and the finding of Hardy-Weinberg disequilibrium in the original study, suggests possible reasons for the discrepancies between studies.

A genetic electrophoretic variant of high-sulfur hair proteins for forensic hair comparisons. I. Characterization of variant high-sulfur proteins of human hair.

Science.gov (United States)

Miyake, B

1989-02-01

In a survey of the proteins from human hair, a genetic electrophoretic variant has been observed in the high-sulfur protein region. S-carboxymethylated proteins were examined by 15% polyacrylamide gel electrophoresis at pH 8.9. Out of 150 unrelated samples of Japanese head hairs analyzed, 107 showed 6 major high-sulfur protein bands (normal) and the remaining 43 samples showed an additional high-sulfur protein band (variant). Of 21 Caucasian samples analyzed only one variant sample was found. Characterization of the proteins by two-dimensional electrophoresis evidenced a variant protein spot which showed an apparent molecular weight of 30 k Da. Isoelectric points of the high-sulfur proteins ranged from 3.25-3.55 and that of variant protein band from 3.3-3.4. Family studies of 21 matings resulting in 49 children indicated that this variant was inherited in an autosomal fashion.

Levels-of-processing effect on frontotemporal function in schizophrenia during word encoding and recognition.

Science.gov (United States)

Ragland, J Daniel; Gur, Ruben C; Valdez, Jeffrey N; Loughead, James; Elliott, Mark; Kohler, Christian; Kanes, Stephen; Siegel, Steven J; Moelter, Stephen T; Gur, Raquel E

2005-10-01

Patients with schizophrenia improve episodic memory accuracy when given organizational strategies through levels-of-processing paradigms. This study tested if improvement is accompanied by normalized frontotemporal function. Event-related blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) was used to measure activation during shallow (perceptual) and deep (semantic) word encoding and recognition in 14 patients with schizophrenia and 14 healthy comparison subjects. Despite slower and less accurate overall word classification, the patients showed normal levels-of-processing effects, with faster and more accurate recognition of deeply processed words. These effects were accompanied by left ventrolateral prefrontal activation during encoding in both groups, although the thalamus, hippocampus, and lingual gyrus were overactivated in the patients. During word recognition, the patients showed overactivation in the left frontal pole and had a less robust right prefrontal response. Evidence of normal levels-of-processing effects and left prefrontal activation suggests that patients with schizophrenia can form and maintain semantic representations when they are provided with organizational cues and can improve their word encoding and retrieval. Areas of overactivation suggest residual inefficiencies. Nevertheless, the effect of teaching organizational strategies on episodic memory and brain function is a worthwhile topic for future interventional studies.

Longitudinal patterns of semantic and episodic memory in frontotemporal lobar degeneration and Alzheimer's disease.

Science.gov (United States)

Xie, Sharon X; Libon, David J; Wang, Xingmei; Massimo, Lauren; Moore, Peachie; Vesely, Luisa; Khan, Alea; Chatterjee, Anjan; Coslett, H Branch; Hurtig, Howard I; Liang, Tsao-Wei; Grossman, Murray

2010-03-01

The longitudinal assessment of episodic and semantic memory was obtained from 236 patients diagnosed with Alzheimer's disease (AD, n = 128) and with frontotemporal lobar degeneration (FTLD, n = 108), including patients with a social comportment/dysexecutive (SOC/EXEC) disorder, progressive nonfluent aphasia (PNFA), semantic dementia (SemD), and corticobasal syndrome (CBS). At the initial assessment, AD patients obtained a lower score on the delayed free recall test than other patients. Longitudinal analyses for delayed free recall found converging performance, with all patients reaching the same level of impairment as AD patients. On the initial evaluation for delayed recognition, AD patients also obtained lower scores than other groups. Longitudinal analyses for delayed recognition test performance found that AD patients consistently produced lower scores than other groups and no convergence between AD and other dementia groups was seen. For semantic memory, there were no initial between-group differences. However, longitudinal analyses for semantic memory revealed group differences over illness duration, with worse performance for SemD versus AD, PNFA, SOC/EXEC, and CBS patients. These data suggest the presence of specific longitudinal patterns of impairment for episodic and semantic memory in AD and FTLD patients suggesting that all forms of dementia do not necessarily converge into a single phenotype.

ABCA7 rare variants and Alzheimer disease risk.

Science.gov (United States)

Le Guennec, Kilan; Nicolas, Gaël; Quenez, Olivier; Charbonnier, Camille; Wallon, David; Bellenguez, Céline; Grenier-Boley, Benjamin; Rousseau, Stéphane; Richard, Anne-Claire; Rovelet-Lecrux, Anne; Bacq, Delphine; Garnier, Jean-Guillaume; Olaso, Robert; Boland, Anne; Meyer, Vincent; Deleuze, Jean-François; Amouyel, Philippe; Munter, Hans Markus; Bourque, Guillaume; Lathrop, Mark; Frebourg, Thierry; Redon, Richard; Letenneur, Luc; Dartigues, Jean-François; Pasquier, Florence; Rollin-Sillaire, Adeline; Génin, Emmanuelle; Lambert, Jean-Charles; Hannequin, Didier; Campion, Dominique

2016-06-07

To study the association between ABCA7 rare coding variants and Alzheimer disease (AD) in a case-control setting. We conducted a whole exome analysis among 484 French patients with early-onset AD and 590 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of ABCA7 loss of function (LOF) and predicted damaging missense variants in cases (odds ratio [OR] 3.40, 95% confidence interval [CI] 1.68-7.35, p = 0.0002). Performing a meta-analysis with previously published data, we found that in a combined sample of 1,256 patients and 1,347 controls from France and Belgium, the OR was 2.81 (95% CI 1.89-4.20, p = 3.60 × 10(-7)). These results confirm that ABCA7 LOF variants are enriched in patients with AD and extend this finding to predicted damaging missense variants. © 2016 American Academy of Neurology.

Electrophoretic variants of blood proteins in Japanese, 7

International Nuclear Information System (INIS)

Satoh, Chiyoko; Takahashi, Norio; Kimura, Yasukazu; Miura, Akiko; Kaneko, Junko; Fujita, Mikio; Toyama, Kyoko.

1986-11-01

A total of 16,835 children, of whom 11,737 are unrelated, from Hiroshima and Nagasaki were examined for erythrocyte cytoplasmic glutamate-oxaloacetate transaminase (GOT1) by starch gel electrophoresis. A variant allele named GOT1*2HR1 which seems to be identical with GOT1*2 was encountered in polymorphic frequency. Five kinds of rare variants, 3NG1, 4NG1, 5NG1, 6HR1, and 7NG1 were encountered in a total of 109 children. Except for 7NG1 for which complete family study was unable, family studies confirmed the genetic nature of these rare variants, since for all instances in which both parents could be examined, one of the parents exhibited the same variant as that of their child. Thermostability profiles of these six variants were normal. The enzyme activities of five were decreased, while the value of one was normal compared to that of GOT1 1. (author)

Identifying noncoding risk variants using disease-relevant gene regulatory networks.

Science.gov (United States)

Gao, Long; Uzun, Yasin; Gao, Peng; He, Bing; Ma, Xiaoke; Wang, Jiahui; Han, Shizhong; Tan, Kai

2018-02-16

Identifying noncoding risk variants remains a challenging task. Because noncoding variants exert their effects in the context of a gene regulatory network (GRN), we hypothesize that explicit use of disease-relevant GRNs can significantly improve the inference accuracy of noncoding risk variants. We describe Annotation of Regulatory Variants using Integrated Networks (ARVIN), a general computational framework for predicting causal noncoding variants. It employs a set of novel regulatory network-based features, combined with sequence-based features to infer noncoding risk variants. Using known causal variants in gene promoters and enhancers in a number of diseases, we show ARVIN outperforms state-of-the-art methods that use sequence-based features alone. Additional experimental validation using reporter assay further demonstrates the accuracy of ARVIN. Application of ARVIN to seven autoimmune diseases provides a holistic view of the gene subnetwork perturbed by the combinatorial action of the entire set of risk noncoding mutations.

COMPARISON OF THE TEST VARIANTS IN ENTRANCE EXAMINATIONS

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KLŮFA, Jindřich

2016-12-01

Full Text Available The paper contains an analysis of the differences of number of points in the test in mathematics between test variants, which were used in the entrance examinations at the Faculty of Business Administration at University of Economics in Prague in 2015. The differences may arise due to the varying difficulty of variants for students, but also because of the different level of knowledge of students who write these variants. This problem we shall study in present paper. The aim of this paper is to study dependence of the results of entrance examinations in mathematics on test variants. The results obtained will be used for further improvement of the admission process at University of Economics.

Superior and inferior vena cavae: Embryology, variants, and pathology

International Nuclear Information System (INIS)

Mendelson, D.S.; Mitty, H.; Janus, C.; Gendal, E.; Berson, B.

1987-01-01

The superior and inferior venae cavae may be involved in a host of disease processes. Knowledge of the normal anatomy and variants of these structures is valuable in interpreting plain films and the results of angiographic procedures and all cross-sectional modalities. The authors review the embryology of venae cavae and proceed to describe their normal anatomy and variants. An awareness of the variants can prevent mistaking variants for pathologic processes. Finally, the authors describe pathology involving these vessels and demonstrate the radiographic manifestations

Golden Rule of Morphology and Variants of Word forms

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Hlaváčová Jaroslava

2017-12-01

Full Text Available In many languages, some words can be written in several ways. We call them variants. Values of all their morphological categories are identical, which leads to an identical morphological tag. Together with the identical lemma, we have two or more wordforms with the same morphological description. This ambiguity may cause problems in various NLP applications. There are two types of variants – those affecting the whole paradigm (global variants and those affecting only wordforms sharing some combinations of morphological values (inflectional variants. In the paper, we propose means how to tag all wordforms, including their variants, unambiguously. We call this requirement “Golden rule of morphology”. The paper deals mainly with Czech, but the ideas can be applied to other languages as well.

N-terminal nesprin-2 variants regulate β-catenin signalling

Energy Technology Data Exchange (ETDEWEB)

Zhang, Qiuping; Minaisah, Rose-Marie; Ferraro, Elisa; Li, Chen; Porter, Lauren J.; Zhou, Can; Gao, Fang; Zhang, Junyi; Rajgor, Dipen; Autore, Flavia; Shanahan, Catherine M.; Warren, Derek T., E-mail: derek.warren@kcl.ac.uk

2016-07-15

The spatial compartmentalisation of biochemical signalling pathways is essential for cell function. Nesprins are a multi-isomeric family of proteins that have emerged as signalling scaffolds, herein, we investigate the localisation and function of novel nesprin-2 N-terminal variants. We show that these nesprin-2 variants display cell specific distribution and reside in both the cytoplasm and nucleus. Immunofluorescence microscopy revealed that nesprin-2 N-terminal variants colocalised with β-catenin at cell-cell junctions in U2OS cells. Calcium switch assays demonstrated that nesprin-2 and β-catenin are lost from cell-cell junctions in low calcium conditions whereas emerin localisation at the NE remained unaltered, furthermore, an N-terminal fragment of nesprin-2 was sufficient for cell-cell junction localisation and interacted with β-catenin. Disruption of these N-terminal nesprin-2 variants, using siRNA depletion resulted in loss of β-catenin from cell-cell junctions, nuclear accumulation of active β-catenin and augmented β-catenin transcriptional activity. Importantly, we show that U2OS cells lack nesprin-2 giant, suggesting that the N-terminal nesprin-2 variants regulate β-catenin signalling independently of the NE. Together, these data identify N-terminal nesprin-2 variants as novel regulators of β-catenin signalling that tether β-catenin to cell-cell contacts to inhibit β-catenin transcriptional activity. - Highlights: • N-terminal nesprin-2 variants display cell specific expression patterns. • N-terminal spectrin repeats of nesprin-2 interact with β-catenin. • N-terminal nesprin-2 variants scaffold β-catenin at cell-cell junctions.. • Nesprin-2 variants play multiple roles in β-catenin signalling.

Consumer behaviour analysis and the behavioural perspective model.

OpenAIRE

Foxall, G.R.; Oliveira-Castro, J.M.; James, V.K.; Schrezenmaier, T.C.

2011-01-01

This is the FIRST of TWO linked articles on consumer behavioural analysis. Cognitive theories have dominated the field of consumer behaviour for the last few decades, however, an observed lack of consistency between attitudes and behaviour has suggested the need to investigate more thoroughly situational and behavioural variables. Consumer behaviour analysis can be viewed as an alternative theoretical approach that emphasizes situational variables and measures of behaviour. Within consumer be...

Fundamental Characteristics of Industrial Variant Specification Systems

DEFF Research Database (Denmark)

Hansen, Benjamin Loer; Hvam, Lars

2004-01-01

fundamental concepts related to this task, which are relevant to understand for academia and practitioners working with the subject. This is done through a description of variant specification tasks and typical aspects of system solutions. To support the description of variant specification tasks and systems...

Microsatellite Instability Use in Mismatch Repair Gene Sequence Variant Classification

Directory of Open Access Journals (Sweden)

Bryony A. Thompson

2015-03-01

Full Text Available Inherited mutations in the DNA mismatch repair genes (MMR can cause MMR deficiency and increased susceptibility to colorectal and endometrial cancer. Microsatellite instability (MSI is the defining molecular signature of MMR deficiency. The clinical classification of identified MMR gene sequence variants has a direct impact on the management of patients and their families. For a significant proportion of cases sequence variants of uncertain clinical significance (also known as unclassified variants are identified, constituting a challenge for genetic counselling and clinical management of families. The effect on protein function of these variants is difficult to interpret. The presence or absence of MSI in tumours can aid in determining the pathogenicity of associated unclassified MMR gene variants. However, there are some considerations that need to be taken into account when using MSI for variant interpretation. The use of MSI and other tumour characteristics in MMR gene sequence variant classification will be explored in this review.

Distinct Neurodegenerative Changes in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia Linked to Mutant TAU Protein

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Marc Ehrlich

2015-07-01

Full Text Available Frontotemporal dementia (FTD is a frequent form of early-onset dementia and can be caused by mutations in MAPT encoding the microtubule-associated protein TAU. Because of limited availability of neural cells from patients’ brains, the underlying mechanisms of neurodegeneration in FTD are poorly understood. Here, we derived induced pluripotent stem cells (iPSCs from individuals with FTD-associated MAPT mutations and differentiated them into mature neurons. Patient iPSC-derived neurons demonstrated pronounced TAU pathology with increased fragmentation and phospho-TAU immunoreactivity, decreased neurite extension, and increased but reversible oxidative stress response to inhibition of mitochondrial respiration. Furthermore, FTD neurons showed an activation of the unfolded protein response, and a transcriptome analysis demonstrated distinct, disease-associated gene expression profiles. These findings indicate distinct neurodegenerative changes in FTD caused by mutant TAU and highlight the unique opportunity to use neurons differentiated from patient-specific iPSCs to identify potential targets for drug screening purposes and therapeutic intervention.

Exploratory behaviour in the open field test adapted for larval zebrafish: impact of environmental complexity.

Science.gov (United States)

Ahmad, Farooq; Richardson, Michael K

2013-01-01

This study aimed to develop and characterize a novel (standard) open field test adapted for larval zebrafish. We also developed and characterized a variant of the same assay consisting of a colour-enriched open field; this was used to assess the impact of environmental complexity on patterns of exploratory behaviours as well to determine natural colour preference/avoidance. We report the following main findings: (1) zebrafish larvae display characteristic patterns of exploratory behaviours in the standard open field, such as thigmotaxis/centre avoidance; (2) environmental complexity (i.e. presence of colours) differentially affects patterns of exploratory behaviours and greatly attenuates natural zone preference; (3) larvae displayed the ability to discriminate colours. As reported previously in adult zebrafish, larvae showed avoidance towards blue and black; however, in contrast to the reported adult behaviour, larvae displayed avoidance towards red. Avoidance towards yellow and preference for green and orange are shown for the first time, (4) compared to standard open field tests, exposure to the colour-enriched open field resulted in an enhanced expression of anxiety-like behaviours. To conclude, we not only developed and adapted a traditional rodent behavioural assay that serves as a gold standard in preclinical drug screening, but we also provide a version of the same test that affords the possibility to investigate the impact of environmental stress on behaviour in larval zebrafish while representing the first test for assessment of natural colour preference/avoidance in larval zebrafish. In the future, these assays will improve preclinical drug screening methodologies towards the goal to uncover novel drugs. This article is part of a Special Issue entitled: insert SI title. Copyright © 2012 Elsevier B.V. All rights reserved.

HFE gene variants affect iron in the brain.

Science.gov (United States)

Nandar, Wint; Connor, James R

2011-04-01

Iron accumulation in the brain and increased oxidative stress are consistent observations in many neurodegenerative diseases. Thus, we have begun examination into gene mutations or allelic variants that could be associated with loss of iron homeostasis. One of the mechanisms leading to iron overload is a mutation in the HFE gene, which is involved in iron metabolism. The 2 most common HFE gene variants are C282Y (1.9%) and H63D (8.9%). The C282Y HFE variant is more commonly associated with hereditary hemochromatosis, which is an autosomal recessive disorder, characterized by iron overload in a number of systemic organs. The H63D HFE variant appears less frequently associated with hemochromatosis, but its role in the neurodegenerative diseases has received more attention. At the cellular level, the HFE mutant protein resulting from the H63D HFE gene variant is associated with iron dyshomeostasis, increased oxidative stress, glutamate release, tau phosphorylation, and alteration in inflammatory response, each of which is under investigation as a contributing factor to neurodegenerative diseases. Therefore, the HFE gene variants are proposed to be genetic modifiers or a risk factor for neurodegenerative diseases by establishing an enabling milieu for pathogenic agents. This review will discuss the current knowledge of the association of the HFE gene variants with neurodegenerative diseases: amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and ischemic stroke. Importantly, the data herein also begin to dispel the long-held view that the brain is protected from iron accumulation associated with the HFE mutations.

Differential Expression Profile of ZFX Variants Discriminates Breast Cancer Subtypes

Science.gov (United States)

Pourkeramati, Fatemeh; Asadi, Malek Hossein; Shakeri, Shahryar; Farsinejad, Alireza

2018-05-13

ZFX is a transcriptional regulator in embryonic stem cells that plays an important role in pluripotency and self-renewal. ZFX is widely expressed in pluripotent stem cells and is down-regulated during differentiation of embryonic stem cells. ZFX has five different variants that encode three different protein isoforms. While several reports have determined the overexpression of ZFX in a variety of somatic cancers, the expression of ZFX-spliced variants in cancer cells is not well-understood. We investigated the expression of ZFX variants in a series of breast cancer tissues and cell lines using quantitative PCR. The expression of ZFX variant 1/3 was higher in tumor tissue compared to marginal tissue. In contrast, the ZFX variant 5 was down-regulated in tumor tissues. While the ZFX variant 1/3 and ZFX variant 5 expression significantly increased in low-grade tumors, ZFX variant 4 was strongly expressed in high-grade tumors and demonstrating lymphatic invasion. In addition, our result revealed a significant association between the HER2 status and the expression of ZFX-spliced variants. Our data suggest that the expression of ZFX-spliced transcripts varies between different types of breast cancer and may contribute to their tumorigenesis process. Hence, ZFX-spliced transcripts could be considered as novel tumor markers with a probable value in diagnosis, prognosis, and therapy of breast cancer.

Genotype–phenotype correlations in individuals with pathogenic RERE variants

Science.gov (United States)

Jordan, Valerie K.; Fregeau, Brieana; Ge, Xiaoyan; Giordano, Jessica; Wapner, Ronald J.; Balci, Tugce B.; Carter, Melissa T.; Bernat, John A.; Moccia, Amanda N.; Srivastava, Anshika; Martin, Donna M.; Bielas, Stephanie L.; Pappas, John; Svoboda, Melissa D.; Rio, Marlène; Boddaert, Nathalie; Cantagrel, Vincent; Lewis, Andrea M.; Scaglia, Fernando; Kohler, Jennefer N.; Bernstein, Jonathan A.; Dries, Annika M.; Rosenfeld, Jill A.; DeFilippo, Colette; Thorson, Willa; Yang, Yaping; Sherr, Elliott H.; Bi, Weimin; Scott, Daryl A.

2018-01-01

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7. PMID:29330883

Neuropsychological Testing in Pathologically Verified Alzheimer Disease and Frontotemporal Dementia: How Well Do the Uniform Data Set Measures Differentiate Between Diseases?

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Ritter, Aaron R; Leger, Gabriel C; Miller, Justin B; Banks, Sarah J

2017-01-01

Differences in cognition between frontotemporal dementia (FTD) and Alzheimer disease (AD) are well described in clinical cohorts, but have rarely been confirmed in studies with pathologic verification. For emerging therapeutics to succeed, determining underlying pathology early in the disease course is increasingly important. Neuropsychological evaluation is an important component of the diagnostic workup for AD and FTD. Patients with FTD are thought to have greater deficits in language and executive function while patients with AD are more likely to have deficits in memory. To determine if performance on initial cognitive testing can reliably distinguish between patients with frontotemporal lobar degeneration (FTLD) and AD neuropathology. In addition, are there other factors of the neuropsychological assessment that can be used to enhance the accuracy of underlying pathology? Using a logistic regression we retrospectively compared neurocognitive performance on initial evaluation of 106 patients with pathologically verified FTLD (pvFTLD), with 558 pathologically verified AD (pvAD) patients from the National Alzheimer's Coordinating Center using data from the Uniform Data Set (UDS) and the neuropathology data set. As expected, pvFTLD patients were younger, demonstrated better memory performance, and had more neuropsychiatric symptoms than pvAD patients. Other results were less predictable: pvFTLD patients performed better on one test of executive function (trail making test part B) but worse on another (digit span backward). Performance on language testing did not strongly distinguish the 2 groups. To determine what factors led to a misdiagnosis of AD in patients with FTLD, we further analyzed a small group of pvFTLD patients. These patients demonstrated older age and lower Neuropsychiatric Inventory Questionnaire counts compared with accurately diagnosed cases. Other than memory, numerical scores of neurocognitive performance on the UDS are of limited value in

Poisson Approximation-Based Score Test for Detecting Association of Rare Variants.

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Fang, Hongyan; Zhang, Hong; Yang, Yaning

2016-07-01

Genome-wide association study (GWAS) has achieved great success in identifying genetic variants, but the nature of GWAS has determined its inherent limitations. Under the common disease rare variants (CDRV) hypothesis, the traditional association analysis methods commonly used in GWAS for common variants do not have enough power for detecting rare variants with a limited sample size. As a solution to this problem, pooling rare variants by their functions provides an efficient way for identifying susceptible genes. Rare variant typically have low frequencies of minor alleles, and the distribution of the total number of minor alleles of the rare variants can be approximated by a Poisson distribution. Based on this fact, we propose a new test method, the Poisson Approximation-based Score Test (PAST), for association analysis of rare variants. Two testing methods, namely, ePAST and mPAST, are proposed based on different strategies of pooling rare variants. Simulation results and application to the CRESCENDO cohort data show that our methods are more powerful than the existing methods. © 2016 John Wiley & Sons Ltd/University College London.

Cellulase variants with improved expression, activity and stability, and use thereof

Science.gov (United States)

Aehle, Wolfgang; Bott, Richard R; Bower, Benjamin; Caspi, Jonathan; Estell, David A; Goedegebuur, Frits; Hommes, Ronaldus W.J.; Kaper, Thijs; Kelemen, Bradley; Kralj, Slavko; Van Lieshout, Johan; Nikolaev, Igor; Van Stigt Thans, Sander; Wallace, Louise; Vogtentanz, Gudrun; Sandgren, Mats

2014-03-25

The present disclosure relates to cellulase variants. In particular the present disclosure relates to cellulase variants having improved expression, activity and/or stability. Also described are nucleic acids encoding the cellulase variants, compositions comprising the cellulase variants, and methods of use thereof.

Cellulase variants with improved expression, activity and stability, and use thereof

Energy Technology Data Exchange (ETDEWEB)

Aehle, Wolfgang; Bott, Richard R.; Bower, Benjamin S.; Caspi, Jonathan; Goedegebuur, Frits; Hommes, Ronaldus Wilhelmus Joannes; Kaper, Thijs; Kelemen, Bradley R.; Kralj, Slavko; Van Lieshout, Johannes Franciscus Thomas; Nikolaev, Igor; Wallace, Louise; Van Stigt Thans, Sander; Vogtentanz, Gudrun; Sandgren, Mats

2016-12-20

The present disclosure relates to cellulase variants. In particular the present disclosure relates to cellulase variants having improved expression, activity and/or stability. Also described are nucleic acids encoding the cellulase variants, compositions comprising the cellulase variants, and methods of use thereof.

Genetic variants of ghrelin in metabolic disorders.

Science.gov (United States)

Ukkola, Olavi

2011-11-01

An increasing understanding of the role of genes in the development of obesity may reveal genetic variants that, in combination with conventional risk factors, may help to predict an individual's risk for developing metabolic disorders. Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis and it is a reasonable candidate gene for obesity-related co-morbidities. In cross-sectional studies low total ghrelin concentrations and some genetic polymorphisms of ghrelin have been associated with obesity-associated diseases. The present review highlights many of the important problems in association studies of genetic variants and complex diseases. It is known that population-specific differences in reported associations exist. We therefore conclude that more studies on variants of ghrelin gene are needed to perform in different populations to get deeper understanding on the relationship of ghrelin gene and its variants to obesity. Copyright © 2011 Elsevier Inc. All rights reserved.

Isolation of a variant of Candida albicans.

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Buckley, H R; Price, M R; Daneo-Moore, L

1982-01-01

During the course of Candida albicans antigen production, a variant of this organism was encountered which did not produce hyphae at 37 degrees C. Presented here are some of the characteristics of this variant. It produces hyphae at 25 degrees C on cornmeal agar and synthetic medium plus N-acetylglucosamine and Tween 80. At 37 degrees C, it does not produce hyphae on these media, although C. albicans normally does produce hyphae under these circumstances. In liquid synthetic medium, this variant does not produce hyphae at 37 degrees C. The variant strain was analyzed for DNA, RNA, protein content, and particle size. After 50 to 70 h in balanced exponential-phase growth, particle size distribution was narrow, and there were no differences in the DNA, RNA, or protein content per particle in the two strains. When balanced exponential-phase cultures were brought into stationary phase, both strains contained the same amount of DNA per cell. Images PMID:6752021

Isolation of a variant of Candida albicans.

Science.gov (United States)

Buckley, H R; Price, M R; Daneo-Moore, L

1982-09-01

During the course of Candida albicans antigen production, a variant of this organism was encountered which did not produce hyphae at 37 degrees C. Presented here are some of the characteristics of this variant. It produces hyphae at 25 degrees C on cornmeal agar and synthetic medium plus N-acetylglucosamine and Tween 80. At 37 degrees C, it does not produce hyphae on these media, although C. albicans normally does produce hyphae under these circumstances. In liquid synthetic medium, this variant does not produce hyphae at 37 degrees C. The variant strain was analyzed for DNA, RNA, protein content, and particle size. After 50 to 70 h in balanced exponential-phase growth, particle size distribution was narrow, and there were no differences in the DNA, RNA, or protein content per particle in the two strains. When balanced exponential-phase cultures were brought into stationary phase, both strains contained the same amount of DNA per cell.

The Mini-Addenbrooke's Cognitive Examination: a new assessment tool for dementia.

Science.gov (United States)

Hsieh, Sharpley; McGrory, Sarah; Leslie, Felicity; Dawson, Kate; Ahmed, Samrah; Butler, Chris R; Rowe, James B; Mioshi, Eneida; Hodges, John R

2015-01-01

We developed and validated the Mini-Addenbrooke's Cognitive Examination (M-ACE) in dementia patients. Comparisons were also made with the Mini Mental State Examination (MMSE). The M-ACE was developed using Mokken scaling analysis in 117 dementia patients [behavioural variant frontotemporal dementia (bvFTD), n = 25; primary progressive aphasia (PPA), n = 49; Alzheimer's disease (AD), n = 34; corticobasal syndrome (CBS), n = 9] and validated in an independent sample of 164 dementia patients (bvFTD, n = 23; PPA, n = 82; AD, n = 38; CBS, n = 21) and 78 controls, who also completed the MMSE. The M-ACE consists of 5 items with a maximum score of 30. Two cut-offs were identified: (1) ≤25/30 has both high sensitivity and specificity, and (2) ≤21/30 is almost certainly a score to have come from a dementia patient regardless of the clinical setting. The M-ACE is more sensitive than the MMSE and is less likely to have ceiling effects. The M-ACE is a brief and sensitive cognitive screening tool for dementia. Two cut-offs (25 or 21) are recommended. © 2014 S. Karger AG, Basel.

The Role of the Innate Immune System in Alzheimer’s Disease and Frontotemporal Lobar Degeneration: An Eye on Microglia

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Elisa Ridolfi

2013-01-01

Full Text Available In the last few years, genetic and biomolecular mechanisms at the basis of Alzheimer’s disease (AD and frontotemporal lobar degeneration (FTLD have been unraveled. A key role is played by microglia, which represent the immune effector cells in the central nervous system (CNS. They are extremely sensitive to the environmental changes in the brain and are activated in response to several pathologic events within the CNS, including altered neuronal function, infection, injury, and inflammation. While short-term microglial activity has generally a neuroprotective role, chronic activation has been implicated in the pathogenesis of neurodegenerative disorders, including AD and FTLD. In this framework, the purpose of this review is to give an overview of clinical features, genetics, and novel discoveries on biomolecular pathogenic mechanisms at the basis of these two neurodegenerative diseases and to outline current evidence regarding the role played by activated microglia in their pathogenesis.

TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

International Nuclear Information System (INIS)

Arai, Tetsuaki; Hasegawa, Masato; Akiyama, Haruhiko; Ikeda, Kenji; Nonaka, Takashi; Mori, Hiroshi; Mann, David; Tsuchiya, Kuniaki; Yoshida, Mari; Hashizume, Yoshio; Oda, Tatsuro

2006-01-01

Ubiquitin-positive tau-negative neuronal cytoplasmic inclusions and dystrophic neurites are common pathological features in frontotemporal lobar degeneration (FTLD) with or without symptoms of motor neuron disease and in amyotrophic lateral sclerosis (ALS). Using biochemical and immunohistochemical analyses, we have identified a TAR DNA-binding protein of 43 kDa (TDP-43), a nuclear factor that functions in regulating transcription and alternative splicing, as a component of these structures in FTLD. Furthermore, skein-like inclusions, neuronal intranuclear inclusions, and glial inclusions in the spinal cord of ALS patients are also positive for TDP-43. Dephosphorylation treatment of the sarkosyl insoluble fraction has shown that abnormal phosphorylation takes place in accumulated TDP-43. The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of TDP-43

Dataset of mitochondrial genome variants in oncocytic tumors

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Lihua Lyu

2018-04-01

Full Text Available This dataset presents the mitochondrial genome variants associated with oncocytic tumors. These data were obtained by Sanger sequencing of the whole mitochondrial genomes of oncocytic tumors and the adjacent normal tissues from 32 patients. The mtDNA variants are identified after compared with the revised Cambridge sequence, excluding those defining haplogroups of our patients. The pathogenic prediction for the novel missense variants found in this study was performed with the Mitimpact 2 program.

Biochemical characteristics of glucose-6-phosphate dehydrogenase variants among the Malays of Singapore with report of a new non-deficient (GdSingapore) and three deficient variants.

Science.gov (United States)

Saha, N; Hong, S H; Wong, H A; Jeyaseelan, K; Tay, J S

1991-12-01

Biochemical characteristics of one non-deficient fast G6PD variant (GdSingapore) and six different deficient variants (three new, two Mahidol, one each of Indonesian and Mediterranean) were studied among the Malays of Singapore. The GdSingapore variant had normal enzyme activity (82%) and fast electrophoretic mobilities (140% in TEB buffer, 160% in phosphate and 140% in Tris-HCl buffer systems respectively). This variant is further characterized by normal Km for G6P; utilization of analogues (Gal6P, 2dG6P; dAmNADP), heat stability and pH optimum. The other six deficient G6PD variants had normal electrophoretic mobility in TEB buffer with enzyme activities ranging from 1 to 12% of GdB+. The biochemical characteristics identity them to be 2 Mahidol, 1 Indonesian and 1 Mediterranean variants and three new deficient variants.

Characterization of form variants of Xenorhabdus luminescens.

NARCIS (Netherlands)

Gerritsen, L.J.M.; Raay, de G.; Smits, P.H.

1992-01-01

From Xenorhabdus luminescens XE-87.3 four variants were isolated. One, which produced a red pigment and antibiotics, was luminescent, and could take up dye from culture media, was considered the primary form (XE-red). A pink-pigmented variant (XE-pink) differed from the primary form only in

Portuguese family with the co-occurrence of frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis phenotypes due to progranulin gene mutation.

Science.gov (United States)

Almeida, Maria R; Macário, Maria C; Ramos, Lina; Baldeiras, Inês; Ribeiro, Maria H; Santana, Isabel

2016-05-01

We and others have reported heterozygous progranulin mutations as an important cause of frontotemporal lobar degeneration (FTLD). It has been identified a complete progranulin deficiency because of a homozygous mutation in a sibling pair with neuronal ceroid lipofuscinosis (NCL). Here, we describe the first case of NCL caused by a homozygous progranulin mutation segregating in a family with neuropathological confirmed FTLD. In this FTLD-NCL family, we detail the clinical phenotype, neuropsychological evaluation and imaging data of our proband harboring a homozygous mutation, c.900_901dupGT, with serum progranulin level (progranulin levels in suspected recessive adult-onset NCL cases. Overall, a more holistic neurologic intervention is needed to guarantee a proper genetic counseling in cases like the present family where two distinct phenotypes are generated according to the individuals' mutation state. Copyright © 2016 Elsevier Inc. All rights reserved.

Identificação de variantes de hemoglobina em doadores de sangue Identification of hemoglobin variants in blood donor

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Ana C. Bonini-Domingos

2004-03-01

Full Text Available Hemoglobinopathies are the most common genetic diseases and affect a great number of individuals in the world, with diverse clinical complications ranging from the almost unnoticeable to lethal consequences. In Brazil the occurrence of hemoglobinopathies is very frequent and influenced by the ethnical groups that are the basis of populations in different regions. The phenotype may be influenced by environmental and genetic factors and by migration. An understanding of these genetic diseases is important for the health and quality of life of the population. In this work we assessed the presence of Hb variants in blood donors from São José do Rio Preto and region, and we observed the occurrence of variants including Hb S and Hb C but in particular the so-called "S-Like" variants. Good determination of the forms of variant hemoglobins is very important to give better guidance to blood donors and their families, and to improve the quality of blood transfusion.

Mouse ribosomal RNA genes contain multiple differentially regulated variants.

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Hung Tseng

2008-03-01

Full Text Available Previous cytogenetic studies suggest that various rDNA chromosomal loci are not equally active in different cell types. Consistent with this variability, rDNA polymorphism is well documented in human and mouse. However, attempts to identify molecularly rDNA variant types, which are regulated individually (i.e., independent of other rDNA variants and tissue-specifically, have not been successful. We report here the molecular cloning and characterization of seven mouse rDNA variants (v-rDNA. The identification of these v-rDNAs was based on restriction fragment length polymorphisms (RFLPs, which are conserved among individuals and mouse strains. The total copy number of the identified variants is less than 100 and the copy number of each individual variant ranges from 4 to 15. Sequence analysis of the cloned v-rDNA identified variant-specific single nucleotide polymorphisms (SNPs in the transcribed region. These SNPs were used to develop a set of variant-specific PCR assays, which permitted analysis of the v-rDNAs' expression profiles in various tissues. These profiles show that three v-rDNAs are expressed in all tissues (constitutively active, two are expressed in some tissues (selectively active, and two are not expressed (silent. These expression profiles were observed in six individuals from three mouse strains, suggesting the pattern is not randomly determined. Thus, the mouse rDNA array likely consists of genetically distinct variants, and some are regulated tissue-specifically. Our results provide the first molecular evidence for cell-type-specific regulation of a subset of rDNA.

Ultrasonographic imaging of papillary thyroid carcinoma variants

Energy Technology Data Exchange (ETDEWEB)

Shin, Jung Hee [Dept. of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

2017-04-15

Ultrasonography (US) is routinely used to evaluate thyroid nodules. The US features of papillary thyroid carcinoma (PTC), the most common thyroid malignancy, include hypoechogenicity, spiculated/microlobulated margins, microcalcifications, and a nonparallel orientation. However, many PTC variants have been identified, some of which differ from the classic type of PTC in terms of biological behavior and clinical outcomes. This review describes the US features and clinical implications of the variants of PTC. With the introduction of active surveillance replacing immediate biopsy or surgical treatment of indolent, small PTCs, an understanding of the US characteristics of PTC variants will facilitate the individualized management of patients with PTC.

Moderators of the intention-behaviour and perceived behavioural control-behaviour relationships for leisure-time physical activity

Directory of Open Access Journals (Sweden)

Godin Gaston

2008-02-01

Full Text Available Abstract Background Intention is a key determinant of action. However, there is a gap between intention and behavioural performance that remains to be explained. Therefore, the aim of this study was to identify moderators of the intention-behaviour and perceived behavioural control (PBC- behaviour relationships for leisure-time physical activity. Method This was tested in reference to Ajzen's Theory of Planned Behaviour. A sample of 300 volunteers, 192 women and 108 men, aged 18 to 55, participated in the study. At baseline, the participants completed a self-administrated psychosocial questionnaire assessing Ajzen's theory variables (i.e., intention and perceived behavioural control. The behavioural measure was obtained by mail three months later. Results Multiple hierarchical regression analyses indicated that age and annual income moderated the intention-behaviour and PBC-behaviour relationships. However, in the final model predicting behaviour (R2 = .46, only the interaction term of PBC by annual income (β = .24, p = 0.0003 significantly contributed to the prediction of behaviour along with intention (β = .49, p = 0.0009 and past behaviour (β = .44, p Conclusion Physical activity promotion programs would benefit not only from focusing on increasing the intention of low intenders, but also from targeting factors that moderate the perceived behavioural control-behaviour relationships.

Treatment of spelling variants in Setswana monolingual dictionaries

African Journals Online (AJOL)

user

. ..... Table 8: Variants of Names of persons and places. Setswana variants. English. Aforika, Aferika. Africa. Baebele, Babele, Beibele. Bible. Ennyelane, Engelane ..... MWEs. As in variation amongst individual words, the MWEs such as idioms.

Human papillomavirus variants among Inuit women in northern Quebec, Canada.

Science.gov (United States)

Gauthier, Barbara; Coutlée, Francois; Franco, Eduardo L; Brassard, Paul

2015-01-01

Inuit communities in northern Quebec have high rates of human papillomavirus (HPV) infection, cervical cancer and cervical cancer-related mortality as compared to the Canadian population. HPV types can be further classified as intratypic variants based on the extent of homology in their nucleotide sequences. There is limited information on the distribution of intratypic variants in circumpolar areas. Our goal was to describe the HPV intratypic variants and associated baseline characteristics. We collected cervical cell samples in 2002-2006 from 676 Inuit women between the ages of 15 and 69 years in Nunavik. DNA isolates from high-risk HPVs were sequenced to determine the intratypic variant. There were 149 women that were positive for HPVs 16, 18, 31, 33, 35, 45, 52, 56 or 58 during follow-up. There were 5 different HPV16 variants, all of European lineage, among the 57 women positive for this type. There were 8 different variants of HPV18 present and all were of European lineage (n=21). The majority of samples of HPV31 (n=52) were of lineage B. The number of isolates and diversity of the other HPV types was low. Age was the only covariate associated with HPV16 variant category. These frequencies are similar to what was seen in another circumpolar region of Canada, although there appears to be less diversity as only European variants were detected. This study shows that most variants were clustered in one lineage for each HPV type.

Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B

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Yu Zhang

2017-03-01

Full Text Available The truncated mutant form of the charged multivesicular body protein 2B (CHMP2B is causative for frontotemporal dementia linked to chromosome 3 (FTD3. CHMP2B is a constituent of the endosomal sorting complex required for transport (ESCRT and, when mutated, disrupts endosome-to-lysosome trafficking and substrate degradation. To understand the underlying molecular pathology, FTD3 patient induced pluripotent stem cells (iPSCs were differentiated into forebrain-type cortical neurons. FTD3 neurons exhibited abnormal endosomes, as previously shown in patients. Moreover, mitochondria of FTD3 neurons displayed defective cristae formation, accompanied by deficiencies in mitochondrial respiration and increased levels of reactive oxygen. In addition, we provide evidence for perturbed iron homeostasis, presenting an in vitro patient-specific model to study the effects of iron accumulation in neurodegenerative diseases. All phenotypes observed in FTD3 neurons were rescued in CRISPR/Cas9-edited isogenic controls. These findings illustrate the relevance of our patient-specific in vitro models and open up possibilities for drug target development.

Genetic variants influencing phenotypic variance heterogeneity.

Science.gov (United States)

Ek, Weronica E; Rask-Andersen, Mathias; Karlsson, Torgny; Enroth, Stefan; Gyllensten, Ulf; Johansson, Åsa

2018-03-01

Most genetic studies identify genetic variants associated with disease risk or with the mean value of a quantitative trait. More rarely, genetic variants associated with variance heterogeneity are considered. In this study, we have identified such variance single-nucleotide polymorphisms (vSNPs) and examined if these represent biological gene × gene or gene × environment interactions or statistical artifacts caused by multiple linked genetic variants influencing the same phenotype. We have performed a genome-wide study, to identify vSNPs associated with variance heterogeneity in DNA methylation levels. Genotype data from over 10 million single-nucleotide polymorphisms (SNPs), and DNA methylation levels at over 430 000 CpG sites, were analyzed in 729 individuals. We identified vSNPs for 7195 CpG sites (P mean DNA methylation levels. We further showed that variance heterogeneity between genotypes mainly represents additional, often rare, SNPs in linkage disequilibrium (LD) with the respective vSNP and for some vSNPs, multiple low frequency variants co-segregating with one of the vSNP alleles. Therefore, our results suggest that variance heterogeneity of DNA methylation mainly represents phenotypic effects by multiple SNPs, rather than biological interactions. Such effects may also be important for interpreting variance heterogeneity of more complex clinical phenotypes.

Method of generating ploynucleotides encoding enhanced folding variants

Energy Technology Data Exchange (ETDEWEB)

Bradbury, Andrew M.; Kiss, Csaba; Waldo, Geoffrey S.

2017-05-02

The invention provides directed evolution methods for improving the folding, solubility and stability (including thermostability) characteristics of polypeptides. In one aspect, the invention provides a method for generating folding and stability-enhanced variants of proteins, including but not limited to fluorescent proteins, chromophoric proteins and enzymes. In another aspect, the invention provides methods for generating thermostable variants of a target protein or polypeptide via an internal destabilization baiting strategy. Internally destabilization a protein of interest is achieved by inserting a heterologous, folding-destabilizing sequence (folding interference domain) within DNA encoding the protein of interest, evolving the protein sequences adjacent to the heterologous insertion to overcome the destabilization (using any number of mutagenesis methods), thereby creating a library of variants. The variants in the library are expressed, and those with enhanced folding characteristics selected.

Influenza A (H3N2) Variant Virus

Science.gov (United States)

... Swine Variant Pandemic Other Influenza A (H3N2) Variant Virus Language: English (US) Español Recommend on Facebook Tweet Share Compartir Influenza viruses that normally circulate in pigs are called “variant” ...

Ankle fracture spur sign is pathognomonic for a variant ankle fracture.

Science.gov (United States)

Hinds, Richard M; Garner, Matthew R; Lazaro, Lionel E; Warner, Stephen J; Loftus, Michael L; Birnbaum, Jacqueline F; Burket, Jayme C; Lorich, Dean G

2015-02-01

The hyperplantarflexion variant ankle fracture is composed of a posterior tibial lip fracture with posterolateral and posteromedial fracture fragments separated by a vertical fracture line. This infrequently reported injury pattern often includes an associated "spur sign" or double cortical density at the inferomedial tibial metaphysis. The objective of this study was to quantitatively establish the association of the ankle fracture spur sign with the hyperplantarflexion variant ankle fracture. Our clinical database of operative ankle fractures was retrospectively reviewed for the incidence of hyperplantarflexion variant and nonvariant ankle fractures as determined by assessment of injury radiographs, preoperative advanced imaging, and intraoperative observation. Injury radiographs were then evaluated for the presence of the spur sign, and association between the spur sign and variant fractures was analyzed. The incidence of the hyperplantarflexion variant fracture among all ankle fractures was 6.7% (43/640). The spur sign was present in 79% (34/43) of variant fractures and absent in all nonvariant fractures, conferring a specificity of 100% in identifying variant fractures. Positive predictive value and negative predictive value were 100% and 99%, respectively. The ankle fracture spur sign was pathognomonic for the hyperplantarflexion variant ankle fracture. It is important to identify variant fractures preoperatively as patient positioning, operative approach, and fixation construct of variant fractures often differ from those employed for osteosynthesis of nonvariant fractures. Identification of the spur sign should prompt acquisition of advanced imaging to formulate an appropriate operative plan to address the variant fracture pattern. Level III, retrospective comparative study. © The Author(s) 2014.

Holoprosencephaly Variant

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J Gordon Millichap

2003-01-01

Full Text Available The clinical manifestations in 15 patients (6 boys and 9 girls with middle interhemispheric variant (MIH of holoprosencephaly (HPE were compared with classic subtypes (alobar, semilobar, and lobar of HPE in a multicenter study at Stanford University School of Medicine and Lucile Packard Children’s Hospital; Children’s Hospital of Philadelphia; University of California at San Francisco; Texas Scottish Rite Hospital, Dallas; and Kennedy Krieger Institute, Baltimore, MD.

Investigation of the role of TCF4 rare sequence variants in schizophrenia.

Science.gov (United States)

Basmanav, F Buket; Forstner, Andreas J; Fier, Heide; Herms, Stefan; Meier, Sandra; Degenhardt, Franziska; Hoffmann, Per; Barth, Sandra; Fricker, Nadine; Strohmaier, Jana; Witt, Stephanie H; Ludwig, Michael; Schmael, Christine; Moebus, Susanne; Maier, Wolfgang; Mössner, Rainald; Rujescu, Dan; Rietschel, Marcella; Lange, Christoph; Nöthen, Markus M; Cichon, Sven

2015-07-01

Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci and is supported by several genetic and functional lines of evidence. While numerous studies have implicated common genetic variation at TCF4 in schizophrenia risk, the role of rare, small-sized variants at this locus-such as single nucleotide variants and short indels which are below the resolution of chip-based arrays requires further exploration. The aim of the present study was to investigate the association between rare TCF4 sequence variants and schizophrenia. Exon-targeted resequencing was performed in 190 German schizophrenia patients. Six rare variants at the coding exons and flanking sequences of the TCF4 gene were identified, including two missense variants and one splice site variant. These six variants were then pooled with nine additional rare variants identified in 379 European participants of the 1000 Genomes Project, and all 15 variants were genotyped in an independent German sample (n = 1,808 patients; n = 2,261 controls). These data were then analyzed using six statistical methods developed for the association analysis of rare variants. No significant association (P power analyses suggest that further research into the possible involvement of rare TCF4 sequence variants in schizophrenia risk is warranted by the assessment of larger cohorts with higher statistical power to identify rare variant associations. © 2015 Wiley Periodicals, Inc.