Tail-flick test response in 3×Tg-AD mice at early and advanced stages of disease.

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Baeta-Corral, Raquel; Defrin, Ruti; Pick, Chagi G; Giménez-Llort, Lydia

2015-07-23

Despite the impact of pain in cognitive dysfunctions and affective disorders has been largely studied, the research that examines pain dimensions in cognitive impairment or dementia is still scarce. In patients with Alzheimer's disease (AD) and related dementias, management of pain is challenging. While the sensory-discriminative dimension of pain is preserved, the cognitive-evaluative and the affective-motivational pain dimensions are affected. Due to the complexity of the disease and the poor self-reports, pain is underdiagnosed and undertreated. In confluence with an impaired thermoregulatory behavior, the patients' ability to confront environmental stressors such as cold temperature can put them at risk of fatal accidental hypothermia. Here, 3xTg-AD mice demonstrate that the sensorial-discriminative threshold to a noxious cold stimulus, as measured by the latency of tail-flicking, was preserved at early and advances stages of disease (7 and 11 month-old, respectively) as compared to age-matched (adulthood and middle aged, respectively) non-transgenic mice (NTg). In both genotypes, the sensory deterioration and poor thermoregulatory behavior associated to age was observed as an increase of tail-flick response and poor sensorimotor performance. At both stages studied, 3xTg-AD mice exhibited BPSD (Behavioral and Psychological Symptoms of Dementia)-like alterations in the corner, open-field, dark-light box and the T-maze tests. In the adult NTg mice, this nociceptive withdrawal response was correlated with copying with stress-related behaviors. This integrative behavioral profile was lost in both groups of 3xTg-AD mice and middle aged controls, suggesting derangements in their subjacent networks and the complex interplay between the pain dimensions in the elderly with dementia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Color perception differentiates Alzheimer's Disease (AD) from Vascular Dementia (VaD) patients.

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Arnaoutoglou, N A; Arnaoutoglou, M; Nemtsas, P; Costa, V; Baloyannis, S J; Ebmeier, K P

2017-08-01

Alzheimer's Disease (AD) and Vascular Dementia (VaD) are the most common causes of dementia in older people. Both diseases appear to have similar clinical symptoms, such as deficits in attention and executive function, but specific cognitive domains are affected. Current cohort studies have shown a close relationship between αβ deposits and age-related macular degeneration (Johnson et al., 2002; Ratnayaka et al., 2015). Additionally, a close link between the thinning of the retinal nerve fiber (RNFL) and AD patients has been described, while it has been proposed that AD patients suffer from a non-specific type of color blindness (Pache et al., 2003). Our study included 103 individuals divided into three groups: A healthy control group (n = 35), AD (n = 32) according to DSM-IV-TR, NINCDS-ADRDA criteria, and VaD (n = 36) based on ΝΙΝDS-AIREN, as well as Magnetic Resonance Imaging (MRI) results. The severity of patient's cognitive impairment, was measured with the Mini-Mental State Examination (MMSE) and was classified according to the Reisberg global deterioration scale (GDS). Visual perception was examined using the Ishihara plates: "Ishihara Color Vision Test - 38 Plate." The three groups were not statistically different for demographic data (age, gender, and education). The Ishihara color blindness test has a sensitivity of 80.6% and a specificity of 87.5% to discriminate AD and VaD patients when an optimal (32.5) cut-off value of performance is used. Ishihara Color Vision Test - 38 Plate is a promising potential method as an easy and not time-consuming screening test for the differential diagnosis of dementia between AD and VaD.

Primary motor cortex alterations in Alzheimer disease: A study in the 3xTg-AD model.

Science.gov (United States)

Orta-Salazar, E; Feria-Velasco, A I; Díaz-Cintra, S

2017-04-19

In humans and animal models, Alzheimer disease (AD) is characterised by accumulation of amyloid-β peptide (Aβ) and hyperphosphorylated tau protein, neuronal degeneration, and astrocytic gliosis, especially in vulnerable brain regions (hippocampus and cortex). These alterations are associated with cognitive impairment (loss of memory) and non-cognitive impairment (motor impairment). The purpose of this study was to identify cell changes (neurons and glial cells) and aggregation of Aβ and hyperphosphorylated tau protein in the primary motor cortex (M1) in 3xTg-AD mouse models at an intermediate stage of AD. We used female 3xTg-AD mice aged 11 months and compared them to non-transgenic mice of the same age. In both groups, we assessed motor performance (open field test) and neuronal damage in M1 using specific markers: BAM10 (extracellular Aβ aggregates), tau 499 (hyperphosphorylated tau protein), GFAP (astrocytes), and Klüver-Barrera staining (neurons). Female 3xTg-AD mice in intermediate stages of the disease displayed motor and cellular alterations associated with Aβ and hyperphosphorylated tau protein deposition in M1. Patients with AD display signs and symptoms of functional impairment from early stages. According to our results, M1 cell damage in intermediate-stage AD affects motor function, which is linked to progression of the disease. Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Ocular changes in TgF344-AD rat model of Alzheimer's disease.

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Tsai, Yuchun; Lu, Bin; Ljubimov, Alexander V; Girman, Sergey; Ross-Cisneros, Fred N; Sadun, Alfredo A; Svendsen, Clive N; Cohen, Robert M; Wang, Shaomei

2014-01-29

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive decline in learning, memory, and executive functions. In addition to cognitive and behavioral deficits, vision disturbances have been reported in early stage of AD, well before the diagnosis is clearly established. To further investigate ocular abnormalities, a novel AD transgenic rat model was analyzed. Transgenic (Tg) rats (TgF344-AD) heterozygous for human mutant APPswe/PS1ΔE9 and age-matched wild type (WT) rats, as well as 20 human postmortem retinal samples from both AD and healthy donors were used. Visual function in the rodent was analyzed using the optokinetic response and luminance threshold recording from the superior colliculus. Immunohistochemistry on retinal and brain sections was used to detect various markers including amyloid-β (Aβ) plaques. As expected, Aβ plaques were detected in the hippocampus, cortex, and retina of Tg rats. Plaque-like structures were also found in two AD human whole-mount retinas. The choroidal thickness was significantly reduced in both Tg rat and in AD human eyes when compared with age-matched controls. Tg rat eyes also showed hypertrophic retinal pigment epithelial cells, inflammatory cells, and upregulation of complement factor C3. Although visual acuity was lower in Tg than in WT rats, there was no significant difference in the retinal ganglion cell number and retinal vasculature. In this study, we observed pathological changes in the choroid and in RPE cells in the TgF344-AD rat model; choroidal thinning was observed further in human AD retina. Along with Ab deposition, the inflammatory response was manifested by microglial recruitment and complement activation. Further studies are needed to elucidate the significance and mechanisms of these pathological changes [corrected].

Immunotherapy of Alzheimer's disease (AD): from murine models to anti-amyloid beta (Abeta) human monoclonal antibodies.

Science.gov (United States)

Geylis, Valeria; Steinitz, Michael

2006-01-01

The deposition of amyloid beta (Abeta) protein is a key pathological feature in Alzheimer's disease (AD). In murine models of AD, both active and passive immunization against Abeta induce a marked reduction in amyloid brain burden and an improvement in cognitive functions. Preliminary results of a prematurely terminated clinical trial where AD patients were actively vaccinated with aggregated Abeta bear resemblance to those documented in murine models. Passive immunization of AD patients with anti-Abeta antibodies, in particular human antibodies, is a strategy that provides a more cautious management and control of any undesired side effects. Sera of all healthy adults contain anti-Abeta IgG autoimmune antibodies. Hence antigen-committed human B-cells are easily immortalized by Epstein-Barr virus (EBV) into anti-Abeta secreting cell lines. Two anti-Abeta human monoclonal antibodies which we recently prepared bind to the N-terminus of Abeta peptide and were shown to stain amyloid plaques in non-fixed brain sections from an AD patient. It is anticipated that specifically selected anti-Abeta human monoclonal antibodies could reduce and inhibit deposits of amyloid in brain while avoiding the cognitive decline that characterizes AD. In the future, this type of antibody may prove to be a promising immune therapy for the disease.

Tensor-based morphometry as a neuroimaging biomarker for Alzheimer's disease: an MRI study of 676 AD, MCI, and normal subjects.

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Hua, Xue; Leow, Alex D; Parikshak, Neelroop; Lee, Suh; Chiang, Ming-Chang; Toga, Arthur W; Jack, Clifford R; Weiner, Michael W; Thompson, Paul M

2008-11-15

In one of the largest brain MRI studies to date, we used tensor-based morphometry (TBM) to create 3D maps of structural atrophy in 676 subjects with Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy elderly controls, scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Using inverse-consistent 3D non-linear elastic image registration, we warped 676 individual brain MRI volumes to a population mean geometric template. Jacobian determinant maps were created, revealing the 3D profile of local volumetric expansion and compression. We compared the anatomical distribution of atrophy in 165 AD patients (age: 75.6+/-7.6 years), 330 MCI subjects (74.8+/-7.5), and 181 controls (75.9+/-5.1). Brain atrophy in selected regions-of-interest was correlated with clinical measurements--the sum-of-boxes clinical dementia rating (CDR-SB), mini-mental state examination (MMSE), and the logical memory test scores - at voxel level followed by correction for multiple comparisons. Baseline temporal lobe atrophy correlated with current cognitive performance, future cognitive decline, and conversion from MCI to AD over the following year; it predicted future decline even in healthy subjects. Over half of the AD and MCI subjects carried the ApoE4 (apolipoprotein E4) gene, which increases risk for AD; they showed greater hippocampal and temporal lobe deficits than non-carriers. ApoE2 gene carriers--1/6 of the normal group--showed reduced ventricular expansion, suggesting a protective effect. As an automated image analysis technique, TBM reveals 3D correlations between neuroimaging markers, genes, and future clinical changes, and is highly efficient for large-scale MRI studies.

Lipopolysaccharide (LPS Accumulates in Neocortical Neurons of Alzheimer’s Disease (AD Brain and Impairs Transcription in Human Neuronal-Glial Primary Co-cultures

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Yuhai Zhao

2017-12-01

Full Text Available Several independent laboratories have recently reported the detection of bacterial nucleic acid sequences or bacterial-derived neurotoxins, such as highly inflammatory lipopolysaccharide (LPS, within Alzheimer’s disease (AD affected brain tissues. Whether these bacterial neurotoxins originate from the gastrointestinal (GI tract microbiome, a possible brain microbiome or some dormant pathological microbiome is currently not well understood. Previous studies indicate that the co-localization of pro-inflammatory LPS with AD-affected brain cell nuclei suggests that there may be a contribution of this neurotoxin to genotoxic events that support inflammatory neurodegeneration and failure in homeostatic gene expression. In this report we provide evidence that in sporadic AD, LPS progressively accumulates in neuronal parenchyma and appears to preferentially associate with the periphery of neuronal nuclei. Run-on transcription studies utilizing [α-32P]-uridine triphosphate incorporation into newly synthesized total RNA further indicates that human neuronal-glial (HNG cells in primary co-culture incubated with LPS exhibit significantly reduced output of DNA transcription products. These studies suggest that in AD LPS may impair the efficient readout of neuronal genetic information normally required for the homeostatic operation of brain cell function and may contribute to a progressive disruption in the read-out of genetic information.

Chronic Anatabine Treatment Reduces Alzheimer's Disease (AD)-Like Pathology and Improves Socio-Behavioral Deficits in a Transgenic Mouse Model of AD.

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Verma, Megha; Beaulieu-Abdelahad, David; Ait-Ghezala, Ghania; Li, Rena; Crawford, Fiona; Mullan, Michael; Paris, Daniel

2015-01-01

Anatabine is a minor tobacco alkaloid, which is also found in plants of the Solanaceae family and displays a chemical structure similarity with nicotine. We have shown previously that anatabine displays some anti-inflammatory properties and reduces microgliosis and tau phosphorylation in a pure mouse model of tauopathy. We therefore investigated the effects of a chronic oral treatment with anatabine in a transgenic mouse model (Tg PS1/APPswe) of Alzheimer's disease (AD) which displays pathological Aβ deposits, neuroinflammation and behavioral deficits. In the elevated plus maze, Tg PS1/APPswe mice exhibited hyperactivity and disinhibition compared to wild-type mice. Six and a half months of chronic oral anatabine treatment, suppressed hyperactivity and disinhibition in Tg PS1/APPswe mice compared to Tg PS1/APPswe receiving regular drinking water. Tg PS1/APPswe mice also elicited profound social interaction and social memory deficits, which were both alleviated by the anatabine treatment. We found that anatabine reduces the activation of STAT3 and NFκB in the vicinity of Aβ deposits in Tg PS1/APPswe mice resulting in a reduction of the expression of some of their target genes including Bace1, iNOS and Cox-2. In addition, a significant reduction in microgliosis and pathological deposition of Aβ was observed in the brain of Tg PS1/APPswe mice treated with anatabine. This is the first study to investigate the impact of chronic anatabine treatment on AD-like pathology and behavior in a transgenic mouse model of AD. Overall, our data show that anatabine reduces β-amyloidosis, neuroinflammation and alleviates some behavioral deficits in Tg PS1/APPswe, supporting further exploration of anatabine as a possible disease modifying agent for the treatment of AD.

Chronic Anatabine Treatment Reduces Alzheimer's Disease (AD-Like Pathology and Improves Socio-Behavioral Deficits in a Transgenic Mouse Model of AD.

Directory of Open Access Journals (Sweden)

Megha Verma

Full Text Available Anatabine is a minor tobacco alkaloid, which is also found in plants of the Solanaceae family and displays a chemical structure similarity with nicotine. We have shown previously that anatabine displays some anti-inflammatory properties and reduces microgliosis and tau phosphorylation in a pure mouse model of tauopathy. We therefore investigated the effects of a chronic oral treatment with anatabine in a transgenic mouse model (Tg PS1/APPswe of Alzheimer's disease (AD which displays pathological Aβ deposits, neuroinflammation and behavioral deficits. In the elevated plus maze, Tg PS1/APPswe mice exhibited hyperactivity and disinhibition compared to wild-type mice. Six and a half months of chronic oral anatabine treatment, suppressed hyperactivity and disinhibition in Tg PS1/APPswe mice compared to Tg PS1/APPswe receiving regular drinking water. Tg PS1/APPswe mice also elicited profound social interaction and social memory deficits, which were both alleviated by the anatabine treatment. We found that anatabine reduces the activation of STAT3 and NFκB in the vicinity of Aβ deposits in Tg PS1/APPswe mice resulting in a reduction of the expression of some of their target genes including Bace1, iNOS and Cox-2. In addition, a significant reduction in microgliosis and pathological deposition of Aβ was observed in the brain of Tg PS1/APPswe mice treated with anatabine. This is the first study to investigate the impact of chronic anatabine treatment on AD-like pathology and behavior in a transgenic mouse model of AD. Overall, our data show that anatabine reduces β-amyloidosis, neuroinflammation and alleviates some behavioral deficits in Tg PS1/APPswe, supporting further exploration of anatabine as a possible disease modifying agent for the treatment of AD.

Supergravity one-loop corrections on AdS7 and AdS3, higher spins and AdS/CFT

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Matteo Beccaria

2015-03-01

Full Text Available As was shown earlier, the one-loop correction in 10d supergravity on AdS5×S5 corresponds to the contributions to the vacuum energy and 4d boundary conformal anomaly which are minus the values for one N=4 Maxwell supermultiplet, thus reproducing the subleading term in the N2−1 coefficient in the dual SU(N SYM theory. We perform similar one-loop computations in 11d supergravity on AdS7×S4 and 10d supergravity on AdS3×S3×T4. In the AdS7 case we find that the corrections to the 6d conformal anomaly a-coefficient and the vacuum energy are again minus the ones for one (2,0 tensor multiplet, suggesting that the total a-anomaly coefficient for the dual (2,0 theory is 4N3−9/4N−7/4 and thus vanishes for N=1. In the AdS3 case the one-loop correction to the vacuum energy or 2d central charge turns out to be equal to that of one free (4,4 scalar multiplet, i.e. is c=+6. This reproduces the subleading term in the central charge c=6(Q1Q5+1 of the dual 2d CFT describing decoupling limit of D5–D1 system. We also present the expressions for the 6d a-anomaly coefficient and vacuum energy contributions of general-symmetry higher spin field in AdS7 and consider their application to tests of vectorial AdS/CFT with the boundary conformal 6d theory represented by free scalars, spinors or rank-2 antisymmetric tensors.

Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer's Disease (AD: Detection of Lipopolysaccharide (LPS in AD Hippocampus

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Yuhai Zhao

2017-07-01

Full Text Available Although the potential contribution of the human gastrointestinal (GI tract microbiome to human health, aging, and disease is becoming increasingly acknowledged, the molecular mechanics and signaling pathways of just how this is accomplished is not well-understood. Major bacterial species of the GI tract, such as the abundant Gram-negative bacilli Bacteroides fragilis (B. fragilis and Escherichia coli (E. coli, secrete a remarkably complex array of pro-inflammatory neurotoxins which, when released from the confines of the healthy GI tract, are pathogenic and highly detrimental to the homeostatic function of neurons in the central nervous system (CNS. For the first time here we report the presence of bacterial lipopolysaccharide (LPS in brain lysates from the hippocampus and superior temporal lobe neocortex of Alzheimer's disease (AD brains. Mean LPS levels varied from two-fold increases in the neocortex to three-fold increases in the hippocampus, AD over age-matched controls, however some samples from advanced AD hippocampal cases exhibited up to a 26-fold increase in LPS over age-matched controls. This “Perspectives” paper will further highlight some very recent research on GI tract microbiome signaling to the human CNS, and will update current findings that implicate GI tract microbiome-derived LPS as an important internal contributor to inflammatory degeneration in the CNS.

The Guinea Pig as a Model for Sporadic Alzheimer’s Disease (AD): The Impact of Cholesterol Intake on Expression of AD-Related Genes

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Ong, Daniel; Wijaya, Linda; Laws, Simon M.; Taddei, Kevin; Newman, Morgan; Lardelli, Michael; Martins, Ralph N.; Verdile, Giuseppe

2013-01-01

We investigated the guinea pig, Cavia porcellus, as a model for Alzheimer’s disease (AD), both in terms of the conservation of genes involved in AD and the regulatory responses of these to a known AD risk factor - high cholesterol intake. Unlike rats and mice, guinea pigs possess an Aβ peptide sequence identical to human Aβ. Consistent with the commonality between cardiovascular and AD risk factors in humans, we saw that a high cholesterol diet leads to up-regulation of BACE1 (β-secretase) transcription and down-regulation of ADAM10 (α-secretase) transcription which should increase release of Aβ from APP. Significantly, guinea pigs possess isoforms of AD-related genes found in humans but not present in mice or rats. For example, we discovered that the truncated PS2V isoform of human PSEN2, that is found at raised levels in AD brains and that increases γ-secretase activity and Aβ synthesis, is not uniquely human or aberrant as previously believed. We show that PS2V formation is up-regulated by hypoxia and a high-cholesterol diet while, consistent with observations in humans, Aβ concentrations are raised in some brain regions but not others. Also like humans, but unlike mice, the guinea pig gene encoding tau, MAPT, encodes isoforms with both three and four microtubule binding domains, and cholesterol alters the ratio of these isoforms. We conclude that AD-related genes are highly conserved and more similar to human than the rat or mouse. Guinea pigs represent a superior rodent model for analysis of the impact of dietary factors such as cholesterol on the regulation of AD-related genes. PMID:23805206

Intake of added sugar in Malaysia: a review.

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Amarra, Maria Sofia V; Khor, Geok Lin; Chan, Pauline

2016-01-01

The term 'added sugars' refers to sugars and syrup added to foods during processing or preparation, and sugars and syrups added at the table. Calls to limit the daily intakes of added sugars and its sources arose from evidence analysed by WHO, the American Heart Association and other organizations. The present review examined the best available evidence regarding levels of added sugar consumption among different age and sex groups in Malaysia and sources of added sugars. Information was extracted from food balance sheets, household expenditure surveys, nutrition surveys and published studies. Varying results emerged, as nationwide information on intake of sugar and foods with added sugar were obtained at different times and used different assessment methods. Data from the 2003 Malaysian Adult Nutrition Survey (MANS) using food frequency questionnaires suggested that on average, Malaysian adults consumed 30 grams of sweetened condensed milk (equivalent to 16 grams sugar) and 21 grams of table sugar per day, which together are below the WHO recommendation of 50 grams sugar for every 2000 kcal/day to reduce risk of chronic disease. Published studies suggested that, for both adults and the elderly, frequently consumed sweetened foods were beverages (tea or coffee) with sweetened condensed milk and added sugar. More accurate data should be obtained by conducting population-wide studies using biomarkers of sugar intake (e.g. 24-hour urinary sucrose and fructose excretion or serum abundance of the stable isotope 13C) to determine intake levels, and multiple 24 hour recalls to identify major food sources of added sugar.

Penrose inequality for asymptotically AdS spaces

International Nuclear Information System (INIS)

Itkin, Igor; Oz, Yaron

2012-01-01

In general relativity, the Penrose inequality relates the mass and the entropy associated with a gravitational background. If the inequality is violated by an initial Cauchy data, it suggests a creation of a naked singularity, thus providing means to consider the cosmic censorship hypothesis. We propose a general form of Penrose inequality for asymptotically locally AdS spaces.

Penrose inequality for asymptotically AdS spaces

Energy Technology Data Exchange (ETDEWEB)

Itkin, Igor [Raymond and Beverly Sackler School of Physics and Astronomy, Tel-Aviv University, Tel-Aviv 69978 (Israel); Oz, Yaron, E-mail: yaronoz@post.tau.ac.il [Raymond and Beverly Sackler School of Physics and Astronomy, Tel-Aviv University, Tel-Aviv 69978 (Israel)

2012-02-28

In general relativity, the Penrose inequality relates the mass and the entropy associated with a gravitational background. If the inequality is violated by an initial Cauchy data, it suggests a creation of a naked singularity, thus providing means to consider the cosmic censorship hypothesis. We propose a general form of Penrose inequality for asymptotically locally AdS spaces.

The Existence of Primary Age-Related Tauopathy Suggests that not all the Cases with Early Braak Stages of Neurofibrillary Pathology are Alzheimer's Disease.

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Giaccone, Giorgio

2015-01-01

The distinction between Alzheimer's disease (AD) and Primary Age-Related Tauopathy (PART) is a hotly debated issue. As most lines of evidence support the tenet that tau pathology occurs downstream of amyloid-β deposition, it seems reasonable to consider PART as a separate disease process not necessarily related to Aβ and hence AD. Following this view, the early stages of neurofibrillary pathology may not always be the forerunner of diffuse neurofibrillary changes and AD. The ongoing debate further enhances the need for greater caution against any future predictions using tau cerebrospinal fluid and imaging biomarkers.

Application of the PredictAD Decision Support Tool to a Danish Cohort of Patients with Alzheimer's Disease and Other Dementias

DEFF Research Database (Denmark)

Simonsen, A H; Mattila, J; Hejl, A M

2013-01-01

Background: The diagnosis of Alzheimer's disease (AD) is based on an ever-increasing body of data and knowledge making it a complex task. The PredictAD tool integrates heterogeneous patient data using an interactive user interface to provide decision support. The aim of this project was to invest......Background: The diagnosis of Alzheimer's disease (AD) is based on an ever-increasing body of data and knowledge making it a complex task. The PredictAD tool integrates heterogeneous patient data using an interactive user interface to provide decision support. The aim of this project...... forest. Results: The DSI performed best for this realistic dataset with an accuracy of 76.6% compared to the accuracies for the naïve Bayesian classifier and random forest of 67.4 and 66.7%, respectively. Furthermore, the DSI differentiated between the four diagnostic groups with a p value of ....0001. Conclusion: In this dataset, the DSI method used by the PredictAD tool showed a superior performance for the differentiation between patients with AD and those with other dementias. However, the methods need to be refined further in order to optimize the differential diagnosis between AD, FTD, VaD and DLB....

Parkinson disease and Alzheimer disease: environmental risk factors.

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Campdelacreu, J

2014-01-01

The purpose of this review is to update and summarise available evidence on environmental risk factors that have been associated with risk of Parkinson disease (PD) or Alzheimer disease (AD) and discuss their potential mechanisms. Evidence consistently suggests that a higher risk of PD is associated with pesticides and that a higher risk of AD is associated with pesticides, hypertension and high cholesterol levels in middle age, hyperhomocysteinaemia, smoking, traumatic brain injury and depression. There is weak evidence suggesting that higher risk of PD is associated with high milk consumption in men, high iron intake, chronic anaemia and traumatic brain injury. Weak evidence also suggests that a higher risk of AD is associated with high aluminium intake through drinking water, excessive exposure to electromagnetic fields from electrical grids, DM and hyperinsulinaemia, obesity in middle age, excessive alcohol consumption and chronic anaemia. Evidence consistently suggests that a lower risk of PD is associated with hyperuricaemia, tobacco and coffee use, while a lower risk of AD is associated with moderate alcohol consumption, physical exercise, perimenopausal hormone replacement therapy and good cognitive reserve. Weak evidence suggests that lower risk of PD is associated with increased vitamin E intake, alcohol, tea, NSAIDs, and vigorous physical exercise, and that lower risk of AD is associated with the Mediterranean diet, coffee and habitual NSAID consumption. Several environmental factors contribute significantly to risk of PD and AD. Some may already be active in the early stages of life, and some may interact with other genetic factors. Population-based strategies to modify such factors could potentially result in fewer cases of PD or AD. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Stress steroids as accelerators of Alzheimer's disease. : Effects of chronically elevated levels of allopregnanolone in transgenic AD models.

OpenAIRE

Bengtsson, Sara

2013-01-01

Background Alzheimer’s disease (AD) and dementia are devastating con­ditions not only for the affected patients but also for their families.  The economical costs for the society are tremendous. Mid-life psychological stress, psychosocial stress and post-traumatic stress disorder cause cognitive dysfunction and lead to increased risk for dementia. However, the mecha­nisms behind stress-induced AD and dementia are not known. AD is char­acterized by solid amyloid plaques in the CNS. However, ov...

Streptozotocin Intracerebroventricular-Induced Neurotoxicity and Brain Insulin Resistance: a Therapeutic Intervention for Treatment of Sporadic Alzheimer's Disease (sAD)-Like Pathology.

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Kamat, Pradip K; Kalani, Anuradha; Rai, Shivika; Tota, Santosh Kumar; Kumar, Ashok; Ahmad, Abdullah S

2016-09-01

Alzheimer's disease (AD) is a neurodegenerative disorder that is remarkably characterized by pathological hallmarks which include amyloid plaques, neurofibrillary tangles, neuronal loss, and progressive cognitive loss. Several well-known genetic mutations which are being used for the development of a transgenic model of AD lead to an early onset familial AD (fAD)-like condition. However, these settings are only reasons for a small percentage of the total AD cases. The large majorities of AD cases are considered as a sporadic in origin and are less influenced by a single mutation of a gene. The etiology of sporadic Alzheimer's disease (sAD) remains unclear, but numerous risk factors have been identified that increase the chance of developing AD. Among these risk factors are insulin desensitization/resistance state, oxidative stress, neuroinflammation, synapse dysfunction, tau hyperphosphorylation, and deposition of Aβ in the brain. Subsequently, these risk factors lead to development of sAD. However, the underlying molecular mechanism is not so clear. Streptozotocin (STZ) produces similar characteristic pathology of sAD such as altered glucose metabolism, insulin signaling, synaptic dysfunction, protein kinases such as protein kinase B/C, glycogen synthase-3β (GSK-3β) activation, tau hyperphosphorylation, Aβ deposition, and neuronal apoptosis. Further, STZ also leads to inhibition of Akt/PKB, insulin receptor (IR) signaling molecule, and insulin resistance in brain. These alterations mediated by STZ can be used to explore the underlying molecular and pathophysiological mechanism of AD (especially sAD) and their therapeutic intervention for drug development against AD pathology.

Cluster analysis of Helicobacter pylori genomic DNA fingerprints suggests gastroduodenal disease-specific associations.

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Go, M F; Chan, K Y; Versalovic, J; Koeuth, T; Graham, D Y; Lupski, J R

1995-07-01

Helicobacter pylori infection is now accepted as the most common cause of chronic active gastritis and peptic ulcer disease. The etiologies of many infectious diseases have been attributed to specific or clonal strains of bacterial pathogens. Polymerase chain reaction (PCR) amplification of DNA between repetitive DNA sequences, REP elements (REP-PCR), has been utilized to generate DNA fingerprints to examine similarity among strains within a bacterial species. Genomic DNA from H. pylori isolates obtained from 70 individuals (39 duodenal ulcers and 31 simple gastritis) was PCR-amplified using consensus probes to repetitive DNA elements. The H. pylori DNA fingerprints were analyzed for similarity and correlated with disease presentation using the NTSYS-pc computer program. Each H. pylori strain had a distinct DNA fingerprint except for two pairs. Single-colony DNA fingerprints of H. pylori from the same patient were identical, suggesting that each patient harbors a single strain. Computer-assisted cluster analysis of the REP-PCR DNA fingerprints showed two large clusters of isolates, one associated with simple gastritis and the other with duodenal ulcer disease. Cluster analysis of REP-PCR DNA fingerprints of H. pylori strains suggests that duodenal ulcer isolates, as a group, are more similar to one another and different from gastritis isolates. These results suggest that disease-specific strains may exist.

Attention in Parkinson’s Disease Mimicking Suggestion in Psychogenic Movement Disorder

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Jong Sam Baik

2012-10-01

Full Text Available The various reported psychogenic movement disorders (PMDs include tremor, dystonia, myoclonus, gait disorder, Parkinsonism, tics, and chorea. Although it is not easy to diagnose PMDs, several features such as distractibility, entrainment, suggestion and placebo trial are quite helpful to diagnose. Especially, distractibility or suggestion is a good tool to do in outpatient clinic easily. We describe a patient with parkinsonian features which were improved by internal suggestion to focusing attention. Initially, we suspected her diagnosis as PMDs; however she was confirmed with organic Parkinson’s disease later.

Antismoking Ads at the Point of Sale: The Influence of Ad Type and Context on Ad Reactions.

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Kim, Annice; Nonnemaker, James; Guillory, Jamie; Shafer, Paul; Parvanta, Sarah; Holloway, John; Farrelly, Matthew

2017-06-01

Efforts are underway to educate consumers about the dangers of smoking at the point of sale (POS). Research is limited about the efficacy of POS antismoking ads to guide campaign development. This study experimentally tests whether the type of antismoking ad and the context in which ads are viewed influence people's reactions to the ads. A national convenience sample of 7,812 adult current smokers and recent quitters was randomized to 1 of 39 conditions. Participants viewed one of the four types of antismoking ads (negative health consequences-graphic, negative social consequences-intended emotive, benefits of quitting-informational, benefits of quitting-graphic) in one of the three contexts (alone, next to a cigarette ad, POS tobacco display). We assessed participants' reactions to the ads, including perceived effectiveness, negative emotion, affective dissonance, and motivational reaction. Graphic ads elicited more negative emotion and affective dissonance than benefits of quitting ads. Graphic ads elicited higher perceived effectiveness and more affective dissonance than intended emotive ads. Antismoking ads fared best when viewed alone, and graphic ads were least influenced by the context in which they were viewed. These results suggest that in developing POS campaigns, it is important to consider the competitive pro-tobacco context in which antismoking ads will be viewed.

Position space analysis of the AdS (in)stability problem

NARCIS (Netherlands)

Dimitrakopoulos, F.V.; Freivogel, B.; Lippert, M.; Yang, I.S.

2015-01-01

We investigate whether arbitrarily small perturbations in global AdS space are generically unstable and collapse into black holes on the time scale set by gravitational interactions. We argue that current evidence, combined with our analysis, strongly suggests that a set of nonzero measure in the

Disrupted Structural Brain Network in AD and aMCI: A Finding of Long Fiber Degeneration.

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Fang, Rong; Yan, Xiao-Xiao; Wu, Zhi-Yuan; Sun, Yu; Yin, Qi-Hua; Wang, Ying; Tang, Hui-Dong; Sun, Jun-Feng; Miao, Fei; Chen, Sheng-Di

2015-01-01

Although recent evidence has emerged that Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) patients show both regional brain abnormalities and topological degeneration in brain networks, our understanding of the effects of white matter fiber aberrations on brain network topology in AD and aMCI is still rudimentary. In this study, we investigated the regional volumetric aberrations and the global topological abnormalities in AD and aMCI patients. The results showed a widely distributed atrophy in both gray and white matters in the AD and aMCI groups. In particular, AD patients had weaker connectivity with long fiber length than aMCI and normal control (NC) groups, as assessed by fractional anisotropy (FA). Furthermore, the brain networks of all three groups exhibited prominent economical small-world properties. Interestingly, the topological characteristics estimated from binary brain networks showed no significant group effect, indicating a tendency of preserving an optimal topological architecture in AD and aMCI during degeneration. However, significantly longer characteristic path length was observed in the FA weighted brain networks of AD and aMCI patients, suggesting dysfunctional global integration. Moreover, the abnormality of the characteristic path length was negatively correlated with the clinical ratings of cognitive impairment. Thus, the results therefore suggested that the topological alterations in weighted brain networks of AD are induced by the loss of connectivity with long fiber lengths. Our findings provide new insights into the alterations of the brain network in AD and may indicate the predictive value of the network metrics as biomarkers of disease development.

Microglial TNF and IL-1 as early disease-modifiers in Alzheimer's-like disease in mice

DEFF Research Database (Denmark)

Ilkjær, Laura; Babcock, Alicia; Finsen, Bente

2015-01-01

In Alzheimer's disease (AD) signs of microglial activation is evident already in prodromal and early AD. This and other evidence suggest that neuroinflammation contributes to the progression of the early disease development in AD. Microglial cells have the capacity to produce cytokines such as TNF...... in the APPswe/PS1DE9 mouse model of AD. In these mice, cortical As plaque load shows a sigmoidal trajectory with age, as it does in AD. At 12 months of age, when As pathology is welldeveloped, TNF and IL-1s are produced in significantly higher proportions of microglia in the APPswe/PS1DE9 mice, than in wildtype...

Adding Recognition Discriminability Index to the Delayed Recall Is Useful to Predict Conversion from Mild Cognitive Impairment to Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative.

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Russo, María J; Campos, Jorge; Vázquez, Silvia; Sevlever, Gustavo; Allegri, Ricardo F

2017-01-01

Background: Ongoing research is focusing on the identification of those individuals with mild cognitive impairment (MCI) who are most likely to convert to Alzheimer's disease (AD). We investigated whether recognition memory tasks in combination with delayed recall measure of episodic memory and CSF biomarkers can predict MCI to AD conversion at 24-month follow-up. Methods: A total of 397 amnestic-MCI subjects from Alzheimer's disease Neuroimaging Initiative were included. Logistic regression modeling was done to assess the predictive value of all RAVLT measures, risk factors such as age, sex, education, APOE genotype, and CSF biomarkers for progression to AD. Estimating adjusted odds ratios was used to determine which variables would produce an optimal predictive model, and whether adding tests of interaction between the RAVLT Delayed Recall and recognition measures (traditional score and d-prime) would improve prediction of the conversion from a-MCI to AD. Results: 112 (28.2%) subjects developed dementia and 285 (71.8%) subjects did not. Of the all included variables, CSF Aβ1-42 levels, RAVLT Delayed Recall, and the combination of RAVLT Delayed Recall and d-prime were predictive of progression to AD (χ 2 = 38.23, df = 14, p < 0.001). Conclusions: The combination of RAVLT Delayed Recall and d-prime measures may be predictor of conversion from MCI to AD in the ADNI cohort, especially in combination with amyloid biomarkers. A predictive model to help identify individuals at-risk for dementia should include not only traditional episodic memory measures (delayed recall or recognition), but also additional variables (d-prime) that allow the homogenization of the assessment procedures in the diagnosis of MCI.

Churg-Strauss syndrome concomitant with chronic symmetrical dacryoadenitis suggesting Mikulicz's disease.

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Hanioka, Yusuke; Yamagami, Keiko; Yoshioka, Katsunobu; Nakamura, Tomomi; Kishida, Masatsugu; Nakamura, Tomoyuki; Yamaguchi, Toshimasa; Koshimo, Naomi; Inoue, Takeshi; Imanishi, Masahito

2012-01-01

A case of Churg-Strauss syndrome complicated by chronic symmetrical dacryoadenitis suggestive of Mikulicz's disease is herein presented. A 72-year-old Japanese man, who had been previously diagnosed with asthma, presented with weakness of the left leg and purpura on the lower extremities. A neurological examination showed multiple mononeuropathies and a laboratory examination revealed elevated eosinophil counts, IgE levels and the presence of Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCAs). Churg-Strauss syndrome was diagnosed, although the patient also exhibited bilateral swelling of the lachrymal glands. Furthermore, elevated serum IgG4 levels, an infiltration of a relatively large number of IgG4-positive plasmacytes in the nasal mucosa and hypocomplementemia were also observed. These findings were consistent with a diagnosis of Mikulicz's disease (MD). Oral prednisolone (30 mg) was administered and the swelling of the lachrymal glands resolved. Churg-Strauss syndrome may be accompanied by Mikulicz's disease (an IgG4-related disease), and common pathogeneses between Churg-Strauss syndrome and IgG4-related disease may exist.

Concurrence of High Fat Diet and APOE Gene Induces Allele Specific Metabolic and Mental Stress Changes in an AD Model

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Yifat Segev

2016-09-01

Full Text Available Aging is the main risk factor for neurodegenerative diseases, including Alzheimer’s disease (AD. However, evidence indicates that the pathological process begins long before actual cognitive or pathological symptoms are apparent. The long asymptomatic phase and complex integration between genetic, environmental, and metabolic factors make it one of the most challenging diseases to understand and cure. In the present study, we asked whether an environmental factor such as high-fat diet would synergize with a genetic factor to affect the metabolic and cognitive state in the ApoE4 mouse model of AD. Our data suggest that a high-fat diet induces diabetes mellitus-like metabolism in ApoE4 mice, as well as changes in BACE1 protein levels between the two ApoE strains. Furthermore, high-fat diet induces anxiety in this AD mouse model. Our results suggest that young ApoE4 carriers are prone to psychological stress and metabolic abnormalities related to AD, which can easily be triggered via high-fat nutrition.

Effect of Citalopram on Agitation in Alzheimer's Disease – The CitAD Randomized Controlled Trial

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Porsteinsson, Anton P.; Drye, Lea T.; Pollock, Bruce G.; Devanand, D.P.; Frangakis, Constantine; Ismail, Zahinoor; Marano, Christopher; Meinert, Curtis L.; Mintzer, Jacobo E.; Munro, Cynthia A.; Pelton, Gregory; Rabins, Peter V.; Rosenberg, Paul B.; Schneider, Lon S.; Shade, David M.; Weintraub, Daniel; Yesavage, Jerome; Lyketsos, Constantine G.

2014-01-01

Importance Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer's disease (AD). Pharmacological treatment options, including antipsychotics are not satisfactory. Objective The primary objective was to evaluate the efficacy of citalopram for agitation in patients with AD. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability. Design, Setting and Participants The Citalopram for Agitation in Alzheimer's Disease Study (CitAD) was a multicenter, randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable AD and clinically significant agitation from eight academic centers in the US and Canada from August 2009 to January 2013. Interventions Participants (n=186) were randomized to receive a psychosocial intervention plus either citalopram (n=94) or placebo (n=92) for 9 weeks. Dose began at 10 mg/d with planned titration to 30 mg/d over 3 weeks based on response and tolerability. Main Outcomes and Measures Primary outcome measures were the Neurobehavioral Rating Scale, agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC) Other outcomes were the Cohen-Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory (NPI), activities of daily living (ADLs), caregiver distress, cognitive safety (MMSE), and adverse events. Results Participants on citalopram showed significant improvement compared to placebo on both primary outcome measures. NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was −0.93 [95% CI: −1.80 to −0.06], p = 0.036. mADCS-CGIC results showed 40% of citalopram participants having moderate or marked improvement from baseline compared to 26% on placebo, with estimated treatment effect (odds ratio of being at or better than a given CGIC category) of 2.13 [95% CI 1.23 to 3.69], p = 0

Are Abeta and its derivatives causative agents or innocent bystanders in AD?

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Robakis, Nikolaos K

2010-01-01

Alzheimer's disease (AD) is characterized by neurodegeneration in neocortical regions of the brain. Currently, Abeta-based theories, including amyloid depositions and soluble Abeta, form the basis of most therapeutic approaches to AD. It remains unclear, however, whether Abeta and its derivatives are the primary causative agents of neuronal loss in AD. Reported studies show no significant correlations between brain amyloid depositions and either degree of dementia or loss of neurons, and brain amyloid loads similar to AD are often found in normal individuals. Furthermore, behavioral abnormalities in animal models overexpressing amyloid precursor protein seem independent of amyloid depositions. Soluble Abeta theories propose toxic Abeta42 or its oligomers as the agents that promote cell death in AD. Abeta peptides, however, are normal components of human serum and CSF, and it is unclear under what conditions these peptides become toxic. Presently, there is little evidence of disease-associated abnormalities in soluble Abeta and no toxic oligomers specific to AD have been found. That familial AD mutations of amyloid precursor protein, PS1 and PS2 promote neurodegeneration suggests the biological functions of these proteins play critical roles in neuronal survival. Evidence shows that the PS/gamma-secretase system promotes production of peptides involved in cell surface-to-nucleus signaling and gene expression, providing support for the hypothesis that familial AD mutations may contribute to neurodegeneration by inhibiting PS-dependent signaling pathways. Copyright 2010 S. Karger AG, Basel.

Are Aβ and Its Derivatives Causative Agents or Innocent Bystanders in AD?

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Robakis, Nikolaos K.

2010-01-01

Alzheimer's disease (AD) is characterized by neurodegeneration in neocortical regions of the brain. Currently, Aβ-based theories, including amyloid depositions and soluble Aβ, form the basis of most therapeutic approaches to AD. It remains unclear, however, whether Aβ and its derivatives are the primary causative agents of neuronal loss in AD. Reported studies show no significant correlations between brain amyloid depositions and either degree of dementia or loss of neurons, and brain amyloid loads similar to AD are often found in normal individuals. Furthermore, behavioral abnormalities in animal models overexpressing amyloid precursor protein seem independent of amyloid depositions. Soluble Aβ theories propose toxic Aβ42 or its oligomers as the agents that promote cell death in AD. Aβ peptides, however, are normal components of human serum and CSF, and it is unclear under what conditions these peptides become toxic. Presently, there is little evidence of disease-associated abnormalities in soluble Aβ and no toxic oligomers specific to AD have been found. That familial AD mutations of amyloid precursor protein, PS1 and PS2 promote neurodegeneration suggests the biological functions of these proteins play critical roles in neuronal survival. Evidence shows that the PS/γ-secretase system promotes production of peptides involved in cell surface-to-nucleus signaling and gene expression, providing support for the hypothesis that familial AD mutations may contribute to neurodegeneration by inhibiting PS-dependent signaling pathways. PMID:20160455

Anxiety-like behavior as an early endophenotype in the TgF344-AD rat model of Alzheimer's disease.

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Pentkowski, Nathan S; Berkowitz, Laura E; Thompson, Shannon M; Drake, Emma N; Olguin, Carlos R; Clark, Benjamin J

2018-01-01

Alzheimer's disease (AD) is characterized by progressive cognitive decline and the presence of aggregates of amyloid beta (plaques) and hyperphosphorylated tau (tangles). Early diagnosis through neuropsychological testing is difficult due to comorbidity of symptoms between AD and other types of dementia. As a result, there is a need to identify the range of behavioral phenotypes expressed in AD. In the present study, we utilized a transgenic rat (TgF344-AD) model that bears the mutated amyloid precursor protein as well as presenilin-1 genes, resulting in progressive plaque and tangle pathogenesis throughout the cortex. We tested young adult male and female TgF344-AD rats in a spatial memory task in the Morris water maze and for anxiety-like behavior in the elevated plus-maze. Results indicated that regardless of sex, TgF344-AD rats exhibited increased anxiety-like behavior in the elevated plus-maze, which occurred without significant deficits in the spatial memory. Together, these results indicate that enhanced anxiety-like behavior represents an early-stage behavioral marker in the TgF344-AD rat model. Copyright © 2017 Elsevier Inc. All rights reserved.

Black hole formation in AdS Einstein-Gauss-Bonnet gravity

Energy Technology Data Exchange (ETDEWEB)

Deppe, Nils [Cornell Center for Astrophysics and Planetary Science andDepartment of Physics, Cornell University,122 Sciences Drive, Ithaca, New York 14853 (United States); Kolly, Allison [Department of Atmospheric and Oceanic Sciences, McGill University,805 Sherbrooke Street West, Montréal, Québec H3A 0B9 (Canada); Frey, Andrew R.; Kunstatter, Gabor [Department of Physics and Winnipeg Institute for Theoretical Physics, University of Winnipeg,515 Portage Avenue, Winnipeg, Manitoba R3B 2E9 (Canada)

2016-10-17

AdS spacetime has been shown numerically to be unstable against a large class of arbitrarily small perturbations. In http://dx.doi.org/10.1103/PhysRevLett.114.071102, the authors presented a preliminary study of the effects on stability of changing the local dynamics by adding a Gauss-Bonnet term to the Einstein action. Here we provide further details as well as new results with improved numerical methods. In particular, we elucidate new structure in Choptuik scaling plots. We also provide evidence of chaotic behavior at the transition between immediate horizon formation and horizon formation after the matter pulse reflects from the AdS conformal boundary. Finally, we present data suggesting the formation of naked singularities in spacetimes with ADM mass below the algebraic bound for black hole formation.

Synopsis on the linkage of Alzheimer's and Parkinson's disease with chronic diseases.

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Jabir, Nasimudeen R; Firoz, Chelapram K; Baeesa, Saleh S; Ashraf, Ghulam Md; Akhtar, Suhail; Kamal, Warda; Kamal, Mohammad A; Tabrez, Shams

2015-01-01

Neurodegeneration is the progressive loss of neuronal structure and function, which ultimately leads to neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis, and Huntington's disease. Even after the recent significant advances in neurobiology, the above-mentioned disorders continue to haunt the global population. Several studies have suggested the role of specific environmental and genetic risk factors associated with these disorders. However, the exact mechanism associated with the progression of these disorders still needs to be elucidated. In the recent years, sophisticated research has revealed interesting association of prominent neurodegenerative disorders such as AD and PD with chronic diseases such as cancer, diabetes, and cardiovascular diseases. Several common molecular mechanisms such as generation of free radicals, oxidative DNA damage, aberrations in mitochondrial DNA, and dysregulation of apoptosis have been highlighted as possible points of connection. The present review summarizes the possible mechanism of coexistence of AD and PD with other chronic diseases. © 2014 John Wiley & Sons Ltd.

Enthalpy and the mechanics of AdS black holes

International Nuclear Information System (INIS)

Kastor, David; Traschen, Jennie; Ray, Sourya

2009-01-01

We present geometric derivations of the Smarr formula for static AdS black holes and an expanded first law that includes variations in the cosmological constant. These two results are further related by a scaling argument based on Euler's theorem. The key new ingredient in the constructions is a two-form potential for the static Killing field. Surface integrals of the Killing potential determine the coefficient of the variation of Λ in the first law. This coefficient is proportional to a finite, effective volume for the region outside the AdS black hole horizon, which can also be interpreted as minus the volume excluded from a spatial slice by the black hole horizon. This effective volume also contributes to the Smarr formula. Since Λ is naturally thought of as a pressure, the new term in the first law has the form of effective volume times change in pressure that arises in the variation of the enthalpy in classical thermodynamics. This and related arguments suggest that the mass of an AdS black hole should be interpreted as the enthalpy of the spacetime.

Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families.

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Carlos Cruchaga

Full Text Available Pathogenic mutations in APP, PSEN1, PSEN2, MAPT and GRN have previously been linked to familial early onset forms of dementia. Mutation screening in these genes has been performed in either very small series or in single families with late onset AD (LOAD. Similarly, studies in single families have reported mutations in MAPT and GRN associated with clinical AD but no systematic screen of a large dataset has been performed to determine how frequently this occurs. We report sequence data for 439 probands from late-onset AD families with a history of four or more affected individuals. Sixty sequenced individuals (13.7% carried a novel or pathogenic mutation. Eight pathogenic variants, (one each in APP and MAPT, two in PSEN1 and four in GRN three of which are novel, were found in 14 samples. Thirteen additional variants, present in 23 families, did not segregate with disease, but the frequency of these variants is higher in AD cases than controls, indicating that these variants may also modify risk for disease. The frequency of rare variants in these genes in this series is significantly higher than in the 1,000 genome project (p = 5.09 × 10⁻⁵; OR = 2.21; 95%CI = 1.49-3.28 or an unselected population of 12,481 samples (p = 6.82 × 10⁻⁵; OR = 2.19; 95%CI = 1.347-3.26. Rare coding variants in APP, PSEN1 and PSEN2, increase risk for or cause late onset AD. The presence of variants in these genes in LOAD and early-onset AD demonstrates that factors other than the mutation can impact the age at onset and penetrance of at least some variants associated with AD. MAPT and GRN mutations can be found in clinical series of AD most likely due to misdiagnosis. This study clearly demonstrates that rare variants in these genes could explain an important proportion of genetic heritability of AD, which is not detected by GWAS.

Mitophagy and Alzheimer's Disease

DEFF Research Database (Denmark)

Kerr, Jesse S.; Adriaanse, Bryan A.; Greig, Nigel H.

2017-01-01

Neurons affected in Alzheimer's disease (AD) experience mitochondrial dysfunction and a bioenergetic deficit that occurs early and promotes the disease-defining amyloid beta peptide (Aβ) and Tau pathologies. Emerging findings suggest that the autophagy/lysosome pathway that removes damaged...

Effect of Sodium Selenate on Hippocampal Proteome of 3×Tg-AD Mice-Exploring the Antioxidant Dogma of Selenium against Alzheimer's Disease.

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Iqbal, Javed; Zhang, Kaoyuan; Jin, Na; Zhao, Yuxi; Liu, Qiong; Ni, Jiazuan; Shen, Liming

2018-04-19

Selenium (Se), an antioxidant trace element, is an important nutrient for maintaining brain functions and is reported to be involved in Alzheimer's disease (AD) pathologies. The present study has been designed to elucidate the protein changes in hippocampus of 3×Tg-AD mice after supplementing sodium selenate as an inorganic source of selenium. By using iTRAQ proteomics technology, 113 differentially expressed proteins (DEPs) are found in AD/WT mice with 37 upregulated and 76 downregulated proteins. Similarly, in selenate-treated 3×Tg-AD (ADSe/AD) mice, 115 DEPs are found with 98 upregulated and 17 downregulated proteins. The third group of mice (ADSe/WT) showed 75 DEPs with 46 upregulated and 29 downregulated proteins. Among these results, 42 proteins (40 downregulated and 2 upregulated) in the diseased group showed reverse expression when treated with selenate. These DEPs are analyzed with different bioinformatics tools and are found associated with various AD pathologies and pathways. Based on their functions, selenate-reversed proteins are classified as structural proteins, metabolic proteins, calcium regulating proteins, synaptic proteins, signaling proteins, stress related proteins, and transport proteins. Six altered AD associated proteins are successfully validated by Western blot analysis. This study shows that sodium selenate has a profound effect on the hippocampus of the triple transgenic AD mice. This might be established as an effective therapeutic agent after further investigation.

Long-term Treatment with Low-Dose Caffeine Worsens BPSD-Like Profile in 3xTg-AD Mice Model of Alzheimer’s Disease and Affects Mice with Normal Aging

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Raquel Baeta-Corral

2018-02-01

Full Text Available Coffee or caffeine has recently been suggested as prophylaxis for dementia. Although memory problems are hallmarks of Alzheimer’s disease, this dementia is also characterized by neuropsychiatric symptoms called Behavioral and Psychological Symptoms of Dementia (BPSD. The impact of preventive/therapeutic strategies on both cognitive and non-cognitive symptoms can be addressed in the 3xTg-AD mice, since they exhibit cognitive but also BPSD-like profiles. Here, we studied the long-term effects of a low dose of caffeine in male 3xTg-AD mice and as compared to age-matched non-transgenic (NTg counterparts with normal aging. Animals were treated (water or caffeine in drinking water from adulthood (6 months of age until middle-aged (13 months of age, that in 3xTg-AD mice correspond to onset of cognitive impairment and advanced stages, respectively. The low caffeine dosing used (0.3 mg/ml was previously found to give a plasma concentration profile in mice roughly equivalent to that of a human coffee drinker. There were significant effects of caffeine on most behavioral variables, especially those related to neophobia and other anxiety-like behaviors, emotionality, and cognitive flexibility. The 3xTg-AD and NTg mice were differently influenced by caffeine. Overall, the increase of neophobia and other anxiety-related behaviors resulted in an exacerbation of BPSD-like profile in 3xTg-AD mice. Learning and memory, strongly influenced by anxiety in 3xTg-AD mice, got little benefit from caffeine, only shown after a detailed analysis of navigation strategies. The worsened pattern in NTg mice and the use of search strategies in 3xTg-AD mice make both groups more similar. Circadian motor activity showed genotype differences, which were found to be enhanced by caffeine. Selective effects of caffeine on NTg were found in the modulation of behaviors related to emotional profile and risk assessment. Caffeine normalized splenomegaly of 3xTg-AD mice, a physical

Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits.

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Jiao, Shu-Sheng; Yao, Xiu-Qing; Liu, Yu-Hui; Wang, Qing-Hua; Zeng, Fan; Lu, Jian-Jun; Liu, Jia; Zhu, Chi; Shen, Lin-Lin; Liu, Cheng-Hui; Wang, Ye-Ran; Zeng, Gui-Hua; Parikh, Ankit; Chen, Jia; Liang, Chun-Rong; Xiang, Yang; Bu, Xian-Le; Deng, Juan; Li, Jing; Xu, Juan; Zeng, Yue-Qin; Xu, Xiang; Xu, Hai-Wei; Zhong, Jin-Hua; Zhou, Hua-Dong; Zhou, Xin-Fu; Wang, Yan-Jiang

2015-04-21

Alzheimer's disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aβ aggregation and attenuating Aβ-induced oxidation in vitro. When given before or after the onset of Aβ deposition via i.p. injection, Edaravone substantially reduces Aβ deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis.

Endogenous murine tau promotes neurofibrillary tangles in 3xTg-AD mice without affecting cognition.

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Baglietto-Vargas, David; Kitazawa, Masashi; Le, Elaine J; Estrada-Hernandez, Tatiana; Rodriguez-Ortiz, Carlos J; Medeiros, Rodrigo; Green, Kim N; LaFerla, Frank M

2014-02-01

Recent studies on tauopathy animal models suggest that the concomitant expression of the endogenous murine tau delays the pathological accumulation of human tau, and interferes with the disease progression. To elucidate the role of endogenous murine tau in a model with both plaques and tangles, we developed a novel transgenic mouse model by crossing 3xTg-AD with mtauKO mice (referred to as 3xTg-AD/mtauKO mice). Therefore, this new model allows us to determine the pathological consequences of the murine tau. Here, we show that 3xTg-AD/mtauKO mice have lower tau loads in both soluble and insoluble fractions, and lower tau hyperphosphorylation level in the soluble fraction relative to 3xTg-AD mice. In the 3xTg-AD model endogenous mouse tau is hyperphosphorylated and significantly co-aggregates with human tau. Despite the deletion of the endogenous tau gene in 3xTg-AD/mtauKO mice, cognitive dysfunction was equivalent to 3xTg-AD mice, as there was no additional impairment on a spatial memory task, and thus despite increased tau phosphorylation, accumulation and NFTs in 3xTg-AD mice no further effects on cognition are seen. These findings provide better understanding about the role of endogenous tau to Alzheimer's disease (AD) pathology and for developing new AD models. © 2013.

Aleutian Disease: An Emerging Disease in Free-Ranging Striped Skunks (Mephitis mephitis) From California.

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LaDouceur, E E B; Anderson, M; Ritchie, B W; Ciembor, P; Rimoldi, G; Piazza, M; Pesti, D; Clifford, D L; Giannitti, F

2015-11-01

Aleutian disease virus (ADV, Amdovirus, Parvoviridae) primarily infects farmed mustelids (mink and ferrets) but also other fur-bearing animals and humans. Three Aleutian disease (AD) cases have been described in captive striped skunks; however, little is known about the relevance of AD in free-ranging carnivores. This work describes the pathological findings and temporospatial distribution in 7 cases of AD in free-ranging striped skunks. All cases showed neurologic disease and were found in a 46-month period (2010-2013) within a localized geographical region in California. Lesions included multisystemic plasmacytic and lymphocytic inflammation (ie, interstitial nephritis, myocarditis, hepatitis, meningoencephalitis, pneumonia, and splenitis), glomerulonephritis, arteritis with or without fibrinoid necrosis in several organs (ie, kidney, heart, brain, and spleen), splenomegaly, ascites/hydrothorax, and/or encephalomalacia with cerebral microangiopathy. ADV infection was confirmed in all cases by specific polymerase chain reaction and/or in situ hybridization. The results suggest that AD is an emerging disease in free-ranging striped skunks in California. © The Author(s) 2014.

Position space analysis of the AdS (in)stability problem

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Dimitrakopoulos, Fotios V.; Freivogel, Ben; Lippert, Matthew; Yang, I.-Sheng

2015-08-01

We investigate whether arbitrarily small perturbations in global AdS space are generically unstable and collapse into black holes on the time scale set by gravitational interactions. We argue that current evidence, combined with our analysis, strongly suggests that a set of nonzero measure in the space of initial conditions does not collapse on this time scale. We perform an analysis in position space to study this puzzle, and our formalism allows us to directly study the vanishing-amplitude limit. We show that gravitational self-interaction leads to tidal deformations which are equally likely to focus or defocus energy, and we sketch the phase diagram accordingly. We also clarify the connection between gravitational evolution in global AdS and holographic thermalization.

Position space analysis of the AdS (in)stability problem

Energy Technology Data Exchange (ETDEWEB)

Dimitrakopoulos, Fotios V.; Freivogel, Ben; Lippert, Matthew; Yang, I-Sheng [ITFA and GRAPPA, Universiteit van Amsterdam,Science Park 904, 1090 GL Amsterdam (Netherlands)

2015-08-17

We investigate whether arbitrarily small perturbations in global AdS space are generically unstable and collapse into black holes on the time scale set by gravitational interactions. We argue that current evidence, combined with our analysis, strongly suggests that a set of nonzero measure in the space of initial conditions does not collapse on this time scale. We perform an analysis in position space to study this puzzle, and our formalism allows us to directly study the vanishing-amplitude limit. We show that gravitational self-interaction leads to tidal deformations which are equally likely to focus or defocus energy, and we sketch the phase diagram accordingly. We also clarify the connection between gravitational evolution in global AdS and holographic thermalization.

Interpolating from Bianchi attractors to Lifshitz and AdS spacetimes

International Nuclear Information System (INIS)

Kachru, Shamit; Kundu, Nilay; Saha, Arpan; Samanta, Rickmoy; Trivedi, Sandip P.

2014-01-01

We construct classes of smooth metrics which interpolate from Bianchi attractor geometries of Types II, III, VI and IX in the IR to Lifshitz or AdS 2 ×S 3 geometries in the UV. While we do not obtain these metrics as solutions of Einstein gravity coupled to a simple matter field theory, we show that the matter sector stress-energy required to support these geometries (via the Einstein equations) does satisfy the weak, and therefore also the null, energy condition. Since Lifshitz or AdS 2 ×S 3 geometries can in turn be connected to AdS 5 spacetime, our results show that there is no barrier, at least at the level of the energy conditions, for solutions to arise connecting these Bianchi attractor geometries to AdS 5 spacetime. The asymptotic AdS 5 spacetime has no non-normalizable metric deformation turned on, which suggests that furthermore, the Bianchi attractor geometries can be the IR geometries dual to field theories living in flat space, with the breaking of symmetries being either spontaneous or due to sources for other fields. Finally, we show that for a large class of flows which connect two Bianchi attractors, a C-function can be defined which is monotonically decreasing from the UV to the IR as long as the null energy condition is satisfied. However, except for special examples of Bianchi attractors (including AdS space), this function does not attain a finite and non-vanishing constant value at the end points

Supersymmetric AdS3, AdS2 and bubble solutions

International Nuclear Information System (INIS)

Gauntlett, Jerome P.; Waldram, Daniel; Kim, Nakwoo

2007-01-01

We present new supersymmetric AdS 3 solutions of type IIB supergravity and AdS 2 solutions of D = 11 supergravity. The former are dual to conformal field theories in two dimensions with N = (0, 2) supersymmetry while the latter are dual to conformal quantum mechanics with two supercharges. Our construction also includes AdS 2 solutions of D = 11 supergravity that have non-compact internal spaces which are dual to three-dimensional N = 2 superconformal field theories coupled to point-like defects. We also present some new bubble-type solutions, corresponding to BPS states in conformal theories, that preserve four supersymmetries

NF-kB as a mediator of brain inflammation in AD.

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Hong, Jin Tae

2017-08-07

Alzheimer's disease is the most common form of dementia. It is characterized by beta-amyloid peptide fibrils which are extracellular deposition of a specific protein, and is accompanied by extensive neuroinflammation. Various studies show the presence of a number of inflammation markers in the AD brain: elevated inflammatory cytokines and chemokines, and an accumulation of activated microglia in the damaged regions. NF-kB is a redox of transcriptional factors, and it is known to be located in the genes involved in amyloidogenesis and inflammation. Epidemiological studies have shown that NF-kB is elevated in the AD patient brain, and long-term use of non-steroidal anti-inflammatory drugs suppresses the progression of AD and delays its onset, suggesting that there is a close correlation between NF-kB and AD pathogenesis. This study is (1) to assess the association between NF-kB activity and AD through discussion of a variety of experimental and clinical studies on AD and (2) to review treatment strategies designed to treat or prevent AD with NF-kB inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Astrocytic Disruption in Traumatic Brain Injury and Alzheimer’s Disease

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2014-10-01

AD), with a growing body of evidence suggesting that TBI is a risk factor for AD. Using a TBI induction protocol that effectively models the injury...these pathologies overlap with those observed in Alzheimer’s disease (AD), with a growing body of evidence suggesting that TBI is a risk factor for

Intrinsic atopic dermatitis (AD) shows similar Th2 and higher Th17 immune activation compared to extrinsic AD

Science.gov (United States)

Suárez-Fariñas, M; Dhingra, N; Gittler, J; Shemer, A; Cardinale, I; de Guzman Strong, C; Krueger, JG; Guttman-Yassky, E

2013-01-01

Background Atopic dermatitis (AD) is classified as extrinsic (ADe) and intrinsic (ADi), representing approximately 80% and 20% of patients, respectively. While sharing a similar clinical phenotype, only ADe is characterized by high serum IgE. Since most AD patients exhibit high IgE, an “allergic”/IgE-mediated disease pathogenesis was hypothesized. However, current models associate AD with T-cell activation, particularly Th2/Th22 polarization, and epidermal barrier defects. Objective To define if both variants share a common pathogenesis. Methods We stratified 51 severe AD patients as ADe (42) and ADi (9) (with similar mean disease activity/SCORAD), and analyzed the molecular and cellular skin pathology of lesional and non-lesional ADi and ADe using gene-expression (RT-PCR) and immunohistochemistry. Results A significant correlation between IgE levels and SCORAD (r=0.76, pextrinsic and intrinsic AD variants might be treated with T-cell targeted therapeutics or agents that modify keratinocyte responses. PMID:23777851

Impaired cognition in depression and Alzheimer (AD: a gradient from depression to depression in AD

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Narahyana Bom de Araujo

2014-09-01

Full Text Available Objective To assess cognition in major depressed (MD, Alzheimer's disease (AD, and depression in AD elderly. Method Subjects were evaluated by Mini Mental, Rey Auditory Verbal Learning Test, Rey Complex Figure, Digit Span, Similarities, Trail Making A/B, Verbal Fluency and Stroop. One-way ANOVA and multivariate models were used to compare the performance of each group on neuropsychological tests. Results We evaluated 212 subjects. Compared to MD, attention, working memory, processing speed and recall showed significantly better in controls. Controls showed significantly higher performance in all cognitive measures, except in attention compared to AD. Verbal fluency, memory, processing speed and abstract reasoning in MD was significantly higher compared to AD. AD was significantly better in general cognitive state than depression in AD. All other cognitive domains were similar. Conclusion A decreasing gradient in cognition appeared from the control to depression in AD, with MD and AD in an intermediate position.

Combined Creutzfeldt-Jakob/ Alzheimer's Disease Cases are Important in Search for Microbes in Alzheimer's Disease.

Science.gov (United States)

Bastian, Frank O

2017-01-01

The question whether Alzheimer's disease is infectious as brought up in the recent editorial published in the Journal of Alzheimer's Disease is complicated by the controversy whether the causal agent is a microbe or a misfolded host protein (amyloid). The replicating amyloid (prion) theory, based upon data from studies of Creutzfeldt-Jakob disease (CJD) and other transmissible spongiform encephalopathies (TSEs), has been challenged since the prion can be separated from TSE infectivity, and spiroplasma, a wall-less bacterium, has been shown to be involved in the pathogenesis of CJD. Further support for a microbial cause for AD comes from occurrence of mixed CJD/AD cases involving up to 15% of AD brains submitted to brain banks. The association of CJD with AD suggests a common etiology rather than simply being a medical curiosity. A co-infection with the transmissible agent of CJD, which we propose to be a Spiroplasma sp., would explain the diversity of bacteria shown to be associated with cases of AD.

Edaravone alleviates Alzheimer’s disease-type pathologies and cognitive deficits

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Jiao, Shu-Sheng; Yao, Xiu-Qing; Liu, Yu-Hui; Wang, Qing-Hua; Zeng, Fan; Lu, Jian-Jun; Liu, Jia; Zhu, Chi; Shen, Lin-Lin; Liu, Cheng-Hui; Wang, Ye-Ran; Zeng, Gui-Hua; Parikh, Ankit; Chen, Jia; Liang, Chun-Rong; Xiang, Yang; Bu, Xian-Le; Deng, Juan; Li, Jing; Xu, Juan; Zeng, Yue-Qin; Xu, Xiang; Xu, Hai-Wei; Zhong, Jin-Hua; Zhou, Hua-Dong; Zhou, Xin-Fu; Wang, Yan-Jiang

2015-01-01

Alzheimer’s disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aβ aggregation and attenuating Aβ-induced oxidation in vitro. When given before or after the onset of Aβ deposition via i.p. injection, Edaravone substantially reduces Aβ deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis. PMID:25847999

Role of Liver X Receptor in AD Pathophysiology.

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Adrián G Sandoval-Hernández

Full Text Available Alzheimer's disease (AD is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1 and Apolipoprotein E (ApoE, changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD. Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment. The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12% are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.

Network Medicine for Alzheimer's Disease and Traditional Chinese Medicine.

Science.gov (United States)

Jarrell, Juliet T; Gao, Li; Cohen, David S; Huang, Xudong

2018-05-11

Alzheimer’s Disease (AD) is a neurodegenerative condition that currently has no known cure. The principles of the expanding field of network medicine (NM) have recently been applied to AD research. The main principle of NM proposes that diseases are much more complicated than one mutation in one gene, and incorporate different genes, connections between genes, and pathways that may include multiple diseases to create full scale disease networks. AD research findings as a result of the application of NM principles have suggested that functional network connectivity, myelination, myeloid cells, and genes and pathways may play an integral role in AD progression, and may be integral to the search for a cure. Different aspects of the AD pathology could be potential targets for drug therapy to slow down or stop the disease from advancing, but more research is needed to reach definitive conclusions. Additionally, the holistic approaches of network pharmacology in traditional Chinese medicine (TCM) research may be viable options for the AD treatment, and may lead to an effective cure for AD in the future.

Added sugars: Definitions, classifications, metabolism and health implications

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Tailane SCAPIN

Full Text Available ABSTRACT The sugars added to foods have been featured in recent scientific research, including the publication of the World Health Organization recommendation to limit consumption of added sugars, based on studies on weight gain and dental caries. However, it is possible that there is evidence of an association between excessive consumption and other pathologies, but scientific studies have yet to investigate these associations. Moreover, there is no consensus on the descriptions and definitions of these sugars, with several terms and components used to designate them. In Brazil, there are few studies investigating added sugars, identifying a lack of discussion on this subject. This paper presents a literature review of sugars added to foods, from their definitions and classifications to the metabolism and health effects. The search was performed without limiting dates in the following databases: Web of Science, Scopus, PubMed and SciELO, as well as in national and international official sites. Keywords in Portuguese and English related to sugars added to foods were used, in combination with terms related to systematic review and meta-analysis studies, in order to find research linking added sugars consumption with health damage. The literature indicates that there is a relationship between excessive consumption of added sugars and various health outcomes, including weight gain, type 2 diabetes Mellitus, cancer, and cardiovascular diseases. The different descriptions of sugars in foods may confuse both food consumers and researchers, since each term includes different components. Thus, it is suggested to use the standardized term “added sugar” as the most suitable term for the broader population to understand, because it indicates that those sugars are not natural food components.

Alzheimer's disease due to loss of function

DEFF Research Database (Denmark)

Kepp, Kasper Planeta

2016-01-01

Alzheimer's Disease (AD) is a highly complex disease involving a broad range of clinical, cellular, and biochemical manifestations that are currently not understood in combination. This has led to many views of AD, e.g. the amyloid, tau, presenilin, oxidative stress, and metal hypotheses....... The amyloid hypothesis has dominated the field with its assumption that buildup of pathogenic β-amyloid (Aβ) peptide causes disease. This paradigm has been criticized, yet most data suggest that Aβ plays a key role in the disease. Here, a new loss-of-function hypothesis is synthesized that accounts...

Alzheimer’s disease and anesthesia

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Marie-Amélie ePapon

2011-01-01

Full Text Available Cognitive disorders such as post-operative cognitive dysfunction, confusion, and delirium, are common following anesthesia in the elderly, with symptoms persisting for months or years in some patients. Alzheimer's disease (AD patients appear to be particularly at risk of cognitive deterioration following anesthesia, and some studies suggest that exposure to anesthetics may increase the risk of AD. Here, we review the literature linking anesthesia to AD, with a focus on the biochemical consequences of anesthetic exposure on AD pathogenic pathways.

Cerebral blood flow in Binswanger's disease

International Nuclear Information System (INIS)

Kawabata, Keita; Tachibana, Hisao; Sugita, Minoru

1991-01-01

Eight patients with a clinical diagnosis of Binswanger's disease (BD) were evaluated with I-123 IMP SPECT. The SPECT findings were compared with those in 7 other patients with Alzheimer's disease (AD) and 9 normal subjects. The ratios of I-123 IMP in the temporal cortex, thalamus, and basal ganglia to that in the cerebellum were lower in the BD group than the normal group. The BD group had a higher ratio of the occipital cortex/the cerebellum than the control group, suggesting a decreased blood flow in the cerebellum. When I-123 IMP ratio in various areas to that in the occipital cortex was examined, both the BD and AD groups seemed to have a decreased blood flow over the whole cerebrum. The BD group had a lower I-123 IMP uptake in the thalamus and basal ganglia, and the AD group had it in the parietal cortex, relative to the occipital cortex. Blood flow patterns for BD were found to be different from those for AD. This suggests the difference in areas responsible for etiology between BD and AD. (N.K.)

The PredictAD project

DEFF Research Database (Denmark)

Antila, Kari; Lötjönen, Jyrki; Thurfjell, Lennart

2013-01-01

Alzheimer's disease (AD) is the most common cause of dementia affecting 36 million people worldwide. As the demographic transition in the developed countries progresses towards older population, the worsening ratio of workers per retirees and the growing number of patients with age-related illnes...... candidates and implement the framework in software. The results are currently used in several research projects, licensed to commercial use and being tested for clinical use in several trials....... objective of the PredictAD project was to find and integrate efficient biomarkers from heterogeneous patient data to make early diagnosis and to monitor the progress of AD in a more efficient, reliable and objective manner. The project focused on discovering biomarkers from biomolecular data...

Closed-String Tachyons and the Hagedorn Transition in AdS Space

CERN Document Server

Barbón, José L F

2002-01-01

We discuss some aspects of the behaviour of a string gas at the Hagedorn temperature from a Euclidean point of view. Using AdS space as an infrared regulator, the Hagedorn tachyon can be effectively quasi-localized and its dynamics controled by a finite energetic balance. We propose that the off-shell RG flow matches to an Euclidean AdS black hole geometry in a generalization of the string/black-hole correspondence principle. The final stage of the RG flow can be interpreted semiclassically as the growth of a cool black hole in a hotter radiation bath. The end-point of the condensation is the large Euclidan AdS black hole, and the part of spacetime behind the horizon has been removed. In the flat-space limit, holography is manifest by the system creating its own transverse screen at infinity. This leads to an argument, based on the energetics of the system, explaining why the non-supersymmetric type 0A string theory decays into the supersymmetric type IIB vacuum. We also suggest a notion of `boundary entropy'...

Effective ads: new technology answers old questions

OpenAIRE

Couwenberg, Linda

2017-01-01

markdownabstractMarketing experts commonly refer to ads as either “emotional” or “rational” in their appeal to consumers. This dichotomy of “thinking versus feeling” is most evident when it comes to discussions around what makes an ad effective. Some studies suggest that an ad that pulls on the heart strings will pack the most punch; others suggest a blend of logic and emotion. However, new research reveals which areas of the brain are stimulated by different ad appeals – and the brain activi...

Identification of age- and disease-related alterations in circulating miRNAs in a mouse model of Alzheimer's disease

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Sylvia eGarza-Manero

2015-02-01

Full Text Available Alzheimer's disease (AD is a neurodegenerative disorder characterized clinically by the progressive decline of memory and cognition. Histopathologically, two main hallmarks have been identified in AD: amyloid-β peptide extracellular neuritic plaques and neurofibrillary tangles formed by posttranslational modified tau protein. A definitive diagnosis can only be achieved after the post mortem verification of the histological mentioned alterations. Therefore the development of biomarkers that allow an early diagnosis and/or predict disease progression is imperative. The prospect of a blood-based biomarker is possible with the finding of circulating microRNAs (miRNAs, a class of small non-coding RNAs of 22-25 nucleotides length that regulate mRNA translation rate. miRNAs travel through blood and recent studies performed in potential AD cases suggest the possibility of finding pathology-associated differences in circulating miRNA levels that may serve to assist in early diagnosis of the disease. However, these studies analyzed samples at a single time-point, limiting the use of miRNAs as biomarkers in AD progression. In this study we evaluated miRNA levels in plasma samples at different time-points of the evolution of an AD-like pathology in a transgenic mouse model of the disease (3xTg-AD. We performed multiplex qRT-PCR and compared the plasmatic levels of 84 miRNAs previously associated to central nervous system development and disease. No significant differences were detected between WT and transgenic young mice. However, age-related significant changes in miRNA abundance were observed for both WT and transgenic mice, and some of these were specific for the 3xTg-AD. In agreement, variations in the levels of particular miRNAs were identified between WT and transgenic old mice thus suggesting that the age-dependent evolution of the AD-like pathology, rather than the presence and expression of the transgenes, modifies the circulating miRNA levels in

Developing global climate anomalies suggest potential disease risks for 2006-2007.

Science.gov (United States)

Anyamba, Assaf; Chretien, Jean-Paul; Small, Jennifer; Tucker, Compton J; Linthicum, Kenneth J

2006-12-28

El Niño/Southern Oscillation (ENSO) related climate anomalies have been shown to have an impact on infectious disease outbreaks. The Climate Prediction Center of the National Oceanic and Atmospheric Administration (NOAA/CPC) has recently issued an unscheduled El Niño advisory, indicating that warmer than normal sea surface temperatures across the equatorial eastern Pacific may have pronounced impacts on global tropical precipitation patterns extending into the northern hemisphere particularly over North America. Building evidence of the links between ENSO driven climate anomalies and infectious diseases, particularly those transmitted by insects, can allow us to provide improved long range forecasts of an epidemic or epizootic. We describe developing climate anomalies that suggest potential disease risks using satellite generated data. Sea surface temperatures (SSTs) in the equatorial east Pacific ocean have anomalously increased significantly during July - October 2006 indicating the typical development of El Niño conditions. The persistence of these conditions will lead to extremes in global-scale climate anomalies as has been observed during similar conditions in the past. Positive Outgoing Longwave Radiation (OLR) anomalies, indicative of severe drought conditions, have been observed across all of Indonesia, Malaysia and most of the Philippines, which are usually the first areas to experience ENSO-related impacts. This dryness can be expected to continue, on average, for the remainder of 2006 continuing into the early part of 2007. During the period November 2006 - January 2007 climate forecasts indicate that there is a high probability for above normal rainfall in the central and eastern equatorial Pacific Islands, the Korean Peninsula, the U.S. Gulf Coast and Florida, northern South America and equatorial east Africa. Taking into consideration current observations and climate forecast information, indications are that the following regions are at increased

Age-related changes in core body temperature and activity in triple-transgenic Alzheimer's disease (3xTgAD) mice.

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Knight, Elysse M; Brown, Timothy M; Gümüsgöz, Sarah; Smith, Jennifer C M; Waters, Elizabeth J; Allan, Stuart M; Lawrence, Catherine B

2013-01-01

Alzheimer's disease (AD) is characterised, not only by cognitive deficits and neuropathological changes, but also by several non-cognitive behavioural symptoms that can lead to a poorer quality of life. Circadian disturbances in core body temperature and physical activity are reported in AD patients, although the cause and consequences of these changes are unknown. We therefore characterised circadian patterns of body temperature and activity in male triple transgenic AD mice (3xTgAD) and non-transgenic (Non-Tg) control mice by remote radiotelemetry. At 4 months of age, daily temperature rhythms were phase advanced and by 6 months of age an increase in mean core body temperature and amplitude of temperature rhythms were observed in 3xTgAD mice. No differences in daily activity rhythms were seen in 4- to 9-month-old 3xTgAD mice, but by 10 months of age an increase in mean daily activity and the amplitude of activity profiles for 3xTgAD mice were detected. At all ages (4-10 months), 3xTgAD mice exhibited greater food intake compared with Non-Tg mice. The changes in temperature did not appear to be solely due to increased food intake and were not cyclooxygenase dependent because the temperature rise was not abolished by chronic ibuprofen treatment. No β-amyloid (Aβ) plaques or neurofibrillary tangles were noted in the hypothalamus of 3xTgAD mice, a key area involved in temperature regulation, although these pathological features were observed in the hippocampus and amygdala of 3xTgAD mice from 10 months of age. These data demonstrate age-dependent changes in core body temperature and activity in 3xTgAD mice that are present before significant AD-related neuropathology and are analogous to those observed in AD patients. The 3xTgAD mouse might therefore be an appropriate model for studying the underlying mechanisms involved in non-cognitive behavioural changes in AD.

Alzheimer disease and anesthesia.

Science.gov (United States)

Inan, Gözde; Özköse Satirlar, Zerrin

2015-01-01

Alzheimer disease (AD) is one of the most common neurodegenerative diseases and the most prevalent form of dementia. Some factors in the development of AD, age being the best-known one, have been suggested; however, no causes have been found yet. The pathophysiology of the disease is highly complex, current therapies are palliative, and a cure is still lacking. Adverse effects of anesthetics in the elderly have been reported since the 1950s; however, awareness of this old problem has recently gained inportance again. Whether exposure to surgery and general anesthesia (GA) is associated with the development of AD has been questioned. As the population is aging, many elderly patients will need to be anesthetized, and maybe some were already anesthetized before they were diagnosed. Exposure to anesthetics has been demonstrated to promote pathogenesis of AD in both in vitro and in vivo studies. However, to date, there have not been any clinical trials to address a link between exposure to GA and the development of AD in humans. Therefore, before making any conclusions we need further studies, but we should be aware of the potential risks and take cautions with vulnerable elderly patients.

Insulin Resistance and Alzheimer’s Disease: Bioenergetic Linkages

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Bryan J. Neth

2017-10-01

Full Text Available Metabolic dysfunction is a well-established feature of Alzheimer’s disease (AD, evidenced by brain glucose hypometabolism that can be observed potentially decades prior to the development of AD symptoms. Furthermore, there is mounting support for an association between metabolic disease and the development of AD and related dementias. Individuals with insulin resistance, type 2 diabetes mellitus (T2D, hyperlipidemia, obesity, or other metabolic disease may have increased risk for the development of AD and similar conditions, such as vascular dementia. This association may in part be due to the systemic mitochondrial dysfunction that is common to these pathologies. Accumulating evidence suggests that mitochondrial dysfunction is a significant feature of AD and may play a fundamental role in its pathogenesis. In fact, aging itself presents a unique challenge due to inherent mitochondrial dysfunction and prevalence of chronic metabolic disease. Despite the progress made in understanding the pathogenesis of AD and in the development of potential therapies, at present we remain without a disease-modifying treatment. In this review, we will discuss insulin resistance as a contributing factor to the pathogenesis of AD, as well as the metabolic and bioenergetic disruptions linking insulin resistance and AD. We will also focus on potential neuroimaging tools for the study of the metabolic dysfunction commonly seen in AD with hopes of developing therapeutic and preventative targets.

Gribov ambiguity in asymptotically AdS three-dimensional gravity

International Nuclear Information System (INIS)

Anabalon, Andres; Canfora, Fabrizio; Giacomini, Alex; Oliva, Julio

2011-01-01

In this paper the zero modes of the de Donder gauge Faddeev-Popov operator for three-dimensional gravity with negative cosmological constant are analyzed. It is found that the AdS 3 vacuum produces (infinitely many) normalizable smooth zero modes of the Faddeev-Popov operator. On the other hand, it is found that the Banados-Teitelboim-Zanelli black hole (including the zero mass black hole) does not generate zero modes. This differs from the usual Gribov problem in QCD where, close to the maximally symmetric vacuum, the Faddeev-Popov determinant is positive definite while 'far enough' from the vacuum it can vanish. This suggests that the zero mass Banados-Teitelboim-Zanelli black hole could be a suitable ground state of three-dimensional gravity with negative cosmological constant. Because of the kinematic origin of this result, it also applies for other covariant gravity theories in three dimensions with AdS 3 as maximally symmetric solution, such as new massive gravity and topologically massive gravity. The relevance of these results for supersymmetry breaking is pointed out.

Critical Phenomena in Higher Curvature Charged AdS Black Holes

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Arindam Lala

2013-01-01

Full Text Available In this paper, we have studied the critical phenomena in higher curvature charged AdS black holes. We have considered Lovelock-Born-Infeld-AdS black hole as an example. The thermodynamics of the black hole have been studied which reveals the onset of a higher-order phase transition in the black hole in the canonical ensemble (fixed charge ensemble framework. We have analytically derived the critical exponents associated with these thermodynamic quantities. We find that our results fit well with the thermodynamic scaling laws and consistent with the mean field theory approximation. The suggestive values of the other two critical exponents associated with the correlation function and correlation length on the critical surface have been derived.

Holography beyond conformal invariance and AdS isometry?

CERN Document Server

Barvinsky, A.O.

2015-01-01

We suggest that the principle of holographic duality can be extended beyond conformal invariance and AdS isometry. Such an extension is based on a special relation between functional determinants of the operators acting in the bulk and on its boundary, provided that the boundary operator represents the inverse propagators of the theory induced on the boundary by the Dirichlet boundary value problem from the bulk spacetime. This relation holds for operators of general spin-tensor structure on generic manifolds with boundaries irrespective of their background geometry and conformal invariance, and it apparently underlies numerous $O(N^0)$ tests of AdS/CFT correspondence, based on direct calculation of the bulk and boundary partition functions, Casimir energies and conformal anomalies. The generalized holographic duality is discussed within the concept of the "double-trace" deformation of the boundary theory, which is responsible in the case of large $N$ CFT coupled to the tower of higher spin gauge fields for t...

NGS testing for cardiomyopathy: Utility of adding RASopathy-associated genes.

Science.gov (United States)

Ceyhan-Birsoy, Ozge; Miatkowski, Maya M; Hynes, Elizabeth; Funke, Birgit H; Mason-Suares, Heather

2018-04-25

RASopathies include a group of syndromes caused by pathogenic germline variants in RAS-MAPK pathway genes and typically present with facial dysmorphology, cardiovascular disease, and musculoskeletal anomalies. Recently, variants in RASopathy-associated genes have been reported in individuals with apparently nonsyndromic cardiomyopathy, suggesting that subtle features may be overlooked. To determine the utility and burden of adding RASopathy-associated genes to cardiomyopathy panels, we tested 11 RASopathy-associated genes by next-generation sequencing (NGS), including NGS-based copy number variant assessment, in 1,111 individuals referred for genetic testing for hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). Disease-causing variants were identified in 0.6% (four of 692) of individuals with HCM, including three missense variants in the PTPN11, SOS1, and BRAF genes. Overall, 36 variants of uncertain significance (VUSs) were identified, averaging ∼3VUSs/100 cases. This study demonstrates that adding a subset of the RASopathy-associated genes to cardiomyopathy panels will increase clinical diagnoses without significantly increasing the number of VUSs/case. © 2018 Wiley Periodicals, Inc.

Towards an improved duality between tensor network states and AdS spacetime

Energy Technology Data Exchange (ETDEWEB)

Papadopoulos, Charalampos; Orus, Roman [Institute of Physics, Johannes Gutenberg University, 55099 Mainz (Germany)

2016-07-01

The conjectured AdS/CFT Correspondence, which states that a Conformal Field Theory (CFT) in Minkowski spacetime has a gravity dual in an asymptotically Anti-de Sitter space (AdS), is one of the best understood examples of the holographic principle, and has important applications in condensed matter physics. Tensor Networks (TNs) are a efficient way to calculate low-energy properties for strongly-correlated quantum many-body systems. The Multi-scale Entanglement Renormalization Ansatz (MERA) is a specific TN for a efficient description of critical quantum systems (CFTs). It was recently suggested that the MERA provides naturally a discretization of AdS spacetime on a lattice. It is however known that a conventional MERA can not reproduce the so-called ''Bousso Bound'', also called holographic entropy bound, which is a bound on the bulk entropy in spacetime. In this context, our aim is to generalize the proposed AdS/MERA correspondence to a more general AdS/TN duality, where the Bousso bound is satisfied. Progress in this direction as well as connections to strongly correlated systems will be discussed.

Adding delayed recall to the ADAS-cog improves measurement precision in mild Alzheimer's disease: Implications for predicting instrumental activities of daily living.

Science.gov (United States)

Lowe, Deborah A; Balsis, Steve; Benge, Jared F; Doody, Rachelle S

2015-12-01

As research increasingly focuses on preclinical stages of Alzheimer's disease (AD), instruments must be retooled to identify early cognitive markers of AD. A supplemental delayed recall subtest for the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog; Mohs, Rosen, & Davis, 1983; Rosen, Mohs, & Davis, 1984) is commonly implemented, but it is not known precisely where along the spectrum of cognitive dysfunction this subtest yields incremental information beyond what is gained from the standard ADAS-cog, or whether it can improve prediction of functional outcomes. An item response theory approach can analyze this in a psychometrically rigorous way. Seven hundred eighty-eight patients with AD or amnestic complaints or impairment completed a battery including the ADAS-cog and 2 activities of daily living measures. The delayed recall subtest slightly improved the ADAS-cog's measurement precision in the mild range of cognitive dysfunction and increased prediction of instrumental activities of daily living for individuals with subjective memory impairment. (c) 2015 APA, all rights reserved).

Moving forward with nutrition in Alzheimer's disease.

Science.gov (United States)

Scheltens, P

2009-09-01

Alzheimer's disease (AD) is the epidemic of the 21st century but still relatively little is known about the causes of the disease. Nutrient deficiencies, associated with loss of cognitive function, are frequently reported in patients with AD and currently available epidemiologic evidence suggests that an increased intake of certain nutrients may lower the risk of AD. Current treatment options offer only symptomatic relief, however, there is a growing body of evidence that nutrition in general and 'nutritional intervention' in a clinical setting may be able to play a key role in the management of the disease. However, randomized clinical trials are needed to test this approach. The Souvenir study is the first randomized, controlled, double-blind, multi-centre study designed to evaluate the efficacy of a multi-nutrient dietary approach on cognitive performance in drug-naïve early AD patients.

Blood platelets in the progression of Alzheimer's disease.

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Nina S Gowert

Full Text Available Alzheimer's disease (AD is characterized by neurotoxic amyloid-ß plaque formation in brain parenchyma and cerebral blood vessels known as cerebral amyloid angiopathy (CAA. Besides CAA, AD is strongly related to vascular diseases such as stroke and atherosclerosis. Cerebrovascular dysfunction occurs in AD patients leading to alterations in blood flow that might play an important role in AD pathology with neuronal loss and memory deficits. Platelets are the major players in hemostasis and thrombosis, but are also involved in neuroinflammatory diseases like AD. For many years, platelets were accepted as peripheral model to study the pathophysiology of AD because platelets display the enzymatic activities to generate amyloid-ß (Aß peptides. In addition, platelets are considered to be a biomarker for early diagnosis of AD. Effects of Aß peptides on platelets and the impact of platelets in the progression of AD remained, however, ill-defined. The present study explored the cellular mechanisms triggered by Aß in platelets. Treatment of platelets with Aß led to platelet activation and enhanced generation of reactive oxygen species (ROS and membrane scrambling, suggesting enhanced platelet apoptosis. More important, platelets modulate soluble Aß into fibrillar structures that were absorbed by apoptotic but not vital platelets. This together with enhanced platelet adhesion under flow ex vivo and in vivo and platelet accumulation at amyloid deposits of cerebral vessels of AD transgenic mice suggested that platelets are major contributors of CAA inducing platelet thrombus formation at vascular amyloid plaques leading to vessel occlusion critical for cerebrovascular events like stroke.

Mitochondrial Bioenergetics Is Altered in Fibroblasts from Patients with Sporadic Alzheimer's Disease

Science.gov (United States)

Pérez, María J.; Ponce, Daniela P.; Osorio-Fuentealba, Cesar; Behrens, Maria I.; Quintanilla, Rodrigo A.

2017-01-01

The identification of an early biomarker to diagnose Alzheimer's disease (AD) remains a challenge. Neuropathological studies in animal and AD patients have shown that mitochondrial dysfunction is a hallmark of the development of the disease. Current studies suggest the use of peripheral tissues, like skin fibroblasts as a possibility to detect the early pathological alterations present in the AD brain. In this context, we studied mitochondrial function properties (bioenergetics and morphology) in cultured fibroblasts obtained from AD, aged-match and young healthy patients. We observed that AD fibroblasts presented a significant reduction in mitochondrial length with important changes in the expression of proteins that control mitochondrial fusion. Moreover, AD fibroblasts showed a distinct alteration in proteolytic processing of OPA1, a master regulator of mitochondrial fusion, compared to control fibroblasts. Complementary to these changes AD fibroblasts showed a dysfunctional mitochondrial bioenergetics profile that differentiates these cells from aged-matched and young patient fibroblasts. Our findings suggest that the human skin fibroblasts obtained from AD patients could replicate mitochondrial impairment observed in the AD brain. These promising observations suggest that the analysis of mitochondrial bioenergetics could represent a promising strategy to develop new diagnostic methods in peripheral tissues of AD patients. PMID:29056898

Sleep Disorders Associated With Alzheimer's Disease: A Perspective

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Anna Brzecka

2018-05-01

Full Text Available Sleep disturbances, as well as sleep-wake rhythm disturbances, are typical symptoms of Alzheimer's disease (AD that may precede the other clinical signs of this neurodegenerative disease. Here, we describe clinical features of sleep disorders in AD and the relation between sleep disorders and both cognitive impairment and poor prognosis of the disease. There are difficulties of the diagnosis of sleep disorders based on sleep questionnaires, polysomnography or actigraphy in the AD patients. Typical disturbances of the neurophysiological sleep architecture in the course of the AD include deep sleep and paradoxical sleep deprivation. Among sleep disorders occurring in patients with AD, the most frequent disorders are sleep breathing disorders and restless legs syndrome. Sleep disorders may influence circadian fluctuations of the concentrations of amyloid-β in the interstitial brain fluid and in the cerebrovascular fluid related to the glymphatic brain system and production of the amyloid-β. There is accumulating evidence suggesting that disordered sleep contributes to cognitive decline and the development of AD pathology. In this mini-review, we highlight and discuss the association between sleep disorders and AD.

Mechanisms of AD neurodegeneration may be independent of Aβ and its derivatives.

Science.gov (United States)

Robakis, Nikolaos K

2011-03-01

Alzheimer's disease (AD) is the most common cause of dementia in the aged population. Most cases are sporadic although a small percent are familial (FAD) linked to genetic mutations. AD is caused by severe neurodegeneration in the hippocampus and neocortical regions of the brain but the cause of this neuronal loss is unclear. A widely discussed theory posits that amyloid depositions of Aβ peptides or their soluble forms are the causative agents of AD. Extensive research in the last 20 years however, failed to produce convincing evidence that brain amyloid is the main cause of AD neurodegeneration. Moreover, a number of observations, including absence of correlations between amyloid deposits and cognition, detection in normal individuals of amyloid loads similar to AD, and animal models with behavioral abnormalities independent of amyloid, are inconsistent with this theory. Other theories propose soluble Aβ peptides or their oligomers as agents that promote AD. These peptides, however, are normal components of human CSF and serum and there is little evidence of disease-associated increases in soluble Aβ and oligomers. That mutants of amyloid precursor protein (APP) and presenilin (PS) promote FAD suggests these proteins play crucial roles in neuronal function and survival. Accordingly, PS regulates production of signaling peptides and cell survival pathways while APP functions in cell death and may promote endosomal abnormalities. Evidence that FAD mutations inhibit the biological functions of PS combined with absence of haploinsufficiency mutants, support a model of allelic interference where inactive FAD mutant alleles promote autosomal dominant neurodegeneration by also inhibiting the functions of wild type alleles. Copyright © 2011 Elsevier Inc. All rights reserved.

Age-related changes in core body temperature and activity in triple-transgenic Alzheimer’s disease (3xTgAD mice

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Elysse M. Knight

2013-01-01

Alzheimer’s disease (AD is characterised, not only by cognitive deficits and neuropathological changes, but also by several non-cognitive behavioural symptoms that can lead to a poorer quality of life. Circadian disturbances in core body temperature and physical activity are reported in AD patients, although the cause and consequences of these changes are unknown. We therefore characterised circadian patterns of body temperature and activity in male triple transgenic AD mice (3xTgAD and non-transgenic (Non-Tg control mice by remote radiotelemetry. At 4 months of age, daily temperature rhythms were phase advanced and by 6 months of age an increase in mean core body temperature and amplitude of temperature rhythms were observed in 3xTgAD mice. No differences in daily activity rhythms were seen in 4- to 9-month-old 3xTgAD mice, but by 10 months of age an increase in mean daily activity and the amplitude of activity profiles for 3xTgAD mice were detected. At all ages (4–10 months, 3xTgAD mice exhibited greater food intake compared with Non-Tg mice. The changes in temperature did not appear to be solely due to increased food intake and were not cyclooxygenase dependent because the temperature rise was not abolished by chronic ibuprofen treatment. No β-amyloid (Aβ plaques or neurofibrillary tangles were noted in the hypothalamus of 3xTgAD mice, a key area involved in temperature regulation, although these pathological features were observed in the hippocampus and amygdala of 3xTgAD mice from 10 months of age. These data demonstrate age-dependent changes in core body temperature and activity in 3xTgAD mice that are present before significant AD-related neuropathology and are analogous to those observed in AD patients. The 3xTgAD mouse might therefore be an appropriate model for studying the underlying mechanisms involved in non-cognitive behavioural changes in AD.

Age-related changes in core body temperature and activity in triple-transgenic Alzheimer’s disease (3xTgAD) mice

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Knight, Elysse M.; Brown, Timothy M.; Gümüsgöz, Sarah; Smith, Jennifer C. M.; Waters, Elizabeth J.; Allan, Stuart M.; Lawrence, Catherine B.

2013-01-01

SUMMARY Alzheimer’s disease (AD) is characterised, not only by cognitive deficits and neuropathological changes, but also by several non-cognitive behavioural symptoms that can lead to a poorer quality of life. Circadian disturbances in core body temperature and physical activity are reported in AD patients, although the cause and consequences of these changes are unknown. We therefore characterised circadian patterns of body temperature and activity in male triple transgenic AD mice (3xTgAD) and non-transgenic (Non-Tg) control mice by remote radiotelemetry. At 4 months of age, daily temperature rhythms were phase advanced and by 6 months of age an increase in mean core body temperature and amplitude of temperature rhythms were observed in 3xTgAD mice. No differences in daily activity rhythms were seen in 4- to 9-month-old 3xTgAD mice, but by 10 months of age an increase in mean daily activity and the amplitude of activity profiles for 3xTgAD mice were detected. At all ages (4–10 months), 3xTgAD mice exhibited greater food intake compared with Non-Tg mice. The changes in temperature did not appear to be solely due to increased food intake and were not cyclooxygenase dependent because the temperature rise was not abolished by chronic ibuprofen treatment. No β-amyloid (Aβ) plaques or neurofibrillary tangles were noted in the hypothalamus of 3xTgAD mice, a key area involved in temperature regulation, although these pathological features were observed in the hippocampus and amygdala of 3xTgAD mice from 10 months of age. These data demonstrate age-dependent changes in core body temperature and activity in 3xTgAD mice that are present before significant AD-related neuropathology and are analogous to those observed in AD patients. The 3xTgAD mouse might therefore be an appropriate model for studying the underlying mechanisms involved in non-cognitive behavioural changes in AD. PMID:22864021

Brief psychosocial therapy for the treatment of agitation in Alzheimer disease (the CALM-AD trial).

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Ballard, Clive; Brown, Richard; Fossey, Jane; Douglas, Simon; Bradley, Paul; Hancock, Judith; James, Ian A; Juszczak, Edmund; Bentham, Peter; Burns, Alistair; Lindesay, James; Jacoby, Robin; O'Brien, John; Bullock, Roger; Johnson, Tony; Holmes, Clive; Howard, Robert

2009-09-01

Good practice guidelines state that a psychological intervention should usually precede pharmacotherapy, but there are no data evaluating the feasibility of psychological interventions used in this way. At the first stage of a randomized blinded placebo-controlled trial, 318 patients with Alzheimer disease (AD) with clinically significant agitated behavior were treated in an open design with a psychological intervention (brief psychosocial therapy [BPST]) for 4 weeks, preceding randomization to pharmacotherapy. The therapy involved social interaction, personalized music, or removal of environmental triggers. Overall, 318 patients with AD completed BPST with an improvement of 5.6 points on the total Cohen-Mansfield Agitation Inventory (CMAI; mean [SD], 63.3 [16.0] to 57.7 [18.4], t = 4.8, df = 317, p 95% of patients. More detailed evaluation of outcome was completed for the 198 patients with AD from these centers, who experienced a mean improvement of 6.6 points on the total CMAI (mean [SD], 62.2 [14.3] to 55.6 [15.8], t = 6.5, df = 197, p < 0.0001). Overall, 43% of participants achieved a 30% improvement in their level of agitation. The specific attributable benefits of BPST cannot be determined from an open trial. However, the BPST therapy was feasible and was successfully delivered according to an operationalized manual. The encouraging outcome indicates the need for a randomized controlled trial of BPST.

Mathematical model on Alzheimer's disease.

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Hao, Wenrui; Friedman, Avner

2016-11-18

Alzheimer disease (AD) is a progressive neurodegenerative disease that destroys memory and cognitive skills. AD is characterized by the presence of two types of neuropathological hallmarks: extracellular plaques consisting of amyloid β-peptides and intracellular neurofibrillary tangles of hyperphosphorylated tau proteins. The disease affects 5 million people in the United States and 44 million world-wide. Currently there is no drug that can cure, stop or even slow the progression of the disease. If no cure is found, by 2050 the number of alzheimer's patients in the U.S. will reach 15 million and the cost of caring for them will exceed $ 1 trillion annually. The present paper develops a mathematical model of AD that includes neurons, astrocytes, microglias and peripheral macrophages, as well as amyloid β aggregation and hyperphosphorylated tau proteins. The model is represented by a system of partial differential equations. The model is used to simulate the effect of drugs that either failed in clinical trials, or are currently in clinical trials. Based on these simulations it is suggested that combined therapy with TNF- α inhibitor and anti amyloid β could yield significant efficacy in slowing the progression of AD.

Hairy AdS solitons

International Nuclear Information System (INIS)

Anabalón, Andrés; Astefanesei, Dumitru; Choque, David

2016-01-01

We construct exact hairy AdS soliton solutions in Einstein-dilaton gravity theory. We examine their thermodynamic properties and discuss the role of these solutions for the existence of first order phase transitions for hairy black holes. The negative energy density associated to hairy AdS solitons can be interpreted as the Casimir energy that is generated in the dual filed theory when the fermions are antiperiodic on the compact coordinate.

Hairy AdS solitons

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Anabalón, Andrés, E-mail: andres.anabalon@uai.cl [Departamento de Ciencias, Facultad de Artes Liberales and Facultad de Ingeniería y Ciencias, Universidad Adolfo Ibáñez, Av. Padre Hurtado 750, Viña del Mar (Chile); Astefanesei, Dumitru, E-mail: dumitru.astefanesei@pucv.cl [Instituto de Física, Pontificia Universidad Católica de Valparaíso, Casilla 4059, Valparaíso (Chile); Choque, David, E-mail: brst1010123@gmail.com [Instituto de Física, Pontificia Universidad Católica de Valparaíso, Casilla 4059, Valparaíso (Chile); Universidad Técnica Federico Santa María, Av. España 1680, Valparaíso (Chile)

2016-11-10

We construct exact hairy AdS soliton solutions in Einstein-dilaton gravity theory. We examine their thermodynamic properties and discuss the role of these solutions for the existence of first order phase transitions for hairy black holes. The negative energy density associated to hairy AdS solitons can be interpreted as the Casimir energy that is generated in the dual filed theory when the fermions are antiperiodic on the compact coordinate.

Modeling and Predicting AD Progression by Regression Analysis of Sequential Clinical Data

KAUST Repository

Xie, Qing

2016-02-23

Alzheimer\\'s Disease (AD) is currently attracting much attention in elders\\' care. As the increasing availability of massive clinical diagnosis data, especially the medical images of brain scan, it is highly significant to precisely identify and predict the potential AD\\'s progression based on the knowledge in the diagnosis data. In this paper, we follow a novel sequential learning framework to model the disease progression for AD patients\\' care. Different from the conventional approaches using only initial or static diagnosis data to model the disease progression for different durations, we design a score-involved approach and make use of the sequential diagnosis information in different disease stages to jointly simulate the disease progression. The actual clinical scores are utilized in progress to make the prediction more pertinent and reliable. We examined our approach by extensive experiments on the clinical data provided by the Alzheimer\\'s Disease Neuroimaging Initiative (ADNI). The results indicate that the proposed approach is more effective to simulate and predict the disease progression compared with the existing methods.

Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort

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Morgadinho Ana S

2006-07-01

Full Text Available Abstract Background Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer (AD and Parkinson diseases (PD. Iron metabolism is associated with the gene hemochromatosis (HFE Human genome nomenclature committee ID:4886, and mutations in HFE are a cause of the iron mismetabolism disease, hemochromatosis. Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results. Methods Genotypes were analysed for the two most common variants of HFE in a series of 130 AD, 55 Mild Cognitive Impairment (MCI and 132 PD patients. Additionally, a series of 115 healthy age-matched controls was also screened. Results A statistically significant association was found in the PD group when compared to controls, showing that the presence of the C282Y variant allele may confer higher risk for developing the disease. Conclusion Taken together these results suggest that the common variants in HFE may be a risk factor for PD, but not for AD in the Portuguese population.

Oxidative Stress in Alzheimer’s Disease: Why Did Antioxidant Therapy Fail?

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Torbjörn Persson

2014-01-01

Full Text Available Alzheimer’s disease (AD is the most common form of dementia in the elderly, with increasing prevalence and no disease-modifying treatment available yet. A remarkable amount of data supports the hypothesis that oxidative stress is an early and important pathogenic operator in AD. However, all clinical studies conducted to date did not prove a clear beneficial effect of antioxidant treatment in AD patients. In the current work, we review the current knowledge about oxidative stress in AD pathogeny and we suggest future paths that are worth to be explored in animal models and clinical studies, in order to get a better approach of oxidative imbalance in this inexorable neurodegenerative disease.

AdS solutions through transgression

International Nuclear Information System (INIS)

Donos, Aristomenis; Gauntlett, Jerome P.; Kim, Nakwoo

2008-01-01

We present new classes of explicit supersymmetric AdS 3 solutions of type IIB supergravity with non-vanishing five-form flux and AdS 2 solutions of D = 11 supergravity with electric four-form flux. The former are dual to two-dimensional SCFTs with (0,2) supersymmetry and the latter to supersymmetric quantum mechanics with two supercharges. We also investigate more general classes of AdS 3 solutions of type IIB supergravity and AdS 2 solutions of D = 11 supergravity which in addition have non-vanishing three-form flux and magnetic four-form flux, respectively. The construction of these more general solutions makes essential use of the Chern-Simons or 'transgression' terms in the Bianchi identity or the equation of motion of the field strengths in the supergravity theories. We construct infinite new classes of explicit examples and for some of the type IIB solutions determine the central charge of the dual SCFTs. The type IIB solutions with non-vanishing three-form flux that we construct include a two-torus, and after two T-dualities and an S-duality, we obtain new AdS 3 solutions with only the NS fields being non-trivial.

Developing global climate anomalies suggest potential disease risks for 2006 – 2007

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Tucker Compton J

2006-12-01

Full Text Available Abstract Background El Niño/Southern Oscillation (ENSO related climate anomalies have been shown to have an impact on infectious disease outbreaks. The Climate Prediction Center of the National Oceanic and Atmospheric Administration (NOAA/CPC has recently issued an unscheduled El Niño advisory, indicating that warmer than normal sea surface temperatures across the equatorial eastern Pacific may have pronounced impacts on global tropical precipitation patterns extending into the northern hemisphere particularly over North America. Building evidence of the links between ENSO driven climate anomalies and infectious diseases, particularly those transmitted by insects, can allow us to provide improved long range forecasts of an epidemic or epizootic. We describe developing climate anomalies that suggest potential disease risks using satellite generated data. Results Sea surface temperatures (SSTs in the equatorial east Pacific ocean have anomalously increased significantly during July – October 2006 indicating the typical development of El Niño conditions. The persistence of these conditions will lead to extremes in global-scale climate anomalies as has been observed during similar conditions in the past. Positive Outgoing Longwave Radiation (OLR anomalies, indicative of severe drought conditions, have been observed across all of Indonesia, Malaysia and most of the Philippines, which are usually the first areas to experience ENSO-related impacts. This dryness can be expected to continue, on average, for the remainder of 2006 continuing into the early part of 2007. During the period November 2006 – January 2007 climate forecasts indicate that there is a high probability for above normal rainfall in the central and eastern equatorial Pacific Islands, the Korean Peninsula, the U.S. Gulf Coast and Florida, northern South America and equatorial east Africa. Taking into consideration current observations and climate forecast information, indications

Diminished neuronal metabolic activity in Alzheimer's disease. Review article

NARCIS (Netherlands)

Salehi, A.; Swaab, D. F.

1999-01-01

An increasing number of studies have appeared in the literature suggesting that Alzheimer's disease (AD) is a hypometabolic brain disorder. Decreased metabolism in AD has been revealed by a variety of in vivo and postmortem methods and techniques including positron emission tomography and glucose

Effective ads: new technology answers old questions

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L.E. Couwenberg (Linda)

2017-01-01

markdownabstractMarketing experts commonly refer to ads as either “emotional” or “rational” in their appeal to consumers. This dichotomy of “thinking versus feeling” is most evident when it comes to discussions around what makes an ad effective. Some studies suggest that an ad that pulls on the

Six psychotropics for pre-symptomatic & early Alzheimer's (MCI, Parkinson's, and Huntington's disease modification

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Edward C Lauterbach

2016-01-01

Full Text Available The quest for neuroprotective drugs to slow the progression of neurodegenerative diseases (NDDs, including Alzheimer's disease (AD, Parkinson's disease (PD, and Huntington's disease (HD, has been largely unrewarding. Preclinical evidence suggests that repurposing quetiapine, lithium, valproate, fluoxetine, donepezil, and memantine for early and pre-symptomatic disease-modification in NDDs may be promising and can spare regulatory barriers. The literature of these psychotropics in early stage and pre-symptomatic AD, PD, and HD is reviewed and propitious findings follow. Mild cognitive impairment (MCI phase of AD: salutary human randomized controlled trial findings for low-dose lithium and, in selected patients, donepezil await replication. Pre-symptomatic AD: human epidemiological data indicate that lithium reduces AD risk. Animal model studies (AMS reveal encouraging results for quetiapine, lithium, donepezil, and memantine. Early PD: valproate AMS findings show promise. Pre-symptomatic PD: lithium and valproate AMS findings are encouraging. Early HD: uncontrolled clinical data indicate non-progression with lithium, fluoxetine, donepezil, and memantine. Pre-symptomatic HD: lithium and valproate are auspicious in AMS. Many other promising findings awaiting replication (valproate in MCI; lithium, valproate, fluoxetine in pre-symptomatic AD; lithium in early PD; lithium, valproate, fluoxetine in pre-symptomatic PD; donepezil in early HD; lithium, fluoxetine, memantine in pre-symptomatic HD are reviewed. Dose- and stage-dependent effects are considered. Suggestions for signal-enhancement in human trials are provided for each NDD stage.

'Alzheimer's Progression Score': Development of a Biomarker Summary Outcome for AD Prevention Trials.

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Leoutsakos, J-M; Gross, A L; Jones, R N; Albert, M S; Breitner, J C S

2016-01-01

Alzheimer's disease (AD) prevention research requires methods for measurement of disease progression not yet revealed by symptoms. Preferably, such measurement should encompass multiple disease markers. Evaluate an item response theory (IRT) model-based latent variable Alzheimer Progression Score (APS) that uses multi-modal disease markers to estimate pre-clinical disease progression. Estimate APS scores in the BIOCARD observational study, and in the parallel PREVENT-AD Cohort and its sister INTREPAD placebo-controlled prevention trial. Use BIOCARD data to evaluate whether baseline and early APS trajectory predict later progression to MCI/dementia. Similarly, use longitudinal PREVENT-AD data to assess test measurement invariance over time. Further, assess portability of the PREVENT-AD IRT model to baseline INTREPAD data, and explore model changes when CSF markers are added or withdrawn. BIOCARD was established in 1995 and participants were followed up to 20 years in Baltimore, USA. The PREVENT-AD and INTREPAD trial cohorts were established between 2011-2015 in Montreal, Canada, using nearly identical entry criteria to enroll high-risk cognitively normal persons aged 60+ then followed for several years. 349 cognitively normal, primarily middle-aged participants in BIOCARD, 125 high-risk participants aged 60+ in PREVENT-AD, and 217 similar subjects in INTREPAD. 106 INTREPAD participants donated up to four serial CSF samples. Global cognitive assessment and multiple structural, functional, and diffusion MRI metrics, sensori-neural tests, and CSF concentrations of tau, Aβ42 and their ratio. Both baseline values and early slope of APS scores in BIOCARD predicted later progression to MCI or AD. Presence of CSF variables strongly improved such prediction. A similarly derived APS in PREVENT-AD showed measurement invariance over time and portability to the parallel INTREPAD sample. An IRT-based APS can summarize multimodal information to provide a longitudinal measure of

Suggestibility as a predictor of response to antidepressants: A preliminary prospective trial.

Science.gov (United States)

Nitzan, Uri; Chalamish, Yossi; Krieger, Israel; Erez, Hany Burstein; Braw, Yoram; Lichtenberg, Pesach

2015-10-01

The growing awareness that so many do not respond adequately to antidepressant (AD) pharmacotherapy has sparked research seeking to characterize those who do. While the pharmacological mechanisms of AD treatment have been extensively evaluated, much remains unknown about the placebo component of the response to medication. This study examined the association between suggestibility levels and response to ADs amongst depressed patients. Twenty unipolar depression outpatients, recruited before starting AD monotherapy, received clear, standardized instructions that the therapeutic effects of AD, though not side effects, would require 2-4 weeks. At baseline (T1), 1 week (T2), and 1 month (T3), participants were evaluated for depressive symptoms, using the Hamilton Rating Scale for Depression-17 items (HAM-D); for anxiety by the Hamilton Rating Scale for Anxiety (HAM-A); for side effects by the Antidepressant Side Effect Checklist (ASEC); and for suggestibility, using the Multidimensional Iowa Suggestibility Scale (MISS). High levels of baseline suggestibility were associated with less improvement in depression level and more side-effects during the first week. In accordance with our hypothesis the more suggestible patients improved more between T2 and T3. No significant correlations were found between baseline suggestibility levels and change in anxiety. Small sample size and a self-report questionnaire assessing suggestibility were limitations. This study offers a potentially new and clinically useful approach to understanding and predicting who will respond to AD treatment. Suggestibility seems to play a role, presumably by shaping expectation, in response to AD treatment. We hope that this avenue will be further explored. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of music on autobiographical verbal narration in Alzheimer's disease

NARCIS (Netherlands)

El Haj, M.; Clement, S.; Fasotti, L.; Allain, P.

2013-01-01

There is a growing body of evidence suggesting a beneficial effect of music exposure on autobiographical memory in patients with Alzheimer's Disease (AD). Our paper was aimed at revealing the linguistic characteristics of these music-evoked autobiographical narrations. Eighteen AD patients and 18

Warped AdS3 black holes

International Nuclear Information System (INIS)

Anninos, Dionysios; Li Wei; Padi, Megha; Song Wei; Strominger, Andrew

2009-01-01

Three dimensional topologically massive gravity (TMG) with a negative cosmological constant -l -2 and positive Newton constant G admits an AdS 3 vacuum solution for any value of the graviton mass μ. These are all known to be perturbatively unstable except at the recently explored chiral point μl = 1. However we show herein that for every value of μl ≠ 3 there are two other (potentially stable) vacuum solutions given by SL(2,R) x U(1)-invariant warped AdS 3 geometries, with a timelike or spacelike U(1) isometry. Critical behavior occurs at μl = 3, where the warping transitions from a stretching to a squashing, and there are a pair of warped solutions with a null U(1) isometry. For μl > 3, there are known warped black hole solutions which are asymptotic to warped AdS 3 . We show that these black holes are discrete quotients of warped AdS 3 just as BTZ black holes are discrete quotients of ordinary AdS 3 . Moreover new solutions of this type, relevant to any theory with warped AdS 3 solutions, are exhibited. Finally we note that the black hole thermodynamics is consistent with the hypothesis that, for μl > 3, the warped AdS 3 ground state of TMG is holographically dual to a 2D boundary CFT with central charges c R -formula and c L -formula.

The sleep-wake cycle and Alzheimer's disease: what do we know?

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Lim, Miranda M; Gerstner, Jason R; Holtzman, David M

2014-01-01

Sleep-wake disturbances are a highly prevalent and often disabling feature of Alzheimer's disease (AD). A cardinal feature of AD includes the formation of amyloid plaques, associated with the extracellular accumulation of the amyloid-β (Aβ) peptide. Evidence from animal and human studies suggests that Aβ pathology may disrupt the sleep-wake cycle, in that as Aβ accumulates, more sleep-wake fragmentation develops. Furthermore, recent research in animal and human studies suggests that the sleep-wake cycle itself may influence Alzheimer's disease onset and progression. Chronic sleep deprivation increases amyloid plaque deposition, and sleep extension results in fewer plaques in experimental models. In this review geared towards the practicing clinician, we discuss possible mechanisms underlying the reciprocal relationship between the sleep-wake cycle and AD pathology and behavior, and present current approaches to therapy for sleep disorders in AD.

Quantitative assessment of finger tapping characteristics in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease.

Science.gov (United States)

Roalf, David R; Rupert, Petra; Mechanic-Hamilton, Dawn; Brennan, Laura; Duda, John E; Weintraub, Daniel; Trojanowski, John Q; Wolk, David; Moberg, Paul J

2018-06-01

Fine motor impairments are common in neurodegenerative disorders, yet standardized, quantitative measurements of motor abilities are uncommonly used in neurological practice. Thus, understanding and comparing fine motor abilities across disorders have been limited. The current study compared differences in finger tapping, inter-tap interval, and variability in Alzheimer's disease (AD), Parkinson's disease (PD), mild cognitive impairment (MCI), and healthy older adults (HOA). Finger tapping was measured using a highly sensitive light-diode finger tapper. Total number of finger taps, inter-tap interval, and intra-individual variability (IIV) of finger tapping was measured and compared in AD (n = 131), PD (n = 63), MCI (n = 46), and HOA (n = 62), controlling for age and sex. All patient groups had fine motor impairments relative to HOA. AD and MCI groups produced fewer taps with longer inter-tap interval and higher IIV compared to HOA. The PD group, however, produced more taps with shorter inter-tap interval and higher IIV compared to HOA. Disease-specific changes in fine motor function occur in the most common neurodegenerative diseases. The findings suggest that alterations in finger tapping patterns are common in AD, MCI, and PD. In addition, the present results underscore the importance of motor dysfunction even in neurodegenerative disorders without primary motor symptoms.

Voxel-based analysis of cerebral glucose metabolism in AD and non-AD degenerative dementia using statistical parametric mapping

International Nuclear Information System (INIS)

Li Zugui; Gao Shuo; Zhang Benshu; Ma Aijun; Cai Li; Li Dacheng; Li Yansheng; Liu Lei

2008-01-01

Objective: It is know that Alzheimer's disease (AD) and non-AD degenerative dementia have some clinical features in common. The aim of this study was to investigate the specific patterns of regional, cerebral glucose metabolism of AD and non-AD degenerative dementia patients, using a voxel-based 18 F-fluorodeoxyglucose (FDG) PET study. Methods: Twenty-three AD patients and 24 non-AD degenerative dementia patients including 9 Parkinson's disease with dementia(PDD), 7 frontal-temporal dementia (FTD), 8 dementia of Lewy bodies (DLB) patients, and 40 normal controls (NC)were included in the study. To evaluate the relative cerebral metabolic rate of glucose (rCMRglc), 18 F-FDG PET imaging was performed in all subjects. Subsequently, statistical comparison of PET data with NC was performed using statistical parametric mapping (SPM). Results: The AD-associated FDG imaging pattern typically presented as focal cortical hypometabolism in bilateral parietotemporal association cortes and(or) frontal lobe and the posterior cingulate gyms. As compared with the comparative NC, FTD group demonstrated significant regional reductions in rCMRglc in bilateral frontal, parietal lobes, the cingulate gyri, insulae, left precuneus, and the subcortical structures (including right putamen, right medial dorsal nucleus and ventral anterior nucleus). The PDD group showed regional reductions in rCMRglc in bilateral frontal cortexes, parietotemporal association cortexes, and the subcortical structures (including left caudate, right putamen, the dorsomedial thalamus, lateral posterior nucleus, and pulvinar). By the voxel-by-voxel comparison between the DLB group and NC group, regional reductions in rCMRglc included bilateral occipital cortexes, precuneuses, frontal and parietal lobes, left anterior cingulate gyms, right superior temporal cortex, and the subcortical structures including putamen, caudate, lateral posterior nucleus, and pulvinar. Conclusions: The rCMRglc was found to be different

Low-dose ionizing radiation alleviates Aβ42-induced defective phenotypes in Drosophila Alzheimer's disease models

International Nuclear Information System (INIS)

Hwang, SooJin; Jeong, Hae Min; Nam, Seon Young

2017-01-01

Alzheimer's disease (AD) is the most common neurodegenerative disease that is characterized by amyloid plaques, progressive neuronal loss, and gradual deterioration of memory. Amyloid imaging using positron emission tomography (PET) radiotracers have been developed and approved for clinical use in the evaluation of suspected neurodegenerative disease, including AD. Particularly, previous studies involving low-dose ionizing radiation on Aβ 42-treated mouse hippocampal neurons have suggested a potential role for low-dose ionizing radiation in the treatment of AD. However, associated in vivo studies involving the therapy effects of low-dose ionizing radiation on AD are still insufficient. As a powerful cell biological system, Drosophila AD models have been generated and established a useful model organism for study on the etiology of human AD. In this study, we investigated the hormesis effects of low-dose ionizing radiation on Drosophila AD models. Our results suggest that low-dose ionizing radiation have the beneficial effects on not only the Aβ42-induced developmental defective phenotypes but also motor defects in Drosophila AD models. These results might be due to a regulation of apoptosis, and provide insight into the hormesis effects of low-dose ionizing radiation. Our results suggest that low-dose ionizing radiation have the beneficial effects on not only the Aβ42-induced developmental defective phenotypes but also motor defects in Drosophila AD models. These results might be due to a regulation of apoptosis, and provide insight into the hormesis effects of low-dose ionizing radiation.

Fine Grained Chaos in AdS_{2} Gravity.

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Haehl, Felix M; Rozali, Moshe

2018-03-23

Quantum chaos can be characterized by an exponential growth of the thermal out-of-time-order four-point function up to a scrambling time u[over ^]_{*}. We discuss generalizations of this statement for certain higher-point correlation functions. For concreteness, we study the Schwarzian theory of a one-dimensional time reparametrization mode, which describes two-dimensional anti-de Sitter space (AdS_{2}) gravity and the low-energy dynamics of the Sachdev-Ye-Kitaev model. We identify a particular set of 2k-point functions, characterized as being both "maximally braided" and "k-out of time order," which exhibit exponential growth until progressively longer time scales u[over ^]_{*}^{(k)}∼(k-1)u[over ^]_{*}. We suggest an interpretation as scrambling of increasingly fine grained measures of quantum information, which correspondingly take progressively longer time to reach their thermal values.

Fine Grained Chaos in AdS2 Gravity

Science.gov (United States)

Haehl, Felix M.; Rozali, Moshe

2018-03-01

Quantum chaos can be characterized by an exponential growth of the thermal out-of-time-order four-point function up to a scrambling time u^*. We discuss generalizations of this statement for certain higher-point correlation functions. For concreteness, we study the Schwarzian theory of a one-dimensional time reparametrization mode, which describes two-dimensional anti-de Sitter space (AdS2 ) gravity and the low-energy dynamics of the Sachdev-Ye-Kitaev model. We identify a particular set of 2 k -point functions, characterized as being both "maximally braided" and "k -out of time order," which exhibit exponential growth until progressively longer time scales u^*(k)˜(k -1 )u^*. We suggest an interpretation as scrambling of increasingly fine grained measures of quantum information, which correspondingly take progressively longer time to reach their thermal values.

Treatment efficacy and immune stimulation by AdCD40L gene therapy of spontaneous canine malignant melanoma.

Science.gov (United States)

Westberg, Sara; Sadeghi, Arian; Svensson, Emma; Segall, Thomas; Dimopoulou, Maria; Korsgren, Olle; Hemminki, Akseli; Loskog, Angelica S I; Tötterman, Thomas H; von Euler, Henrik

2013-01-01

Malignant melanoma is a serious disease in both humans and dogs, and the high metastatic potential results in poor prognosis for many patients. Its similarities with human melanoma make spontaneous canine melanoma an excellent model for comparative studies of novel therapies and tumor biology. We report a pilot study of local adenovector CD40L (AdCD40L) immunogene treatment in 19 cases of canine melanoma (14 oral, 4 cutaneous, and 1 conjunctival). Three patients were World Health Organization stage I, 2 were stage II, 10 stage III, and 4 stage IV. One to 6 intratumoral injections of AdCD40L were given every 7 days, followed by cytoreductive surgery in 9 cases and only immunotherapy in 10 cases. Tumor tissue was infiltrated with T and B lymphocytes after treatment, suggesting immune stimulation. The best overall response included 5 complete responses, 8 partial responses, and 4 stable and 2 progressive disease statuses according to the World Health Organization response criteria. Median survival was 160 days (range, 20-1141 d), with 3 dogs still alive at submission. Our results suggest that local AdCD40L therapy is safe and could have beneficial effects in dogs, supporting further treatment development. Clinical translation to human patients is in progress.

Altered protein glycosylation predicts Alzheimer's disease and modulates its pathology in disease model Drosophila.

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Frenkel-Pinter, Moran; Stempler, Shiri; Tal-Mazaki, Sharon; Losev, Yelena; Singh-Anand, Avnika; Escobar-Álvarez, Daniela; Lezmy, Jonathan; Gazit, Ehud; Ruppin, Eytan; Segal, Daniel

2017-08-01

The pathological hallmarks of Alzheimer's disease (AD) are pathogenic oligomers and fibrils of misfolded amyloidogenic proteins (e.g., β-amyloid and hyper-phosphorylated tau in AD), which cause progressive loss of neurons in the brain and nervous system. Although deviations from normal protein glycosylation have been documented in AD, their role in disease pathology has been barely explored. Here our analysis of available expression data sets indicates that many glycosylation-related genes are differentially expressed in brains of AD patients compared with healthy controls. The robust differences found enabled us to predict the occurrence of AD with remarkable accuracy in a test cohort and identify a set of key genes whose expression determines this classification. We then studied in vivo the effect of reducing expression of homologs of 6 of these genes in transgenic Drosophila overexpressing human tau, a well-established invertebrate AD model. These experiments have led to the identification of glycosylation genes that may augment or ameliorate tauopathy phenotypes. Our results indicate that OstDelta, l(2)not and beta4GalT7 are tauopathy suppressors, whereas pgnat5 and CG33303 are enhancers, of tauopathy. These results suggest that specific alterations in protein glycosylation may play a causal role in AD etiology. Copyright © 2017 Elsevier Inc. All rights reserved.

Hawking radiation from AdS black holes

International Nuclear Information System (INIS)

Hubeny, Veronika E; Rangamani, Mukund; Marolf, Donald

2010-01-01

We study Hartle-Hawking-like states of quantum field theories on asymptotically AdS black hole backgrounds, with particular regard to the phase structure of interacting theories. By a suitable analytic continuation we show that the equilibrium dynamics of field theories on large asymptotically AdS black holes can be related to the low-temperature states of the same field theory on the AdS soliton (or pure AdS) background. This allows us to gain insight into Hartle-Hawking-like states on large-radius Schwarzschild- or rotating-AdS black holes. Furthermore, we exploit the AdS/CFT correspondence to explore the physics of strongly coupled large N theories on asymptotically AdS black holes. In particular, we exhibit a plausibly complete set of phases for the M2-brane world-volume superconformal field theory on a BTZ black hole background. Our analysis partially resolves puzzles previously raised in connection with Hawking radiation on large AdS black holes.

The suggestion of common cause of disease, characteristics of human body, and medical treatment

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Byung-Jun Cho

2011-06-01

Full Text Available Objectives & Methods: This suggestion was attempted to be elevated the recognition of common characteristics in disease. So, we performed to analyze the correlation of common cause of disease, characteristics of human body, and medical treatment. And the results are as follows. Results: 1. The cause of disease is consist of genetic factor, aging, habit, food of not good in health, weather, environment, deficit of the physical activity, stress and so on. 2. Generally, human has common and individual weakness. Individual weakness is appeared similar to the occurrence of volcano and lapse. 3. The correlation of disease and medical treatments is possible to explain using the quotation of the law of motion made by Isaac Newton, the great physicist. 4. When the process of the medical treatment was not progressed, the prognosis is determined by the correlation of the homeostasis(H' in human body and the homeostasis(H of disease. 5. The prognosis of disease is determined by the relationship between the energy of disease(F and medical treatment(F'. 6. The exact diagnosis is possible to predict the treatment sequence, and the facts that homeostasis in human body and disease, relationship between the energy of disease(F and medical treatment(F', action and reaction are important to determine the prognosis. 7. The careful observation of improving response and worsening action of disease becomes available for exact prognosis. Conclusion: The above described contents may be useful in clinical studies, and the concrete clinical reports about this will be made afterward.

Polarised Black Holes in AdS

CERN Document Server

Costa, Miguel S.; Oliveira, Miguel; Penedones, João; Santos, Jorge E.

2016-05-03

We consider solutions in Einstein-Maxwell theory with a negative cosmological constant that asymptote to global $AdS_{4}$ with conformal boundary $S^{2}\\times\\mathbb{R}_{t}$. At the sphere at infinity we turn on a space-dependent electrostatic potential, which does not destroy the asymptotic $AdS$ behaviour. For simplicity we focus on the case of a dipolar electrostatic potential. We find two new geometries: (i) an $AdS$ soliton that includes the full backreaction of the electric field on the $AdS$ geometry; (ii) a polarised neutral black hole that is deformed by the electric field, accumulating opposite charges in each hemisphere. For both geometries we study boundary data such as the charge density and the stress tensor. For the black hole we also study the horizon charge density and area, and further verify a Smarr formula. Then we consider this system at finite temperature and compute the Gibbs free energy for both $AdS$ soliton and black hole phases. The corresponding phase diagram generalizes the Hawkin...

A Systematic Review of Longitudinal Studies Which Measure Alzheimer's Disease Biomarkers.

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Lawrence, Emma; Vegvari, Carolin; Ower, Alison; Hadjichrysanthou, Christoforos; De Wolf, Frank; Anderson, Roy M

2017-01-01

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease, with no effective treatment or cure. A gold standard therapy would be treatment to slow or halt disease progression; however, knowledge of causation in the early stages of AD is very limited. In order to determine effective endpoints for possible therapies, a number of quantitative surrogate markers of disease progression have been suggested, including biochemical and imaging biomarkers. The dynamics of these various surrogate markers over time, particularly in relation to disease development, are, however, not well characterized. We reviewed the literature for studies that measured cerebrospinal fluid or plasma amyloid-β and tau, or took magnetic resonance image or fluorodeoxyglucose/Pittsburgh compound B-positron electron tomography scans, in longitudinal cohort studies. We summarized the properties of the major cohort studies in various countries, commonly used diagnosis methods and study designs. We have concluded that additional studies with repeat measures over time in a representative population cohort are needed to address the gap in knowledge of AD progression. Based on our analysis, we suggest directions in which research could move in order to advance our understanding of this complex disease, including repeat biomarker measurements, standardization and increased sample sizes.

Disease-modifying drugs in Alzheimer's disease

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Ghezzi L

2013-12-01

Full Text Available Laura Ghezzi, Elio Scarpini, Daniela Galimberti Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy Abstract: Alzheimer's disease (AD is an age-dependent neurodegenerative disorder and the most common cause of dementia. The early stages of AD are characterized by short-term memory loss. Once the disease progresses, patients experience difficulties in sense of direction, oral communication, calculation, ability to learn, and cognitive thinking. The median duration of the disease is 10 years. The pathology is characterized by deposition of amyloid beta peptide (so-called senile plaques and tau protein in the form of neurofibrillary tangles. Currently, two classes of drugs are licensed by the European Medicines Agency for the treatment of AD, ie, acetylcholinesterase inhibitors for mild to moderate AD, and memantine, an N-methyl-D-aspartate receptor antagonist, for moderate and severe AD. Treatment with acetylcholinesterase inhibitors or memantine aims at slowing progression and controlling symptoms, whereas drugs under development are intended to modify the pathologic steps leading to AD. Herein, we review the clinical features, pharmacologic properties, and cost-effectiveness of the available acetylcholinesterase inhibitors and memantine, and focus on disease-modifying drugs aiming to interfere with the amyloid beta peptide, including vaccination, passive immunization, and tau deposition. Keywords: Alzheimer's disease, acetylcholinesterase inhibitors, memantine, disease-modifying drugs, diagnosis, treatment

Nutritional approaches in the risk reduction and management of Alzheimer's disease.

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Mi, Weiqian; van Wijk, Nick; Cansev, Mehmet; Sijben, John W C; Kamphuis, Patrick J G H

2013-09-01

Alzheimer's disease (AD) is a heterogeneous and devastating neurodegenerative disease with increasing socioeconomic burden for society. In the past 30 y, notwithstanding advances in the understanding of the pathogenesis of the disease and consequent development of therapeutic approaches to novel pathogenic targets, no cure has so far emerged. This contribution focuses on recent nutritional approaches in the risk reduction and management of AD with emphasis on factors providing a rationale for nutritional approaches in AD, including compromised nutritional status, altered nutrient uptake and metabolism, and nutrient requirements for synapse formation. Collectively these factors are believed to result in specific nutritional requirement in AD. The chapter also emphasizes investigated nutritional interventions in patients with AD, including studies with single nutrients and with the specific nutrient combination Fortasyn Connect and discusses the current shift of paradigm to intervene in earlier stages of AD, which offers opportunities for investigating nutritional strategies to reduce the risk for disease progression. Fortasyn Connect was designed to enhance synapse formation and function in AD by addressing the putative specific nutritional requirements and contains docosahexaenoic acid, eicosapentaenoic acid, uridine-5'-mono-phosphate, choline, phospholipids, antioxidants, and B vitamins. Two randomized controlled trials (RCTs) with the medical food Souvenaid, containing Fortasyn Connect, showed that this intervention improved memory performance in mild, drug-naïve patients with AD. Electroencephalography outcome in one of these clinical studies suggests that Souvenaid has an effect on brain functional connectivity, which is a derivative of changed synaptic activity. Thus, these studies suggest that nutritional requirements in AD can be successfully addressed and result in improvements in behavioral and neuro-physiological alterations that are characteristic to AD

Alzheimer's Disease: Lessons Learned from Amyloidocentric Clinical Trials.

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Soejitno, Andreas; Tjan, Anastasia; Purwata, Thomas Eko

2015-06-01

Alzheimer's disease (AD) is one of the most debilitating neurodegenerative diseases and is predicted to affect 1 in 85 people by 2050. Despite much effort to discover a therapeutic strategy to prevent progression or to cure AD, to date no effective disease-modifying agent is available that can prevent, halt, or reverse the cognitive and functional decline of patients with AD. Several underlying etiologies to this failure are proposed. First, accumulating evidence from past trials suggests a preventive as opposed to therapeutic paradigm, and the precise temporal and mechanistic relationship of β-amyloid (Aβ) and tau protein should be elucidated to confirm this hypothesis. Second, we are in urgent need of revised diagnostic criteria to support future trials. Third, various technical and methodological improvements are required, based on the lessons learned from previous failed trials.

Palaeopathological Evidence of Infectious Disease in a Skeletal Population from Late Medieval Riga, Latvia (15Th-17Th Centuries AD

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Gerhards Guntis

2017-04-01

Full Text Available The aim of this study was to evaluate the presence of infectious disease in the Dome Church (Riga Cathedral Cemetery population, dating from the late medieval period (15th-17th centuries AD. A total of 274 individuals were macroscopically observed for evidence of infectious disease, and seven individuals with lesions possibly associated with a bacterial infection affecting the skeleton were selected for further analysis. Pathological changes on the outer table of the skull and in the long bones of legs characteristic of venereal syphilis were observed in four female and one male individual. Likewise, changes possibly related to late congenital syphilis were observed in a 14-15-year-old non-adult individual. All these individuals were buried in a small area adjacent to the northern wall of the Dome Church, which possibly belonged to a hospital or a shelter. The evidence for venereal syphilis from the cemetery complements historical data about the spread of the disease in Riga during the 16th-17th centuries AD. One adult male individual had destructive changes in the lower spine, which could be associated with tuberculosis (TB. So far, this is the first individual with possible TB from the archaeological populations of Riga. This research provides unique evidence about infectious disease in skeletal populations from the late medieval period in Latvia, and the results will be used as the basis for future research in the subject, including extraction of ancient pathogen DNA.

Plasma testosterone levels in Alzheimer and Parkinson diseases.

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Okun, M S; DeLong, M R; Hanfelt, J; Gearing, M; Levey, A

2004-02-10

Testosterone deficiency, a treatable condition commonly seen in aging men, has been linked to Parkinson disease (PD) and Alzheimer disease (AD). In normal subjects, low testosterone levels are associated with cognitive and neuropsychiatric symptoms, yet the relationship between testosterone levels and cognitive function in PD and AD remains unclear. To examine the relationship of testosterone levels to age and cognitive function in PD and AD. Plasma testosterone levels were determined in men enrolled in a clinical registry of subjects with PD and AD, and neuropsychological testing was performed on subjects who consented. Testosterone levels in men with PD were compared with those in men with AD. In both groups, the relationship between testosterone levels and neuropsychological test scores was analyzed, adjusting for age and education. Linear regression analysis revealed that testosterone levels decreased with age in male PD patients (p frontal lobe dysfunction in normal aged men, together with these results, suggest that the hormonal deficiency may act as a "second hit" to impair cognitive function in neurodegenerative disease.

Pleiotropic Protective Effects of Phytochemicals in Alzheimer's Disease

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Sergio Davinelli

2012-01-01

Full Text Available Alzheimer’s disease (AD is a severe chronic neurodegenerative disorder of the brain characterised by progressive impairment in memory and cognition. In the past years an intense research has aimed at dissecting the molecular events of AD. However, there is not an exhaustive knowledge about AD pathogenesis and a limited number of therapeutic options are available to treat this neurodegenerative disease. Consequently, considering the heterogeneity of AD, therapeutic agents acting on multiple levels of the pathology are needed. Recent findings suggest that phytochemicals compounds with neuroprotective features may be an important resources in the discovery of drug candidates against AD. In this paper we will describe some polyphenols and we will discuss their potential role as neuroprotective agents. Specifically, curcumin, catechins, and resveratrol beyond their antioxidant activity are also involved in antiamyloidogenic and anti-inflammatory mechanisms. We will focus on specific molecular targets of these selected phytochemical compounds highlighting the correlations between their neuroprotective functions and their potential therapeutic value in AD.

Two Alzheimer’s disease risk genes increase entorhinal cortex volume in young adults

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DiBattista, Amanda Marie; Stevens, Benson W.; Rebeck, G. William; Green, Adam E.

2014-01-01

Alzheimer’s disease (AD) risk genes alter brain structure and function decades before disease onset. Apolipoprotein E (APOE) is the strongest known genetic risk factor for AD, and a related gene, apolipoprotein J (APOJ), also affects disease risk. However, the extent to which these genes affect brain structure in young adults remains unclear. Here, we report that AD risk alleles of these two genes, APOE-ε4 and APOJ-C, cumulatively alter brain volume in young adults. Using voxel-based morphometry (VBM) in 57 individuals, we examined the entorhinal cortex, one of the earliest brain regions affected in AD pathogenesis. Apolipoprotein E-ε4 carriers exhibited higher right entorhinal cortex volume compared to non-carriers. Interestingly, APOJ-C risk genotype was associated with higher bilateral entorhinal cortex volume in non-APOE-ε4 carriers. To determine the combined disease risk of APOE and APOJ status per subject, we used cumulative odds ratios as regressors for volumetric measurements. Higher disease risk corresponded to greater right entorhinal cortex volume. These results suggest that, years before disease onset, two key AD genetic risk factors may exert influence on the structure of a brain region where AD pathogenesis takes root. PMID:25339884

Ad hoc method for the assessment on listing and categorisation of animal diseases within the framework of the Animal Health Law

DEFF Research Database (Denmark)

More, Simon J.; Bøtner, Anette; Butterworth, Andrew

2017-01-01

compiled by disease scientists. A mapping was developed to identify which parameters from Article 7 were needed to inform each Article 5, 8 and 9 criterion. Specifically, for Articles 5 and 9 criteria, a categorical assessment was performed, by applying an expert judgement procedure, based on the mapped......The European Commission has requested EFSA to assess animal diseases according to the criteria as laid down in Articles 5, 7, 8 and Annex IV for the purpose of categorisation of diseases in accordance with Article 9 of the Regulation (EU) No 2016/429 (Animal Health Law). This scientific opinion...... addresses the ad hoc method developed for assessing any animal disease for the listing and categorisation of diseases within the Animal Health Law (AHL) framework. The assessment of individual diseases is addressed in distinct scientific opinions that are published separately. The assessment of Articles 5...

Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease

DEFF Research Database (Denmark)

Weiner, H L; Lemere, C A; Maron, R

2000-01-01

Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease-implicated ......Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease...... cerebral Abeta deposition, suggesting a novel mucosal immunological approach for the treatment and prevention of AD....

[Effects of adding straw carbon source to root knot nematode diseased soil on soil microbial biomass and protozoa abundance].

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Zhang, Si-Hui; Lian, Jian-Hong; Cao, Zhi-Ping; Zhao, Li

2013-06-01

A field experiment with successive planting of tomato was conducted to study the effects of adding different amounts of winter wheat straw (2.08 g x kg(-1), 1N; 4.16 g x kg(-1), 2N; and 8.32 g x kg(-1), 4N) to the soil seriously suffered from root knot nematode disease on the soil microbial biomass and protozoa abundance. Adding straw carbon source had significant effects on the contents of soil microbial biomass carbon (MBC) and microbial biomass nitrogen (MBN) and the abundance of soil protozoa, which all decreased in the order of 4N > 2N > 1N > CK. The community structure of soil protozoa also changed significantly under straw addition. In the treatments with straw addition, the average proportion of fagellate, amoeba, and ciliates accounted for 36.0%, 59.5%, and 4.5% of the total protozoa, respectively. Under the same adding amounts of wheat straw, there was an increase in the soil MBC and MBN contents, MBC/MBN ratio, and protozoa abundance with increasing cultivation period.

Bimanual Gesture Imitation in Alzheimer's Disease.

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Sanin, G Nter; Benke, Thomas

2017-01-01

Unimanual gesture production or imitation has often been studied in Alzheimer's disease (AD) during apraxia testing. In the present study, it was hypothesized that bimanual motor tasks may be a sensitive method to detect impairments of motor cognition in AD due to increased demands on the cognitive system. We investigated bimanual, meaningless gesture imitation in 45 AD outpatients, 38 subjects with mild cognitive impairment (MCI), and 50 normal controls (NC) attending a memory clinic. Participants performed neuropsychological background testing and three tasks: the Interlocking Finger Test (ILF), Imitation of Alternating Hand Movements (AHM), and Bimanual Rhythm Tapping (BRT). The tasks were short and easy to administer. Inter-rater reliability was high across all three tests. AD patients performed significantly poorer than NC and MCI participants; a deficit to imitate bimanual gestures was rarely found in MCI and NC participants. Sensitivity to detect AD ranged from 0.5 and 0.7, specificity beyond 0.9. ROC analyses revealed good diagnostic accuracy (0.77 to 0.92). Impairment to imitate bimanual gestures was mainly predicted by diagnosis and disease severity. Our findings suggest that an impairment to imitate bimanual, meaningless gestures is a valid disease marker of mild to moderate AD and can easily be assessed in memory clinic settings. Based on our preliminary findings, it appears to be a separate impairment which can be distinguished from other cognitive deficits.

String Theory on AdS Spaces

NARCIS (Netherlands)

de Boer, J.

2000-01-01

In these notes we discuss various aspects of string theory in AdS spaces. We briefly review the formulation in terms of Green-Schwarz, NSR, and Berkovits variables, as well as the construction of exact conformal field theories with AdS backgrounds. Based on lectures given at the Kyoto YITP Workshop

Microbial production of value-added nutraceuticals.

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Wang, Jian; Guleria, Sanjay; Koffas, Mattheos Ag; Yan, Yajun

2016-02-01

Nutraceuticals are important natural bioactive compounds that confer health-promoting and medical benefits to humans. Globally growing demands for value-added nutraceuticals for prevention and treatment of human diseases have rendered nutraceuticals a multi-billion dollar market. However, supply limitations and extraction difficulties from natural sources such as plants, animals or fungi, restrict the large-scale use of nutraceuticals. Metabolic engineering via microbial production platforms has been advanced as an eco-friendly alternative approach for production of value-added nutraceuticals from simple carbon sources. Microbial platforms like the most widely used Escherichia coli and Saccharomyces cerevisiae have been engineered as versatile cell factories for production of diverse and complex value-added chemicals such as phytochemicals, prebiotics, polysaccaharides and poly amino acids. This review highlights the recent progresses in biological production of value-added nutraceuticals via metabolic engineering approaches. Copyright © 2015 Elsevier Ltd. All rights reserved.

There are no differences in IL-6, CRP and homocystein concentrations between women whose mothers had AD and women whose mothers did not have AD.

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Devčić, Sanja; Glamuzina, Ljubomir; Ruljancic, Nedjeljka; Mihanovic, Mate

2014-12-30

A wide range of recent studies have detected inflammation as one of the most influent factors in the appearance and spreading of neurodegenerative brain diseases. We aimed to understand the influence of Interleukin-6 (IL-6), C-reactive protein (CRP) and homocysteine (Hcy) on patients suffering from Alzheimer׳s disease (AD) and on their descendants. Three groups of subjects were analyzed: 55 patients suffering from AD, 51 middle-aged daughters of the patients of the first group, and 53 subjects without positive family history of AD. The results of the conducted research are in accordance with the present scientific knowledge, namely a statistically significant difference for examined parameters has been determined between women suffering from AD and their daughters and control group examinees. No difference was found in serum concentrations of IL-6, highly sensitive C-reactive protein (hsCRP) and Hcy between the groups of the middle-aged descendants of patients with AD and healthy controls without family history of AD. This finding supports the hypothesis that these markers may not play causal role in the development of AD. This is supported by the obtained positive correlation between IL-6 and hsCRP and IL-6 and Hcy in AD patients while there is no such correlation between female subjects with or without a family history of AD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Open strings on AdS2 branes

International Nuclear Information System (INIS)

Lee, Peter; Ooguri, Hirosi.; Park, Jongwon; Tannenhauser, Jonathan

2001-01-01

We study the spectrum of open strings on AdS 2 branes in AdS 3 in an NS-NS background, using the SL(2,R) WZW model. When the brane carries no fundamental string charge, the open string spectrum is the holomorphic square root of the spectrum of closed strings in AdS 3 . It contains short and long strings, and is invariant under spectral flow. When the brane carries fundamental string charge, the open string spectrum again contains short and long strings in all winding sectors. However, branes with fundamental string charge break half the spectral flow symmetry. This has different implications for short and long strings. As the fundamental string charge increases, the brane approaches the boundary of AdS 3 . In this limit, the induced electric field on the worldvolume reaches its critical value, producing noncommutative open string theory on AdS 2

Low-dose ionizing radiation alleviates Aβ42-induced defective phenotypes in Drosophila Alzheimer's disease models

Energy Technology Data Exchange (ETDEWEB)

Hwang, SooJin; Jeong, Hae Min; Nam, Seon Young [Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro & Nuclear Power Co. Ltd., Daejeon (Korea, Republic of)

2017-04-15

Alzheimer's disease (AD) is the most common neurodegenerative disease that is characterized by amyloid plaques, progressive neuronal loss, and gradual deterioration of memory. Amyloid imaging using positron emission tomography (PET) radiotracers have been developed and approved for clinical use in the evaluation of suspected neurodegenerative disease, including AD. Particularly, previous studies involving low-dose ionizing radiation on Aβ 42-treated mouse hippocampal neurons have suggested a potential role for low-dose ionizing radiation in the treatment of AD. However, associated in vivo studies involving the therapy effects of low-dose ionizing radiation on AD are still insufficient. As a powerful cell biological system, Drosophila AD models have been generated and established a useful model organism for study on the etiology of human AD. In this study, we investigated the hormesis effects of low-dose ionizing radiation on Drosophila AD models. Our results suggest that low-dose ionizing radiation have the beneficial effects on not only the Aβ42-induced developmental defective phenotypes but also motor defects in Drosophila AD models. These results might be due to a regulation of apoptosis, and provide insight into the hormesis effects of low-dose ionizing radiation. Our results suggest that low-dose ionizing radiation have the beneficial effects on not only the Aβ42-induced developmental defective phenotypes but also motor defects in Drosophila AD models. These results might be due to a regulation of apoptosis, and provide insight into the hormesis effects of low-dose ionizing radiation.

Diagnosis of Alzheimer's disease using brain SPECT with three-dimensional stereotactic surface projections

International Nuclear Information System (INIS)

Hanyu, Haruo; Asano, Tetsuichi; Kogure, Daiji; Abe, Shine; Iwamoto, Toshihiko; Takasaki, Masaru

2001-01-01

We compared the diagnostic usefulness of three-dimensional stereotactic surface projection (3D-SSP) with that of standard transaxial images in brain SPECT in patients with Alzheimer's disease (AD). The subjects consisted of 69 patients with AD and 60 patients with non-AD, including vascular dementia, Parkinson's disease with dementia, frontotemporal dementia, other dementing diseases and neuropsychiatric diseases. Standard transaxial section and 3D-SSP SPECT images with N-isopropyl-p-[ 123 I] iodoamphetamine were blindly interpreted by three examiners and were classified into the following three patterns: typical AD, atypical AD, and not indicative AD patterns. The 3D-SSP images demonstrated reductions of cerebral blood flow in the parieto-temporal association cortex and posterior cingulate gyrus more clearly and easily than the standard transaxial images. The diagnostic sensitivity and specificity were 93% and 85% with 3D-SSP and 83% and 82% with standard transaxial section respectively. 3D-SSP was especially useful for early or atypical AD which showed no characteristic perfusion abnormalities on standard transaxial images. These results suggest that SPECT with 3D-SSP provides an sensitive as well as accurate tool for the diagnosis of AD. (author)

Genetic incorporation of the protein transduction domain of Tat into Ad5 fiber enhances gene transfer efficacy

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Siegal Gene P

2007-10-01

Full Text Available Abstract Background Human adenovirus serotype 5 (Ad5 has been widely explored as a gene delivery vector for a variety of diseases. Many target cells, however, express low levels of Ad5 native receptor, the Coxsackie-Adenovirus Receptor (CAR, and thus are resistant to Ad5 infection. The Protein Transduction Domain of the HIV Tat protein, namely PTDtat, has been shown to mediate protein transduction in a wide range of cells. We hypothesize that re-targeting Ad5 vector via the PTDtat motif would improve the efficacy of Ad5-mediated gene delivery. Results In this study, we genetically incorporated the PTDtat motif into the knob domain of Ad5 fiber, and rescued the resultant viral vector, Ad5.PTDtat. Our data showed the modification did not interfere with Ad5 binding to its native receptor CAR, suggesting Ad5 infection via the CAR pathway is retained. In addition, we found that Ad5.PTDtat exhibited enhanced gene transfer efficacy in all of the cell lines that we have tested, which included both low-CAR and high-CAR decorated cells. Competitive inhibition assays suggested the enhanced infectivity of Ad5.PTDtat was mediated by binding of the positively charged PTDtat peptide to the negatively charged epitopes on the cells' surface. Furthermore, we investigated in vivo gene delivery efficacy of Ad5.PTDtat using subcutaneous tumor models established with U118MG glioma cells, and found that Ad5.PTDtat exhibited enhanced gene transfer efficacy compared to unmodified Ad5 vector as analyzed by a non-invasive fluorescence imaging technique. Conclusion Genetic incorporation of the PTDtat motif into Ad5 fiber allowed Ad5 vectors to infect cells via an alternative PTDtat targeting motif while retaining the native CAR-mediated infection pathway. The enhanced infectivity was demonstrated in both cultured cells and in in vivo tumor models. Taken together, our study identifies a novel tropism expanded Ad5 vector that may be useful for clinical gene therapy

Conical singularities in AdS space time

International Nuclear Information System (INIS)

Ferreira, Cristine Nunes

2011-01-01

Full text: In recent years, the study of conformal gauge theories from 10-D has been motivated by the AdS d+1 /CFT d correspondence, first conjectured by J. Maldacena. The aim of this work is to consider the d = 4 case by analysing the configuration of the N coincident D3 branes. In this context, the work shows that there is a duality between type IIB string theory in AdS 5 x S 5 and N = 4 SU(N) Super Yang-Mills Theory in the IR. The AdS 5 /CFT 4 correspondence brought also new approaches to the strong coupling problem in QCD. Nowadays, there is a whole line of works that focus on the low dimensional correspondence AdS 4 /CFT 3 , like the application to graphene and topological insulators, and the AdS 3 /CFT 2 correspondence, related with the entanglement entropy. In this work, we consider the vortex configuration solution to the AdS 4 and AdS 3 space-time. The most important motivation is to discuss the boundary theory resulting from these solutions. We have examined a straightforward approach to a holographic computation of the graphene and entanglement entropy in the presence of the conical singularity. After this analysis, we consider the scalar field in the bulk in the presence of this metrics and work out the compactification modes. Taking the holographic point of view, we study and discuss the resulting Green function. (author)

Auditory system dysfunction in Alzheimer disease and its prodromal states: A review.

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Swords, Gabriel M; Nguyen, Lydia T; Mudar, Raksha A; Llano, Daniel A

2018-04-06

Recent findings suggest that both peripheral and central auditory system dysfunction occur in the prodromal stages of Alzheimer Disease (AD), and therefore may represent early indicators of the disease. In addition, loss of auditory function itself leads to communication difficulties, social isolation and poor quality of life for both patients with AD and their caregivers. Developing a greater understanding of auditory dysfunction in early AD may shed light on the mechanisms of disease progression and carry diagnostic and therapeutic importance. Herein, we review the literature on hearing abilities in AD and its prodromal stages investigated through methods such as pure-tone audiometry, dichotic listening tasks, and evoked response potentials. We propose that screening for peripheral and central auditory dysfunction in at-risk populations is a low-cost and effective means to identify early AD pathology and provides an entry point for therapeutic interventions that enhance the quality of life of AD patients. Copyright © 2018 Elsevier B.V. All rights reserved.

Myeloid cells in Alzheimer's disease: culprits, victims or innocent bystanders?

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Meyer-Luehmann, Melanie; Prinz, Marco

2015-10-01

Several recent genome-wide association studies (GWAS) in patients with neurodegenerative disorders have shed new light on the brain immune system, suggesting that it plays a pivotal role in disease pathogenesis. Mononuclear phagocytes are blatantly involved in Alzheimer's disease (AD) of the central nervous system (CNS), but the specific functions of resident microglia, perivascular or meningeal macrophages, and circulating myeloid cells have not yet been fully resolved. Next-generation sequencing, high-throughput immune profiling technologies, and novel genetic tools have recently revolutionized the characterization of innate immune responses during AD. These studies advocate selective and non-redundant roles for myeloid subsets, which could be a target for novel disease-modifying therapies in AD. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Morphological analysis of the hippocampal region associated with an innate behaviour task in the transgenic mouse model (3xTg-AD) for Alzheimer disease].

Science.gov (United States)

Orta-Salazar, E; Feria-Velasco, A; Medina-Aguirre, G I; Díaz-Cintra, S

2013-10-01

Different animal models for Alzheimer disease (AD) have been designed to support the hypothesis that the neurodegeneration (loss of neurons and synapses with reactive gliosis) associated with Aβ and tau deposition in these models is similar to that in the human brain. These alterations produce functional changes beginning with decreased ability to carry out daily and social life activities, memory loss, and neuropsychiatric disorders in general. Neuronal alteration plays an important role in early stages of the disease, especially in the CA1 area of hippocampus in both human and animal models. Two groups (WT and 3xTg-AD) of 11-month-old female mice were used in a behavioural analysis (nest building) and a morphometric analysis of the CA1 region of the dorsal hippocampus. The 3xTg-AD mice showed a 50% reduction in nest quality associated with a significant increase in damaged neurons in the CA1 hippocampal area (26%±6%, Pde Neurología. Published by Elsevier Espana. All rights reserved.

Rivastigmine in Alzheimer's disease and Parkinson's disease dementia: an ADAS-cog factor analysis.

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Weintraub, Daniel; Somogyi, Monique; Meng, Xiangyi

2011-09-01

Rivastigmine treatment is associated with significant improvements on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) in patients with mild-to-moderate Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). Both AD and PDD are purported to have different profiles of cognitive impairment, which may respond differentially to rivastigmine treatment. This was a retrospective analysis of 3 randomized, double-blind, rivastigmine trial databases (Investigation of transDermal Exelon in ALzheimer's disease [IDEAL; AD], EXelon in PaRkinson's disEaSe dementia Study [EXPRESS; PDD], and Alzheimer's Disease with ENA 713 [ADENA; AD]). Factor analyses of the 11 baseline ADAS-cog items derived the same factors in the 2 diseases, that is, "memory" and "language". Rivastigmine-treated AD and PDD patients showed significant improvements (P < .0001 versus placebo) on both factors. For both AD and PDD, rivastigmine had a numerically greater effect on memory than language. Treatment effect sizes were numerically greater in PDD compared with AD. Rivastigmine treatment is associated with improvement in memory and language in AD and PDD. The numerically greater response in PDD is consistent with greater cholinergic deficits in this disease state.

Modeling and Predicting AD Progression by Regression Analysis of Sequential Clinical Data

KAUST Repository

Xie, Qing; Wang, Su; Zhu, Jia; Zhang, Xiangliang

2016-01-01

Alzheimer's Disease (AD) is currently attracting much attention in elders' care. As the increasing availability of massive clinical diagnosis data, especially the medical images of brain scan, it is highly significant to precisely identify and predict the potential AD's progression based on the knowledge in the diagnosis data. In this paper, we follow a novel sequential learning framework to model the disease progression for AD patients' care. Different from the conventional approaches using only initial or static diagnosis data to model the disease progression for different durations, we design a score-involved approach and make use of the sequential diagnosis information in different disease stages to jointly simulate the disease progression. The actual clinical scores are utilized in progress to make the prediction more pertinent and reliable. We examined our approach by extensive experiments on the clinical data provided by the Alzheimer's Disease Neuroimaging Initiative (ADNI). The results indicate that the proposed approach is more effective to simulate and predict the disease progression compared with the existing methods.

Two Alzheimer’s disease risk genes increase entorhinal cortex volume in young adults

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Amanda Marie Dibattista

2014-10-01

Full Text Available Alzheimer’s disease (AD risk genes alter brain structure and function decades before disease onset. Apolipoprotein E (APOE is the strongest known genetic risk factor for Alzheimer’s disease, and a related gene, apolipoprotein J (APOJ, also affects disease risk. However, the extent to which these genes affect brain structure in young adults remains unclear. Here, we report that AD risk alleles of these two genes, APOE-ε4 and APOJ-C, cumulatively alter brain volume in young adults. Using voxel-based morphometry in 57 individuals, we examined the entorhinal cortex, one of the earliest brain regions affected in AD pathogenesis. APOE-ε4 carriers exhibited higher right entorhinal cortex volume compared to non-carriers. Interestingly, APOJ-C risk genotype was associated with higher bilateral entorhinal cortex volume in non-APOE-ε4 carriers. To determine the combined disease risk of APOE and APOJ status per subject, we used cumulative odds ratios as regressors for volumetric measurements. Higher disease risk corresponded to greater right entorhinal cortex volume. These results suggest that, years before disease onset, two key AD genetic risk factors may exert influence on the structure of a brain region where AD pathogenesis takes root.

Deficient symbol processing in Alzheimer disease.

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Toepper, Max; Steuwe, Carolin; Beblo, Thomas; Bauer, Eva; Boedeker, Sebastian; Thomas, Christine; Markowitsch, Hans J; Driessen, Martin; Sammer, Gebhard

2014-01-01

Symbols and signs have been suggested to improve the orientation of patients suffering from Alzheimer disease (AD). However, there are hardly any studies that confirm whether AD patients benefit from signs or symbols and which symbol characteristics might improve or impede their symbol comprehension. To address these issues, 30 AD patients and 30 matched healthy controls performed a symbol processing task (SPT) with 4 different item categories. A repeated-measures analysis of variance was run to identify impact of different item categories on performance accuracy in both the experimental groups. Moreover, SPT scores were correlated with neuropsychological test scores in a broad range of other cognitive domains. Finally, diagnostic accuracy of the SPT was calculated by a receiver-operating characteristic curve analysis. Results revealed a global symbol processing dysfunction in AD that was associated with semantic memory and executive deficits. Moreover, AD patients showed a disproportional performance decline at SPT items with visual distraction. Finally, the SPT total score showed high sensitivity and specificity in differentiating between AD patients and healthy controls. The present findings suggest that specific symbol features impede symbol processing in AD and argue for a diagnostic benefit of the SPT in neuropsychological assessment.

Epigenetic Alterations in Alzheimer's Disease

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Johannes eGräff

2015-12-01

Full Text Available Alzheimer’s disease (AD is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD.

Epigenetic Alterations in Alzheimer's Disease.

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Sanchez-Mut, Jose V; Gräff, Johannes

2015-01-01

Alzheimer's disease (AD) is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD.

Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease.

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Gong, C-X; Iqbal, K

2008-01-01

Alzheimer disease (AD) is the most common cause of dementia in adults. The current therapy for AD has only moderate efficacy in controlling symptoms, and it does not cure the disease. Recent studies have suggested that abnormal hyperphosphorylation of tau in the brain plays a vital role in the molecular pathogenesis of AD and in neurodegeneration. This article reviews the current advances in understanding of tau protein, regulation of tau phosphorylation, and the role of its abnormal hyperphosphorylation in neurofibrillary degeneration. Furthermore, several therapeutic strategies for treating AD on the basis of the important role of tau hyperphosphorylation in the pathogenesis of the disease are described. These strategies include (1) inhibition of glycogen synthase kinase-3beta (GSK-3beta), cyclin-dependent kinase 5 (cdk5), and other tau kinases; (2) restoration of PP2A activity; and (3) targeting tau O-GlcNAcylation. Development of drugs on the basis of these strategies is likely to lead to disease-modifying therapies for AD.

Molecular subtypes of Alzheimer's disease.

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Di Fede, Giuseppe; Catania, Marcella; Maderna, Emanuela; Ghidoni, Roberta; Benussi, Luisa; Tonoli, Elisa; Giaccone, Giorgio; Moda, Fabio; Paterlini, Anna; Campagnani, Ilaria; Sorrentino, Stefano; Colombo, Laura; Kubis, Adriana; Bistaffa, Edoardo; Ghetti, Bernardino; Tagliavini, Fabrizio

2018-02-19

Protein misfolding and aggregation is a central feature of several neurodegenerative disorders including Alzheimer's disease (AD), in which assemblies of amyloid β (Aβ) peptides accumulate in the brain in the form of parenchymal and/or vascular amyloid. A widely accepted concept is that AD is characterized by distinct clinical and neuropathological phenotypes. Recent studies revealed that Aβ assemblies might have structural differences among AD brains and that such pleomorphic assemblies can correlate with distinct disease phenotypes. We found that in both sporadic and inherited forms of AD, amyloid aggregates differ in the biochemical composition of Aβ species. These differences affect the physicochemical properties of Aβ assemblies including aggregation kinetics, resistance to degradation by proteases and seeding ability. Aβ-amyloidosis can be induced and propagated in animal models by inoculation of brain extracts containing aggregated Aβ. We found that brain homogenates from AD patients with different molecular profiles of Aβ are able to induce distinct patterns of Aβ-amyloidosis when injected into mice. Overall these data suggest that the assembly of mixtures of Aβ peptides into different Aβ seeds leads to the formation of distinct subtypes of amyloid having distinctive physicochemical and biological properties which result in the generation of distinct AD molecular subgroups.

Monoacylglycerol Lipase Is a Therapeutic Target for Alzheimer's Disease

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Rongqing Chen

2012-11-01

Full Text Available Alzheimer's disease (AD is the most common cause of dementia among older people. There are no effective medications currently available to prevent and treat AD and halt disease progression. Monoacylglycerol lipase (MAGL is the primary enzyme metabolizing the endocannabinoid 2-arachidonoylglycerol in the brain. We show here that inactivation of MAGL robustly suppressed production and accumulation of β-amyloid (Aβ associated with reduced expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1 in a mouse model of AD. MAGL inhibition also prevented neuroinflammation, decreased neurodegeneration, maintained integrity of hippocampal synaptic structure and function, and improved long-term synaptic plasticity, spatial learning, and memory in AD animals. Although the molecular mechanisms underlying the beneficial effects produced by MAGL inhibition remain to be determined, our results suggest that MAGL, which regulates endocannabinoid and prostaglandin signaling, contributes to pathogenesis and neuropathology of AD, and thus is a promising therapeutic target for the prevention and treatment of AD.

Oncolytic adenovirus Ad657 for systemic virotherapy against prostate cancer

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Nguyen TV

2018-05-01

Full Text Available Tien V Nguyen,1,* Catherine M Crosby,2,* Gregory J Heller,3 Zachary I Mendel,3 Mary E Barry,1 Michael A Barry1,4,5 1Department of Internal Medicine, Division of Infectious Diseases, 2Virology and Gene Therapy Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, 3Postbaccalaureate Research Education Program, Mayo Clinic Graduate School of Biomedical Sciences, 4Department of Immunology, 5Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA *These authors contributed equally to this work Background: Human species C adenovirus serotype 5 (Ad5 is the archetype oncolytic adenovirus and has been used in the vast majority of preclinical and clinical tests. While Ad5 can be robust, species C Ad6 has lower seroprevalence, side effects, and appears to be more potent as a systemic therapy against a number of tumors than Ad5. Historically, there have only been four species C human adenoviruses: serotypes 1, 2, 5, and 6. More recently a new species C adenovirus, Ad57, was identified. Ad57 is most similar to Ad6 with virtually all variation in their capsid proteins occurring in the hypervariable regions (HVRs of their hexon proteins. Most adenovirus neutralizing antibodies target the HVRs on adenoviruses. This led us to replace the hexon HVRs in Ad6 with those from Ad57 to create a new virus called Ad657 and explore this novel species C platform’s utility as an oncolytic virus. Methods: The HVR region from Ad57 was synthesized and used to replace the Ad6 HVR region by homologous recombination in bacteria generating a new viral platform that we call Ad657. Replication-competent Ad5, Ad6, and Ad657 were compared in vitro and in vivo for liver damage and oncolytic efficacy against prostate cancers after single intravenous treatment in mice. Results: Ad5, Ad6, and Ad657 had similar in vitro oncolytic activity against human prostate cancer cells. Ad5 provoked the highest level of liver toxicity after intravenous injection and Ad657

Globally regular instability of AdS_3

OpenAIRE

Bizon, P.; Jałmużna, J.

2013-01-01

We consider three-dimensional AdS gravity minimally coupled to a massless scalar field and study numerically the evolution of small smooth circularly symmetric perturbations of the $AdS_3$ spacetime. As in higher dimensions, for a large class of perturbations, we observe a turbulent cascade of energy to high frequencies which entails instability of $AdS_3$. However, in contrast to higher dimensions, the cascade cannot be terminated by black hole formation because small perturbations have ener...

INDIRECT EVIDENCE: MILD ALZHEIMER’S DISEASE & CANNABIS AFFECT THE SECOND STAGE OF FREE RECALL SUGGESTING LOCALIZATION IN HIPPOCAMPAL CA1

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Eugen Tarnow

2016-12-01

Full Text Available Recently it was shown explicitly that free recall consists of two stages: the first few recalls empty working memory and a second stage, a reactivation stage, concludes the recall ([20]; for a review of the theoretical prediction see [15]. Here it is shown that the serial position curve changes in mild Alzheimer’s disease (AD and acute cannabis usage - lowered total recall and lessened primacy - are similar to second stage recall and different from working memory recall.Since cannabis and AD affect the second stage of free recall, the intersection of the two localizes the second stage of free recall to the CA1 area of the hippocampus. Since the second stage of recall uses a retrieval process that is accompanied by a linear rise in the error rate [18] this error generating mechanism should give clues to the structure of the corresponding neural network.

Intraindividual variability as a marker of neurological dysfunction: a comparison of Alzheimer's disease and Parkinson's disease.

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Burton, Catherine L; Strauss, Esther; Hultsch, David F; Moll, Alex; Hunter, Michael A

2006-01-01

Individuals with certain neurological conditions may demonstrate greater inconsistency (i.e., intraindividual variability) on cognitive tasks compared to healthy controls. Several researchers have suggested that intraindividual variability may be a behavioral marker of compromised neurobiological mechanisms associated with aging, disease, or injury. The present study sought to investigate whether intraindividual variability is associated with general nervous system compromise, or rather, with certain types of neurological disturbances by comparing healthy adults, adults with Alzheimer's disease (AD), and Parkinson's disease (PD). Participants were assessed on four separate occasions using measures of reaction time and memory. Results indicated that inconsistency was correlated with indices of severity of impairment suggesting a dose-response relationship between cognitive disturbance and intraindividual variability: the more severe the cognitive disturbance, the greater the inconsistency. However, participants with AD were more inconsistent than those with PD, with both groups being more variable than the healthy group, even when controlling for group differences in overall severity of cognitive impairment or cognitive decline. Consequently, intraindividual variability may index both the severity of cognitive impairment and the nature of the neurological disturbance.

Cross-View Neuroimage Pattern Analysis for Alzheimer's Disease Staging

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Sidong eLiu

2016-02-01

Full Text Available The research on staging of pre-symptomatic and prodromal phase of neurological disorders, e.g., Alzheimer's disease (AD, is essential for prevention of dementia. New strategies for AD staging with a focus on early detection, are demanded to optimize potential efficacy of disease-modifying therapies that can halt or slow the disease progression. Recently, neuroimaging are increasingly used as additional research-based markers to detect AD onset and predict conversion of MCI and normal control (NC to AD. Researchers have proposed a variety of neuroimaging biomarkers to characterize the patterns of the pathology of AD and MCI, and suggested that multi-view neuroimaging biomarkers could lead to better performance than single-view biomarkers in AD staging. However, it is still unclear what leads to such synergy and how to preserve or maximize. In an attempt to answer these questions, we proposed a cross-view pattern analysis framework for investigating the synergy between different neuroimaging biomarkers. We quantitatively analyzed 9 types of biomarkers derived from FDG-PET and T1-MRI, and evaluated their performance in a task of classifying AD, MCI and NC subjects obtained from the ADNI baseline cohort. The experiment results showed that these biomarkers could depict the pathology of AD from different perspectives, and output distinct patterns that are significantly associated with the disease progression. Most importantly, we found that these features could be separated into clusters, each depicting a particular aspect; and the inter-cluster features could always achieve better performance than the intra-cluster features in AD staging.

Noradrenergic dysfunction in Alzheimer’s disease

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Mary eGannon

2015-06-01

Full Text Available The brain noradrenergic system supplies the neurotransmitter norepinephrine throughout the brain via widespread efferent projections, and plays a pivotal role in modulating cognitive activities in the cortex. Profound noradrenergic degeneration in Alzheimer’s disease (AD patients has been observed for decades, with recent research suggesting that the locus coeruleus (where noradrenergic neurons are mainly located is a predominant site where AD-related pathology begins. Mounting evidence indicate that the loss of noradrenergic innervation greatly exacerbates AD pathogenesis and progression, although the precise roles of noradrenergic components in AD pathogenesis remain unclear. The aim of this review is to summarize current findings on noradrenergic dysfunction in AD, as well as to point out deficiencies in our knowledge where more research is needed.

Risk of incident clinical diagnosis of AD-type dementia attributable to pathology-confirmed vascular disease

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Dodge, Hiroko H.; Zhu, Jian; Woltjer, Randy; Nelson, Peter T.; Bennett, David A.; Cairns, Nigel J.; Fardo, David W.; Kaye, Jeffrey A.; Lyons, Deniz-Erten; Mattek, Nora; Schneider, Julie A; Silbert, Lisa C.; Xiong, Chengjie; Yu, Lei; Schmitt, Frederick A.; Kryscio, Richard J.; Abner, Erin L.

2016-01-01

Introduction Presence of cerebrovascular pathology may increase the risk of clinical diagnosis of AD. Methods We examined excess risk of incident clinical diagnosis of AD (probable and possible AD) posed by the presence of lacunes and large infarcts beyond AD pathology using data from the Statistical Modelling of Aging and Risk of Transition (SMART) study, a consortium of longitudinal cohort studies with over 2000 autopsies. We created six mutually exclusive pathology patterns combining three levels of AD pathology (low, moderate or high AD pathology) and two levels of vascular pathology (without lacunes and large infarcts or with lacunes and/or large infarcts). Results The coexistence of lacunes and large infarcts results in higher likelihood of clinical diagnosis of AD only when AD pathology burden is low. Discussion Our results reinforce the diagnostic importance of AD pathology in clinical AD. Further harmonization of assessment approaches for vascular pathologies is required. PMID:28017827

Ocular Changes in TgF344-AD Rat Model of Alzheimer's Disease

OpenAIRE

Tsai, Yuchun; Lu, Bin; Ljubimov, Alexander V.; Girman, Sergey; Ross-Cisneros, Fred N.; Sadun, Alfredo A.; Svendsen, Clive N.; Cohen, Robert M.; Wang, Shaomei

2014-01-01

In this study, we observed pathological changes in the choroid and in RPE cells in the TgF344-AD rat model; choroidal thinning was further observed in human AD retina. Along with Aβ deposition, the inflammatory response was manifested by microglial recruitment and complement activation.

Manifestly T-dual formulation of AdS space

International Nuclear Information System (INIS)

Hatsuda, Machiko; Kamimura, Kiyoshi; Siegel, Warren

2017-01-01

We present a manifestly T-dual formulation of curved spaces such as an AdS space. For group manifolds related by the orthogonal vielbein fields the three form H=dB in the doubled space is universal at least locally. We construct an affine nondegenerate doubled bosonic AdS algebra to define the AdS space with the Ramond-Ramond flux. The non-zero commutator of the left and right momenta leads to that the left momentum is in an AdS space while the right momentum is in a dS space. Dimensional reduction constraints and the physical AdS algebra are shown to preserve all the doubled coordinates.

Manifestly T-dual formulation of AdS space

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Hatsuda, Machiko [Physics Division, Faculty of Medicine, Juntendo University,Chiba 270-1695 (Japan); KEK Theory Center, High Energy Accelerator Research Organization,Tsukuba, Ibaraki 305-0801 (Japan); Kamimura, Kiyoshi [Physics Division, Faculty of Medicine, Juntendo University,Chiba 270-1695 (Japan); Siegel, Warren [C.N. Yang Institute for Theoretical Physics, Stony Brook University,Stony Brook, NY 11794-3840 (United States)

2017-05-12

We present a manifestly T-dual formulation of curved spaces such as an AdS space. For group manifolds related by the orthogonal vielbein fields the three form H=dB in the doubled space is universal at least locally. We construct an affine nondegenerate doubled bosonic AdS algebra to define the AdS space with the Ramond-Ramond flux. The non-zero commutator of the left and right momenta leads to that the left momentum is in an AdS space while the right momentum is in a dS space. Dimensional reduction constraints and the physical AdS algebra are shown to preserve all the doubled coordinates.

Diagnosis of gastro-oesophageal reflux disease is enhanced by adding oesophageal histology and excluding epigastric pain.

Science.gov (United States)

Vakil, N; Vieth, M; Wernersson, B; Wissmar, J; Dent, J

2017-05-01

The diagnosis of gastro-oesophageal reflux disease (GERD) in clinical practice is limited by the sensitivity and specificity of symptoms and diagnostic testing. To determine if adding histology as a criterion and excluding patients with epigastric pain enhances the diagnosis for GERD. Patients with frequent upper gastrointestinal symptoms who had not taken a proton pump inhibitor in the previous 2 months and who had evaluable distal oesophageal biopsies were included (Diamond study: NCT00291746). Epithelial hyperplasia was identified when total epithelial thickness was at least 430 μm. Investigation-based GERD criteria were: presence of erosive oesophagitis, pathological oesophageal acid exposure and/or positive symptom-acid association probability. Symptoms were assessed using the Reflux Disease Questionnaire and a pre-specified checklist. Overall, 127 (55%) of the 231 included patients met investigation-based GERD criteria and 195 (84%) met symptom-based criteria. Epithelial hyperplasia was present in 89 individuals, of whom 61 (69%) met investigation-based criteria and 83 (93%) met symptom-based criteria. Adding epithelial hyperplasia as a criterion increased the number of patients diagnosed with GERD on investigation by 28 [12%; number needed to diagnose (NND): 8], to 155 (67%). The proportion of patients with a symptom-based GERD diagnosis who met investigation-based criteria including epithelial hyperplasia was significantly greater when concomitant epigastric pain was absent than when it was present (P < 0.05; NND: 8). Histology increases diagnosis of GERD and should be performed when clinical suspicion is high and endoscopy is negative. Excluding patients with epigastric pain enhances sensitivity for the diagnosis of GERD. © 2017 John Wiley & Sons Ltd.

Applications of Neuroimaging to Disease-Modification Trials in Alzheimer’s Disease

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Adam S. Fleisher

2009-01-01

Full Text Available Critical to development of new therapies for Alzheimer’s disease (AD is the ability to detect clinical or pathological change over time. Clinical outcome measures typically used in therapeutic trials have unfortunately proven to be relatively variable and somewhat insensitive to change in this slowly progressive disease. For this reason, development of surrogate biomarkers that identify significant disease-associated brain changes are necessary to expedite treatment development in AD. Since AD pathology is present in the brain many years prior to clinical manifestation, ideally we want to develop biomarkers of disease that identify abnormal brain structure or function even prior to cognitive decline. Magnetic resonance imaging, fluorodeoxyglucose positron emission tomography, new amyloid imaging techniques, and spinal fluid markers of AD all have great potential to provide surrogate endpoint measures for AD pathology. The Alzheimer’s disease neuroimaging initiative (ADNI was developed for the distinct purpose of evaluating surrogate biomarkers for drug development in AD. Recent evidence from ADNI demonstrates that imaging may provide more sensitive, and earlier, measures of disease progression than traditional clinical measures for powering clinical drug trials in Alzheimer's disease. This review discusses recently presented data from the ADNI dataset, and the importance of imaging in the future of drug development in AD.

Mixed-symmetry fields in AdS(5), conformal fields, and AdS/CFT

Energy Technology Data Exchange (ETDEWEB)

Metsaev, R.R. [Department of Theoretical Physics, P.N. Lebedev Physical Institute,Leninsky prospect 53, Moscow 119991 (Russian Federation)

2015-01-15

Mixed-symmetry arbitrary spin massive, massless, and self-dual massive fields in AdS(5) are studied. Light-cone gauge actions for such fields leading to decoupled equations of motion are constructed. Light-cone gauge formulation of mixed-symmetry anomalous conformal currents and shadows in 4d flat space is also developed. AdS/CFT correspondence for normalizable and non-normalizable modes of mixed-symmetry AdS fields and the respective boundary mixed-symmetry anomalous conformal currents and shadows is studied. We demonstrate that the light-cone gauge action for massive mixed-symmetry AdS field evaluated on solution of the Dirichlet problem amounts to the light-cone gauge 2-point vertex of mixed-symmetry anomalous shadow. Also we show that UV divergence of the action for mixed-symmetry massive AdS field with some particular value of mass parameter evaluated on the Dirichlet problem amounts to the action of long mixed-symmetry conformal field, while UV divergence of the action for mixed-symmetry massless AdS field evaluated on the Dirichlet problem amounts to the action of short mixed-symmetry conformal field. We speculate on string theory interpretation of a model which involves short low-spin conformal fields and long higher-spin conformal fields.

Unraveling Alzheimer's: Making Sense of the Relationship between Diabetes and Alzheimer's Disease1.

Science.gov (United States)

Schilling, Melissa A

2016-01-01

Numerous studies have documented a strong association between diabetes and Alzheimer's disease (AD). The nature of the relationship, however, has remained a puzzle, in part because of seemingly incongruent findings. For example, some studies have concluded that insulin deficiency is primarily at fault, suggesting that intranasal insulin or inhibiting the insulin-degrading enzyme (IDE) could be beneficial. Other research has concluded that hyperinsulinemia is to blame, which implies that intranasal insulin or the inhibition of IDE would exacerbate the disease. Such antithetical conclusions pose a serious obstacle to making progress on treatments. However, careful integration of multiple strands of research, with attention to the methods used in different studies, makes it possible to disentangle the research on AD. This integration suggests that there is an important relationship between insulin, IDE, and AD that yields multiple pathways to AD depending on the where deficiency or excess in the cycle occurs. I review evidence for each of these pathways here. The results suggest that avoiding excess insulin, and supporting robust IDE levels, could be important ways of preventing and lessening the impact of AD. I also describe what further tests need to be conducted to verify the arguments made in the paper, and their implications for treating AD.

Lorentzian AdS, Wormholes and Holography

CERN Document Server

Arias, Raul E; Silva, Guillermo A

2011-01-01

We investigate the structure of two point functions for the QFT dual to an asymptotically Lorentzian AdS-wormhole. The bulk geometry is a solution of 5-dimensional second order Einstein Gauss Bonnet gravity and causally connects two asymptotically AdS space times. We revisit the GKPW prescription for computing two-point correlation functions for dual QFT operators O in Lorentzian signature and we propose to express the bulk fields in terms of the independent boundary values phi_0^\\pm at each of the two asymptotic AdS regions, along the way we exhibit how the ambiguity of normalizable modes in the bulk, related to initial and final states, show up in the computations. The independent boundary values are interpreted as sources for dual operators O^\\pm and we argue that, apart from the possibility of entanglement, there exists a coupling between the degrees of freedom leaving at each boundary. The AdS_(1+1) geometry is also discussed in view of its similar boundary structure. Based on the analysis, we propose a ...

Nonlinear realization of supersymmetric AdS space isometries

International Nuclear Information System (INIS)

Clark, T. E.; Love, S. T.

2006-01-01

The isometries of AdS 5 space and supersymmetric AdS 5 xS 1 space are nonlinearly realized on four-dimensional Minkowski space. The resultant effective actions in terms of the Nambu-Goldstone modes are constructed. The dilatonic mode governing the motion of the Minkowski space probe brane into the covolume of supersymmetric AdS 5 space is found to be unstable and the bulk of the AdS 5 space is unable to sustain the brane. No such instability appears in the nonsupersymmetric case

Optimal treatment of Alzheimer’s disease psychosis: challenges and solutions

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Koppel J

2014-11-01

Full Text Available Jeremy Koppel,1,2 Blaine S Greenwald2 1The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, NY, USA; 2Zucker Hillside Hospital, Hofstra North Shore-Long Island Jewish School of Medicine, Glen Oaks, NY, USA Abstract: Psychotic symptoms emerging in the context of neurodegeneration as a consequence of Alzheimer’s disease was recognized and documented by Alois Alzheimer himself in his description of the first reported case of the disease. Over a quarter of a century ago, in the context of attempting to develop prognostic markers of disease progression, psychosis was identified as an independent predictor of a more-rapid cognitive decline. This finding has been subsequently well replicated, rendering psychotic symptoms an important area of exploration in clinical history taking – above and beyond treatment necessity – as their presence has prognostic significance. Further, there is now a rapidly accreting body of research that suggests that psychosis in Alzheimer’s disease (AD+P is a heritable disease subtype that enjoys neuropathological specificity and localization. There is now hope that the elucidation of the neurobiology of the syndrome will pave the way to translational research eventuating in new treatments. To date, however, the primary treatments employed in alleviating the suffering caused by AD+P are the atypical antipsychotics. These agents are approved by the US Food and Drug Administration for the treatment of schizophrenia, but they have only marginal efficacy in treating AD+P and are associated with troubling levels of morbidity and mortality. For clinical approaches to AD+P to be optimized, this syndrome must be disentangled from other primary psychotic disorders, and recent scientific advances must be translated into disease-specific therapeutic interventions. Here we provide a review of atypical antipsychotic efficacy in AD+P, followed by an overview of critical

Targeting HDACs: A Promising Therapy for Alzheimer's Disease

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Ke Xu

2011-01-01

Full Text Available Epigenetic modifications like DNA methylation and histone acetylation play an important role in a wide range of brain disorders. Histone deacetylases (HDACs regulate the homeostasis of histone acetylation. Histone deacetylase inhibitors, which initially were used as anticancer drugs, are recently suggested to act as neuroprotectors by enhancing synaptic plasticity and learning and memory in a wide range of neurodegenerative and psychiatric disorders, such as Alzheimer's disease (AD and Parkinson's disease (PD. To reveal the physiological roles of HDACs may provide us with a new perspective to understand the mechanism of AD and to develop selective HDAC inhibitors. This paper focuses on the recent research progresses of HDAC proteins and their inhibitors on the roles of the treatment for AD.

Internal consistency and construct validity of the Quality of Life in Alzheimer's Disease (QoL-AD) proxy – a secondary data analysis

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Hylla, Jonas; Schwab, Christian G G; Isfort, Michael; Halek, Margareta; Dichter, Martin N

2016-07-01

Background: The maintenance and promotion of Quality of Life (QoL) of people with dementia is a major outcome in intervention studies and health care. The Quality of Life Alzheimer's Disease (QoL-AD) is an internationally recommended QoL measurement also available in German language. Until now, only a few results on the psychometric properties of the German QoL-AD were available. Objective: Evaluation of internal consistency and construct validity of the QoL-AD proxy. Method: A principal component analysis (secondary data analysis) of the 13 QoL-AD items was carried out based on the total sample of 234 people with dementia from nine nursing homes in Germany. Subsequently, the internal consistency of the identified factors was examined using Cronbach's alpha. Results: Two factors physical and mental health and social network were determined. Both factors explain 53 % of the total variance. The stability of both factors was validated in two sensitivity analyses. The internal consistency is good for both factors with a Cronbach's alpha of 0.88 (physical and mental health) and 0.75 (social network). Conclusion: The QoL-AD proxy allows the assessment of two relevant health-related QoL domains of people with dementia. However, in future studies especially the inter-rater reliability of the QoL-AD proxy has to be examined.

Non-relativistic AdS branes and Newton-Hooke superalgebra

International Nuclear Information System (INIS)

Sakaguchi, Makoto; Yoshida, Kentaroh

2006-01-01

We examine a non-relativistic limit of D-branes in AdS 5 x S 5 and M-branes in AdS 4/7 x S 7/4 . First, Newton-Hooke superalgebras for the AdS branes are derived from AdS x S superalgebras as Inoenue-Wigner contractions. It is shown that the directions along which the AdS-brane worldvolume extends are restricted by requiring that the isometry on the AdS-brane worldvolume and the Lorentz symmetry in the transverse space naturally extend to the super-isometry. We also derive Newton-Hooke superalgebras for pp-wave branes and show that the directions along which a brane worldvolume extends are restricted. Then the Wess-Zumino terms of the AdS branes are derived by using the Chevalley-Eilenberg cohomology on the super-AdS x S algebra, and the non-relativistic limit of the AdS-brane actions is considered. We show that the consistent limit is possible for the following branes: Dp (even,even) for p = 1 mod 4 and Dp (odd,odd) for p = 3 mod 4 in AdS 5 x S 5 , and M2 (0,3), M2 (2,1), M5 (1,5) and M5 (3,3) in AdS 4 x S 7 and S 4 x AdS 7 . We furthermore present non-relativistic actions for the AdS branes

Cerebrospinal liquid nerve growth factor levels in patients with Alzheimer's disease

International Nuclear Information System (INIS)

Mashayakhi, F.; Salehi, Z.

2006-01-01

Alzheimer's disease (AD) is the most common cause of dementia in the Western countries and in Japan. Numerous blood and cerebrospinal fluid (CSF) tests based on the disease pathology have been proposed for early detection of AD. By comparing the CSF proteome of AD patients and controls it might be possible to identify proteins that play a role in the disease process and thus study the pathogenesis of AD. Samples of CSF from normal (n=20) and AD patients (n=20) were collected by lumbar puncture. The total concentration of proteins in the CSF of normal subjects and AD patients was determined by Bio-Rad protein assay based on the Bradford dye binding procedures. The presence and level of NGF in the CSF of normal and AD patients was measured by enzyme linked immunosorbant assay (ELISA), SDS-PAGE and western blot. The total protein concentration of all samples was within the normal range (0.10-0.44). a western blot analysis using anti-NGF antibody showed the presence of NGF in human CSF. By ELISA the level of NGF in the CSF of AD patients was higher than in the CSF of normal subjects (81.5+-15.03 pg/mt, P,0.0001). We suggest that the NGF level in the CSF may provide additional information in the differential diagnosis of Alzheimer disease. We also conclude that NGF could be significantly involved in the pathophysiology of AD. (author)

Lifelong Bilingualism and Neural Reserve against Alzheimer’s disease: A Review of Findings and Potential Mechanisms

OpenAIRE

Gold, Brian T.

2014-01-01

Alzheimer’s disease (AD) is a progressive brain disorder that initially affects medial temporal lobe circuitry and memory functions. Current drug treatments have only modest effects on the symptomatic course of the disease. In contrast, a growing body of evidence suggests that lifelong bilingualism may delay the onset of clinical AD symptoms by several years. The purpose of the present review is to summarize evidence for bilingualism as a reserve variable against AD and discuss potential unde...

Into the Fourth Dimension: Dysregulation of Genome Architecture in Aging and Alzheimer's Disease.

Science.gov (United States)

Winick-Ng, Warren; Rylett, R Jane

2018-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by synapse dysfunction and cognitive impairment. Understanding the development and progression of AD is challenging, as the disease is highly complex and multifactorial. Both environmental and genetic factors play a role in AD pathogenesis, highlighted by observations of complex DNA modifications at the single gene level, and by new evidence that also implicates changes in genome architecture in AD patients. The four-dimensional structure of chromatin in space and time is essential for context-dependent regulation of gene expression in post-mitotic neurons. Dysregulation of epigenetic processes have been observed in the aging brain and in patients with AD, though there is not yet agreement on the impact of these changes on transcription. New evidence shows that proteins involved in genome organization have altered expression and localization in the AD brain, suggesting that the genomic landscape may play a critical role in the development of AD. This review discusses the role of the chromatin organizers and epigenetic modifiers in post-mitotic cells, the aging brain, and in the development and progression of AD. How these new insights can be used to help determine disease risk and inform treatment strategies will also be discussed.

Translation and implementation of added sugars consumption recommendations: a conference report from the American Heart Association Added Sugars Conference 2010.

Science.gov (United States)

Van Horn, Linda; Johnson, Rachel K; Flickinger, Brent D; Vafiadis, Dorothea K; Yin-Piazza, Shirley

2010-12-07

science also reinforces the importance of preventing, rather than simply treating diseases, especially overweight and obesity, diabetes mellitus, high blood pressure, heart disease, and stroke. Reducing added sugars consumption is a good target for addressing obesity, along with other sources of excess calories. However, the potential unintended consequences of substituting added sugars with ingredients that may not reduce calories and of increasing other macronutrients or food groups that may not result in a net health gain must be considered. Although there are many challenges to incorporating added sugars to the food label as was discussed during the conference, disclosure of added sugars content on food and beverage labels is an essential element in consumer education and can provide the information and motivation for making healthier food choices. This conference demonstrated the value of interactive dialogue among multiple sectors and disciplines. More disciplines should be at the table to bring expertise to discuss cross-cutting issues related to public policies and offer diverse insights to finding a solution.

Adding smoking to the Fardal model of cost-effectiveness for the life-time treatment of periodontal diseases.

Science.gov (United States)

Fardal, Øystein; Grytten, Jostein; Martin, John; Ellingsen, Stig; Fardal, Patrick; Heasman, Peter; Linden, Gerard J

2018-05-16

Little is known about the financial costs that smoking adds to the life-time treatment of periodontal disease. The total life-time cost of periodontal treatment was modelled using data from private periodontal practice. The costs of initial and supportive therapy, re-treatment and tooth replacements (with bridgework or implants) were identified using average dental charges from the American Dental Association survey. Smoking costs at $6 and $10 for 20 cigarettes were compared to the costs of life-time periodontal treatment for stable and unstable compliant patients. Smoking added 8.8% to the financial cost of the life-time cost of periodontal therapy in stable maintenance patients, 40.1% in patients who needed one extra maintenance visit and 71.4% in patients who needed two extra maintenance visits per year in addition to added re-treatment. The cost of smoking far exceeded the cost of periodontal treatment; For patients who smoked 10 to 40 cigarettes per day at the cost of $6 or $10 a pack, the cost of smoking exceeded the cost of life-time periodontal treatment by between 2.7 and 17.9 times. Smoking 40 cigarettes at $10 a packet for 3.4 years would pay for the entire life-time cost of periodontal treatment. Smoking adds considerable extra financial costs to the life-time treatment of periodontal diseases. The cost of smoking itself exceeds the cost of periodontal therapy. This article is protected by copyright. All rights reserved. © 2018 American Academy of Periodontology.

Developing Disease-Modifying Treatments in Alzheimer's Disease - A Perspective from Roche and Genentech.

Science.gov (United States)

Doody, R

2017-01-01

Alzheimer's disease (AD) is a chronic neurodegenerative disease for which no preventative or disease-modifying treatments currently exist. Pathological hallmarks include amyloid plaques and neurofibrillary tangles composed of hyper-phosphorylated tau protein. Evidence suggests that both pathologies are self-propagating once established. However, the lag time between neuropathological changes in the brain and the onset of even subtle clinical symptomatology means that patients are often diagnosed late when pathology, and neurodegeneration secondary to these changes, may have been established for several years. Complex pathological pathways associated with susceptibility to AD and changes that occur downstream of the neuropathologic process further contribute to the challenging endeavour of developing novel disease-modifying therapy. Recognising this complexity, effective management of AD must include reliable screening and early diagnosis in combination with effective therapeutic management of the pathological processes. Roche and Genentech are committed to addressing these unmet needs through developing a comprehensive portfolio of diagnostics and novel therapies. Beginning with the most scientifically supported targets, this approach includes two targeted amyloid-β monoclonal antibody therapies, crenezumab and gantenerumab, and an anti-tau monoclonal antibody, RO7105705, as well as a robust biomarker platform to aid in the early identification of people at risk or in the early stages of AD. Identification and implementation of diagnostic tools will support the enrolment of patients into clinical trials; furthermore, these tools should also support evaluation of the clinical efficacy and safety profile of the novel therapeutic agents tested in these trials. This review discusses the therapeutic agents currently under clinical development.

A closer look at two AdS4 branes in an AdS5 bulk

International Nuclear Information System (INIS)

Thambyahpillai, Shiyamala

2005-01-01

We investigate a scenario with two AdS 4 branes in an AdS 5 bulk. In this scenario there are two gravitons and we investigate the role played by each of them for different positions of the second brane. We show that both gravitons play a significant role only when the turn-around point in the warp factor is approximately equidistant from both branes. We find that the ultralight mode becomes heavy as the second brane approaches the turn-around point, and the physics begins to resemble that of the RS model. Thus we demonstrate the crucial role played by the turn-around in the warp factor in enabling the presence of both gravitons. (author)

Cognitive reserve and lifestyle: moving towards preclinical Alzheimer’s disease

Directory of Open Access Journals (Sweden)

Eider M Arenaza-Urquijo

2015-08-01

Full Text Available The large majority of neuroimaging studies in Alzheimer’s disease (AD patients have supported the idea that lifestyle factors may protect against the clinical manifestations of AD rather than influence AD neuropathological processes (the cognitive reserve hypothesis. This evidence argues in favor of the hypothesis that lifestyle factors act as moderators between AD pathology and cognition, i.e. through indirect compensatory mechanisms. In this review, we identify emerging evidence in cognitively normal older people that relate lifestyle factors to established AD neuroimaging biomarkers. While some of these investigations are in agreement with the compensatory view of cognitive reserve, other studies have revealed new clues on the neural mechanisms underlying beneficial effects of lifestyle factors on the brain. Specifically, they provide novel evidence suggesting direct effects of lifestyle factors on AD neuropathological processes. Here, we review current findings on the effects of lifestyle factors on AD neuroimaging biomarkers in cognitively normal older people. We propose a tentative theoretical model where lifestyle factors may act via direct neuroprotective and/or indirect compensatory pathways. Importantly, we suggest that neuroprotective mechanisms may have a major role during early stages and compensatory pathways in later stages of the disease. In the absence of an effective treatment for AD and considering the potential of lifestyle factors in AD prevention, understanding the neural mechanisms underlying lifestyle effects on the brain seems crucial. We hope to provide an integrative view that may help to better understand the complex effects of lifestyle factors on AD neuropathological processes, starting from the preclinical stage.

Assessment of PET & ASL metabolism in the hippocampal subfields of MCI and AD using simultaneous PET-MR

Energy Technology Data Exchange (ETDEWEB)

Goubran, Maged; Douglas, David; Chao, Steven; Quon, Andrew; Tripathi, Pragya; Holley, Dawn; Vasanawala, Minal; Zaharchuk, Greg; Zeineh, Michael [Stanford University (United States)

2015-05-18

Alzheimer’s disease (AD) has been reported to show decreased metabolic activity in the hippocampus using FDG PET-MR. Histological data suggests that the hippocampal subfields are selectively affected in AD. Given the simultaneous imaging nature of integrated PET-MR scanners and the multimodal capabilities of PET-MR, our purpose here is to assess FDG activity, as well as ASL perfusion in the subfields of MCI and AD patients. 10 consecutive subjects were recruited for this study 3 MCI, 3 AD patients and 4 age-matched controls. The scanning was performed on a simultaneous 3T PET/MR scanner. To delineate the hippocampal subfields, automatic segmentation of hippocampal subfields (ASHS) was employed. Static FDG-PET series were reconstructed for analysis at 45-75 min for all subjects. All imaging sequences were automatically registered to the oblique coronal T2-weighted images (segmentation space). PET standardized uptake values (SUV) in the hippocampal subfields were normalized by the pons. FDG PET metabolism was reduced significantly in AD, as well as MCI patients as compared to controls, with the highest effect demonstrated in the CA3/DG and CA1/2 (p = 0.047, subfields. Patients (MCI and AD combined) had decreased metabolism as compared to controls in CA1/2 and significantly smaller volumes the Subiculum. When assessing CBF across groups, a significant decrease in CBF was found in the Subiculum. Our preliminary results demonstrate that PET-MRI may potentially be a sensitive biomarker and tool for early diagnosis of AD. They also confirm the importance of assessing metabolic and structural changes of neurodegenerative diseases at the subfield level.

Sex modifies the APOE-related risk of developing Alzheimer disease.

Science.gov (United States)

Altmann, Andre; Tian, Lu; Henderson, Victor W; Greicius, Michael D

2014-04-01

The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Case-control studies suggest the APOE4 link to AD is stronger in women. We examined the APOE4-by-sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels. Cox proportional hazards analysis was used to compute hazard ratios (HRs) for an APOE-by-sex interaction on conversion in controls (n = 5,496) and MCI patients (n = 2,588). The interaction was also tested in CSF biomarker levels of 980 subjects from the Alzheimer's Disease Neuroimaging Initiative. Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR = 1.81 for women; HR = 1.27 for men; interaction: p = 0.011). The interaction remained significant in a predefined subanalysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, both male and female APOE4 carriers were more likely to convert to AD (HR = 2.16 for women; HR = 1.64 for men); the interaction was not significant (p = 0.14). In the subanalysis restricted to APOE3/3 and APOE3/4 genotypes, the interaction was significant (p = 0.02; HR = 2.17 for women; HR = 1.51 for men). The APOE4-by-sex interaction on biomarker levels was significant for MCI patients for total tau and the tau-to-Aβ ratio (p = 0.009 and p = 0.02, respectively; more AD-like in women). APOE4 confers greater AD risk in women. Biomarker results suggest that increased APOE-related risk in women may be associated with tau pathology. These findings have important clinical implications and suggest novel research approaches into AD pathogenesis. © 2014 American Neurological Association.

A disease state fingerprint for evaluation of Alzheimer's disease

DEFF Research Database (Denmark)

Mattila, Jussi; Koikkalainen, Juha; Virkki, Arho

2011-01-01

Diagnostic processes of Alzheimer's disease (AD) are evolving. Knowledge about disease-specific biomarkers is constantly increasing and larger volumes of data are being measured from patients. To gain additional benefits from the collected data, a novel statistical modeling and data visualization...... interpretation of the information. To model the AD state from complex and heterogeneous patient data, a statistical Disease State Index (DSI) method underlying the DSF has been developed. Using baseline data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the ability of the DSI to model disease......'s degree of similarity to previously diagnosed disease population. A summary of patient data and results of the computation are displayed in a succinct Disease State Fingerprint (DSF) visualization. The visualization clearly discloses how patient data contributes to the AD state, facilitating rapid...

β-secretase inhibitor; a promising novel therapeutic drug in AD

Directory of Open Access Journals (Sweden)

Kelly Willemijn Menting

2014-07-01

Full Text Available Alzheimer’s disease (AD and vascular dementia are responsible for up to 90% of dementia cases. According to the World Health Organization (WHO, a staggering number of 35.6 million people are currently diagnosed with dementia. Blocking disease progression or preventing AD altogether is desirable for both social and economic reasons and recently focus has shifted to a new and promising drug: the β-secretase inhibitor. Much of AD research has investigated the amyloid cascade hypothesis, which postulates that AD is caused by changes in amyloid beta (Aβ stability and aggregation. Blocking Aβ production by inhibiting the first protease required for its generation, β-secretase/BACE1, may be the next step in blocking AD progression. In April 2012, promising phase I data on inhibitor MK-8931 was presented. This drug reduced Aβ CSF levels up to 92% and was well tolerated by patients. In March 2013 data was added from a one week trial in 32 mild to moderate AD patients, showing CSF Aβ levels decreased up to 84%. However, BACE1 inhibitors require further research. First, greatly reducing Aβ levels through BACE1 inhibition may have harmful side effects. Second, BACE1 inhibitors have yet to pass clinical trial phase II/III and no data on possible side effects on AD patients are available. And third, there remains doubt about the clinical efficacy of BACE1 inhibitors. In moderate AD patients, Aβ plaques have already been formed. BACE1 inhibitors prevent production of new Aβ plaques, but hypothetically do not influence already existing Aβ peptides. Therefore, BACE1 inhibitors are potentially better at preventing AD instead of having therapeutic use.

Immunotherapeutic Strategies for Alzheimer's Disease Treatment

Directory of Open Access Journals (Sweden)

Beka Solomon

2009-01-01

Full Text Available Naturally occurring antibodies against amyloid-β peptides have been found in human cerebrospinal fluid and in the plasma of healthy individuals, but were significantly lower in Alzheimer's disease (AD patients, suggesting that AD may be an immunodeficient disorder. The performance of anti-amyloid-β antibodies in transgenic mice models of AD showed that they are delivered to the central nervous system, preventing and dissolving amyloid-β plaques. Moreover, these antibodies protected the mice from learning and age-related memory deficits. Active and/or passive immunization against the amyloid-β peptide has been proposed as a method for preventing and/or treating AD. Immunotherapy represents fascinating ways to test the amyloid hypothesis and offers genuine opportunities for AD treatment, but requires careful antigen and antibody selection to maximize efficacy and minimize adverse events.

Epigenetic Alterations in Alzheimer’s Disease

Science.gov (United States)

Sanchez-Mut, Jose V.; Gräff, Johannes

2015-01-01

Alzheimer’s disease (AD) is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD. PMID:26734709

Evaporation of large black holes in AdS

International Nuclear Information System (INIS)

Rocha, Jorge V

2010-01-01

The AdS/CFT correspondence offers a new perspective on the long-standing black hole information paradox. However, to be able to use the available gauge/gravity machinery one is forced to consider so-called 'large' black holes in AdS, and these objects are thermodynamically stable - they do not evaporate. We describe a simple toy model that allows large AdS black holes to decay, by coupling the emitted radiation to an external scalar field propagating in an auxiliary space. This effectively changes the properties of the boundary of AdS, making it partly absorbing. We demonstrate that the evaporation process never ceases by explicitly presenting (a) the transmission coefficient for a wave scattering from the bulk into auxiliary space and (b) the greybody factor for a black 3-brane in an AdS background. Therefore, the model provides an interesting framework to address the information paradox using AdS/CFT techniques.

Medical Treatment of Diverticular Disease: Antibiotics.

Science.gov (United States)

Lué, Alberto; Laredo, Viviana; Lanas, Angel

2016-10-01

Diverticular disease (DD) of the colon represents the most common disease affecting the large bowel in western countries. Its prevalence is increasing. Recent studies suggest that changes in gut microbiota could contribute to development of symptoms and complication. For this reason antibiotics play a key role in the management of both uncomplicated and complicated DD. Rifaximin has demonstrated to be effective in obtaining symptoms relief at 1 year in patients with uncomplicated DD and to improve symptoms and maintain periods of remission following acute colonic diverticulitis (AD). Despite absence of data that supports the routine use of antibiotic in uncomplicated AD, they are recommended in selected patients. In patients with AD that develop an abscess, conservative treatment with broad-spectrum antibiotics is successful in up to 70% of cases. In patients on conservative treatment where percutaneous drainage fails or peritonitis develops, surgery is considered the standard therapy. In conclusion antibiotics seem to remain the mainstay of treatment in symptomatic uncomplicated DD and AD. Inpatient management and intravenous antibiotics are necessary in complicated AD, while outpatient management is considered the best strategy in the majority of uncomplicated patients.

Elevated serum pesticide levels and risk for Alzheimer disease.

Science.gov (United States)

Richardson, Jason R; Roy, Ananya; Shalat, Stuart L; von Stein, Richard T; Hossain, Muhammad M; Buckley, Brian; Gearing, Marla; Levey, Allan I; German, Dwight C

2014-03-01

The causes of late-onset Alzheimer disease (AD) are not yet understood but likely include a combination of genetic, environmental, and lifestyle factors. Limited epidemiological studies suggest that occupational pesticide exposures are associated with AD. Previously, we reported that serum levels of dichlorodiphenyldichloroethylene (DDE), the metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were elevated in a small number of patients with AD (n=20). To evaluate the association between serum levels of DDE and AD and whether the apolipoprotein E (APOE) genotype modifies the association. A case-control study consisting of existing samples from patients with AD and control participants from the Emory University Alzheimer's Disease Research Center and the University of Texas Southwestern Medical School's Alzheimer's Disease Center. Serum levels of DDE were measured in 79 control and 86 AD cases. Serum DDE levels, AD diagnosis, severity of AD measured by the Mini-Mental State Examination score, and interaction with APOE4 status. Levels of DDE were 3.8-fold higher in the serum of those with AD (mean [SEM], 2.64 [0.35] ng/mg cholesterol) when compared with control participants (mean [SEM], 0.69 [0.1] ng/mg cholesterol; P risk for AD (95% CI, 2.54-5.82; P risk for AD and carriers of an APOE4 ε4 allele may be more susceptible to the effects of DDE. Both DDT and DDE increase amyloid precursor protein levels, providing mechanistic plausibility for the association of DDE exposure with AD. Identifying people who have elevated levels of DDE and carry an APOE ε4 allele may lead to early identification of some cases of AD.

Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease.

Directory of Open Access Journals (Sweden)

Maria Victoria Fernández

2017-11-01

Full Text Available Alzheimer disease (AD, Frontotemporal lobar degeneration (FTD, Amyotrophic lateral sclerosis (ALS and Parkinson disease (PD have a certain degree of clinical, pathological and molecular overlap. Previous studies indicate that causative mutations in AD and FTD/ALS genes can be found in clinical familial AD. We examined the presence of causative and low frequency coding variants in the AD, FTD, ALS and PD Mendelian genes, in over 450 families with clinical history of AD and over 11,710 sporadic cases and cognitive normal participants from North America. Known pathogenic mutations were found in 1.05% of the sporadic cases, in 0.69% of the cognitively normal participants and in 4.22% of the families. A trend towards enrichment, albeit non-significant, was observed for most AD, FTD and PD genes. Only PSEN1 and PINK1 showed consistent association with AD cases when we used ExAC as the control population. These results suggest that current study designs may contain heterogeneity and contamination of the control population, and that current statistical methods for the discovery of novel genes with real pathogenic variants in complex late onset diseases may be inadequate or underpowered to identify genes carrying pathogenic mutations.

Gene-Environment Interaction Research and Transgenic Mouse Models of Alzheimer's Disease

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L. Chouliaras

2010-01-01

Full Text Available The etiology of the sporadic form of Alzheimer's disease (AD remains largely unknown. Recent evidence has suggested that gene-environment interactions (GxE may play a crucial role in its development and progression. Whereas various susceptibility loci have been identified, like the apolipoprotein E4 allele, these cannot fully explain the increasing prevalence of AD observed with aging. In addition to such genetic risk factors, various environmental factors have been proposed to alter the risk of developing AD as well as to affect the rate of cognitive decline in AD patients. Nevertheless, aside from the independent effects of genetic and environmental risk factors, their synergistic participation in increasing the risk of developing AD has been sparsely investigated, even though evidence points towards such a direction. Advances in the genetic manipulation of mice, modeling various aspects of the AD pathology, have provided an excellent tool to dissect the effects of genes, environment, and their interactions. In this paper we present several environmental factors implicated in the etiology of AD that have been tested in transgenic animal models of the disease. The focus lies on the concept of GxE and its importance in a multifactorial disease like AD. Additionally, possible mediating mechanisms and future challenges are discussed.

What is the appropriate upper limit for added sugars consumption?

Science.gov (United States)

Rippe, James M; Sievenpiper, John L; Lê, Kim-Anne; White, John S; Clemens, Roger; Angelopoulos, Theodore J

2017-01-01

Dramatic increases in obesity and diabetes have occurred worldwide over the past 30 years. Some investigators have suggested that these increases may be due, in part, to increased added sugars consumption. Several scientific organizations, including the World Health Organization, the Scientific Advisory Council on Nutrition, the Dietary Guidelines Advisory Committee 2015, and the American Heart Association, have recommended significant restrictions on upper limits of sugars consumption. In this review, the scientific evidence related to sugars consumption and its putative link to various chronic conditions such as obesity, diabetes, heart disease, nonalcoholic fatty liver disease, and the metabolic syndrome is examined. While it appears prudent to avoid excessive calories from sugars, the scientific basis for restrictive guidelines is far from settled. © The Author(s) 2016. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Cholesterol Balance in Prion Diseases and Alzheimer’s Disease

Science.gov (United States)

Hannaoui, Samia; Shim, Su Yeon; Cheng, Yo Ching; Corda, Erica; Gilch, Sabine

2014-01-01

Prion diseases are transmissible and fatal neurodegenerative disorders of humans and animals. They are characterized by the accumulation of PrPSc, an aberrantly folded isoform of the cellular prion protein PrPC, in the brains of affected individuals. PrPC is a cell surface glycoprotein attached to the outer leaflet of the plasma membrane by a glycosyl-phosphatidyl-inositol (GPI) anchor. Specifically, it is associated with lipid rafts, membrane microdomains enriched in cholesterol and sphinoglipids. It has been established that inhibition of endogenous cholesterol synthesis disturbs lipid raft association of PrPC and prevents PrPSc accumulation in neuronal cells. Additionally, prion conversion is reduced upon interference with cellular cholesterol uptake, endosomal export, or complexation at the plasma membrane. Altogether, these results demonstrate on the one hand the importance of cholesterol for prion propagation. On the other hand, growing evidence suggests that prion infection modulates neuronal cholesterol metabolism. Similar results were reported in Alzheimer’s disease (AD): whereas amyloid β peptide formation is influenced by cellular cholesterol, levels of cholesterol in the brains of affected individuals increase during the clinical course of the disease. In this review, we summarize commonalities of alterations in cholesterol homeostasis and discuss consequences for neuronal function and therapy of prion diseases and AD. PMID:25419621

Cholesterol Balance in Prion Diseases and Alzheimer’s Disease

Directory of Open Access Journals (Sweden)

Samia Hannaoui

2014-11-01

Full Text Available Prion diseases are transmissible and fatal neurodegenerative disorders of humans and animals. They are characterized by the accumulation of PrPSc, an aberrantly folded isoform of the cellular prion protein PrPC, in the brains of affected individuals. PrPC is a cell surface glycoprotein attached to the outer leaflet of the plasma membrane by a glycosyl-phosphatidyl-inositol (GPI anchor. Specifically, it is associated with lipid rafts, membrane microdomains enriched in cholesterol and sphinoglipids. It has been established that inhibition of endogenous cholesterol synthesis disturbs lipid raft association of PrPC and prevents PrPSc accumulation in neuronal cells. Additionally, prion conversion is reduced upon interference with cellular cholesterol uptake, endosomal export, or complexation at the plasma membrane. Altogether, these results demonstrate on the one hand the importance of cholesterol for prion propagation. On the other hand, growing evidence suggests that prion infection modulates neuronal cholesterol metabolism. Similar results were reported in Alzheimer’s disease (AD: whereas amyloid β peptide formation is influenced by cellular cholesterol, levels of cholesterol in the brains of affected individuals increase during the clinical course of the disease. In this review, we summarize commonalities of alterations in cholesterol homeostasis and discuss consequences for neuronal function and therapy of prion diseases and AD.

Vitamin D and Alzheimer’s Disease: Neurocognition to Therapeutics

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Anindita Banerjee

2015-01-01

Full Text Available Alzheimer’s disease (AD, the major cause of dementia worldwide, is characterized by progressive loss of memory and cognition. The sporadic form of AD accounts for nearly 90% of the patients developing this disease. The last century has witnessed significant research to identify various mechanisms and risk factors contributing to the complex etiopathogenesis of AD by analyzing postmortem AD brains and experimenting with animal and cell culture based models. However, the treatment strategies, as of now, are only symptomatic. Accumulating evidences suggested a significant association between vitamin D deficiency, dementia, and AD. This review encompasses the beneficial role of vitamin D in neurocognition and optimal brain health along with epidemiological evidence of the high prevalence of hypovitaminosis D among aged and AD population. Moreover, disrupted signaling, altered utilization of vitamin D, and polymorphisms of several related genes including vitamin D receptor (VDR also predispose to AD or AD-like neurodegeneration. This review explores the relationship between this gene-environmental influence and long term vitamin D deficiency as a risk factor for development of sporadic AD along with the role and rationale of therapeutic trials with vitamin D. It is, therefore, urgently warranted to further establish the role of this potentially neuroprotective vitamin in preventing and halting progressive neurodegeneration in AD patients.

‘Alzheimer’s Progression Score’: Development of a Biomarker Summary Outcome for AD Prevention Trials

Science.gov (United States)

Leoutsakos, J.-M.; Gross, A.L.; Jones, R.N.; Albert, M.S.; Breitner, J.C.S.

2017-01-01

BACKGROUND Alzheimer’s disease (AD) prevention research requires methods for measurement of disease progression not yet revealed by symptoms. Preferably, such measurement should encompass multiple disease markers. OBJECTIVES Evaluate an item response theory (IRT) model-based latent variable Alzheimer Progression Score (APS) that uses multi-modal disease markers to estimate pre-clinical disease progression. DESIGN Estimate APS scores in the BIOCARD observational study, and in the parallel PREVENT-AD Cohort and its sister INTREPAD placebo-controlled prevention trial. Use BIOCARD data to evaluate whether baseline and early APS trajectory predict later progression to MCI/dementia. Similarly, use longitudinal PREVENT-AD data to assess test measurement invariance over time. Further, assess portability of the PREVENT-AD IRT model to baseline INTREPAD data, and explore model changes when CSF markers are added or withdrawn. SETTING BIOCARD was established in 1995 and participants were followed up to 20 years in Baltimore, USA. The PREVENT-AD and INTREPAD trial cohorts were established between 2011–2015 in Montreal, Canada, using nearly identical entry criteria to enroll high-risk cognitively normal persons aged 60+ then followed for several years. PARTICIPANTS 349 cognitively normal, primarily middle-aged participants in BIOCARD, 125 high-risk participants aged 60+ in PREVENT-AD, and 217 similar subjects in INTREPAD. 106 INTREPAD participants donated up to four serial CSF samples. MEASUREMENTS Global cognitive assessment and multiple structural, functional, and diffusion MRI metrics, sensori-neural tests, and CSF concentrations of tau, Aβ42 and their ratio. RESULTS Both baseline values and early slope of APS scores in BIOCARD predicted later progression to MCI or AD. Presence of CSF variables strongly improved such prediction. A similarly derived APS in PREVENT-AD showed measurement invariance over time and portability to the parallel INTREPAD sample. CONCLUSIONS An

Regulation of sorLA in general and in Alzheimer's disease

DEFF Research Database (Denmark)

Andersen, Olav Michael; Poulsen, Annemarie Svane Aavild; Zole, Egija

Background: The Sortillin-related receptor (sorLA) is involved in cellular trafficking and processing of the Amyloid precursor protein (APP). A decrease in sorLA expression has been identified in brain tissue from patients suffering from Alzheimer's disease (AD), suggesting that sorLA may be a key...... tissue from patients with Alzheimer's disease. Conclusions: We have investigated the regulation of sorLA expression and identified several cis - and trans -regulatory elements important for the proper expression of sorLA. These studies may help to elucidate the mechanisms underlying the observ ed down...... regulation of sorLA and the linkage to disease onset of SORL1 SNPs in AD patients....

AdS Black Hole with Phantom Scalar Field

Directory of Open Access Journals (Sweden)

Limei Zhang

2017-01-01

Full Text Available We present an AdS black hole solution with Ricci flat horizon in Einstein-phantom scalar theory. The phantom scalar fields just depend on the transverse coordinates x and y, which are parameterized by the parameter α. We study the thermodynamics of the AdS phantom black hole. Although its horizon is a Ricci flat Euclidean space, we find that the thermodynamical properties of the black hole solution are qualitatively the same as those of AdS Schwarzschild black hole. Namely, there exists a minimal temperature and the large black hole is thermodynamically stable, while the smaller one is unstable, so there is a so-called Hawking-Page phase transition between the large black hole and the thermal gas solution in the AdS space-time in Poincare coordinates. We also calculate the entanglement entropy for a strip geometry dual to the AdS phantom black holes and find that the behavior of the entanglement entropy is qualitatively the same as that of the black hole thermodynamical entropy.

Universal regularization prescription for Lovelock AdS gravity

International Nuclear Information System (INIS)

Kofinas, Georgios; Olea, Rodrigo

2007-01-01

A definite form for the boundary term that produces the finiteness of both the conserved quantities and Euclidean action for any Lovelock gravity with AdS asymptotics is presented. This prescription merely tells even from odd bulk dimensions, regardless the particular theory considered, what is valid even for Einstein-Hilbert and Einstein-Gauss-Bonnet AdS gravity. The boundary term is a given polynomial of the boundary extrinsic and intrinsic curvatures (also referred to as Kounterterms series). Only the coupling constant of the boundary term changes accordingly, such that it always preserves a well-posed variational principle for boundary conditions suitable for asymptotically AdS spaces. The background-independent conserved charges associated to asymptotic symmetries are found. In odd bulk dimensions, this regularization produces a generalized formula for the vacuum energy in Lovelock AdS gravity. The standard entropy for asymptotically AdS black holes is recovered directly from the regularization of the Euclidean action, and not only from the first law of thermodynamics associated to the conserved quantities

High prevalence of systemic autoimmune diseases in patients with Menière's disease.

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Irene Gazquez

Full Text Available BACKGROUND: Autoimmunity appears to be associated with the pathophysiology of Meniere's disease (MD, an inner ear disorder characterized by episodes of vertigo associated with hearing loss and tinnitus. However, the prevalence of autoimmune diseases (AD in patients with MD has not been studied in individuals with uni or bilateral sensorineural hearing loss (SNHL. METHODS AND FINDINGS: We estimated the prevalence of AD in 690 outpatients with MD with uni or bilateral SNHL from otoneurology clinics at six tertiary referral hospitals by using clinica criteria and an immune panel (lymphocyte populations, antinuclear antibodies, C3, C4 and proinflammatory cytokines TNFα, INFγ. The observed prevalence of rheumatoid arthritis (RA, systemic lupus erythematosus (SLE and ankylosing spondylitis (AS was higher than expected for the general population (1.39 for RA, 0.87 for SLE and 0.70 for AS, respectively. Systemic AD were more frequently observed in patients with MD and diagnostic criteria for migraine than cases with MD and tension-type headache (p = 0.007. There were clinical differences between patients with uni or bilateral SNHL, but no differences were found in the immune profile. Multiple linear regression showed that changes in lymphocytes subpopulations were associated with hearing loss and persistence of vertigo, suggesting a role for the immune response in MD. CONCLUSIONS: Despite some limitations, MD displays an elevated prevalence of systemic AD such as RA, SLE and AS. This finding, which suggests an autoimmune background in a subset of patients with MD, has important implications for the treatment of MD.

AdS Branes from Partial Breaking of Superconformal Symmetries

International Nuclear Information System (INIS)

Ivanov, E.A.

2005-01-01

It is shown how the static-gauge world-volume superfield actions of diverse superbranes on the AdS d+1 superbackgrounds can be systematically derived from nonlinear realizations of the appropriate AdS supersymmetries. The latter are treated as superconformal symmetries of flat Minkowski superspaces of the bosonic dimension d. Examples include the N = 1 AdS 4 supermembrane, which is associated with the 1/2 partial breaking of the OSp(1|4) supersymmetry down to the N = 1, d = 3 Poincare supersymmetry, and the T-duality related L3-brane on AdS 5 and scalar 3-brane on AdS 5 x S 1 , which are associated with two different patterns of 1/2 breaking of the SU(2, 2|1) supersymmetry. Another (closely related) topic is the AdS/CFT equivalence transformation. It maps the world-volume actions of the codimension-one AdS d+1 (super)branes onto the actions of the appropriate Minkowski (super)conformal field theories in the dimension d

Sex differences in chronic stress responses and Alzheimer's disease.

Science.gov (United States)

Yan, Yan; Dominguez, Sky; Fisher, Daniel W; Dong, Hongxin

2018-02-01

Clinical studies indicate that Alzheimer's disease (AD) disproportionately affects women in both disease prevalence and severity, but the mechanisms underlying this sex divergence are unknown. Though some have suggested this difference in risk is a reflection of known differences in longevity between men and women, mounting clinical and preclinical evidence supports women also having intrinsic susceptibilities towards the disease. While a number of potential risk factors have been hypothesized to affect these differences in risks, none have been definitively verified. In this review, we discuss a novel hypothesis whereby women's susceptibility to chronic stress also mediates increased risk for AD. As stress is a risk factor for AD, and women are twice as likely to develop mood disorders where stress is a major etiology, it is possible that sex dimorphisms in stress responses contribute to the increase in women with AD. In line with this, sex divergence in biochemical responses to stress have been noted along the hypothalamic-pituitary-adrenal (HPA) axis and among known molecular effectors of AD, with crosstalk between these processes also being likely. In addition, activation of the cortical corticotrophin-releasing factor receptor 1 (CRF1) signaling pathway leads to distinct female-biased increases in molecules associated with AD pathogenesis. Therefore, the different biochemical responses to stress between women and men may represent an intrinsic, sex-dependent risk factor for AD.

Comparing Clinical Profiles in Alzheimer's Disease and Parkinson's Disease Dementia

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Martin R. Farlow

2013-09-01

Full Text Available Background: Greater understanding of differences in baseline impairment and disease progression in patients with Alzheimer's disease (AD and Parkinson's disease dementia (PDD may improve the interpretation of drug effects and the design of future studies. Methods: This was a retrospective analysis of three randomized, double-blind rivastigmine databases (one in PDD, two in AD. Impairment on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog, Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL scale, 10-item Neuropsychiatric Inventory (NPI-10 and the ADCS-Clinical Global Impression of Change (CGIC was compared [standardized difference (Cohen's d, similar if Results: Patients with AD or PDD had similar levels of impairment on the ADAS-cog and NPI-10. Scores on the ADCS-ADL scale (standardized difference = 0.47 and the ADAS-cog memory domain (total, 0.33; items, 0.10-0.58 were higher in AD; PDD patients were more impaired in the language (0.23 and praxis (0.34 domains. AD patients receiving placebo showed greater deterioration on the ADAS-cog (0.14 and improvement on the NPI-10 (0.11 compared with patients with PDD. Conclusion: Differing patterns of impairment occur in AD and PDD.

Comparing clinical profiles in Alzheimer's disease and Parkinson's disease dementia.

Science.gov (United States)

Farlow, Martin R; Schmitt, Frederick; Aarsland, Dag; Grossberg, George T; Somogyi, Monique; Meng, Xiangyi

2013-01-01

Greater understanding of differences in baseline impairment and disease progression in patients with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) may improve the interpretation of drug effects and the design of future studies. This was a retrospective analysis of three randomized, double-blind rivastigmine databases (one in PDD, two in AD). Impairment on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, 10-item Neuropsychiatric Inventory (NPI-10) and the ADCS-Clinical Global Impression of Change (CGIC) was compared [standardized difference (Cohen's d), similar if <0.1]. Patients with AD or PDD had similar levels of impairment on the ADAS-cog and NPI-10. Scores on the ADCS-ADL scale (standardized difference = 0.47) and the ADAS-cog memory domain (total, 0.33; items, 0.10-0.58) were higher in AD; PDD patients were more impaired in the language (0.23) and praxis (0.34) domains. AD patients receiving placebo showed greater deterioration on the ADAS-cog (0.14) and improvement on the NPI-10 (0.11) compared with patients with PDD. Differing patterns of impairment occur in AD and PDD.

Alzheimer's disease and intelligence.

Science.gov (United States)

Yeo, R A; Arden, R; Jung, R E

2011-06-01

A significant body of evidence has accumulated suggesting that individual variation in intellectual ability, whether assessed directly by intelligence tests or indirectly through proxy measures, is related to risk of developing Alzheimer's disease (AD) in later life. Important questions remain unanswered, however, such as the specificity of risk for AD vs. other forms of dementia, and the specific links between premorbid intelligence and development of the neuropathology characteristic of AD. Lower premorbid intelligence has also emerged as a risk factor for greater mortality across myriad health and mental health diagnoses. Genetic covariance contributes importantly to these associations, and pleiotropic genetic effects may impact diverse organ systems through similar processes, including inefficient design and oxidative stress. Through such processes, the genetic underpinnings of intelligence, specifically, mutation load, may also increase the risk of developing AD. We discuss how specific neurobiologic features of relatively lower premorbid intelligence, including reduced metabolic efficiency, may facilitate the development of AD neuropathology. The cognitive reserve hypothesis, the most widely accepted account of the intelligence-AD association, is reviewed in the context of this larger literature.

AdS2 models in an embedding superspace

International Nuclear Information System (INIS)

McKeon, D.G.C.; Sherry, T.N.

2003-01-01

An embedding superspace, whose bosonic part is the flat (2+1)-dimensional embedding space for AdS 2 , is introduced. Superfields and several supersymmetric models are examined in the embedded AdS 2 superspace

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...

AdS. Klein-Gordon equation

OpenAIRE

Bel, Ll.

2014-01-01

I propose a generalization of the Klein-Gordon equation in the framework of AdS space-time and exhibit a four parameter family of solutions among which there is a two parameter family of time-dependent bound states.

Exploring the Association between Alzheimer’s Disease, Oral Health, Microbial Endocrinology and Nutrition

OpenAIRE

Harding, Alice; Gonder, Ulrike; Robinson, Sarita J.; Crean, StJohn; Singhrao, Sim K.

2017-01-01

Longitudinal monitoring of patients suggests a causal link between chronic periodontitis and the development of Alzheimer’s disease (AD). However, the explanation of how periodontitis can lead to dementia remains unclear. A working hypothesis links extrinsic inflammation as a secondary cause of AD. This hypothesis suggests a compromised oral hygiene leads to a dysbiotic oral microbiome whereby Porphyromonas gingivalis, a keystone periodontal pathogen, with its companion species, orchestrates ...

Baby Skyrmions in AdS

Energy Technology Data Exchange (ETDEWEB)

Elliot-Ripley, Matthew; Winyard, Thomas [Department of Mathematical Sciences, Durham University,South Rd, Durham (United Kingdom)

2015-09-01

We study the baby Skyrme model in a pure AdS background without a mass term. The tail decays and scalings of massless radial solutions are demonstrated to take a similar form to those of the massive flat space model, with the AdS curvature playing a similar role to the flat space pion mass. We also numerically find minimal energy solutions for a range of higher topological charges and find that they form concentric ring-like solutions. Popcorn transitions (named in analogy with studies of toy models of holographic QCD) from an n layer to an n+1-layer configuration are observed at topological charges 9 and 27 and further popcorn transitions for higher charges are predicted. Finally, a point-particle approximation for the model is derived and used to successfully predict the ring structures and popcorn transitions for higher charge solitons.

Diabetes Mellitus Induces Alzheimer’s Disease Pathology: Histopathological Evidence from Animal Models

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Nobuyuki Kimura

2016-04-01

Full Text Available Alzheimer’s disease (AD is the major causative disease of dementia and is characterized pathologically by the accumulation of senile plaques (SPs and neurofibrillary tangles (NFTs in the brain. Although genetic studies show that β-amyloid protein (Aβ, the major component of SPs, is the key factor underlying AD pathogenesis, it remains unclear why advanced age often leads to AD. Interestingly, several epidemiological and clinical studies show that type II diabetes mellitus (DM patients are more likely to exhibit increased susceptibility to AD. Moreover, growing evidence suggests that there are several connections between the neuropathology that underlies AD and DM, and there is evidence that the experimental induction of DM can cause cognitive dysfunction, even in rodent animal models. This mini-review summarizes histopathological evidence that DM induces AD pathology in animal models and discusses the possibility that aberrant insulin signaling is a key factor in the induction of AD pathology.

Meta-analysis of crowdsourced data compendia suggests pan-disease transcriptional signatures of autoimmunity [version 1; referees: 2 approved

Directory of Open Access Journals (Sweden)

William W. Lau

2016-12-01

Full Text Available Background: The proliferation of publicly accessible large-scale biological data together with increasing availability of bioinformatics tools have the potential to transform biomedical research. Here we report a crowdsourcing Jamboree that explored whether a team of volunteer biologists without formal bioinformatics training could use OMiCC, a crowdsourcing web platform that facilitates the reuse and (meta- analysis of public gene expression data, to compile and annotate gene expression data, and design comparisons between disease and control sample groups. Methods: The Jamboree focused on several common human autoimmune diseases, including systemic lupus erythematosus (SLE, multiple sclerosis (MS, type I diabetes (DM1, and rheumatoid arthritis (RA, and the corresponding mouse models. Meta-analyses were performed in OMiCC using comparisons constructed by the participants to identify 1 gene expression signatures for each disease (disease versus healthy controls at the gene expression and biological pathway levels, 2 conserved signatures across all diseases within each species (pan-disease signatures, and 3 conserved signatures between species for each disease and across all diseases (cross-species signatures. Results: A large number of differentially expressed genes were identified for each disease based on meta-analysis, with observed overlap among diseases both within and across species. Gene set/pathway enrichment of upregulated genes suggested conserved signatures (e.g., interferon across all human and mouse conditions. Conclusions: Our Jamboree exercise provides evidence that when enabled by appropriate tools, a "crowd" of biologists can work together to accelerate the pace by which the increasingly large amounts of public data can be reused and meta-analyzed for generating and testing hypotheses. Our encouraging experience suggests that a similar crowdsourcing approach can be used to explore other biological questions.

Brain correlates of performance in a free/cued recall task with semantic encoding in Alzheimer disease.

Science.gov (United States)

Lekeu, Françoise; Van der Linden, Martial; Chicherio, Christian; Collette, Fabienne; Degueldre, Christian; Franck, Georges; Moonen, Gustave; Salmon, Eric

2003-01-01

The goal of this study was to explore in patients with Alzheimer's disease (AD) the brain correlates of free and cued recall performance using an adaptation of the procedure developed by Grober and Buschke (1987). This procedure, which ensures semantic processing and coordinates encoding and retrieval, has been shown to be very sensitive to an early diagnosis of AD. Statistical parametric mapping (SPM 99) was used to establish clinicometabolic correlations between performance at free and cued verbal recall and resting brain metabolism in 31 patients with AD. Results showed that patient's score on free recall correlated with metabolic activity in right frontal regions (BA 10 and BA 45), suggesting that performance reflected a strategic retrieval attempt. Poor retrieval performance was tentatively attributed to a loss of functional correlation between frontal and medial temporal regions in patients with AD compared with elderly controls. Performance on cued recall was correlated to residual metabolic activity in bilateral parahippocampal regions (BA 36), suggesting that performance reflected retrieval of semantic associations, without recollection in AD. In conclusion, this study demonstrates that the diagnostic sensitivity for Alzheimer's disease of the cued recall performance in the Grober and Buschke procedure (1987) depends on the activity of parahippocampal regions, one of the earliest targets of the disease. Moreover, the results suggest that the poor performance of patients with AD during free and cued recall is related to a decreased connectivity between parahippocampal regions and frontal areas.

Investigating the genetic relationship between Alzheimer’s disease and cancer using GWAS summary statistics

NARCIS (Netherlands)

Feng, Yen Chen Anne; Cho, Kelly; Lindstrom, Sara; Kraft, Peter; Cormack, Jean; Blalock, Kendra; Campbell, Peter T.; Casey, Graham; Conti, David V.; Edlund, Christopher K.; Figueiredo, Jane; James Gauderman, W.; Gong, Jian; Green, Roger C.; Gruber, Stephen B.; Harju, John F.; Harrison, Tabitha A.; Jacobs, Eric J; Jenkins, Mark A.; Jiao, Shuo; Li, Li; Lin, Yi; Manion, Frank J.; Moreno, Victor; Mukherjee, Bhramar; Peters, Ulrike; Raskin, Leon; Schumacher, Fredrick R.; Seminara, Daniela; Severi, Gianluca; Stenzel, Stephanie L.; Thomas, Duncan C.; Hopper, John L.; Southey, Melissa C.; Makalic, Enes; Schmidt, Daniel F.; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; Dos-Santos-Silva, Isabel; Hunter, David J.; Lindström, Sara; Kraft, Peter; Ahsan, Habib; Whittemore, Alice S.; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel A.; van der Luijt, Rob B.; Uitterlinden, Andre G; Hofman, Albert; Meindl, Alfons; Schmutzler, Rita K.; Müller-Myhsok, Bertram; Lichtner, Peter; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Chang-Claude, Jenny; Hein, Rebecca; Dahmen, Norbert; Beckman, Lars; Crisponi, Laura; Hall, Per; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Easton, Douglas F.; Turnbull, Clare A.; Rahman, Nazneen; Kote-Jarai, Zsofia; Muir, Kenneth; Giles, Graham G.; Severi, Gianluca; Neal, David E.; Donovan, Jenny L.; Hamdy, Freddie C.; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher; Schumacher, Fred; Travis, Ruth C.; Riboli, Elio; Kraft, Peter; Hunter, David J.; Gapstur, Susan M.; Berndt, Sonja I.; Chanock, Stephen J.; Han, Younghun; Su, Li; Wei, Yongyue; Hung, Rayjean J.; Brhane, Yonathan; McLaughlin, John; Brennan, Paul; McKay, James D.; Bickeböller, Heike; Rosenberger, Albert; Houlston, Richard S.; Caporaso, Neil E; Landi, Maria Teresa; Heinrich, Joachim; Risch, Angela; Wu, Xifeng; Ye, Yuanqing; Christiani, David C.; Amos, Christopher I; Liang, Liming; Driver, Jane A.; IGAP Consortium, Colorectal Transdisciplinary Study (CORECT); Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE)

2017-01-01

Growing evidence from both epidemiology and basic science suggest an inverse association between Alzheimer’s disease (AD) and cancer. We examined the genetic relationship between AD and various cancer types using GWAS summary statistics from the IGAP and GAME-ON consortia. Sample size ranged from

Wess-Zumino terms for AdS D-branes

International Nuclear Information System (INIS)

Hatsuda, Machiko; Kamimura, Kiyoshi

2004-01-01

We show that Wess-Zumino terms for Dp branes with p>0 in the anti-de Sitter (AdS) space are given in terms of 'left-invariant' currents on the super-AdS group or the 'expanded' super-AdS group. As a result there is no topological extension of the super-AdS algebra. In the flat limit the global Lorentz rotational charges of the AdS space turn out to be brane charges of the supertranslation algebra representing the BPS mass. We also show that a D-instanton is described by the GL(1) degree of freedom in the Roiban-Siegel formalism based on the GL(4 vertical bar 4)/[Sp(4)xGL(1)]2 coset

Voluntary imitation in Alzheimer’s disease patients

Directory of Open Access Journals (Sweden)

Ambra eBisio

2016-03-01

Full Text Available Although Alzheimer's disease (AD primarily manifests as cognitive deficits, the implicit sensorimotor processes that underlie social interactions, such as automatic imitation, seem to be preserved in mild and moderate stages of the disease, as is the ability to communicate with other persons. Nevertheless, when AD patients face more challenging tasks, which do not rely on automatic processes but on explicit voluntary mechanisms and require the patient to pay attention to external events, the cognitive deficits resulting from the disease might negatively affect patients’ behaviour. The aim of the present study was to investigate whether voluntary motor imitation, i.e. a volitional mechanism that involves observing another person’s action and translating this perception into one’s own action, was affected in patients with Alzheimer’s disease. Further, we tested whether this ability was modulated by the nature of the observed stimulus by comparing the ability to reproduce the kinematic features of a human demonstrator with that of a computerized-stimulus. AD patients showed an intact ability to reproduce the velocity of the observed movements, particularly when the stimulus was a human agent. This result suggests that high-level cognitive processes involved in voluntary imitation might be preserved in mild and moderate stages of AD and that voluntary imitation abilities might benefit from the implicit interpersonal communication established between the patient and the human demonstrator.

Progress in studies of the reciprocal interaction between sleep disorders and Alzheimer's disease

Directory of Open Access Journals (Sweden)

LIU Zhen-yu

2013-06-01

Full Text Available Alzheimer's disease (AD is a common neurodegenerative disease in the elderly, and is the most common cause of dementia. Epidemiological studies have discovered that, 44% of patients with AD are associated with sleep disorders and (or circadian rhythm disorders. Now there are growing evidences indicating that interstitial fluid amyloid-β protein (A β levels exhibit circadian rhythm fluctuation, and sleep disorders will accelerate the process of Aβ deposition, which may act as a risk factor of AD, suggesting the possible reciprocal interaction between sleep disorders and AD. The mechanism is not yet completely clear. Sleep disorders may be related with the impairments of both sleep-wake regulating system, circadian rhythm regulating system and the change of zeitgeber in AD. Sleep disorders would affect neuronal activity, neurotransmitter secretion, and as a stressor affecting A β processing and metabolism, thus accelerate the pathological process of AD. This paper reviewed the progress in the studies of reciprocal interaction between sleep disorders and Alzheimer's disease and the possible mechanisms.

Voluntary Imitation in Alzheimer’s Disease Patients

Science.gov (United States)

Bisio, Ambra; Casteran, Matthieu; Ballay, Yves; Manckoundia, Patrick; Mourey, France; Pozzo, Thierry

2016-01-01

Although Alzheimer’s disease (AD) primarily manifests as cognitive deficits, the implicit sensorimotor processes that underlie social interactions, such as automatic imitation, seem to be preserved in mild and moderate stages of the disease, as is the ability to communicate with other persons. Nevertheless, when AD patients face more challenging tasks, which do not rely on automatic processes but on explicit voluntary mechanisms and require the patient to pay attention to external events, the cognitive deficits resulting from the disease might negatively affect patients’ behavior. The aim of the present study was to investigate whether voluntary motor imitation, i.e., a volitional mechanism that involves observing another person’s action and translating this perception into one’s own action, was affected in patients with AD. Further, we tested whether this ability was modulated by the nature of the observed stimulus by comparing the ability to reproduce the kinematic features of a human demonstrator with that of a computerized-stimulus. AD patients showed an intact ability to reproduce the velocity of the observed movements, particularly when the stimulus was a human agent. This result suggests that high-level cognitive processes involved in voluntary imitation might be preserved in mild and moderate stages of AD and that voluntary imitation abilities might benefit from the implicit interpersonal communication established between the patient and the human demonstrator. PMID:27014056

Dancing in the dark? The status of late-onset Alzheimer's disease genetics.

Science.gov (United States)

Bertram, L; Tanzi, R E

2001-10-01

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. Recent estimates suggest that possibly over 70% of the genetic variance for the disease remains unaccounted for by apolipoprotein E (APOE) and the three known early-onset AD genes (APP, PSEN1, PSEN2). Specifically, one recent segregation analysis predicted the existence of up to four additional susceptibility genes having a similar or greater effect than APOE. However, most of the nearly three dozen putative AD loci proposed to date have only been inconsistently replicated in follow up analyses and more studies are necessary to distinguish false-positive findings from genuine signals. Novel AD genes will not only provide valuable clues for the development of novel therapeutic approaches, but will also allow the development of new genetic risk-profiling strategies that are an essential prerequisite for early prediction/prevention of this devastating disease. In this review, we will present a brief overview of analytic tools in complex disease genetics, as well as a summary of recent linkage and association findings indicating the existence of novel late-onset AD genes on chromosomes 12, 10, and 9.

De novo development of artistic creativity in Alzheimer's disease.

Science.gov (United States)

Chakravarty, Ambar

2011-10-01

The case of an 82-year-old female with probable Alzheimer's disease (AD), who developed unusual artistic creativity after development of her disease, is described. The possible pathogenetic mechanism is discussed. The patient showed no inclination toward visual arts during her premorbid years. However, 4 years after development of AD suggestive symptoms she started painting beautiful pictures rather impulsively. Some such paintings have been appreciated even by a qualified art expert. Such de novo development of artistic creativity had been described earlier in subjects with the semantic form of fronto-temporal dementia (FTD), but not in AD. The prevailing concept of lateralized compromise and paradoxical functional facilitation, proposed in connection with FTD subjects, may not be applicable in AD subjects where the affection is more diffuse and more posterior in the brain. Hence, the likely pathogenetic mechanism involved in the case described may remain uncertain. Possibilities are discussed.

Quinoa Well Tolerated in Patients with Celiac Disease

Science.gov (United States)

... Maryland (January 21, 2014) – Adding quinoa to the gluten-free diet of patients with celiac disease is well-tolerated, ... grain, is traditionally recommended as part of a gluten-free diet. However, in-vitro data suggests that quinoa storage ...

Nature Versus Nurture: Does Proteostasis Imbalance Underlie the Genetic, Environmental, and Age-Related Risk Factors for Alzheimer's Disease?

Science.gov (United States)

Kikis, Elise A

2017-08-22

Aging is a risk factor for a number of "age-related diseases", including Alzheimer's disease (AD). AD affects more than a third of all people over the age of 85, and is the leading cause of dementia worldwide. Symptoms include forgetfulness, memory loss, and cognitive decline, ultimately resulting in the need for full-time care. While there is no cure for AD, pharmacological approaches to alleviate symptoms and target underlying causes of the disease have been developed, albeit with limited success. This review presents the age-related, genetic, and environmental risk factors for AD and proposes a hypothesis for the mechanistic link between genetics and the environment. In short, much is known about the genetics of early-onset familial AD (EO-FAD) and the central role played by the Aβ peptide and protein misfolding, but late-onset AD (LOAD) is not thought to have direct genetic causes. Nonetheless, genetic risk factors such as isoforms of the protein ApoE have been identified. Additional findings suggest that air pollution caused by the combustion of fossil fuels may be an important environmental risk factor for AD. A hypothesis suggesting that poor air quality might act by disrupting protein folding homeostasis (proteostasis) is presented.

The group approach to AdS space propagators

International Nuclear Information System (INIS)

Leonhardt, Thorsten; Manvelyan, Ruben; Ruehl, Werner

2003-01-01

We show that AdS two-point functions can be obtained by connecting two points in the interior of AdS space with one point on its boundary by a dual pair of Dobrev's boundary-to-bulk intertwiners and integrating over the boundary point

Cognitive and neuropathologic correlates of Stroop Color-Word Test performance in Alzheimer's disease.

Science.gov (United States)

Bondi, Mark W; Serody, Adam B; Chan, Agnes S; Eberson-Shumate, Sonja C; Delis, Dean C; Hansen, Lawrence A; Salmon, David P

2002-07-01

The Stroop Color-Word Test (SCWT; C. Golden, 1978) was examined in 59 patients with probable Alzheimer's disease (AD) and in 51 demographically comparable normal control (NC) participants. AD patients produced significantly larger Stroop interference effects than NC participants, and level of dementia severity significantly influenced SCWT performance. Principal-components analyses demonstrated a dissociation in the factor structure of the Stroop trials between NC participants and AD patients, suggesting that disruption of semantic knowledge and speeded verbal processing in AD may be a major contributor to impairment on the incongruent trial. Results of clinicopathologic correlations in an autopsy-confirmed AD subgroup further suggest the invocation of a broad network of integrated cortical regions and executive and language processes underlying successful SCWT performance.

Elevated Serum Pesticide Levels and Risk for Alzheimer Disease

Science.gov (United States)

Richardson, Jason R.; Roy, Ananya; Shalat, Stuart L.; von Stein, Richard T.; Hossain, Muhammad M.; Buckley, Brian; Gearing, Marla; Levey, Allan I.; German, Dwight C.

2014-01-01

IMPORTANCE The causes of late-onset Alzheimer disease (AD) are not yet understood but likely include a combination of genetic, environmental, and lifestyle factors. Limited epidemiological studies suggest that occupational pesticide exposures are associated with AD. Previously, we reported that serum levels of dichlorodiphenyldichloroethylene (DDE), the metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were elevated in a small number of patients with AD (n=20). OBJECTIVE To evaluate the association between serum levels of DDE and AD and whether the apolipoprotein E (APOE) genotype modifies the association. DESIGN, SETTING, AND PARTICIPANTS A case-control study consisting of existing samples from patients with AD and control participants from the Emory University Alzheimer’s Disease Research Center and the University of Texas Southwestern Medical School’s Alzheimer’s Disease Center. Serum levels of DDE were measured in 79 control and 86 AD cases. MAIN OUTCOMES AND MEASURES Serum DDE levels, AD diagnosis, severity of AD measured by the Mini-Mental State Examination score, and interaction with APOE4 status. RESULTS Levels of DDE were 3.8-fold higher in the serum of those with AD (mean [SEM], 2.64 [0.35] ng/mg cholesterol) when compared with control participants (mean [SEM], 0.69 [0.1] ng/mg cholesterol; P risk for AD (95% CI, 2.54–5.82; P risk for AD and carriers of an APOE4 ε4 allele may be more susceptible to the effects of DDE. Both DDT and DDE increase amyloid precursor protein levels, providing mechanistic plausibility for the association of DDE exposure with AD. Identifying people who have elevated levels of DDE and carry an APOE ε4 allele may lead to early identification of some cases of AD. PMID:24473795

Serum Hepatocyte Growth Factor Is Associated with Small Vessel Disease in Alzheimer’s Dementia

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Yanan Zhu

2018-01-01

Full Text Available Background: While hepatocyte growth factor (HGF is known to exert cell growth, migration and morphogenic effects in various organs, recent studies suggest that HGF may also play a role in synaptic maintenance and cerebrovascular integrity. Although increased levels of HGF have been reported in brain and cerebrospinal fluid (CSF samples of patients with Alzheimer’s disease (AD, it is unclear whether peripheral HGF may be associated with cerebrovascular disease (CeVD and dementia. In this study, we examined the association of baseline serum HGF with neuroimaging markers of CeVD in a cohort of pre-dementia (cognitive impaired no dementia, CIND and AD patients.Methods: Serum samples from aged, Non-cognitively impaired (NCI controls, CIND and AD subjects were measured for HGF levels. CeVD (cortical infarcts, microinfarcts, lacunes, white matter hyperintensities (WMH and microbleeds were assessed by magnetic resonance imaging (MRI.Results: After controlling for covariates, higher levels of HGF were associated with both CIND and AD. Among the different CeVD MRI markers in CIND and AD, only small vessel disease, but not large vessel disease markers were associated with higher HGF levels.Conclusion: Serum HGF may be a useful peripheral biomarker for small vessel disease in subjects with cognitive impairment and AD.

Acetylcholine esterase activity in mild cognitive impairment and Alzheimer's disease

International Nuclear Information System (INIS)

Herholz, Karl

2008-01-01

Impairment of cholinergic neurotransmission is a well-established fact in Alzheimer's disease (AD), but there is controversy about its relevance at the early stages of the disease and in mild cognitive impairment (MCI). In vivo positron emission tomography imaging of cortical acetylcholine esterase (AChE) activity as a marker of cholinergic innervation that is expressed by cholinergic axons and cholinoceptive neurons has demonstrated a reduction of this enzyme activity in manifest AD. The technique is also useful to measure the inhibition of cerebral AChE induced by cholinesterase inhibitors for treatment of dementia symptoms. A reduction of cortical AchE activity was found consistently in all studies of AD and in few cases of MCI who later concerted to AD. The in vivo findings in MCI and very mild AD are still preliminary, and studies seem to suggest that cholinergic innervation and AChE as the main degrading enzyme are both reduced, which might result in partial compensation of their effect. (orig.)

Generalized Gribov-Lipatov Reciprocity and AdS/CFT

International Nuclear Information System (INIS)

Beccaria, M.; Macorini, G.; Forini, V.

2010-01-01

Planar □=4 SYM theory and QCD share the gluon sector, suggesting the investigation of Gribov-Lipatov reciprocity in the supersymmetric theory. Since the AdS/CFT correspondence links □=4 SYM and superstring dynamics on AdS 5 x S5, reciprocity is also expected to show up in the quantum corrected energies of certain classical string configurations dual to gauge theory twist-operators. We review recent results confirming this picture and revisiting the old idea of Gribov-Lipatov reciprocity as a modern theoretical tool useful for the study of open problems in AdS/CFT.

Comparing Cerebral White Matter Lesion Burdens between Parkinson’s Disease with and without Dementia

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Sun-Ah Choi

2010-05-01

Full Text Available Cerebral white matter lesions (CWMLs have been suggested to be associated with an increased risk of dementia, disability, and death. CWMLs are more common in individuals with Alzheimer’s disease (AD than in normal elderly individuals of comparable age. Only a few studies have been done to determine whether CWMLs may influence cognitive decline in Parkinson’s disease (PD. Fully developed PD with concurrent AD was reported to likely cause impaired cognition in spite of accumulating evidence suggesting that PD with dementia (PDD is more closely associated with Lewy body (LB pathology. Currently, contradictory data on the neuropathology of dementia in PD require further prospective clinicopathological studies in larger cohorts to elucidate the impact of AD and α-synuclein (SCNA pathologies on the cognitive status in these disorders. Previous reports did not suggest CWMLs to be associated with an increased risk of PDD. After adjusting for age at death, age at onset of PD, and duration of PD, our recent study investigating CWMLs in PDD via autopsy has shown a positive correlation between the burden of CWMLs and PDD. The frequent co-existence of both LB and AD lesions suggests that both pathologies independently or synergistically contribute to both movement disorders and cognitive impairment. The individual and cumulative burden of CWMLs, LB lesions, and AD lesions may synergistically contribute to cognitive decline in LB disorders such as PDD.

Aromatase Expression in the Hippocampus of AD Patients and 5xFAD Mice

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Janine Prange-Kiel

2016-01-01

Full Text Available Numerous studies show that 17β-estradiol (E2 protects against Alzheimer’s disease (AD induced neurodegeneration. The E2-synthesizing enzyme aromatase is expressed in healthy hippocampi, but although the hippocampus is severely affected in AD, little is known about the expression of hippocampal aromatase in AD. To better understand the role of hippocampal aromatase in AD, we studied its expression in postmortem material from patients with AD and in a mouse model for AD (5xFAD mice. In human hippocampi, aromatase-immunoreactivity was observed in the vast majority of principal neurons and signal quantification revealed higher expression of aromatase protein in AD patients compared to age- and sex-matched controls. The tissue-specific first exons of aromatase I.f, PII, I.3, and I.6 were detected in hippocampi of controls and AD patients by RT-PCR. In contrast, 3-month-old, female 5xFAD mice showed lower expression of aromatase mRNA and protein (measured by qRT-PCR and semiquantitative immunohistochemistry than WT controls; no such differences were observed in male mice. Our findings stress the importance of hippocampal aromatase expression in neurodegenerative diseases.

The sleep–wake cycle and Alzheimer’s disease: what do we know?

OpenAIRE

Lim, Miranda M.; Gerstner, Jason R.; Holtzman, David M.

2014-01-01

Sleep–wake disturbances are a highly prevalent and often disabling feature of Alzheimer’s disease (AD). A cardinal feature of AD includes the formation of amyloid plaques, associated with the extracellular accumulation of the amyloid-β (Aβ) peptide. Evidence from animal and human studies suggests that Aβ pathology may disrupt the sleep–wake cycle, in that as Aβ accumulates, more sleep–wake fragmentation develops. Furthermore, recent research in animal and human studies suggests that the sleep...

The role of clusterin in Alzheimer's disease: pathways, pathogenesis, and therapy.

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Yu, Jin-Tai; Tan, Lan

2012-04-01

Genetic variation in clusterin gene, also known as apolipoprotein J, has been associated with Alzheimer's disease (AD) through replicated genome-wide studies, and plasma clusterin levels are associated with brain atrophy, baseline prevalence and severity, and rapid clinical progression in patients with AD, highlighting the importance of clusterin in AD pathogenesis. Emerging data suggest that clusterin contributes to AD through various pathways, including amyloid-β aggregation and clearance, lipid metabolism, neuroinflammation, and neuronal cell cycle control and apoptosis. Moreover, epigenetic regulation of the clusterin expression also seems to play an important role in the pathogenesis of AD. Emerging knowledge of the contribution of clusterin to the pathogenesis of AD presents new opportunities for AD therapy.

Graph theoretical analysis and application of fMRI-based brain network in Alzheimer's disease

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LIU Xue-na

2012-08-01

Full Text Available Alzheimer's disease (AD, a progressive neurodegenerative disease, is clinically characterized by impaired memory and many other cognitive functions. However, the pathophysiological mechanisms underlying the disease are not thoroughly understood. In recent years, using functional magnetic resonance imaging (fMRI as well as advanced graph theory based network analysis approach, several studies of patients with AD suggested abnormal topological organization in both global and regional properties of functional brain networks, specifically, as demonstrated by a loss of small-world network characteristics. These studies provide novel insights into the pathophysiological mechanisms of AD and could be helpful in developing imaging biomarkers for disease diagnosis. In this paper we introduce the essential concepts of complex brain networks theory, and review recent advances of the study on human functional brain networks in AD, especially focusing on the graph theoretical analysis of small-world network based on fMRI. We also propound the existent problems and research orientation.

Holographic description of AdS2 black holes

International Nuclear Information System (INIS)

Castro, Alejandra; Larsen, Finn; Grumiller, Daniel; McNees, Robert

2008-01-01

We develop the holographic renormalization of AdS 2 gravity systematically. We find that a bulk Maxwell term necessitates a boundary mass term for the gauge field and verify that this unusual term is invariant under gauge transformations that preserve the boundary conditions. We determine the energy-momentum tensor and the central charge, recovering recent results by Hartman and Strominger. We show that our expressions are consistent with dimensional reduction of the AdS 3 energy-momentum tensor and the Brown-Henneaux central charge. As an application of our results we interpret the entropy of AdS 2 black holes as the ground state entropy of a dual CFT.

Diversity and disparity in dementia: the impact of ethnoracial differences in Alzheimer disease.

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Chin, Alexander L; Negash, Selamawit; Hamilton, Roy

2011-01-01

Debate exists regarding differences in the prevalence of Alzheimer disease (AD) in African Americans and Hispanics in the United States, with some evidence suggesting that the prevalence of AD may be considerably higher in these groups than in non-Hispanic whites. Despite this possible disparity, patients of minority ethnoracial groups often receive delayed diagnosis or inadequate treatment for dementia. This review investigates these disparities by conceptualizing the dementia disease process as a product of both biological and cultural factors. Ethnoracial differences in biological risk factors, such as genetics and cardiovascular disease, may help to explain disparities in the incidence and prevalence of AD, whereas race-specific cultural factors may impact diagnosis and treatment. Cultural factors include differences in perceptions about what is normal aging and what is not, lack of adequate access to medical care, and issues of trust between minority groups and the medical establishment. The diagnosis of AD in diverse populations may also be complicated by racial biases inherent in cognitive screening tools widely used by clinicians, but controlling for literacy level or using savings scores in psychometric analyses has the potential to mitigate these biases. We also suggest that emerging biomarker-based diagnostic tools may be useful in further characterizing diverse populations with AD. Recognizing the gap in communication that exists between minority communities and the medical research community, we propose that education and outreach are a critical next step in the effort to understand AD as it relates to diverse populations.

Morphological and pathological evolution of the brain microcirculation in aging and Alzheimer's disease.

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Jesse M Hunter

Full Text Available Key pathological hallmarks of Alzheimer's disease (AD, including amyloid plaques, cerebral amyloid angiopathy (CAA and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1 nonagenarians with AD and a high amyloid plaque load; 2 nonagenarians with no dementia and a high amyloid plaque load; 3 nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND group (average age 71 years with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular "dysfunction" compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD.

Comparison of a Mirror Neuron System among Elders with Mild Cognitive Impairment, Alzheimer's Disease, and No Disease

International Nuclear Information System (INIS)

Rattanachayoto, P.; Tritanon, O.; Laothamatas, J.; Sungkarat, W.

2012-01-01

Alzheimer's disease (AD) is the most common cause of dementia. There are lots of old people suffering from the disease. Mild cognitive impairment (MCI) is a transitional state between normal aging and dementia. An individual with MCI has an increased risk of developing AD. The mirror neuron system (MNS), activated during the observation and execution of actions, has been linked with cognitive processes.The objective of this study is to examine the MNS abnormalities in elders with MCI and AD. Ninety-two subjects (5 MCI,7 mild AD, and 80 cognitively normal) were studied by using functional magnetic resonance imaging (fMRI). In the fMRI experiment, subjects were asked to observe a video showing hand movement (tearing a piece of paper) and a control condition (observing a fixation point).The image data were analyzed using SPM2 (Statistical Parametric Mapping).There were significant activations of bilateral inferior frontal lobule and inferior parietal lobule due to the observation of hand movement.The brain activations of the normal group were statistical significant greater than those in the MCI and mild AD groups.There was no significant difference between the MCI and mild AD groups. Elders with MCI and mild AD had fewer MNS activations than the normal controls, suggesting that the dysfunction of MNS may underlie cognitive impairments in MCI and AD patients.These findings imply that fMRI is sufficiently sensitive to detect MNS changes occurring in MCI and AD.

Light-cone AdS/CFT-adapted approach to AdS fields/currents, shadows, and conformal fields

Energy Technology Data Exchange (ETDEWEB)

Metsaev, R.R. [Department of Theoretical Physics, P.N. Lebedev Physical Institute, Leninsky prospect 53, Moscow 119991 (Russian Federation)

2015-10-16

Light-cone gauge formulation of fields in AdS space and conformal field theory in flat space adapted for the study of AdS/CFT correspondence is developed. Arbitrary spin mixed-symmetry fields in AdS space and arbitrary spin mixed-symmetry currents, shadows, and conformal fields in flat space are considered on an equal footing. For the massless and massive fields in AdS and the conformal fields in flat space, simple light-cone gauge actions leading to decoupled equations of motion are found. For the currents and shadows, simple expressions for all 2-point functions are also found. We demonstrate that representation of conformal algebra generators on space of currents, shadows, and conformal fields can be built in terms of spin operators entering the light-cone gauge formulation of AdS fields. This considerably simplifies the study of AdS/CFT correspondence. Light-cone gauge actions for totally symmetric arbitrary spin long conformal fields in flat space are presented. We apply our approach to the study of totally antisymmetric (one-column) and mixed-symmetry (two-column) fields in AdS space and currents, shadows, and conformal fields in flat space.

MR enterography: how to deliver added value

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Dillman, Jonathan R.; Trout, Andrew T.; Smith, Ethan A.

2016-01-01

MR enterography (MRE) is increasingly vital to the diagnosis and follow-up of children with Crohn disease. This diagnostic test, which can provide valuable information regarding the presence of intestinal inflammation, intestinal and intra-abdominal complications, and extra-intestinal disease-related manifestations, has the potential to directly impact both medical and surgical decision-making. Consequently, it is imperative that the interpretation and reporting of these examinations provide as much clinical information as possible. This article reviews specific ways radiologists can provide added value when interpreting MRE examinations in the setting of pediatric Crohn disease by (1) establishing the true extent of disease involvement, (2) subjectively and objectively assessing response to medical treatment and (3) accurately characterizing disease-related complications. (orig.)

Voluntary exercise confers protection against age-related deficits in brain oxygenation in awake mice model of Alzheimer's disease

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Lu, Xuecong; Moeini, Mohammad; Li, Baoqiang; Sakadžić, Sava; Lesage, Frédéric

2018-02-01

Alzheimer's disease (AD) is a neurodegenerative disease characterized by short-term memory loss and cognitive inabilities. This work seeks to study the effects of voluntary exercise on the change in oxygen delivery in awake mice models of Alzheimer's disease by monitoring brain tissue oxygenation. Experiments were performed on Young (AD_Y, 3-4 months, n=8), Old (AD_O, 6-7 months, n=8), and Old with exercise (AD_OEX, 6-7 months, n=8) transgenic APPPS1 mice and their controls. Brain tissue oxygenation was measured by two photon phosphorescence lifetime microscopy on the left sensory motor cortex. We found that the average tissue PO2 decreased with age but were regulated by exercise. The results suggest a potential for exercise to improve brain function with age and AD.

Astrocytes in physiological aging and Alzheimer's disease.

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Rodríguez-Arellano, J J; Parpura, V; Zorec, R; Verkhratsky, A

2016-05-26

Astrocytes are fundamental for homoeostasis, defence and regeneration of the central nervous system. Loss of astroglial function and astroglial reactivity contributes to the aging of the brain and to neurodegenerative diseases. Changes in astroglia in aging and neurodegeneration are highly heterogeneous and region-specific. In animal models of Alzheimer's disease (AD) astrocytes undergo degeneration and atrophy at the early stages of pathological progression, which possibly may alter the homeostatic reserve of the brain and contribute to early cognitive deficits. At later stages of AD reactive astrocytes are associated with neurite plaques, the feature commonly found in animal models and in human diseased tissue. In animal models of the AD reactive astrogliosis develops in some (e.g. in the hippocampus) but not in all regions of the brain. For instance, in entorhinal and prefrontal cortices astrocytes do not mount gliotic response to emerging β-amyloid deposits. These deficits in reactivity coincide with higher vulnerability of these regions to AD-type pathology. Astroglial morphology and function can be regulated through environmental stimulation and/or medication suggesting that astrocytes can be regarded as a target for therapies aimed at the prevention and cure of neurodegenerative disorders. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity.

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Kanae Ando

2016-03-01

Full Text Available Abnormal accumulation of the microtubule-interacting protein tau is associated with neurodegenerative diseases including Alzheimer's disease (AD. β-amyloid (Aβ lies upstream of abnormal tau behavior, including detachment from microtubules, phosphorylation at several disease-specific sites, and self-aggregation into toxic tau species in AD brains. To prevent the cascade of events leading to neurodegeneration in AD, it is essential to elucidate the mechanisms underlying the initial events of tau mismetabolism. Currently, however, these mechanisms remain unclear. In this study, using transgenic Drosophila co-expressing human tau and Aβ, we found that tau phosphorylation at AD-related Ser262/356 stabilized microtubule-unbound tau in the early phase of tau mismetabolism, leading to neurodegeneration. Aβ increased the level of tau detached from microtubules, independent of the phosphorylation status at GSK3-targeted SP/TP sites. Such mislocalized tau proteins, especially the less phosphorylated species, were stabilized by phosphorylation at Ser262/356 via PAR-1/MARK. Levels of Ser262 phosphorylation were increased by Aβ42, and blocking this stabilization of tau suppressed Aβ42-mediated augmentation of tau toxicity and an increase in the levels of tau phosphorylation at the SP/TP site Thr231, suggesting that this process may be involved in AD pathogenesis. In contrast to PAR-1/MARK, blocking tau phosphorylation at SP/TP sites by knockdown of Sgg/GSK3 did not reduce tau levels, suppress tau mislocalization to the cytosol, or diminish Aβ-mediated augmentation of tau toxicity. These results suggest that stabilization of microtubule-unbound tau by phosphorylation at Ser262/356 via the PAR-1/MARK may act in the initial steps of tau mismetabolism in AD pathogenesis, and that such tau species may represent a potential therapeutic target for AD.

Destination Memory in Mild Alzheimer’s Disease

OpenAIRE

El Haj, Mohamad; Postal, Virginie; Le Gall, Didier; Allain, Philippe

2013-01-01

In order to assess their destination memory, sixteen patients with probable mild Alzheimer Disease (AD), sixteen older adults and 16 young adults were asked to tell facts to pictures. On a subsequent task, they were asked to remember whether they had previously told that fact to that face or not. AD patients showed poorer destination recall than the older adults, and the older adults showed poorer destination recall than the young adults. Our results suggest that destination memory is highly ...

A2A-D2 receptor-receptor interaction modulates gliotransmitter release from striatal astrocyte processes.

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Cervetto, Chiara; Venturini, Arianna; Passalacqua, Mario; Guidolin, Diego; Genedani, Susanna; Fuxe, Kjell; Borroto-Esquela, Dasiel O; Cortelli, Pietro; Woods, Amina; Maura, Guido; Marcoli, Manuela; Agnati, Luigi F

2017-01-01

Evidence for striatal A2A-D2 heterodimers has led to a new perspective on molecular mechanisms involved in schizophrenia and Parkinson's disease. Despite the increasing recognition of astrocytes' participation in neuropsychiatric disease vulnerability, involvement of striatal astrocytes in A2A and D2 receptor signal transmission has never been explored. Here, we investigated the presence of D2 and A2A receptors in isolated astrocyte processes prepared from adult rat striatum by confocal imaging; the effects of receptor activation were measured on the 4-aminopyridine-evoked release of glutamate from the processes. Confocal analysis showed that A2A and D2 receptors were co-expressed on the same astrocyte processes. Evidence for A2A-D2 receptor-receptor interactions was obtained by measuring the release of the gliotransmitter glutamate: D2 receptors inhibited the glutamate release, while activation of A2A receptors, per se ineffective, abolished the effect of D2 receptor activation. The synthetic D2 peptide VLRRRRKRVN corresponding to the receptor region involved in electrostatic interaction underlying A2A-D2 heteromerization abolished the ability of the A2A receptor to antagonize the D2 receptor-mediated effect. Together, the findings are consistent with heteromerization of native striatal astrocytic A2A-D2 receptors that via allosteric receptor-receptor interactions could play a role in the control of striatal glutamatergic transmission. These new findings suggest possible new pathogenic mechanisms and/or therapeutic approaches to neuropsychiatric disorders. © 2016 International Society for Neurochemistry.

Central charge for AdS2 quantum gravity

International Nuclear Information System (INIS)

Hartman, Thomas; Strominger, Andrew

2009-01-01

Two-dimensional Maxwell-dilaton quantum gravity on AdS 2 with radius l and a constant electric field E is studied. In conformal gauge, this is equivalent to a CFT on a strip. In order to maintain consistent boundary conditions, the usual conformal diffeomorphisms must be accompanied by a certain U(1) gauge transformation. The resulting conformal transformations are generated by a twisted stress tensor, which has a central charge c = 3kE 2 l 4 /4 where k is the level of the U(1) current. This is an AdS 2 analog of the Brown-Henneaux formula c = 3l/2G for the central charge of quantum gravity on AdS 3 .

Shared genetic contribution to ischemic stroke and Alzheimer's disease

Science.gov (United States)

Adib‐Samii, Poneh; Harold, Denise; Dichgans, Martin; Williams, Julie; Lewis, Cathryn M.; Markus, Hugh S.; Fornage, Myriam; Holliday, Elizabeth G; Sharma, Pankaj; Bis, Joshua C; Psaty, Bruce M; Seshadri, Sudha; Nalls, Mike A; Devan, William J; Boncoraglio, Giorgio; Malik, Rainer; Mitchell, Braxton D; Kittner, Steven J; Ikram, M Arfan; Clarke, Robert; Rosand, Jonathan; Meschia, James F; Sudlow, Cathie; Rothwell, Peter M; Levi, Christopher; Bevan, Steve; Kilarski, Laura L; Walters, Matthew; Thijs, Vincent; Slowik, Agnieszka; Lindgren, Arne; de Bakker, Paul I W; Lambert, Jean‐Charles; Ibrahim‐Verbaas, Carla A; Harold, Denise; Naj, Adam C; Sims, Rebecca; Bellenguez, Céline; Jun, Gyungah; DeStefano, Anita L; Bis, Joshua C; Beecham, Gary W; Grenier‐Boley, Benjamin; Russo, Giancarlo; Thornton‐Wells, Tricia A; Jones, Nicola; Smith, Albert V; Chouraki, Vincent; Thomas, Charlene; Ikram, M Arfan; Zelenika, Diana; Vardarajan, Badri N; Kamatani, Yoichiro; Lin, Chiao‐Feng; Gerrish, Amy; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L; Ruiz, Agustin; Bihoreau, Marie‐Thçrèse; Choi, Seung‐Hoan; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Ramirez, Alfredo; Hanon, Olivier; Fitzpatrick, Annette L; Buxbaum, Joseph D; Campion, Dominique; Crane, Paul K; Baldwin, Clinton; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L; De Jager, Philip L; Deramecourt, Vincent; Johnston, Janet A; Evans, Denis; Lovestone, Simon; Letenneur, Luc; Morón, Francisco J; Rubinsztein, David C; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M; Fiçvet, Nathalie; Huentelman, Matthew J; Gill, Michael; Brown, Kristelle; Kamboh, M Ilyas; Keller, Lina; Barberger‐Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B; Green, Robert; Myers, Amanda J; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, Ekaterina; Gallacher, John; St George‐Hyslop, Peter; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petroula; Collinge, John; Sorbi, Sandro; Sanchez‐Garcia, Florentino; Fox, Nick C; Hardy, John; Deniz Naranjo, Maria Candida; Bosco, Paolo; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Mancuso, Michelangelo; Matthews, Fiona; Moebus, Susanne; Mecocci, Patrizia; Del Zompo, Maria; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Bullido, Maria; Panza, Francesco; Caffarra, Paolo; Nacmias, Benedetta; Gilbert, John R; Mayhaus, Manuel; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M; Ingelsson, Martin; Beekly, Duane; Alvarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G; Coto, Eliecer; Hamilton‐Nelson, Kara L; Gu, Wei; Razquin, Cristina; Pastor, Pau; Mateo, Ignacio; Owen, Michael J; Faber, Kelley M; Jonsson, Palmi V; Combarros, Onofre; O'Donovan, Michael C; Cantwell, Laura B; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H; Bennett, David A; Harris, Tamara B; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee F A G; Passmore, Peter; Montine, Thomas J; Bettens, Karolien; Rotter, Jerome I; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M; Kukull, Walter A; Hannequin, Didier; Powell, John F; Nalls, Michael A; Ritchie, Karen; Lunetta, Kathryn L; Kauwe, John S K; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R; Schmidt, Reinhold; Rujescu, Dan; Wang, Li‐San; Dartigues, Jean‐François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M; Graff, Caroline; Psaty, Bruce M; Jones, Lesley; Haines, Jonathan L; Holmans, Peter A; Lathrop, Mark; Pericak‐Vance, Margaret A; Launer, Lenore J; Farrer, Lindsay A; van Duijn, Cornelia M; Van Broeckhoven, Christine; Moskvina, Valentina; Seshadri, Sudha; Williams, Julie; Schellenberg, Gerard D; Amouyel, Philippe

2016-01-01

Objective Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases. Methods Using genome‐wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype‐level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome‐wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome‐wide single‐nucleotide polymorphism (SNP) data. We then performed a meta‐analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred. Results We found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta‐analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p = 1.8 × 10−8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response. Interpretation Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739–747 PMID:26913989

Skill learning in patients with moderate Alzheimer's disease: a prospective pilot-study of waltz-lessons.

Science.gov (United States)

Rösler, Alexander; Seifritz, Erich; Kräuchi, Kurt; Spoerl, David; Brokuslaus, Ilona; Proserpi, Sara-Maria; Gendre, Annekäthi; Savaskan, Egemen; Hofmann, Marc

2002-12-01

The authors report the effect of a 12-day prospective, blinded dance-learning trial in 5 patients with moderate Alzheimer's disease (AD) and 5 age-matched depressed patients. Patients with AD showed a significant effect in procedural learning whereas depressed patients did not. These findings suggest potential implications for therapeutic interventions in patients with moderate AD. Copyright 2002 John Wiley & Sons, Ltd.

Alzheimer biomarkers and clinical Alzheimer disease were not associated with increased cerebrovascular disease in a memory clinic population.

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Spies, Petra E; Verbeek, Marcel M; Sjogren, Magnus J C; de Leeuw, Frank-Erik; Claassen, Jurgen A H R

2014-01-01

Preclinical and post-mortem studies suggest that Alzheimer disease (AD) causes cerebrovascular dysfunction, and therefore may enhance susceptibility to cerebrovascular disease (CVD). The objective of this study was to investigate this association in a memory clinic population. The AD biomarkers CSF amyloid β42, amyloid β40 and APOE-ε4 status have all been linked to increased CVD risk in AD, and therefore the first aim of this study was to analyze the association between these biomarkers and CVD. In 92 memory clinic patients the cross-sectional association between AD biomarkersand the severity of CVD was investigated with linear regression analysis. Additionally, we studied whether AD biomarkers modified the relation between vascular risk factors and CVD. CVD was assessed on MRI through a visual rating scale.Analyses were adjusted for age. The second aim of this study was to investigate the association between clinical AD and CVD, where 'clinical AD' was defined as follows: impairment in episodic memory, hippocampal atrophy and an aberrant concentration of cerebrospinal fluid (CSF) biomarkers. 47 of the 92 patients had AD. No association between CSF amyloid β42, amyloid β40 or APOE-ε4 status and CVD severity was found, nor did these AD biomarkers modify the relation between vascular risk factors and CVD. Clinical AD was not associated with CVD severity (p=0.83). Patients with more vascular risk factors had more CVD, but this relationship was not convincingly modified by AD (p=0.06). In this memory clinic population, CVD in patients with AD was related to vascular risk factors and age, comparable to patients without AD. Therefore, in our study, the preclinical and post-mortem evidence that AD would predispose to CVD could not be translated clinically. Further work, including replication of this work in a different and larger sample, is warranted.

In vivo PET imaging of neuroinflammation in Alzheimer's disease.

Science.gov (United States)

Lagarde, Julien; Sarazin, Marie; Bottlaender, Michel

2018-05-01

Increasing evidence suggests that neuroinflammation contributes to the pathophysiology of many neurodegenerative diseases, especially Alzheimer's disease (AD). Molecular imaging by PET may be a useful tool to assess neuroinflammation in vivo, thus helping to decipher the complex role of inflammatory processes in the pathophysiology of neurodegenerative diseases and providing a potential means of monitoring the effect of new therapeutic approaches. For this objective, the main target of PET studies is the 18 kDa translocator protein (TSPO), as it is overexpressed by activated microglia. In the present review, we describe the most widely used PET tracers targeting the TSPO, the methodological issues in tracer quantification and summarize the results obtained by TSPO PET imaging in AD, as well as in neurodegenerative disorders associated with AD, in psychiatric disorders and ageing. We also briefly describe alternative PET targets and imaging modalities to study neuroinflammation. Lastly, we question the meaning of PET imaging data in the context of a highly complex and multifaceted role of neuroinflammation in neurodegenerative diseases. This overview leads to the conclusion that PET imaging of neuroinflammation is a promising way of deciphering the enigma of the pathophysiology of AD and of monitoring the effect of new therapies.

Self-propagative replication of Aβ oligomers suggests potential transmissibility in Alzheimer disease.

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Amit Kumar

Full Text Available The aggregation of amyloid-β (Aβ peptide and its deposition in parts of the brain form the central processes in the etiology of Alzheimer disease (AD. The low-molecular weight oligomers of Aβ aggregates (2 to 30 mers are known to be the primary neurotoxic agents whose mechanisms of cellular toxicity and synaptic dysfunction have received substantial attention in the recent years. However, how these toxic agents proliferate and induce widespread amyloid deposition throughout the brain, and what mechanism is involved in the amplification and propagation of toxic oligomer species, are far from clear. Emerging evidence based on transgenic mice models indicates a transmissible nature of Aβ aggregates and implicates a prion-like mechanism of oligomer propagation, which manifests as the dissemination and proliferation of Aβ toxicity. Despite accumulating evidence in support of a transmissible nature of Aβ aggregates, a clear, molecular-level understanding of this intriguing mechanism is lacking. Recently, we reported the characterization of unique replicating oligomers of Aβ42 (12-24 mers in vitro called Large Fatty Acid-derived Oligomers (LFAOs (Kumar et al., 2012, J. Biol. Chem. In the current report, we establish that LFAOs possess physiological activity by activating NF-κB in human neuroblastoma cells, and determine the experimental parameters that control the efficiency of LFAO replication by self-propagation. These findings constitute the first detailed report on monomer - oligomer lateral propagation reactions that may constitute potential mechanism governing transmissibility among Aβ oligomers. These data support the previous reports on transmissible mechanisms observed in transgenic animal models.

AdS5 black holes with fermionic hair

International Nuclear Information System (INIS)

Burrington, Benjamin A.; Liu, James T.; Sabra, W. A.

2005-01-01

The study of new Bogomol'nyi-Prasad-Sommerfield (BPS) objects in AdS 5 has led to a deeper understanding of AdS/CFT. To help complete this picture, and to fully explore the consequences of the supersymmetry algebra, it is also important to obtain new solutions with bulk fermions turned on. In this paper we construct superpartners of the 1/2 BPS black hole in AdS 5 using a natural set of fermion zero modes. We demonstrate that these superpartners, carrying fermionic hair, have conserved charges differing from the original bosonic counterpart. To do so, we find the R-charge and dipole moment of the new system, as well as the mass and angular momentum, defined through the boundary stress tensor. The complete set of superpartners fits nicely into a chiral representation of AdS 5 supersymmetry, and the spinning solutions have the expected gyromagnetic ratio, g=1

Interacting fields in real-time AdS/CFT

Energy Technology Data Exchange (ETDEWEB)

Botta-Cantcheff, Marcelo; Martínez, Pedro J. [Instituto de Física de La Plata, CCT La Plata, CONICET & Departamento de Física,Universidad Nacional de La Plata, C.C. 67, 1900 La Plata (Argentina); Silva, Guillermo A. [Instituto de Física de La Plata, CCT La Plata, CONICET & Departamento de Física,Universidad Nacional de La Plata, C.C. 67, 1900 La Plata (Argentina); Abdus Salam International Centre for Theoretical Physics, Associate Scheme,Strada Costiera 11, 34151 Trieste (Italy)

2017-03-28

We compute time-ordered 2- and 3-pt correlation functions of CFT scalar operators between generic in/out states. The calculation is holographically carried out by considering a non backreacting AdS scalar field with a λϕ{sup 3} self-interaction term on a combination of Euclidean and Lorentzian AdS sections following the Skenderis-van Rees prescription. We show that, although working in an essentially different set up, the final result for the 3-pt correlators agree with those of Rastelli et al. for Euclidean AdS. By analyzing the inner product between the in/out excited states in the large N approximation, we argue that a cubic bulk interaction deforms the excited states from coherent into squeezed. Finally, a diagrammatic interpretation of the results suggests some general properties for the n-point correlation functions between excited states.

Phases of global AdS black holes

International Nuclear Information System (INIS)

Basu, Pallab; Krishnan, Chethan; Subramanian, P.N. Bala

2016-01-01

We study the phases of gravity coupled to a charged scalar and gauge field in an asymptotically Anti-de Sitter spacetime (AdS_4) in the grand canonical ensemble. For the conformally coupled scalar, an intricate phase diagram is charted out between the four relevant solutions: global AdS, boson star, Reissner-Nordstrom black hole and the hairy black hole. The nature of the phase diagram undergoes qualitative changes as the charge of the scalar is changed, which we discuss. We also discuss the new features that arise in the extremal limit.

Discrepancy between stimulus response and tolerance of pain in Alzheimer disease

DEFF Research Database (Denmark)

Jensen-Dahm, Christina; Werner, Mads U; Jensen, Troels Staehelin

2015-01-01

BACKGROUND: Affective-motivational and sensory-discriminative aspects of pain were investigated in patients with mild to moderate Alzheimer disease (AD) and healthy elderly controls using the cold pressor test tolerance and repetitive stimuli of warmth and heat stimuli, evaluating the stimulus....... The results further suggest that the attenuated cold pressor pain tolerance may relate to impairment of coping abilities. Paradoxically, we found an attenuated stimulus-response function, compared to controls, suggesting that AD dementia interferes with pain ratings over time, most likely due to memory...

E-cigarette Ads and Youth PSA (:60)

Centers for Disease Control (CDC) Podcasts

2016-01-05

This 60 second public service announcement is based on the January 2016 CDC Vital Signs report. Most electronic cigarettes, or e-cigarettes, contain nicotine, which is highly addictive and may harm brain development. More than 18 million middle and high school students were exposed to e-cigarette ads. Exposure to these ads may be contributing to an increase in e-cigarette use among youth. Learn what can be done to keep our youth safe and healthy.  Created: 1/5/2016 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 1/5/2016.

Evaluation of Cholinergic Deficiency in Preclinical Alzheimer’s Disease Using Pupillometry

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Shaun Frost

2017-01-01

Full Text Available Cortical cholinergic deficiency is prominent in Alzheimer’s disease (AD, and published findings of diminished pupil flash response in AD suggest that this deficiency may extend to the visual cortical areas and anterior eye. Pupillometry is a low-cost, noninvasive technique that may be useful for monitoring cholinergic deficits which generally lead to memory and cognitive disorders. The aim of the study was to evaluate pupillometry for early detection of AD by comparing the pupil flash response (PFR in AD (N=14 and cognitively normal healthy control (HC, N=115 participants, with the HC group stratified according to high (N=38 and low (N=77 neocortical amyloid burden (NAB. Constriction phase PFR parameters were significantly reduced in AD compared to HC (maximum acceleration p<0.05, maximum velocity p<0.0005, average velocity p<0.005, and constriction amplitude p<0.00005. The high-NAB HC subgroup had reduced PFR response cross-sectionally, and also a greater decline longitudinally, compared to the low-NAB subgroup, suggesting changes to pupil response in preclinical AD. The results suggest that PFR changes may occur in the preclinical phase of AD. Hence, pupillometry has a potential as an adjunct for noninvasive, cost-effective screening for preclinical AD.

New Massive Gravity and AdS4 Counterterms

International Nuclear Information System (INIS)

Jatkar, Dileep P.; Sinha, Aninda

2011-01-01

We show that the recently proposed Dirac-Born-Infeld extension of new massive gravity emerges naturally as a counterterm in four-dimensional anti-de Sitter space (AdS 4 ). The resulting on-shell Euclidean action is independent of the cutoff at zero temperature. We also find that the same choice of counterterm gives the usual area law for the AdS 4 Schwarzschild black hole entropy in a cutoff-independent manner. The parameter values of the resulting counterterm action correspond to a c=0 theory in the context of the duality between AdS 3 gravity and two-dimensional conformal field theory. We rewrite this theory in terms of the gauge field that is used to recast 3D gravity as a Chern-Simons theory.

Genetic Aspects of Alzheimer Disease

Science.gov (United States)

Williamson, Jennifer; Goldman, Jill; Marder, Karen S.

2011-01-01

Background Alzheimer disease (AD) is a genetically complex disorder. Mutations in 3 genes, presenilin 1, amyloid precursor protein, and presenilin 2, lead to early-onset familial AD in rare families with onset of disease occurring prior to age 65. Specific polymorphisms in apolipoprotein E are associated with the more common, late-onset AD occurring after age 65. In this review, we discuss current advances in AD genetics, the implications of the known AD genes, presenilin 1, presenilin 2, amyloid precursor protein, and apolipoprotein E, and other possible genes on the clinical diagnosis, treatment, and genetic counseling of patients and families with early- and late-onset AD. Review Summary In addition to the mutations in 4 known genes associated with AD, mutations in other genes may be implicated in the pathogenesis of the disease. Most recently, 2 different research groups have reported genetic association between 2 genes, sortilin-related receptor and GAB2, and AD. These associations have not changed the diagnostic and medical management of AD. Conclusions New research in the genetics of AD have implicated novel genes as having a role in the disease, but these findings have not been replicated nor have specific disease causing mutations been identified. To date, clinical genetic testing is limited to familial early-onset disease for symptomatic individuals and asymptomatic relatives and, although not recommended, amyloid precursor protein apolipoprotein E testing as an adjunct to diagnosis of symptomatic individuals. PMID:19276785

Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimer's Disease

Science.gov (United States)

de la Monte, Suzanne M

2012-01-01

Alzheimer's disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades. PMID:22329651

CSF studies facilitate DNA diagnosis in familial Alzheimer's disease due to a presenilin-1 mutation

NARCIS (Netherlands)

de Bot, Susanne T; Kremer, H P H; Dooijes, Dennis; Verbeek, Marcel M

2009-01-01

In sporadic Alzheimer's disease (AD), cerebrospinal fluid (CSF) analysis is becoming increasingly relevant to establish an early diagnosis. We present a case of familial AD due to a presenilin-1 mutation in which CSF studies suggested appropriate DNA diagnostics. A 38 year old Dutch man presented

Lifelong bilingualism and neural reserve against Alzheimer's disease: a review of findings and potential mechanisms.

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Gold, Brian T

2015-03-15

Alzheimer's disease (AD) is a progressive brain disorder that initially affects medial temporal lobe circuitry and memory functions. Current drug treatments have only modest effects on the symptomatic course of the disease. In contrast, a growing body of evidence suggests that lifelong bilingualism may delay the onset of clinical AD symptoms by several years. The purpose of the present review is to summarize evidence for bilingualism as a reserve variable against AD and discuss potential underlying neurocognitive mechanisms. Evidence is reviewed suggesting that bilingualism may delay clinical AD symptoms by protecting frontostriatal and frontoparietal executive control circuitry rather than medial temporal lobe memory circuitry. Cellular and molecular mechanisms that may contribute to bilingual cognitive reserve effects are discussed, including those that may affect neuronal metabolic functions, dynamic neuronal-glial interactions, vascular factors, myelin structure and neurochemical signaling. Future studies that may test some of these potential mechanisms of bilingual CR effects are proposed. Copyright © 2014 Elsevier B.V. All rights reserved.

The clinical significance of brain microbleeds in patients with Alzheimer′s disease: Preliminary study

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Jae-Hyeok Heo

2016-01-01

Full Text Available Background: Microbleeds (MBs are observed frequently in Alzheimer′s disease (AD and suggested to play a crucial role in the pathophysiology, but their clinical significance remains unclear. Materials and Methods: The study recruited 100 patients with AD who were diagnosed at the memory clinic in Seoul Medical Center in 2014. For each patient, baseline characteristics, neuropsychological tests, cerebrovascular risk factors, medial temporal lobe atrophy (MTLA, and severity of small vessel disease (SVD according to the existence of MBs were evaluated. Results: The prevalence of MBs in patients with AD was 33%. The percentage of male gender, the severity of SVD and MTLA were significantly increased in MB(+ group. The MB(+ group showed more severe MTLA and SVD than MB(− group. Conclusions: These results suggested that MBs might reflect the burden of amyloid and ischemic vascular pathology.

A disease state fingerprint for evaluation of Alzheimer's disease

DEFF Research Database (Denmark)

Mattila, Jussi; Koikkalainen, Juha; Virkki, Arho

2011-01-01

Diagnostic processes of Alzheimer's disease (AD) are evolving. Knowledge about disease-specific biomarkers is constantly increasing and larger volumes of data are being measured from patients. To gain additional benefits from the collected data, a novel statistical modeling and data visualization...... interpretation of the information. To model the AD state from complex and heterogeneous patient data, a statistical Disease State Index (DSI) method underlying the DSF has been developed. Using baseline data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the ability of the DSI to model disease...

Adding liraglutide to the backbone therapy of biguanide in patients with coronary artery disease and newly diagnosed type-2 diabetes (the AddHope2 study)

DEFF Research Database (Denmark)

Anholm, Christian; Kumarathurai, Preman; Klit, Malene S

2014-01-01

INTRODUCTION: Newly diagnosed type 2 diabetes mellitus (T2DM) in patients with coronary artery disease (CAD) more than doubles the risk of death compared with otherwise matched glucose tolerant patients. The biguanide metformin is the drug of choice in treatment of T2DM and has shown to ameliorate...... cardiovascular morbidity in patients with T2DM and myocardial infarction (MI). The incretin hormone, glucagon-like peptide-1 (GLP-1) improves β-cell function, insulin sensitivity and causes weight loss and has been suggested to have beneficial effects on cardiac function. The GLP-1 receptor agonist (GLP-1RA......), liraglutide, is currently used for treatment of T2DM but its potential effect on cardiac function has not been investigated in detail. We hypothesised that liraglutide added to metformin backbone therapy in patients with CAD and newly diagnosed T2DM will improve β-cell function and left ventricular systolic...

Estimating Free and Added Sugar Intakes in New Zealand

OpenAIRE

Rachael Kibblewhite; Alice Nettleton; Rachael McLean; Jillian Haszard; Elizabeth Fleming; Devonia Kruimer; Lisa Te Morenga

2017-01-01

The reduction of free or added sugar intake (sugars added to food and drinks as a sweetener) is almost universally recommended to reduce the risk of obesity-related diseases and dental caries. The World Health Organisation recommends intakes of free sugars of less than 10% of energy intake. However, estimating and monitoring intakes at the population level is challenging because free sugars cannot be analytically distinguished from naturally occurring sugars and most national food composition...

Regional cerebral blood flow patterns in extremely elderly patients with Alzheimer's disease

International Nuclear Information System (INIS)

Hirao, Kentaro; Hanyu, Haruo; Kanetaka, Hidekazu; Shimizu, Soichiro; Sato, Tomohiko; Iwamoto, Toshihiko

2008-01-01

Clinical and pathologic features in Alzheimer's disease (AD) patients differ depending on the age of onset. The aim of our study was to compare the regional cerebral blood flow (rCBF) patterns of younger, elderly, and extremely elderly patients with AD with that of controls to characterize the rCBF patterns in extremely elderly patients with AD. Single photon emission CT (SPECT) was performed in 113 patients with probable AD, including 34 younger (<70 years), 41 elderly (70-84 years), and 38 extremely elderly (≥85 years) patients divided according to age at examination. The SPECT data were analyzed using three-dimensional stereotactic surface projection (3D-SSP). No significant differences regarding gender, duration of disease, education, and Mini-Mental State Examination score were found among the groups. As compared with controls, younger and elderly AD demonstrated significant reduction of rCBF in the temporo-parietal areas, posterior cingulate cortices and precunei, which is considered to be a characteristic rCBF pattern in AD. On the other hand, the extremely elderly AD group demonstrated significant reduction of rCBF in the frontal and medial temporal areas, in addition to the temporo-parietal areas, posterior cingulate cortices and precunei, but the reductions were milder than in those in younger and elderly AD groups. The extremely elderly patients with AD showed atypical rCBF patterns in AD compared to younger and elderly patients with AD. Our data suggest that pathological features in extremely elderly AD may be different from those in younger and elderly AD and that diseases different from AD, such as senile dementia of the neurofibrillary tangle type may be clinically diagnosed as extremely elderly AD. (author)

Erythrocytes as Potential Link between Diabetes and Alzheimer’s Disease

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Cristiana Carelli-Alinovi

2017-08-01

Full Text Available Many studies support the existence of an association between type 2 diabetes (T2DM and Alzheimer’s disease (AD. In AD, in addition to brain, a number of peripheral tissues and cells are affected, including red blood cell (RBC and because there are currently no reliable diagnostic biomarkers of AD in the blood, a gradually increasing attention has been given to the study of RBC’s alterations. Recently it has been evidenced in diabetes, RBC alterations superimposable to the ones occurring in AD RBC. Furthermore, growing evidence suggests that oxidative stress plays a pivotal role in the development of RBC’s alterations and vice versa. Once again this represents a further evidence of a shared pathway between AD and T2DM. The present review summarizes the two disorders, highlighting the role of RBC in the postulated common biochemical links, and suggests RBC as a possible target for clinical trials.

Comparative Lipidomic Analysis of Mouse and Human Brain with Alzheimer Disease*

Science.gov (United States)

Chan, Robin B.; Oliveira, Tiago G.; Cortes, Etty P.; Honig, Lawrence S.; Duff, Karen E.; Small, Scott A.; Wenk, Markus R.; Shui, Guanghou; Di Paolo, Gilbert

2012-01-01

Lipids are key regulators of brain function and have been increasingly implicated in neurodegenerative disorders including Alzheimer disease (AD). Here, a systems-based approach was employed to determine the lipidome of brain tissues affected by AD. Specifically, we used liquid chromatography-mass spectrometry to profile extracts from the prefrontal cortex, entorhinal cortex, and cerebellum of late-onset AD (LOAD) patients, as well as the forebrain of three transgenic familial AD (FAD) mouse models. Although the cerebellum lacked major alterations in lipid composition, we found an elevation of a signaling pool of diacylglycerol as well as sphingolipids in the prefrontal cortex of AD patients. Furthermore, the diseased entorhinal cortex showed specific enrichment of lysobisphosphatidic acid, sphingomyelin, the ganglioside GM3, and cholesterol esters, all of which suggest common pathogenic mechanisms associated with endolysosomal storage disorders. Importantly, a significant increase in cholesterol esters and GM3 was recapitulated in the transgenic FAD models, suggesting that these mice are relevant tools to study aberrant lipid metabolism of endolysosomal dysfunction associated with AD. Finally, genetic ablation of phospholipase D2, which rescues the synaptic and behavioral deficits of an FAD mouse model, fully normalizes GM3 levels. These data thus unmask a cross-talk between the metabolism of phosphatidic acid, the product of phospholipase D2, and gangliosides, and point to a central role of ganglioside anomalies in AD pathogenesis. Overall, our study highlights the hypothesis generating potential of lipidomics and identifies novel region-specific lipid anomalies potentially linked to AD pathogenesis. PMID:22134919

Body mass index and risk of autoimmune diseases

DEFF Research Database (Denmark)

Harpsøe, Maria C; Basit, Saima; Andersson, Mikael

2014-01-01

.57) and type 1 diabetes mellitus (HR 2.67; 95% CI, 1.71 to 4.17). Risk of dermatitis herpetiformis increased by 14% (95% CI, 1% to 30%) per BMI unit. Conversely, risk of celiac disease and Raynaud's phenomenon decreased by 7% (95% CI, 1% to 13%) and 12% (95% CI, 4% to 19%) per BMI unit, respectively. Further......BACKGROUND: A possible aetiological link between obesity and certain autoimmune diseases (ADs) has been suggested. We investigated the associations between body mass index (BMI, kg/m2) and 43 ADs. METHODS: 75,008 women participating in the Danish National Birth Cohort were followed during a median......-up, 2430 women (3.2%) developed a total of 2607 new-onset ADs. Risk of any autoimmune disease was increased in obese women (HR, 1.27; 95% CI, 1.11 to 1.46) compared with normal weight women (18.5-≤25 kg/m2). Obese women (BMI≥30 kg/m2) were at increased risk of sarcoidosis (HR 3.59; 95% CI, 2.31 to 5...

Expression of novel Alzheimer's disease risk genes in control and Alzheimer's disease brains.

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Celeste M Karch

Full Text Available Late onset Alzheimer's disease (LOAD etiology is influenced by complex interactions between genetic and environmental risk factors. Large-scale genome wide association studies (GWAS for LOAD have identified 10 novel risk genes: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, MS4A6E, and PICALM. We sought to measure the influence of GWAS single nucleotide polymorphisms (SNPs and gene expression levels on clinical and pathological measures of AD in brain tissue from the parietal lobe of AD cases and age-matched, cognitively normal controls. We found that ABCA7, CD33, and CR1 expression levels were associated with clinical dementia rating (CDR, with higher expression being associated with more advanced cognitive decline. BIN1 expression levels were associated with disease progression, where higher expression was associated with a delayed age at onset. CD33, CLU, and CR1 expression levels were associated with disease status, where elevated expression levels were associated with AD. Additionally, MS4A6A expression levels were associated with Braak tangle and Braak plaque scores, with elevated expression levels being associated with more advanced brain pathology. We failed to detect an association between GWAS SNPs and gene expression levels in our brain series. The minor allele of rs3764650 in ABCA7 is associated with age at onset and disease duration, and the minor allele of rs670139 in MS4A6E was associated with Braak tangle and Braak plaque score. These findings suggest that expression of some GWAS genes, namely ABCA7, BIN1, CD33, CLU, CR1 and the MS4A family, are altered in AD brains.

Current status of AdS instability

CERN Multimedia

CERN. Geneva

2016-01-01

arXiv:1403.6471 and thoroughly developed in arXiv:1407.6273. On the other hand the negative cosmological constant allows for the existence of stable, time-periodic, asymptotically AdS solutions of Einstein equations [arXiv:1303.3186].

Loops in AdS from conformal field theory

Science.gov (United States)

Aharony, Ofer; Alday, Luis F.; Bissi, Agnese; Perlmutter, Eric

2017-07-01

We propose and demonstrate a new use for conformal field theory (CFT) crossing equations in the context of AdS/CFT: the computation of loop amplitudes in AdS, dual to non-planar correlators in holographic CFTs. Loops in AdS are largely unexplored, mostly due to technical difficulties in direct calculations. We revisit this problem, and the dual 1 /N expansion of CFTs, in two independent ways. The first is to show how to explicitly solve the crossing equations to the first subleading order in 1 /N 2, given a leading order solution. This is done as a systematic expansion in inverse powers of the spin, to all orders. These expansions can be resummed, leading to the CFT data for finite values of the spin. Our second approach involves Mellin space. We show how the polar part of the four-point, loop-level Mellin amplitudes can be fully reconstructed from the leading-order data. The anomalous dimensions computed with both methods agree. In the case of ϕ 4 theory in AdS, our crossing solution reproduces a previous computation of the one-loop bubble diagram. We can go further, deriving the four-point scalar triangle diagram in AdS, which had never been computed. In the process, we show how to analytically derive anomalous dimensions from Mellin amplitudes with an infinite series of poles, and discuss applications to more complicated cases such as the N = 4 super-Yang-Mills theory.

Catecholamine-based treatment in AD patients: Expectations and delusions

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Alessandro eStefani

2015-05-01

Full Text Available In Alzheimer disease, the gap between excellence of diagnostics and efficacy of therapy is wide. Despite sophisticated imaging and biochemical markers, the efficacy of available therapeutic options is limited.Here we examine the possibility that assessment of endogenous catecholamine levels in cerebrospinal fluid (CSF may fuel new therapeutic strategies.In reviewing the available literature, we consider the effects of levodopa, monoamine oxidase inhibitors (MAOI, and noradraneline (NE modulators, showing disparate results. We present a preliminary assessment of CSF concentrations of dopamine (DA and NE, determined by HPLC, in a small dementia cohort of either Alzheimer’s disease (AD or frontotemporal dementia (FTD patients, compared to control subjects. Our data reveal detectable levels of DA, NE in CSF, though we found no significant alterations in the dementia population as a whole. AD patients exhibit a small impairment of the DA axis and a larger increase of NE concentration, likely to represent a compensatory mechanism.While waiting for preventive strategies, a pragmatic approach to AD may re-evaluate catecholamine modulation, possibly stratified to dementia subtypes, as part of the therapeutic armamentarium.

Supersymmetric warped AdS in extended topologically massive supergravity

International Nuclear Information System (INIS)

Deger, N.S.; Kaya, A.; Samtleben, H.; Sezgin, E.

2014-01-01

We determine the most general form of off-shell N=(1,1) supergravity field configurations in three dimensions by requiring that at least one off-shell Killing spinor exists. We then impose the field equations of the topologically massive off-shell supergravity and find a class of solutions whose properties crucially depend on the norm of the auxiliary vector field. These are spacelike-squashed and timelike-stretched AdS 3 for the spacelike and timelike norms, respectively. At the transition point where the norm vanishes, the solution is null warped AdS 3 . This occurs when the coefficient of the Lorentz–Chern–Simons term is related to the AdS radius by μℓ=2. We find that the spacelike-squashed AdS 3 can be modded out by a suitable discrete subgroup of the isometry group, yielding an extremal black hole solution which avoids closed timelike curves

New supersymmetric AdS4 type II vacua

International Nuclear Information System (INIS)

Tsimpis, D.

2010-01-01

We review the supersymmetric AdS 4 x w M 6 backgrounds of type IIA/IIB supergravity constructed in[1]. In type IIA the supersymmetry is N=2, and the six-dimensional internal space is locally an S 2 bundle over a four-dimensional Kaehler-Einstein base; in IIB the internal space is the direct product of a circle and a five-dimensional squashed Sasaki-Einstein manifold. These backgrounds do not contain any sources, all fluxes (including the Romans mass in IIA) are generally non-zero, and the dilaton and warp factor are non-constant. The IIA solutions include the massive deformations of the IIA reduction of the eleven-dimensional AdS 4 x Y p,q solutions, and had been predicted to exist on the basis of the AdS 4 /CFT 3 correspondence. (Abstract Copyright [2010], Wiley Periodicals, Inc.)

Instantons from geodesics in AdS moduli spaces

Science.gov (United States)

Ruggeri, Daniele; Trigiante, Mario; Van Riet, Thomas

2018-03-01

We investigate supergravity instantons in Euclidean AdS5 × S5/ℤk. These solutions are expected to be dual to instantons of N = 2 quiver gauge theories. On the supergravity side the (extremal) instanton solutions are neatly described by the (lightlike) geodesics on the AdS moduli space for which we find the explicit expression and compute the on-shell actions in terms of the quantised charges. The lightlike geodesics fall into two categories depending on the degree of nilpotency of the Noether charge matrix carried by the geodesic: for degree 2 the instantons preserve 8 supercharges and for degree 3 they are non-SUSY. We expect that these findings should apply to more general situations in the sense that there is a map between geodesics on moduli-spaces of Euclidean AdS vacua and instantons with holographic counterparts.

From Nose to Memory: The Involuntary Nature of Odor-evoked Autobiographical Memories in Alzheimer's Disease.

Science.gov (United States)

El Haj, Mohamad; Gandolphe, Marie Charlotte; Gallouj, Karim; Kapogiannis, Dimitrios; Antoine, Pascal

2017-12-25

Research suggests that odors may serve as a potent cue for autobiographical retrieval. We tested this hypothesis in Alzheimer's disease (AD) and investigated whether odor-evoked autobiographical memory is an involuntary process that shares similarities with music-evoked autobiographical memory. Participants with mild AD and controls were asked to retrieve 2 personal memories after odor exposure, after music exposure, and in an odor-and music-free condition. AD participants showed better specificity, emotional experience, mental time travel, and retrieval time after odor and music exposure than in the control condition. Similar beneficial effects of odor and music exposure were observed for autobiographical characteristics (i.e., specificity, emotional experience, and mental time travel), except for retrieval time which was more improved after odor than after music exposure. Interestingly, regression analyses suggested executive involvement in memories evoked in the control condition but not in those evoked after music or odor exposure. These findings suggest the involuntary nature of odor-evoked autobiographical memory in AD. They also suggest that olfactory cuing could serve as a useful and ecologically valid tool to stimulate autobiographical memory, at least in the mild stage of the disease. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Constrained supermanifolds for AdS M-theory backgrounds

International Nuclear Information System (INIS)

Fre, Pietro; Grassi, Pietro Antonio

2008-01-01

A long standing problem is the supergauge completion of AdS 4 x ({G/H}) 7 or AdS 5 x ({G/H}) 5 backgrounds which preserve less then maximal supersymmetry. In parallel with the supersolvable realization of the AdS 4 x S 7 background based on κ-symmetry, we develop a technique which amounts to solving the above-mentioned problem in a way useful for pure spinor quantization for supermembranes and superstrings. Instead of gauge fixing some of the superspace coordinates using κ-symmetry, we impose an additional constraint on them reproducing the simplifications of the supersolvable representations. The constraints are quadratic, homogeneous, Sp(4,R)-covariant, and consistent from the quantum point of view in the pure spinor approach. Here we provide the geometrical solution which, in a subsequent work, will be applied to the membrane and the superstring sigma models

Lifelong Bilingualism and Neural Reserve against Alzheimer’s disease: A Review of Findings and Potential Mechanisms

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Gold, Brian T.

2014-01-01

Alzheimer’s disease (AD) is a progressive brain disorder that initially affects medial temporal lobe circuitry and memory functions. Current drug treatments have only modest effects on the symptomatic course of the disease. In contrast, a growing body of evidence suggests that lifelong bilingualism may delay the onset of clinical AD symptoms by several years. The purpose of the present review is to summarize evidence for bilingualism as a reserve variable against AD and discuss potential underlying neurocognitive mechanisms. Evidence is reviewed suggesting that bilingualism may delay clinical AD symptoms by protecting frontostriatal and frontoparietal executive control circuitry rather than medial temporal lobe memory circuitry. Cellular and molecular mechanisms that may contribute to bilingual cognitive reserve effects are discussed, including those that may affect neuronal metabolic functions, dynamic neuronal-glial interactions, vascular factors, myelin structure and neurochemical signaling. Future studies that may test some of these potential mechanisms of bilingual CR effects are proposed. PMID:25496781

Triggering receptor expressed on myeloid cells 2 (TREM2): a potential therapeutic target for Alzheimer disease?

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Deming, Yuetiva; Li, Zeran; Benitez, Bruno A; Cruchaga, Carlos

2018-06-20

There are currently no effective therapeutics for Alzheimer disease (AD). Clinical trials targeting amyloid beta thus far have shown very little benefit and only in the earliest stages of disease. These limitations have driven research to identify alternative therapeutic targets, one of the most promising is the triggering receptor expressed on myeloid cells 2 (TREM2). Areas covered: Here, we review the literature to-date and discuss the potentials and pitfalls for targeting TREM2 as a potential therapeutic for AD. We focus on research in animal and cell models for AD and central nervous system injury models which may help in understanding the role of TREM2 in disease. Expert opinion: Studies suggest TREM2 plays a key role in AD pathology; however, results have been conflicting about whether TREM2 is beneficial or harmful. More research is necessary before designing TREM2-targeting therapies. Successful therapeutics will most likely be administered early in disease.

Improving Dual-Task Walking Paradigms to Detect Prodromal Parkinson’s and Alzheimer’s Diseases

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Maroua Belghali

2017-05-01

Full Text Available Gait control is a complex movement, relying on spinal, subcortical, and cortical structures. The presence of deficits in one or more of these structures will result in changes in gait automaticity and control, as is the case in several neurodegenerative diseases, such as Alzheimer’s disease (AD and Parkinson’s disease (PD. By reviewing recent findings in this field of research, current studies have shown that gait performance assessment under dual-task conditions could contribute to predict both of these diseases. Such suggestions are relevant mainly for people at putatively high risk of developing AD (i.e., older adults with mild cognitive impairment subtypes or PD (i.e., older adults with either Mild Parkinsonian signs or LRRK2 G2019S mutation. Despite the major importance of these results, the type of cognitive task that should be used as a concurrent secondary task has to be selected among the plurality of tasks proposed in the literature. Furthermore, the key aspects of gait control that represent sensitive and specific “gait signatures” for prodromal AD or PD need to be determined. In the present perspective article, we suggest the use of a Stroop interference task requiring inhibitory attentional control and a set-shifting task requiring reactive flexibility as being particularly relevant secondary tasks for challenging gait in prodromal AD and PD, respectively. Investigating how inhibition and cognitive flexibility interfere with gait control is a promising avenue for future research aimed at enhancing early detection of AD and PD, respectively.

Multimodal drugs and their future for Alzheimer's and Parkinson's disease.

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Van der Schyf, Cornelis J; Geldenhuys, Werner J

2011-01-01

This chapter discusses the rationale for developing multimodal or multifunctional drugs (also called designed multiple ligands or DMLs) aimed at disease-modifying treatment strategies for the most common neurodegenerative diseases Alzheimer's and Parkinson's disease (AD and PD). Both the prevalence and incidence of AD and PD have seen consistent and dramatic increases, a disconcerting phenomenon which, ironically, has been attributed to extended life expectancy brought about by better health care globally. In spite of these statistics, the development and introduction to the clinic of new therapies proven to prevent or delay the onset of AD and PD have been disappointing. Evidence has accumulated to suggest that the etiopathology of these diseases is extremely complex, with an array of potential drug targets located within a number of deleterious biochemical pathways. Therefore, in these diseases, it is unlikely that the complex pathoetiological cascade leading to disease initiation or progression will be mitigated by any one drug acting on a single pathway or target. The pursuit of novel DMLs may offer far better outcomes. Although certainly not the only, and perhaps not even the best, approach but farthest along the drug development pipeline in the DML paradigm are drugs that combine inhibition of monoamine oxidase with associated etiological targets unique to either AD or PD. These compounds will constitute the major focus of this chapter, which will also explore radically new paradigms that seek to combine cognitive enhancers with proneurogenesis compounds. Copyright © 2011 Elsevier Inc. All rights reserved.

Noncommutative D-branes from covariant AdS superstring

International Nuclear Information System (INIS)

Sakaguchi, Makoto; Yoshida, Kentaroh

2008-01-01

We study noncommutative (NC) D-branes on AdS 5 xS 5 from κ-invariance of covariant Green-Schwarz action of an open string with a non-trivial world-volume flux. Finding boundary conditions to ensure the κ-invariance, we can see possible configurations of the NC D-branes. With this method 1/4 BPS NC D-branes are discussed. The resulting NC Dp-branes are 1/4 BPS at arbitrary position other than the p=1 case. The exceptional D-string is 1/2 BPS at the origin and 1/4 BPS outside the origin. Those are reduced to possible 1/4 BPS or 1/2 BPS AdS D-branes in the commutative limit. The same analysis is applied to an open superstring in a pp-wave and leads to 1/4 BPS configurations of NC D-branes. These D-branes are consistently obtained from AdS D-branes via the Penrose limit

Brain Aging and AD-Like Pathology in Streptozotocin-Induced Diabetic Rats

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Jian-Qin Wang

2014-01-01

Full Text Available Objective. Numerous epidemiological studies have linked diabetes mellitus (DM with an increased risk of developing Alzheimer’s disease (AD. However, whether or not diabetic encephalopathy shows AD-like pathology remains unclear. Research Design and Methods. Forebrain and hippocampal volumes were measured using stereology in serial coronal sections of the brain in streptozotocin- (STZ- induced rats. Neurodegeneration in the frontal cortex, hypothalamus, and hippocampus was evaluated using Fluoro-Jade C (FJC. Aβ aggregation in the frontal cortex and hippocampus was tested using immunohistochemistry and ELISA. Dendritic spine density in the frontal cortex and hippocampus was measured using Golgi staining, and western blot was conducted to detect the levels of synaptophysin. Cognitive ability was evaluated through the Morris water maze and inhibitory avoidant box. Results. Rats are characterized by insulin deficiency accompanied with polydipsia, polyphagia, polyuria, and weight loss after STZ injection. The number of FJC-positive cells significantly increased in discrete brain regions of the diabetic rats compared with the age-matched control rats. Hippocampal atrophy, Aβ aggregation, and synapse loss were observed in the diabetic rats compared with the control rats. The learning and memory of the diabetic rats decreased compared with those of the age-matched control rats. Conclusions. Our results suggested that aberrant metabolism induced brain aging as characterized by AD-like pathologies.

Brain Aging and AD-Like Pathology in Streptozotocin-Induced Diabetic Rats

Science.gov (United States)

Wang, Jian-Qin; Yin, Jie; Song, Yan-Feng; Zhang, Lang; Ren, Ying-Xiang; Wang, De-Gui; Gao, Li-Ping; Jing, Yu-Hong

2014-01-01

Objective. Numerous epidemiological studies have linked diabetes mellitus (DM) with an increased risk of developing Alzheimer's disease (AD). However, whether or not diabetic encephalopathy shows AD-like pathology remains unclear. Research Design and Methods. Forebrain and hippocampal volumes were measured using stereology in serial coronal sections of the brain in streptozotocin- (STZ-) induced rats. Neurodegeneration in the frontal cortex, hypothalamus, and hippocampus was evaluated using Fluoro-Jade C (FJC). Aβ aggregation in the frontal cortex and hippocampus was tested using immunohistochemistry and ELISA. Dendritic spine density in the frontal cortex and hippocampus was measured using Golgi staining, and western blot was conducted to detect the levels of synaptophysin. Cognitive ability was evaluated through the Morris water maze and inhibitory avoidant box. Results. Rats are characterized by insulin deficiency accompanied with polydipsia, polyphagia, polyuria, and weight loss after STZ injection. The number of FJC-positive cells significantly increased in discrete brain regions of the diabetic rats compared with the age-matched control rats. Hippocampal atrophy, Aβ aggregation, and synapse loss were observed in the diabetic rats compared with the control rats. The learning and memory of the diabetic rats decreased compared with those of the age-matched control rats. Conclusions. Our results suggested that aberrant metabolism induced brain aging as characterized by AD-like pathologies. PMID:25197672

Acetylcholine esterase activity in mild cognitive impairment and Alzheimer's disease

Energy Technology Data Exchange (ETDEWEB)

Herholz, Karl [University of Manchester, Wolfson Molecular Imaging Centre, Clinical Neuroscience, Manchester (United Kingdom); University of Cologne, Cologne (Germany)

2008-03-15

Impairment of cholinergic neurotransmission is a well-established fact in Alzheimer's disease (AD), but there is controversy about its relevance at the early stages of the disease and in mild cognitive impairment (MCI). In vivo positron emission tomography imaging of cortical acetylcholine esterase (AChE) activity as a marker of cholinergic innervation that is expressed by cholinergic axons and cholinoceptive neurons has demonstrated a reduction of this enzyme activity in manifest AD. The technique is also useful to measure the inhibition of cerebral AChE induced by cholinesterase inhibitors for treatment of dementia symptoms. A reduction of cortical AchE activity was found consistently in all studies of AD and in few cases of MCI who later concerted to AD. The in vivo findings in MCI and very mild AD are still preliminary, and studies seem to suggest that cholinergic innervation and AChE as the main degrading enzyme are both reduced, which might result in partial compensation of their effect. (orig.)

Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation.

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Kauwe, John S K; Bailey, Matthew H; Ridge, Perry G; Perry, Rachel; Wadsworth, Mark E; Hoyt, Kaitlyn L; Staley, Lyndsay A; Karch, Celeste M; Harari, Oscar; Cruchaga, Carlos; Ainscough, Benjamin J; Bales, Kelly; Pickering, Eve H; Bertelsen, Sarah; Fagan, Anne M; Holtzman, David M; Morris, John C; Goate, Alison M

2014-10-01

Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (pprocessing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.

Twistor description of spinning particles in AdS

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Arvanitakis, Alex S.; Barns-Graham, Alec E.; Townsend, Paul K.

2018-01-01

The two-twistor formulation of particle mechanics in D-dimensional anti-de Sitter space for D = 4 , 5 , 7, which linearises invariance under the AdS isometry group Sp(4; K ) for K=R,C,H, is generalized to the massless N -extended "spinning particle". The twistor variables are gauge invariant with respect to the initial N local worldline supersymmetries; this simplifies aspects of the quantum theory such as implications of global gauge anomalies. We also give details of the two-supertwistor form of the superparticle, in particular the massive superparticle on AdS5.

Holography in Lovelock Chern-Simons AdS gravity

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Cvetković, Branislav; Miskovic, Olivera; Simić, Dejan

2017-08-01

We analyze holographic field theory dual to Lovelock Chern-Simons anti-de Sitter (AdS) gravity in higher dimensions using first order formalism. We first find asymptotic symmetries in the AdS sector showing that they consist of local translations, local Lorentz rotations, dilatations and non-Abelian gauge transformations. Then, we compute 1-point functions of energy-momentum and spin currents in a dual conformal field theory and write Ward identities. We find that the holographic theory possesses Weyl anomaly and also breaks non-Abelian gauge symmetry at the quantum level.

Overexpression of E3 Ubiquitin Ligase Gene AdBiL Contributes to Resistance against Chilling Stress and Leaf Mold Disease in Tomato

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Shuangchen Chen

2017-06-01

Full Text Available Ubiquitination is a common regulatory mechanism, playing a critical role in diverse cellular and developmental processes in eukaryotes. However, a few reports on the functional correlation between E3 ubiquitin ligases and reactive oxygen species (ROS or reactive nitrogen species (RNS metabolism in response to stress are currently available in plants. In the present study, the E3 ubiquitin ligase gene AdBiL (Adi3 Binding E3 Ligase was introduced into tomato line Ailsa Craig via Agrobacterium-mediated method. Transgenic lines were confirmed for integration into the tomato genome using PCR. Transcription of AdBiL in various transgenic lines was determined using real-time PCR. Evaluation of stress tolerance showed that T1 generation of transgenic tomato lines showed only mild symptoms of chilling injury as evident by higher biomass accumulation and chlorophyll content than those of non-transformed plants. Compared with wild-type plants, the contents of AsA, AsA/DHA, GSH and the activity of GaILDH, γ-GCS and GSNOR were increased, while H2O2, O2.−, MDA, NO, SNOs, and GSNO accumulations were significantly decreased in AdBiL overexpressing plants in response to chilling stress. Furthermore, transgenic tomato plants overexpressing AdBiL showed higher activities of enzymes such as G6PDH, 6PGDH, NADP-ICDH, and NADP-ME involved in pentose phosphate pathway (PPP. The transgenic tomato plants also exhibited an enhanced tolerance against the necrotrophic fungus Cladosporium fulvum. Tyrosine nitration protein was activated in the plants infected with leaf mold disease, while the inhibition could be recovered in AdBiL gene overexpressing lines. Taken together, our results revealed a possible physiological role of AdBiL in the activation of the key enzymes of AsA–GSH cycle, PPP and down-regulation of GSNO reductase, thereby reducing oxidative and nitrosative stress in plants. This study demonstrates an optimized transgenic strategy using AdBiL gene for crop

Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer's disease: the OmegAD study.

Science.gov (United States)

Freund Levi, Y; Vedin, I; Cederholm, T; Basun, H; Faxén Irving, G; Eriksdotter, M; Hjorth, E; Schultzberg, M; Vessby, B; Wahlund, L-O; Salem, N; Palmblad, J

2014-04-01

Little is known about the transfer of essential fatty acids (FAs) across the human blood-brain barrier (BBB) in adulthood. In this study, we investigated whether oral supplementation with omega-3 (n-3) FAs would change the FA profile of the cerebrospinal fluid (CSF). A total of 33 patients (18 receiving the n-3 FA supplement and 15 receiving placebo) were included in the study. These patients were participants in the double-blind, placebo-controlled randomized OmegAD study in which 204 patients with mild Alzheimer's disease (AD) received 2.3 g n-3 FA [high in docosahexaenoic acid (DHA)] or placebo daily for 6 months. CSF FA levels were related to changes in plasma FA and to CSF biomarkers of AD and inflammation. At 6 months, the n-3 FA supplement group displayed significant increases in CSF (and plasma) eicosapentaenoic acid (EPA), DHA and total n-3 FA levels (P acid were strongly correlated, in contrast to those of DHA. Changes in DHA levels in CSF were inversely correlated with CSF levels of total and phosphorylated tau, and directly correlated with soluble interleukin-1 receptor type II. Thus, the more DHA increased in CSF, the greater the change in CSF AD/inflammatory biomarkers. Oral supplementation with n-3 FAs conferred changes in the n-3 FA profile in CSF, suggesting transfer of these FAs across the BBB in adults. © 2013 The Association for the Publication of the Journal of Internal Medicine.

Inflammaging as a prodrome to Alzheimer's disease

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Rrapo Elona

2008-11-01

Full Text Available Abstract Recently, the term "inflammaging" was coined by Franceshci and colleagues to characterize a widely accepted paradigm that ageing is accompanied by a low-grade chronic up-regulation of certain pro-inflammatory responses. Inflammaging differs significantly from the traditional five cardinal features of acute inflammation in that it is characterized by a relative decline in adaptive immunity and T-helper 2 responses and is associated with increased innate immunity by cells of the mononuclear phagocyte lineage. While the over-active innate immunity characteristic of inflammaging may remain subclinical in many elderly individuals, a portion of individuals (postulated to have a "high responder inflammatory genotype" may shift from a state of "normal" or "subclinical" inflammaging to one or more of a number of age-associated diseases. We and others have found that IFN-γ and other pro-inflammatory cytokines interact with processing and production of Aβ peptide, the pathological hallmark feature of Alzheimer's disease (AD, suggesting that inflammaging may be a "prodrome" to AD. Although conditions of enhanced innate immune response with overproduction of pro-inflammatory proteins are associated with both healthy aging and AD, it is suggested that those who age "well" demonstrate anti-inflammaging mechanisms and biomarkers that likely counteract the adverse immune response of inflammaging. Thus, opposing the features of inflammaging may prevent or treat the symptoms of AD. In this review, we fully characterize the aging immune system. In addition, we explain how three novel treatments, (1 human umbilical cord blood cells (HUCBC, (2 flavanoids, and (3 Aβ vaccination oppose the forces of inflammaging and AD-like pathology in various mouse models.

Exploring AdS waves via nonminimal coupling

International Nuclear Information System (INIS)

Ayon-Beato, Eloy; Hassaiene, Mokhtar

2006-01-01

We consider nonminimally coupled scalar fields to explore the Siklos spacetimes in three dimensions. Their interpretation as exact gravitational waves propagating on AdS space restrict the source to behave as a pure radiation field. We show that the related pure radiation constraints single out a unique self-interaction potential depending on one coupling constant. For a vanishing coupling constant, this potential reduces to a mass term with a mass fixed in terms of the nonminimal-coupling parameter. This mass dependence allows the existence of several free cases including massless and tachyonic sources. There even exists a particular value of the nonminimal-coupling parameter for which the corresponding mass exactly compensates the contribution generated by the negative scalar curvature, producing a genuinely massless field in this curved background. The self-interacting case is studied in detail for the conformal coupling. The resulting gravitational wave is formed by the superposition of the free and the self-interaction contributions, except for a critical value of the coupling constant where a nonperturbative effect relating the strong and weak regimes of the source appears. We establish a correspondence between the scalar source supporting an AdS wave and a pp wave by showing that their respective pure radiation constraints are conformally related, while their involved backgrounds are not. Finally, we consider the AdS waves for topologically massive gravity and its limit to conformal gravity

Proteins Encoded in Genomic Regions Associated with Immune-Mediated Disease Physically Interact and Suggest Underlying Biology

Science.gov (United States)

Rossin, Elizabeth J.; Lage, Kasper; Raychaudhuri, Soumya; Xavier, Ramnik J.; Tatar, Diana; Benita, Yair

2011-01-01

Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed by these risk variants. It has previously been observed that different genes harboring causal mutations for the same Mendelian disease often physically interact. We sought to evaluate the degree to which this is true of genes within strongly associated loci in complex disease. Using sets of loci defined in rheumatoid arthritis (RA) and Crohn's disease (CD) GWAS, we build protein–protein interaction (PPI) networks for genes within associated loci and find abundant physical interactions between protein products of associated genes. We apply multiple permutation approaches to show that these networks are more densely connected than chance expectation. To confirm biological relevance, we show that the components of the networks tend to be expressed in similar tissues relevant to the phenotypes in question, suggesting the network indicates common underlying processes perturbed by risk loci. Furthermore, we show that the RA and CD networks have predictive power by demonstrating that proteins in these networks, not encoded in the confirmed list of disease associated loci, are significantly enriched for association to the phenotypes in question in extended GWAS analysis. Finally, we test our method in 3 non-immune traits to assess its applicability to complex traits in general. We find that genes in loci associated to height and lipid levels assemble into significantly connected networks but did not detect excess connectivity among Type 2 Diabetes (T2D) loci beyond chance. Taken together, our results constitute evidence that, for many of the complex diseases studied here, common genetic associations implicate regions encoding proteins that physically interact in a preferential manner, in

Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes

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Liu, Ying; Liu, Fei; Grundke-Iqbal, Inge; Iqbal, Khalid; Gong, Cheng-Xin

2015-01-01

Brain glucose metabolism is impaired in Alzheimer’s disease (AD), the most common form of dementia. Type 2 diabetes mellitus (T2DM) is reported to increase the risk for dementia, including AD, but the underlying mechanism is not understood. Here, we investigated the brain insulin–PI3K–AKT signalling pathway in the autopsied frontal cortices from nine AD, 10 T2DM, eight T2DM–AD and seven control cases. We found decreases in the levels and activities of several components of the insulin–PI3K–AKT signalling pathway in AD and T2DM cases. The deficiency of insulin–PI3K–AKT signalling was more severe in individuals with both T2DM and AD (T2DM–AD). This decrease in insulin–PI3K–AKT signalling could lead to activation of glycogen synthase kinase-3β, the major tau kinase. The levels and the activation of the insulin–PI3K–AKT signalling components correlated negatively with the level of tau phosphorylation and positively with protein O-GlcNAcylation, suggesting that impaired insulin–PI3K–AKT signalling might contribute to neurodegeneration in AD through down-regulation of O-GlcNAcylation and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration. The decrease in brain insulin–PI3K–AKT signalling also correlated with the activation of calpain I in the brain, suggesting that the decrease might be caused by calpain over-activation. Our findings provide novel insight into the molecular mechanism by which type 2 diabetes mellitus increases the risk for developing cognitive impairment and dementia in Alzheimer’s disease. PMID:21598254

Asymptotically AdS spacetimes with a timelike Kasner singularity

Energy Technology Data Exchange (ETDEWEB)

Ren, Jie [Racah Institute of Physics, The Hebrew University of Jerusalem, Jerusalem 91904 (Israel)

2016-07-21

Exact solutions to Einstein’s equations for holographic models are presented and studied. The IR geometry has a timelike cousin of the Kasner singularity, which is the less generic case of the BKL (Belinski-Khalatnikov-Lifshitz) singularity, and the UV is asymptotically AdS. This solution describes a holographic RG flow between them. The solution’s appearance is an interpolation between the planar AdS black hole and the AdS soliton. The causality constraint is always satisfied. The entanglement entropy and Wilson loops are discussed. The boundary condition for the current-current correlation function and the Laplacian in the IR is examined. There is no infalling wave in the IR, but instead, there is a normalizable solution in the IR. In a special case, a hyperscaling-violating geometry is obtained after a dimensional reduction.

Estimating Free and Added Sugar Intakes in New Zealand

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Rachael Kibblewhite

2017-11-01

Full Text Available The reduction of free or added sugar intake (sugars added to food and drinks as a sweetener is almost universally recommended to reduce the risk of obesity-related diseases and dental caries. The World Health Organisation recommends intakes of free sugars of less than 10% of energy intake. However, estimating and monitoring intakes at the population level is challenging because free sugars cannot be analytically distinguished from naturally occurring sugars and most national food composition databases do not include data on free or added sugars. We developed free and added sugar estimates for the New Zealand (NZ food composition database (FOODfiles 2010 by adapting a method developed for Australia. We reanalyzed the 24 h recall dietary data collected for 4721 adults aged 15 years and over participating in the nationally representative 2008/09 New Zealand Adult Nutrition Survey to estimate free and added sugar intakes. The median estimated intake of free and added sugars was 57 and 49 g/day respectively and 42% of adults consumed less than 10% of their energy intake from free sugars. This approach provides more direct estimates of the free and added sugar contents of New Zealand foods than previously available and will enable monitoring of adherence to free sugar intake guidelines in future.

Estimating Free and Added Sugar Intakes in New Zealand.

Science.gov (United States)

Kibblewhite, Rachael; Nettleton, Alice; McLean, Rachael; Haszard, Jillian; Fleming, Elizabeth; Kruimer, Devonia; Te Morenga, Lisa

2017-11-27

The reduction of free or added sugar intake (sugars added to food and drinks as a sweetener) is almost universally recommended to reduce the risk of obesity-related diseases and dental caries. The World Health Organisation recommends intakes of free sugars of less than 10% of energy intake. However, estimating and monitoring intakes at the population level is challenging because free sugars cannot be analytically distinguished from naturally occurring sugars and most national food composition databases do not include data on free or added sugars. We developed free and added sugar estimates for the New Zealand (NZ) food composition database (FOODfiles 2010) by adapting a method developed for Australia. We reanalyzed the 24 h recall dietary data collected for 4721 adults aged 15 years and over participating in the nationally representative 2008/09 New Zealand Adult Nutrition Survey to estimate free and added sugar intakes. The median estimated intake of free and added sugars was 57 and 49 g/day respectively and 42% of adults consumed less than 10% of their energy intake from free sugars. This approach provides more direct estimates of the free and added sugar contents of New Zealand foods than previously available and will enable monitoring of adherence to free sugar intake guidelines in future.

Estimating Free and Added Sugar Intakes in New Zealand

Science.gov (United States)

Kibblewhite, Rachael; Nettleton, Alice; McLean, Rachael; Haszard, Jillian; Fleming, Elizabeth; Kruimer, Devonia

2017-01-01

The reduction of free or added sugar intake (sugars added to food and drinks as a sweetener) is almost universally recommended to reduce the risk of obesity-related diseases and dental caries. The World Health Organisation recommends intakes of free sugars of less than 10% of energy intake. However, estimating and monitoring intakes at the population level is challenging because free sugars cannot be analytically distinguished from naturally occurring sugars and most national food composition databases do not include data on free or added sugars. We developed free and added sugar estimates for the New Zealand (NZ) food composition database (FOODfiles 2010) by adapting a method developed for Australia. We reanalyzed the 24 h recall dietary data collected for 4721 adults aged 15 years and over participating in the nationally representative 2008/09 New Zealand Adult Nutrition Survey to estimate free and added sugar intakes. The median estimated intake of free and added sugars was 57 and 49 g/day respectively and 42% of adults consumed less than 10% of their energy intake from free sugars. This approach provides more direct estimates of the free and added sugar contents of New Zealand foods than previously available and will enable monitoring of adherence to free sugar intake guidelines in future. PMID:29186927

Confinement, glueballs and strings from deformed AdS

International Nuclear Information System (INIS)

Apreda, Riccardo; Crooks, David E.; Evans, Nick; Petrini, Michela

2004-01-01

We study aspects of confinement in two deformed versions of the AdS/CFT correspondence - the GPPZ dual of N = 1* Yang Mills, and the Yang Mills* N 0 dual. Both geometries describe discrete glueball spectra which we calculate numerically. The results agree at the 10% level with previous AdS/CFT computations in the Klebanov Strassler background and AdS Schwarzchild respectively. We also calculate the spectra of bound states of the massive fermions in these geometries and show that they are light, so not decoupled from the dynamics. We then study the behaviour of Wilson loops in the 10d lifts of these geometries. We find a transition from AdS-like strings in the UV to strings that interact with the unknown physics of the central singularity of the space in the IR. (author)

Gray matter concentration and effective connectivity changes in Alzheimer's disease: a longitudinal structural MRI study

Energy Technology Data Exchange (ETDEWEB)

Li, Xingfeng; Coyle, Damien; Maguire, Liam; Watson, David R.; McGinnity, Thomas M. [University of Ulster, Intelligent Systems Research Centre, Magee Campus, Derry, Northern Ireland (United Kingdom)

2011-10-15

Understanding disease progression in Alzheimer's disease (AD) awaits the resolution of three fundamental questions: first, can we identify the location of ''seed'' regions where neuropathology is first present? Some studies have suggested the medial temporal lobe while others have suggested the hippocampus. Second, are there similar atrophy rates within affected regions in AD? Third, is there evidence of causality relationships between different affected regions in AD progression ?To address these questions, we conducted a longitudinal MRI study to investigate the gray matter (GM) changes in AD progression. Abnormal brain regions were localized by a standard voxel-based morphometry method, and the absolute atrophy rate in these regions was calculated using a robust regression method. Primary foci of atrophy were identified in the hippocampus and middle temporal gyrus (MTG). A model based upon the Granger causality approach was developed to investigate the cause-effect relationship over time between these regions based on GM concentration. Results show that in the earlier stages of AD, primary pathological foci are in the hippocampus and entorhinal cortex. Subsequently, atrophy appears to subsume the MTG. The causality results show that there is in fact little difference between AD and age-matched healthy control in terms of hippocampus atrophy, but there are larger differences in MTG, suggesting that local pathology in MTG is the predominant progressive abnormality during intermediate stages of AD development. (orig.)

CDC Vital Signs-E-cigarette Ads and Youth

Centers for Disease Control (CDC) Podcasts

2016-01-05

This podcast is based on the January 2016 CDC Vital Signs report. Most electronic cigarettes, or e-cigarettes, contain nicotine, which is highly addictive and may harm brain development. More than 18 million middle and high school students were exposed to e-cigarette ads. Exposure to these ads may be contributing to an increase in e-cigarette use among youth. Learn what can be done to keep our youth safe and healthy.  Created: 1/5/2016 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 1/5/2016.

Repeated cognitive stimulation alleviates memory impairments in an Alzheimer's disease mouse model.

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Martinez-Coria, Hilda; Yeung, Stephen T; Ager, Rahasson R; Rodriguez-Ortiz, Carlos J; Baglietto-Vargas, David; LaFerla, Frank M

2015-08-01

Alzheimer's disease is a neurodegenerative disease associated with progressive memory and cognitive decline. Previous studies have identified the benefits of cognitive enrichment on reducing disease pathology. Additionally, epidemiological and clinical data suggest that repeated exercise, and cognitive and social enrichment, can improve and/or delay the cognitive deficiencies associated with aging and neurodegenerative diseases. In the present study, 3xTg-AD mice were exposed to a rigorous training routine beginning at 3 months of age, which consisted of repeated training in the Morris water maze spatial recognition task every 3 months, ending at 18 months of age. At the conclusion of the final Morris water maze training session, animals subsequently underwent testing in another hippocampus-dependent spatial task, the Barnes maze task, and on the more cortical-dependent novel object recognition memory task. Our data show that periodic cognitive enrichment throughout aging, via multiple learning episodes in the Morris water maze task, can improve the memory performance of aged 3xTg-AD mice in a separate spatial recognition task, and in a preference memory task, when compared to naïve aged matched 3xTg-AD mice. Furthermore, we observed that the cognitive enrichment properties of Morris water maze exposer, was detectable in repeatedly trained animals as early as 6 months of age. These findings suggest early repeated cognitive enrichment can mitigate the diverse cognitive deficits observed in Alzheimer's disease. Published by Elsevier Inc.

Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial.

Science.gov (United States)

Porsteinsson, Anton P; Drye, Lea T; Pollock, Bruce G; Devanand, D P; Frangakis, Constantine; Ismail, Zahinoor; Marano, Christopher; Meinert, Curtis L; Mintzer, Jacobo E; Munro, Cynthia A; Pelton, Gregory; Rabins, Peter V; Rosenberg, Paul B; Schneider, Lon S; Shade, David M; Weintraub, Daniel; Yesavage, Jerome; Lyketsos, Constantine G

2014-02-19

Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory. The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability. The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013. Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability. Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events. Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was -0.93 (95% CI, -1.80 to -0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo

Neuroimaging Characteristics of Small-Vessel Disease in Older Adults with Normal Cognition, Mild Cognitive Impairment, and Alzheimer Disease

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Alberto Mimenza-Alvarado

2018-05-01

Full Text Available Introduction: Cerebral small-vessel disease (SVD represents the most frequent type of vascular brain lesions, often coexisting with Alzheimer disease (AD. By quantifying white matter hyperintensities (WMH and hippocampal and parietal atrophy, we aimed to describe the prevalence and severity of SVD among older adults with normal cognition (NC, mild cognitive impairment (MCI, and probable AD and to describe associated risk factors. Methods: This study included 105 older adults evaluated with magnetic resonance imaging and clinical and neuropsychological tests. We used the Fazekas scale (FS for quantification of WMH, the Scheltens scale (SS for hippocampal atrophy, and the Koedam scale (KS for parietal atrophy. Logistic regression models were performed to determine the association between FS, SS, and KS scores and the presence of NC, MCI, or probable AD. Results: Compared to NC subjects, SVD was more prevalent in MCI and probable AD subjects. After adjusting for confounding factors, logistic regression showed a positive association between higher scores on the FS and probable AD (OR = 7.6, 95% CI 2.7–20, p < 0.001. With the use of the SS and KS (OR = 4.5, 95% CI 3.5–58, p = 0.003 and OR = 8.9, 95% CI 1–72, p = 0.04, respectively, the risk also remained significant for probable AD. Conclusions: These results suggest an association between severity of vascular brain lesions and neurodegeneration.

On thermodynamics of AdS black holes in M-theory

International Nuclear Information System (INIS)

Belhaj, A.; Chabab, M.; Masmar, K.; El Moumni, H.; Sedra, M.B.

2016-01-01

Motivated by recent work on asymptotically AdS 4 black holes in M-theory, we investigate the thermodynamics and thermodynamical geometry of AdS black holes from M2- and M5-branes. Concretely, we consider AdS black holes in AdS p+2 x S 11-p-2 , where p = 2,5 by interpreting the number of M2- (and M5-branes) as a thermodynamical variable. More precisely, we study the corresponding phase transition to examine their stabilities by calculating and discussing various thermodynamical quantities including the chemical potential. Then we compute the thermodynamical curvatures from the Quevedo metric for M2- and M5-branes geometries to reconsider the stability of such black holes. The Quevedo metric singularities recover similar stability results provided by the phase-transition program. It has been shown that similar behaviors are also present in the limit of large N. (orig.)

A Grassmann path from AdS3 to flat space

International Nuclear Information System (INIS)

Krishnan, Chethan; Raju, Avinash; Roy, Shubho

2014-01-01

We show that interpreting the inverse AdS 3 radius 1/l as a Grassmann variable results in a formal map from gravity in AdS 3 to gravity in flat space. The underlying reason for this is the fact that ISO(2,1) is the Inonu-Wigner contraction of SO(2,2). We show how this works for the Chern-Simons actions, demonstrate how the general (Banados) solution in AdS 3 maps to the general flat space solution, and how the Killing vectors, charges and the Virasoro algebra in the Brown-Henneaux case map to the corresponding quantities in the BMS 3 case. Our results straightforwardly generalize to the higher spin case: the recently constructed flat space higher spin theories emerge automatically in this approach from their AdS counterparts. We conclude with a discussion of singularity resolution in the BMS gauge as an application

Genome-Wide Analyses Suggest Mechanisms Involving Early B-Cell Development in Canine IgA Deficiency.

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Mia Olsson

Full Text Available Immunoglobulin A deficiency (IgAD is the most common primary immune deficiency disorder in both humans and dogs, characterized by recurrent mucosal tract infections and a predisposition for allergic and other immune mediated diseases. In several dog breeds, low IgA levels have been observed at a high frequency and with a clinical resemblance to human IgAD. In this study, we used genome-wide association studies (GWAS to identify genomic regions associated with low IgA levels in dogs as a comparative model for human IgAD. We used a novel percentile groups-approach to establish breed-specific cut-offs and to perform analyses in a close to continuous manner. GWAS performed in four breeds prone to low IgA levels (German shepherd, Golden retriever, Labrador retriever and Shar-Pei identified 35 genomic loci suggestively associated (p <0.0005 to IgA levels. In German shepherd, three genomic regions (candidate genes include KIRREL3 and SERPINA9 were genome-wide significantly associated (p <0.0002 with IgA levels. A ~20kb long haplotype on CFA28, significantly associated (p = 0.0005 to IgA levels in Shar-Pei, was positioned within the first intron of the gene SLIT1. Both KIRREL3 and SLIT1 are highly expressed in the central nervous system and in bone marrow and are potentially important during B-cell development. SERPINA9 expression is restricted to B-cells and peaks at the time-point when B-cells proliferate into antibody-producing plasma cells. The suggestively associated regions were enriched for genes in Gene Ontology gene sets involving inflammation and early immune cell development.

Heterogeneity in Red Wine Polyphenolic Contents Differentially Influences Alzheimer's Disease-type Neuropathology and Cognitive Deterioration

Science.gov (United States)

Ho, Lap; Chen, Ling Hong; Wang, Jun; Zhao, Wei; Talcott, Stephen T.; Ono, Kenjiro; Teplow, David; Humala, Nelson; Cheng, Alice; Percival, Susan S.; Ferruzzi, Mario; Janle, Elsa; Dickstein, Dara L.; Pasinetti, Giulio Maria

2009-01-01

We recently found that moderate consumption of two unrelated red wines generate from different grape species, a Cabernet Sauvignon and a muscadine wine that are characterized by distinct component composition of polyphenolic compounds, significantly attenuated the development of Alzheimer's disease (AD)-type brain pathology and memory deterioration in a transgenic AD mouse model. Interestingly, our evidence suggests that the two red wines attenuated AD phenotypes through independent mechanisms. In particular, we previously found that treatment with Cabernet Sauvignon reduced the generation of AD-type amyloid-β (Aβ) peptides. In contrast, evidence from our present study suggests that muscadine treatment attenuates Aβ neuropathology and Aβ-related cognitive deterioration in Tg2576 mice by interfering with the oligomerization of Aβ molecules to soluble high-molecular-weight Aβ oligomer species that are responsible for initiating a cascade of cellular events resulting in cognitive decline. Collectively, our observations suggest that distinct polyphenolic compounds from red wines may be bioavailable at the organism level and beneficially modulate AD phenotypes through multiple Aβ-related mechanisms. Results from these studies suggest the possibility of developing a “combination” of dietary polyphenolic compounds for AD prevention and/or therapy by modulating multiple Aβ-related mechanisms. PMID:19158422

Negative Prospective Memory in Alzheimer's Disease: "Do Not Perform That Action".

Science.gov (United States)

El Haj, Mohamad; Coello, Yann; Kapogiannis, Dimitrios; Gallouj, Karim; Antoine, Pascal

2018-01-01

Relatively to "standard" prospective memory, i.e., remembering to perform a future action, little is known about negative prospective memory, i.e., remembering not to perform a future action. This study investigated the latter ability in Alzheimer's disease (AD). AD participants and healthy older adults were asked to click on the keyboard or not to click on it when a cue word was encountered. Results showed more omissions (i.e., forgetting to click the keyboard when the instruction was to do so) in AD participants than in healthy older adults, suggesting a prospective memory deficit. Interestingly, more commissions (i.e., clicking the keyboard when the instruction was not to do so) were also observed in AD participants than in healthy older adults. Similar levels of commissions and omissions were observed in AD participants and in healthy older adults. Also, commissions and omissions were correlated with performance on an inhibition assessment task. Our findings reveal that AD is characterized by not only difficulty in the retrieval of recent information, but also difficulty to inhibit no-longer appropriate stimulus-response associations previously learned, suggesting a specific deficit of negative prospective memory in AD.

Liver X receptor activation restores memory in aged AD mice without reducing amyloid

NARCIS (Netherlands)

Vanmierlo, Tim; Rutten, Kris; Dederen, Jos; Bloks, Vincent W.; van Vark-van der Zee, Leonie C.; Kuipers, Folkert; Kiliaan, Amanda; Blokland, Arjan; Sijbrands, Eric J. G.; Steinbusch, Harry; Prickaerts, Jos; Luetjohann, Dieter; Mulder, Monique

Alterations in cerebral cholesterol metabolism are thought to play a role in the progression of Alzheimer's disease (AD). Liver X receptors (LXRs) are key regulators of cholesterol metabolism. The synthetic LXR activator, T0901317 has been reported to improve memory functions in animal models for AD

18F-FDG PET diagnostic and prognostic patterns do not overlap in Alzheimer's disease (AD) patients at the mild cognitive impairment (MCI) stage

International Nuclear Information System (INIS)

Morbelli, Silvia; Bauckneht, Matteo; Buschiazzo, Ambra; Nieri, Alberto; Sambuceti, Gianmario; Pagani, Marco; De Carli, Fabrizio

2017-01-01

We aimed to identify the cortical regions where hypometabolism can predict the speed of conversion to dementia in mild cognitive impairment due to Alzheimer's disease (MCI-AD). We selected from the clinical database of our tertiary center memory clinic, eighty-two consecutive MCI-AD that underwent 18F-fluorodeoxyglucose (FDG) PET at baseline during the first diagnostic work-up and were followed up at least until their clinical conversion to AD dementia. The whole group of MCI-AD was compared in SPM8 with a group of age-matched healthy controls (CTR) to verify the presence of AD diagnostic-pattern; then the correlation between conversion time and brain metabolism was assessed to identify the prognostic-pattern. Significance threshold was set at p < 0.05 False-Discovery-Rate (FDR) corrected at peak and at cluster level. Each MCI-AD was then compared with CTR by means of a SPM single-subject analysis and grouped according to presence of AD diagnostic-pattern and prognostic-pattern. Kaplan-Meier-analysis was used to evaluate if diagnostic- and/or prognostic-patterns can predict speed of conversion to dementia. Diagnostic-pattern corresponded to typical posterior hypometabolism (BA 7, 18, 19, 30, 31 and 40) and did not correlate with time to conversion, which was instead correlated with metabolic levels in right middle and inferior temporal gyri as well as in the fusiform gyrus (prognostic-pattern, BA 20, 21 and 38). At Kaplan-Meier analysis, patients with hypometabolism in the prognostic pattern converted to AD-dementia significantly earlier than patients not showing significant hypometabolism in the right middle and inferior temporal cortex (9 versus 19 months; Log rank p < 0.02, Breslow test: p < 0.003, Tarone-Ware test: p < 0.007). The present findings support the role of FDG PET as a robust progression biomarker even in a naturalist population of MCI-AD. However, not the AD-typical diagnostic-pattern in posterior regions but the middle and inferior temporal

18F-FDG PET diagnostic and prognostic patterns do not overlap in Alzheimer's disease (AD) patients at the mild cognitive impairment (MCI) stage

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Morbelli, Silvia; Bauckneht, Matteo; Buschiazzo, Ambra; Nieri, Alberto; Sambuceti, Gianmario [Genoa Univ. (Italy). Dept. of Health Sciences; IRCCS AOU San Martino-IST, Genoa (Italy). Nuclear Medicine Unit; Arnaldi, Dario; Picco, Agnese; Pardini, Matteo; Brugnolo, Andrea; Girtler, Nicola; Nobili, Flavio [Genoa Univ. (Italy). Clinical Neurology, Department of Neuroscience (DINOGMI); IRCCS AOU San Martino-IST, Genoa (Italy); Pagani, Marco [Institute of Cognitive Sciences and Technologies, Rome (Italy); Karolinska Hospital, Stockholm (Sweden). Department of Nuclear Medicine; Chincarini, Andrea [Istituto Nazionale di Fisica Nucleare, Genoa (Italy); De Carli, Fabrizio [National Research Council, Genoa (Italy). Institute of Bioimaging and Molecular Physiology

2017-11-15

We aimed to identify the cortical regions where hypometabolism can predict the speed of conversion to dementia in mild cognitive impairment due to Alzheimer's disease (MCI-AD). We selected from the clinical database of our tertiary center memory clinic, eighty-two consecutive MCI-AD that underwent 18F-fluorodeoxyglucose (FDG) PET at baseline during the first diagnostic work-up and were followed up at least until their clinical conversion to AD dementia. The whole group of MCI-AD was compared in SPM8 with a group of age-matched healthy controls (CTR) to verify the presence of AD diagnostic-pattern; then the correlation between conversion time and brain metabolism was assessed to identify the prognostic-pattern. Significance threshold was set at p < 0.05 False-Discovery-Rate (FDR) corrected at peak and at cluster level. Each MCI-AD was then compared with CTR by means of a SPM single-subject analysis and grouped according to presence of AD diagnostic-pattern and prognostic-pattern. Kaplan-Meier-analysis was used to evaluate if diagnostic- and/or prognostic-patterns can predict speed of conversion to dementia. Diagnostic-pattern corresponded to typical posterior hypometabolism (BA 7, 18, 19, 30, 31 and 40) and did not correlate with time to conversion, which was instead correlated with metabolic levels in right middle and inferior temporal gyri as well as in the fusiform gyrus (prognostic-pattern, BA 20, 21 and 38). At Kaplan-Meier analysis, patients with hypometabolism in the prognostic pattern converted to AD-dementia significantly earlier than patients not showing significant hypometabolism in the right middle and inferior temporal cortex (9 versus 19 months; Log rank p < 0.02, Breslow test: p < 0.003, Tarone-Ware test: p < 0.007). The present findings support the role of FDG PET as a robust progression biomarker even in a naturalist population of MCI-AD. However, not the AD-typical diagnostic-pattern in posterior regions but the middle and inferior temporal

Infantile Refsum's disease: biochemical findings suggesting multiple peroxisomal dysfunction

NARCIS (Netherlands)

Poll-The, B. T.; Saudubray, J. M.; Ogier, H.; Schutgens, R. B.; Wanders, R. J.; Schrakamp, G.; van den Bosch, H.; Trijbels, J. M.; Poulos, A.; Moser, H. W.

1986-01-01

Infantile Refsum's disease was diagnosed in three male patients, presenting with facial dysmorphia, retinitis pigmentosa, neurosensory hearing loss, hepatomegaly, osteopenia and delayed growth and psychomotor development. An elevated plasma phytanic acid concentration and a deficient phytanic acid

Gender-Specific Neuroimmunoendocrine Response to Treadmill Exercise in 3xTg-AD Mice

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Lydia Giménez-Llort

2010-01-01

Full Text Available The 3xTg-AD mouse develops a progressive Alzheimer's disease- (AD- like brain pathology that causes cognitive- and neuropsychiatric-like symptoms of dementia. Since its neuroimmunoendocrine axis is likewise impaired, this mouse is also useful for modelling complex age-related neurodegeneration. This study analyzed behavioral, physiological, neurochemical, pathological and immunoendocrine alterations in male and female 3xTg-AD mice and assayed the effects of a short therapy of forced physical exercise at the moderate pathology stage of 6 months of age. Gender effects were observed in most AD-related pathology and dysfunctions. Five weeks of treadmill training produced beneficial effects, such as the reduction of brain oxidative stress and GABA-A receptor dysfunction in males and improvement of sensorimotor function in females. In both sexes, exercise decreased the brain amyloid 42/40 ratio levels. The results highlight the importance of analyzing experimental therapies in both mouse model genders in order to improve our understanding of the disease and develop more appropriate therapies.

Vacuum degeneracy and Conformal Mass in Lovelock AdS gravity

Science.gov (United States)

Arenas-Henriquez, Gabriel; Miskovic, Olivera; Olea, Rodrigo

2017-11-01

It is shown that the notion of Conformal Mass can be defined within a given anti-de Sitter (AdS) branch of a Lovelock gravity theory as long as the corresponding vacuum is not degenerate. Indeed, conserved charges obtained by the addition of Kounterterms to the bulk action turn out to be proportional to the electric part of the Weyl tensor, when the fall-off of a generic solution in that AdS branch is considered. The factor of proportionality is the degeneracy condition for the vacua in the particular Lovelock AdS theory under study. This last feature explains the obstruction to define Conformal Mass in the degenerate case.

Structural brain differences between monolingual and multilingual patients with mild cognitive impairment and Alzheimer disease: Evidence for cognitive reserve.

Science.gov (United States)

Duncan, Hilary D; Nikelski, Jim; Pilon, Randi; Steffener, Jason; Chertkow, Howard; Phillips, Natalie A

2018-01-31

Two independent lines of research provide evidence that speaking more than one language may 1) contribute to increased grey matter in healthy younger and older adults and 2) delay cognitive symptoms in mild cognitive impairment (MCI) or Alzheimer disease (AD). We examined cortical thickness and tissue density in monolingual and multilingual MCI and AD patients matched (within Diagnosis Groups) on demographic and cognitive variables. In medial temporal disease-related (DR) areas, we found higher tissue density in multilingual MCIs versus monolingual MCIs, but similar or lower tissue density in multilingual AD versus monolingual AD, a pattern consistent with cognitive reserve in AD. In areas related to language and cognitive control (LCC), both multilingual MCI and AD patients had thicker cortex than the monolinguals. Results were largely replicated in our native-born Canadian MCI participants, ruling out immigration as a potential confound. Finally, multilingual patients showed a correlation between cortical thickness in LCC regions and performance on episodic memory tasks. Given that multilinguals and monolinguals were matched on memory functioning, this suggests that increased gray matter in these regions may provide support to memory functioning. Our results suggest that being multilingual may contribute to increased gray matter in LCC areas and may also delay the cognitive effects of disease-related atrophy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer's disease.

Science.gov (United States)

Lee, Jong Kil; Jin, Hee Kyung; Park, Min Hee; Kim, Bo-ra; Lee, Phil Hyu; Nakauchi, Hiromitsu; Carter, Janet E; He, Xingxuan; Schuchman, Edward H; Bae, Jae-sung

2014-07-28

In Alzheimer's disease (AD), abnormal sphingolipid metabolism has been reported, although the pathogenic consequences of these changes have not been fully characterized. We show that acid sphingomyelinase (ASM) is increased in fibroblasts, brain, and/or plasma from patients with AD and in AD mice, leading to defective autophagic degradation due to lysosomal depletion. Partial genetic inhibition of ASM (ASM(+/-)) in a mouse model of familial AD (FAD; amyloid precursor protein [APP]/presenilin 1 [PS1]) ameliorated the autophagocytic defect by restoring lysosomal biogenesis, resulting in improved AD clinical and pathological findings, including reduction of amyloid-β (Aβ) deposition and improvement of memory impairment. Similar effects were noted after pharmacologic restoration of ASM to the normal range in APP/PS1 mice. Autophagic dysfunction in neurons derived from FAD patient induced pluripotent stem cells (iPSCs) was restored by partial ASM inhibition. Overall, these results reveal a novel mechanism of ASM pathogenesis in AD that leads to defective autophagy due to impaired lysosomal biogenesis and suggests that partial ASM inhibition is a potential new therapeutic intervention for the disease. © 2014 Lee et al.

Sources of Added Sugars in Young Children, Adolescents, and Adults with Low and High Intakes of Added Sugars.

Science.gov (United States)

Bailey, Regan L; Fulgoni, Victor L; Cowan, Alexandra E; Gaine, P Courtney

2018-01-17

High intake of added sugars is associated with excess energy intake and poorer diet quality. The objective of this cross-sectional study ( n = 16,806) was to estimate usual intakes and the primary food sources of added sugars across the range of intakes (i.e., deciles) among U.S. children (2-8 years), adolescents and teens (9-18 years), and adults (≥19 years) using the National Health and Nutrition Examination (NHANES) data from 2009-2012. The percent energy contributed by added sugars was 14.3 ± 0.2% (2-8 years), 16.2 ± 0.2% (9-18 years), and 13.1 ± 0.2% (≥19 years), suggesting the highest intakes are among adolescents and teens. However, the primary foods/beverages that contribute to added sugars were remarkably consistent across the range of intakes, with the exception of the lowest decile, and include sweetened beverages and sweet bakery products. Interestingly across all age groups, even those in the lowest decile of added sugars exceed the 10% guidelines. Additional foods contributing to high intakes were candy and other desserts (e.g., ice cream) in children and adolescents, and coffee and teas in adults. Tailoring public health messaging to reduce intakes of these identified food groups may be of utility in designing effective strategies to reduce added sugar intake in the U.S.

Sources of Added Sugars in Young Children, Adolescents, and Adults with Low and High Intakes of Added Sugars

Directory of Open Access Journals (Sweden)

Regan L. Bailey

2018-01-01

Full Text Available High intake of added sugars is associated with excess energy intake and poorer diet quality. The objective of this cross-sectional study (n = 16,806 was to estimate usual intakes and the primary food sources of added sugars across the range of intakes (i.e., deciles among U.S. children (2–8 years, adolescents and teens (9–18 years, and adults (≥19 years using the National Health and Nutrition Examination (NHANES data from 2009–2012. The percent energy contributed by added sugars was 14.3 ± 0.2% (2–8 years, 16.2 ± 0.2% (9–18 years, and 13.1 ± 0.2% (≥19 years, suggesting the highest intakes are among adolescents and teens. However, the primary foods/beverages that contribute to added sugars were remarkably consistent across the range of intakes, with the exception of the lowest decile, and include sweetened beverages and sweet bakery products. Interestingly across all age groups, even those in the lowest decile of added sugars exceed the 10% guidelines. Additional foods contributing to high intakes were candy and other desserts (e.g., ice cream in children and adolescents, and coffee and teas in adults. Tailoring public health messaging to reduce intakes of these identified food groups may be of utility in designing effective strategies to reduce added sugar intake in the U.S.

Sources of Added Sugars in Young Children, Adolescents, and Adults with Low and High Intakes of Added Sugars

Science.gov (United States)

Fulgoni, Victor L.; Cowan, Alexandra E.; Gaine, P. Courtney

2018-01-01

High intake of added sugars is associated with excess energy intake and poorer diet quality. The objective of this cross-sectional study (n = 16,806) was to estimate usual intakes and the primary food sources of added sugars across the range of intakes (i.e., deciles) among U.S. children (2–8 years), adolescents and teens (9–18 years), and adults (≥19 years) using the National Health and Nutrition Examination (NHANES) data from 2009–2012. The percent energy contributed by added sugars was 14.3 ± 0.2% (2–8 years), 16.2 ± 0.2% (9–18 years), and 13.1 ± 0.2% (≥19 years), suggesting the highest intakes are among adolescents and teens. However, the primary foods/beverages that contribute to added sugars were remarkably consistent across the range of intakes, with the exception of the lowest decile, and include sweetened beverages and sweet bakery products. Interestingly across all age groups, even those in the lowest decile of added sugars exceed the 10% guidelines. Additional foods contributing to high intakes were candy and other desserts (e.g., ice cream) in children and adolescents, and coffee and teas in adults. Tailoring public health messaging to reduce intakes of these identified food groups may be of utility in designing effective strategies to reduce added sugar intake in the U.S. PMID:29342109

Imaging epigenetics in Alzheimer's disease.

Science.gov (United States)

Lista, Simone; Garaci, Francesco G; Toschi, Nicola; Hampel, Harald

2013-01-01

Sporadic Alzheimer's disease (AD) is a prevalent, complex and chronically progressive brain disease. Its course is non-linear, dynamic, adaptive to maladaptive, and compensatory to decompensatory, affecting large-scale neural networks through a plethora of mechanistic and signaling pathway alterations that converge into regional and cell type-specific neurodegeneration and, finally, into clinically overt cognitive and behavioral decline. This decline includes reductions in the activities of daily living, quality of life, independence, and life expectancy. Evolving lines of research suggest that epigenetic mechanisms may play a crucial role during AD development and progression. Epigenetics designates molecular mechanisms that alter gene expression without modifications of the genetic code. This topic includes modifications on DNA and histone proteins, the primary elements of chromatin structure. Accumulating evidence has revealed the relevant processes that mediate epigenetic modifications and has begun to elucidate how these processes are apparently dysregulated in AD. This evidence has led to the clarification of the roles of specific classes of therapeutic compounds that affect epigenetic pathways and characteristics of the epigenome. This insight is accompanied by the development of new methods for studying the global patterns of DNA methylation and chromatin alterations. In particular, high-throughput sequencing approaches, such as next-generation DNA sequencing techniques, are beginning to drive the field into the next stage of development. In parallel, genetic imaging is beginning to answer additional questions through its ability to uncover genetic variants, with or without genome-wide significance, that are related to brain structure, function and metabolism, which impact disease risk and fundamental network-based cognitive processes. Neuroimaging measures can further be used to define AD systems and endophenotypes. The integration of genetic neuroimaging

Myelodysplastic Syndromes (MDS) and autoimmune disorders (AD): cause or consequence?

Science.gov (United States)

Braun, Thorsten; Fenaux, Pierre

2013-12-01

Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) are frequently associated with clinical manifestations of autoimmune disorders (AD) and inflammatory response of the immune system. AD accompanying MDS and CMML include vasculitis, seronegative polyarthritis and neutrophilic dermatosis. Rare AD including relapsing polychondritis is strongly associated with MDS as in a high proportion of those patients MDS is diagnosed during disease course. Antinuclear antibodies (ANA) are frequently found among MDS patients without clinical manifestation of AD. In a subset of patients, MDS and resulting cytopenias appear to be the consequence of auto reactive immunologic activity and may respond to immunosuppressive treatment (IST). Increased release of inflammatory cytokines like tumor necrosis factor-(TNF)-α and interferon (IF)-γ triggers apoptosis of myeloid precursor cells leading to cytopenias. Impaired function of immune cells including cytotoxic, regulatory (Treg), helper (Th17) T cells and NK cells also appears to predict response to IST, outcome and occurrence of AD. Copyright © 2013 Elsevier Ltd. All rights reserved.

Angiotensins in Alzheimer's disease - friend or foe?

Science.gov (United States)

Kehoe, Patrick G; Miners, Scott; Love, Seth

2009-12-01

The renin-angiotensin system (RAS) is an important regulator of blood pressure. Observational and experimental studies suggest that alterations in blood pressure and components of the brain RAS contribute to the development and progression of Alzheimer's disease (AD), resulting in changes that can lead or contribute to cognitive decline. The complexity of the RAS and diversity of its interactions with neurological processes have recently become apparent but large gaps in our understanding still remain. Modulation of activity of components of the brain RAS offers substantial opportunities for the treatment and prevention of dementia, including AD. This paper reviews molecular, genetic, experimental and clinical data as well as the therapeutic opportunities that relate to the involvement of the RAS in AD.

Mitochondrial DNA differentiates Alzheimer's disease from Creutzfeldt-Jakob disease.

Science.gov (United States)

Podlesniy, Petar; Llorens, Franc; Golanska, Ewa; Sikorska, Beata; Liberski, Pawel; Zerr, Inga; Trullas, Ramon

2016-05-01

Low content of cell-free mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) is a biomarker of early stage Alzheimer's disease (AD), but whether mtDNA is altered in a rapid neurodegenerative dementia such as Creutzfeldt-Jakob disease is unknown. CSF mtDNA was measured using digital polymerase chain reaction (dPCR) in two independent cohorts comprising a total of 112 patients diagnosed with sporadic Creutzfeldt-Jakob disease (sCJD), probable AD, or non-Alzheimer's type dementia. Patients with AD exhibit low mtDNA content in CSF compared with patients diagnosed with sCJD or with non-Alzheimer's type dementias. The CSF concentration of mtDNA does not correlate with Aβ, t-tau, p-tau, and 14-3-3 protein levels in CSF. Low-CSF mtDNA is not a consequence of brain damage and allows the differential diagnosis of AD from sCJD and other dementias. These results support the hypothesis that mtDNA in CSF is a pathophysiological biomarker of AD. Copyright © 2015 Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Perturbative entanglement thermodynamics for AdS spacetime: renormalization

International Nuclear Information System (INIS)

Mishra, Rohit; Singh, Harvendra

2015-01-01

We study the effect of charged excitations in the AdS spacetime on the first law of entanglement thermodynamics. It is found that ‘boosted’ AdS black holes give rise to a more general form of first law which includes chemical potential and charge density. To obtain this result we have to resort to a second order perturbative calculation of entanglement entropy for small size subsystems. At first order the form of entanglement law remains unchanged even in the presence of charged excitations. But the thermodynamic quantities have to be appropriately ‘renormalized’ at the second order due to the corrections. We work in the perturbative regime where T thermal ≪T E .

Lack of Association between the GPR3 Gene and the Risk for Alzheimer's Disease

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Roberto Dominici

2011-01-01

Full Text Available Alzheimer's disease is the most frequent form of dementia and its incidence is rapidly increasing. Genetic factors are important determinants of the individual susceptibility to the disease and many efforts have been made to identify loci and markers involved. Recent finding describes the GPR3 gene as a modulator of β-amyloid production, suggesting that perturbation of its activity and function may contribute to the pathogenesis of AD. Furthermore, the gene is located at chromosome 1, in a region proposed as a susceptibility locus for the disease. We searched for nucleotide variations in the coding sequence and in the region 5 prime of it by dHPLC and analysed their distribution in a group of 104 AD patients and 109 age-matched controls. We identified 5 types of variation, two in the putative promoter region (g.27718954A>G and g.27719102A>T and the others in exon 2 (c.51C>A, c.80C>G, and c.771C>T. All of them were equally represented in the two cohorts of the study, thus suggesting the absence of an association between GPR3 gene and AD in our population.

Naturalism about health and disease: adding nuance for progress.

Science.gov (United States)

Kingma, Elselijn

2014-12-01

The literature on health and diseases is usually presented as an opposition between naturalism and normativism. This article argues that such a picture is too simplistic: there is not one opposition between naturalism and normativism, but many. I distinguish four different domains where naturalist and normativist claims can be contrasted: (1) ordinary usage, (2) conceptually clean versions of "health" and "disease," (3) the operationalization of dysfunction, and (4) the justification for that operationalization. In the process I present new arguments in response to Schwartz (2007) and Hausman (2012) and expose a link between the arguments made by Schwartz (2007) and Kingma (2010). Distinguishing naturalist claims at these four domains will allow us to make progress by (1) providing more nuanced, intermediate positions about a possible role for values in health and disease; and (2) assisting in the addressing of relativistic worries about the value-ladenness of health and disease. © The Author 2014. Published by Oxford University Press, on behalf of the Journal of Medicine and Philosophy Inc. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Heavy ion collisions in AdS5

International Nuclear Information System (INIS)

Kovchegov, Yuri V.

2011-01-01

We study heavy ion collisions at strong 't Hooft coupling using AdS/CFT correspondence. Heavy ion collisions correspond to gravitational shock wave collisions in AdS 5 . We construct the metric in the forward light cone after the collision perturbatively through expansion of Einstein equations in graviton exchanges. We obtain an analytic expression for the metric including all-order graviton exchanges with one shock wave, while keeping the exchanges with another shock wave at the lowest order. We read off the corresponding energy-momentum tensor of the produced medium. Unfortunately this energy-momentum tensor does not correspond to ideal hydrodynamics, indicating that higher order graviton exchanges are needed to construct the full solution of the problem. We also show that shock waves must completely stop almost immediately after the collision in AdS 5 , which, on the field theory side, corresponds to complete nuclear stopping due to strong coupling effects, likely leading to Landau hydrodynamics. Finally, we perform trapped surface analysis of the shock wave collisions demonstrating that a bulk black hole, corresponding to ideal hydrodynamics on the boundary, has to be created in such collisions, thus constructing a proof of thermalization in heavy ion collisions at strong coupling.

Why Do We Get Alzheimer's Disease?

International Nuclear Information System (INIS)

Wyss-Coray, Tony

2006-01-01

Neurodegenerative diseases and Alzheimer's disease (AD) in particular, are among the major health concerns of the elderly in industrialized societies. The cause of AD is unknown and no disease-modifying treatments are available. The disease is characterized clinically by a progressive dementia and pathologically by the accumulation of protein aggregates in the brain and a profound loss of nerve cells. It has also become clear recently that local immune responses are activated in the AD brain and may have a role in the disease. Our laboratory uses genetic mouse models to understand the disease process and to identify potential therapeutic targets.

Supersymmetric giant graviton solutions in AdS3

International Nuclear Information System (INIS)

Mandal, Gautam; Raju, Suvrat; Smedbaeck, Mikael

2008-01-01

We parametrize all classical probe brane configurations that preserve four supersymmetries in (a) the extremal D1-D5 geometry, (b) the extremal D1-D5-P geometry, (c) the smooth D1-D5 solutions proposed by Lunin and Mathur, and (d) global AdS 3 xS 3 xT 4 /K3. These configurations consist of D1 branes, D5 branes, and bound states of D5 and D1 branes with the property that a particular Killing vector is tangent to the brane world volume at each point. We show that the supersymmetric sector of the D5-brane world volume theory may be analyzed in an effective 1+1 dimensional framework that places it on the same footing as D1 branes. In global AdS and the corresponding Lunin-Mathur solution, the solutions we describe are ''bound'' to the center of AdS for generic parameters and cannot escape to infinity. We show that these probes only exist on the submanifold of moduli space where the background B NS field and theta angle vanish. We quantize these probes in the near-horizon region of the extremal D1-D5 geometry and obtain the theory of long strings discussed by Seiberg and Witten

Analytical study on holographic superfluid in AdS soliton background

International Nuclear Information System (INIS)

Lai, Chuyu; Pan, Qiyuan; Jing, Jiliang; Wang, Yongjiu

2016-01-01

We analytically study the holographic superfluid phase transition in the AdS soliton background by using the variational method for the Sturm–Liouville eigenvalue problem. By investigating the holographic s-wave and p-wave superfluid models in the probe limit, we observe that the spatial component of the gauge field will hinder the phase transition. Moreover, we note that, different from the AdS black hole spacetime, in the AdS soliton background the holographic superfluid phase transition always belongs to the second order and the critical exponent of the system takes the mean-field value in both s-wave and p-wave models. Our analytical results are found to be in good agreement with the numerical findings.

Associations Between Cerebral Small-Vessel Disease and Alzheimer Disease Pathology as Measured by Cerebrospinal Fluid Biomarkers

NARCIS (Netherlands)

Kester, M.I.; Goos, J.D.C.; Teunissen, C.E.; Benedictus, M.R.; Bouwman, F.H.; Wattjes, M.P.; Barkhof, F.; Scheltens, P.; van der Flier, W.M.

2014-01-01

IMPORTANCE: It remains unclear if and how associations between cerebral small-vessel disease and Alzheimer disease (AD) pathology lead to cognitive decline and dementia. OBJECTIVE: To determine associations between small-vessel disease and AD pathology. DESIGN, SETTING, AND PARTICIPANTS:

Genetic association between ghrelin polymorphisms and Alzheimer's disease in a Japanese population.

Science.gov (United States)

Shibata, Nobuto; Ohnuma, Tohru; Kuerban, Bolati; Komatsu, Miwa; Arai, Heii

2011-01-01

Ghrelin has been reported to enter the hippocampus and to bind to the neurons of the hippocampal formation. This peptide also affects neuronal glucose uptake and decreases tau hyperphosphorylation. There is increasing evidence suggesting an association between ghrelin and Alzheimer's disease (AD) pathology. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) of the ghrelin gene are associated with AD. The SNPs were genotyped using TaqMan technology and were analyzed using a case-control study design. Our case-control dataset consisted of 182 AD patients and 143 age-matched controls. Hardy-Weinberg equilibrium and linkage disequilibrium analyses suggest that the region in and around the gene is highly polymorphic. One SNP, rs4684677 (Leu90Gln), showed a marginal association with age of AD onset. We did not detect any association between the other SNPs of the ghrelin gene and AD. There have been few genetic studies on the relationship between circulating ghrelin and functional SNPs. Further multifactorial studies are needed to clarify the relationship between ghrelin and AD. Copyright © 2011 S. Karger AG, Basel.

Agrin in Alzheimer's Disease: Altered Solubility and Abnormal Distribution within Microvasculature and Brain Parenchyma

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Donahue, John E.; Berzin, Tyler M.; Rafii, Michael S.; Glass, David J.; Yancopoulos, George D.; Fallon, Justin R.; Stopa, Edward G.

1999-05-01

Agrin is a heparan sulfate proteoglycan that is widely expressed in neurons and microvascular basal lamina in the rodent and avian central nervous system. Agrin induces the differentiation of nerve-muscle synapses, but its function in either normal or diseased brains is not known. Alzheimer's disease (AD) is characterized by loss of synapses, changes in microvascular architecture, and formation of neurofibrillary tangles and senile plaques. Here we have asked whether AD causes changes in the distribution and biochemical properties of agrin. Immunostaining of normal, aged human central nervous system revealed that agrin is expressed in neurons in multiple brain areas. Robust agrin immunoreactivity was observed uniformly in the microvascular basal lamina. In AD brains, agrin is highly concentrated in both diffuse and neuritic plaques as well as neurofibrillary tangles; neuronal expression of agrin also was observed. Furthermore, patients with AD had microvascular alterations characterized by thinning and fragmentation of the basal lamina. Detergent extraction and Western blotting showed that virtually all the agrin in normal brain is soluble in 1% SDS. In contrast, a large fraction of the agrin in AD brains is insoluble under these conditions, suggesting that it is tightly associated with β -amyloid. Together, these data indicate that the agrin abnormalities observed in AD are closely linked to β -amyloid deposition. These observations suggest that altered agrin expression in the microvasculature and the brain parenchyma contribute to the pathogenesis of AD.

Omega-3 Fatty Acids in Early Prevention of Inflammatory Neurodegenerative Disease: A Focus on Alzheimer’s Disease

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J. Thomas

2015-01-01

Full Text Available Alzheimer’s disease (AD is the leading cause of dementia and the most common neurodegenerative disease in the elderly. Furthermore, AD has provided the most positive indication to support the fact that inflammation contributes to neurodegenerative disease. The exact etiology of AD is unknown, but environmental and genetic factors are thought to contribute, such as advancing age, family history, presence of chronic diseases such as cardiovascular disease (CVD and diabetes, and poor diet and lifestyle. It is hypothesised that early prevention or management of inflammation could delay the onset or reduce the symptoms of AD. Normal physiological changes to the brain with ageing include depletion of long chain omega-3 fatty acids and brains of AD patients have lower docosahexaenoic acid (DHA levels. DHA supplementation can reduce markers of inflammation. This review specifically focusses on the evidence in humans from epidemiological, dietary intervention, and supplementation studies, which supports the role of long chain omega-3 fatty acids in the prevention or delay of cognitive decline in AD in its early stages. Longer term trials with long chain omega-3 supplementation in early stage AD are warranted. We also highlight the importance of overall quality and composition of the diet to protect against AD and dementia.

Joule-Thomson expansion of the charged AdS black holes

International Nuclear Information System (INIS)

Oekcue, Oezguer; Aydiner, Ekrem

2017-01-01

In this paper, we study Joule-Thomson effects for charged AdS black holes. We obtain inversion temperatures and curves. We investigate similarities and differences between van der Waals fluids and charged AdS black holes for the expansion. We obtain isenthalpic curves for both systems in the T-P plane and determine the cooling-heating regions. (orig.)

Joule-Thomson expansion of the charged AdS black holes

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Oekcue, Oezguer; Aydiner, Ekrem [Istanbul University, Department of Physics, Faculty of Science, Vezneciler, Istanbul (Turkey)

2017-01-15

In this paper, we study Joule-Thomson effects for charged AdS black holes. We obtain inversion temperatures and curves. We investigate similarities and differences between van der Waals fluids and charged AdS black holes for the expansion. We obtain isenthalpic curves for both systems in the T-P plane and determine the cooling-heating regions. (orig.)

Type 2 diabetes and/or its treatment leads to less cognitive impairment in Alzheimer's disease patients.

Science.gov (United States)

Domínguez, Raúl O; Marschoff, Enrique R; González, Silvia E; Repetto, Marisa G; Serra, Jorge A

2012-10-01

To evaluate the cognitive performance of a homogeneous population of Alzheimer's disease (AD), non-demented Type 2 Diabetes Mellitus (DIAB), demented with concomitant diseases (AD+DIAB) and healthy control subjects. AD is a progressive dementia disorder characterized clinically by impairment of memory, cognition and behavior. Recently, a major research interest in AD has been placed on early evaluation. Diabetes is one of the clinical conditions that represent the greatest risk of developing oxidative stress and dementia. Glucose overload, leading to the development of impaired-induced insulin secretion in DIAB and has been suggested to slow or deter AD pathogenesis. The degree of cognitive impairment was determined on the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) and the Folstein's Mini Mental State Examination (MMSE); the severity of dementia was quantified applying the Clinical Dementia Rating (CDR) test; the Hamilton test was employed to evaluate depressive conditions; the final population studied was 101 subjects. The cognitive deterioration is statistically significantly lower (pcognitive decline, while diabetic non-demented patients and controls present normal scores. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Bingo! Externally-Supported Performance Intervention for Deficient Visual Search in Normal Aging, Parkinson’s Disease and Alzheimer’s Disease

Science.gov (United States)

Laudate, Thomas M.; Neargarder, Sandy; Dunne, Tracy E.; Sullivan, Karen D.; Joshi, Pallavi; Gilmore, Grover C.; Riedel, Tatiana M.; Cronin-Golomb, Alice

2011-01-01

External support may improve task performance regardless of an individual’s ability to compensate for cognitive deficits through internally-generated mechanisms. We investigated if performance of a complex, familiar visual search task (the game of bingo) could be enhanced in groups with suboptimal vision by providing external support through manipulation of task stimuli. Participants were 19 younger adults, 14 individuals with probable Alzheimer’s disease (AD), 13 AD-matched healthy adults, 17 non-demented individuals with Parkinson’s disease (PD), and 20 PD-matched healthy adults. We varied stimulus contrast, size, and visual complexity during game play. The externally-supported performance interventions of increased stimulus size and decreased complexity resulted in improvements in performance by all groups. Performance improvement through increased stimulus size and decreased complexity was demonstrated by all groups. AD also obtained benefit from increasing contrast, presumably by compensating for their contrast sensitivity deficit. The general finding of improved performance across healthy and afflicted groups suggests the value of visual support as an easy-to-apply intervention to enhance cognitive performance. PMID:22066941

Critical gravity on AdS2 spacetimes

International Nuclear Information System (INIS)

Myung, Yun Soo; Kim, Yong-Wan; Park, Young-Jai

2011-01-01

We study the critical gravity in two-dimensional anti-de Sitter (AdS 2 ) spacetimes, which was obtained from the cosmological topologically massive gravity (TMG Λ ) in three dimensions by using the Kaluza-Klein dimensional reduction. We perform the perturbation analysis around AdS 2 , which may correspond to the near-horizon geometry of the extremal Banados, Teitelboim, and Zanelli (BTZ) black hole obtained from the TMG Λ with identification upon uplifting three dimensions. A massive propagating scalar mode δF satisfies the second-order differential equation away from the critical point of K=l, whose solution is given by the Bessel functions. On the other hand, δF satisfies the fourth-order equation at the critical point. We exactly solve the fourth-order equation, and compare it with the log gravity in two dimensions. Consequently, the critical gravity in two dimensions could not be described by a massless scalar δF ml and its logarithmic partner δF log 4th .

IGF-1: an endogenous link between traumatic brain injury and Alzheimer disease?

Science.gov (United States)

Zheng, Ping; Tong, Wusong

2017-08-01

There is a growing body of evidence that the insulin-like growth factor-1 (IGF-1) is dynamically involved in the regulation of body homeostasis and glucose regulation. Traumatic brain injury (TBI) is considered to be a risk factor for Alzheimer's disease (AD). As alterations of IGF-1 have been implicated in both TBI and AD and the IGF-1 signaling also mediates the neuronal excitability and synaptic plasticity in both diseases, we propose that IGF-1 may act as the endogenous connection between TBI and AD. Growing evidence suggests that dysfunction of this pathway contributes to the progressive loss of neurons in Alzheimer's disease (AD), one of the most frequent neurodegenerative disorders. These findings have led to numerous studies in preclinical models of neurodegenerative disorders targeting IGF-1 signaling with currently available antidiabetics. These studies have shown that exogenous administration of IGF-1 reverses signaling abnormalities and has neuroprotective effects. In the first part of this review, we discuss physiological functions of IGF-1 signaling pathway including its distribution within the brain and its relationship with TBI and AD. In the second part, we undertake a comprehensive overview of IGF-1 signaling in TBI and AD, respectively. We then detail targeted IGF-1 in preclinical models of neurodegeneration and the design of clinical trials that have used anti-diabetics for treating AD patients. We close with future considerations that treat relevant issues for successful translation of these encouraging preclinical results into clinical sessions.

Integration and relative value of biomarkers for prediction of MCI to AD progression: Spatial patterns of brain atrophy, cognitive scores, APOE genotype and CSF biomarkers

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Xiao Da

2014-01-01

Full Text Available This study evaluates the individual, as well as relative and joint value of indices obtained from magnetic resonance imaging (MRI patterns of brain atrophy (quantified by the SPARE-AD index, cerebrospinal fluid (CSF biomarkers, APOE genotype, and cognitive performance (ADAS-Cog in progression from mild cognitive impairment (MCI to Alzheimer's disease (AD within a variable follow-up period up to 6 years, using data from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1. SPARE-AD was first established as a highly sensitive and specific MRI-marker of AD vs. cognitively normal (CN subjects (AUC = 0.98. Baseline predictive values of all aforementioned indices were then compared using survival analysis on 381 MCI subjects. SPARE-AD and ADAS-Cog were found to have similar predictive value, and their combination was significantly better than their individual performance. APOE genotype did not significantly improve prediction, although the combination of SPARE-AD, ADAS-Cog and APOE ε4 provided the highest hazard ratio estimates of 17.8 (last vs. first quartile. In a subset of 192 MCI patients who also had CSF biomarkers, the addition of Aβ1–42, t-tau, and p-tau181p to the previous model did not improve predictive value significantly over SPARE-AD and ADAS-Cog combined. Importantly, in amyloid-negative patients with MCI, SPARE-AD had high predictive power of clinical progression. Our findings suggest that SPARE-AD and ADAS-Cog in combination offer the highest predictive power of conversion from MCI to AD, which is improved, albeit not significantly, by APOE genotype. The finding that SPARE-AD in amyloid-negative MCI patients was predictive of clinical progression is not expected under the amyloid hypothesis and merits further investigation.

A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease

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Justin R. Piro

2012-06-01

Full Text Available Although inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic, and persistent inflammation contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer's disease (AD. Whether anti-inflammatory approaches can be used to treat AD, however, is a major unanswered question. We recently demonstrated that monoacylglycerol lipase (MAGL hydrolyzes endocannabinoids to generate the primary arachidonic acid pool for neuroinflammatory prostaglandins. In this study, we show that genetic inactivation of MAGL attenuates neuroinflammation and lowers amyloid β levels and plaques in an AD mouse model. We also find that pharmacological blockade of MAGL recapitulates the cytokine-lowering effects through reduced prostaglandin production, rather than enhanced endocannabinoid signaling. Our findings thus reveal a role of MAGL in modulating neuroinflammation and amyloidosis in AD etiology and put forth MAGL inhibitors as a potential next-generation strategy for combating AD.

Ad gist : Ad communication in a single eye fixation

NARCIS (Netherlands)

Pieters, R.; Wedel, M.

2012-01-01

Most ads in practice receive no more than a single eye fixation. This study investigates the limits of what ads can communicate under such adverse exposure conditions. We find that consumers already know at maximum levels of accuracy and with high degree of certainty whether something is an ad or is

MicroRNA (miRNA Signaling in the Human CNS in Sporadic Alzheimer’s Disease (AD-Novel and Unique Pathological Features

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Yuhai Zhao

2015-12-01

Full Text Available Of the approximately ~2.65 × 103 mature microRNAs (miRNAs so far identified in Homo sapiens, only a surprisingly small but select subset—about 35–40—are highly abundant in the human central nervous system (CNS. This fact alone underscores the extremely high selection pressure for the human CNS to utilize only specific ribonucleotide sequences contained within these single-stranded non-coding RNAs (ncRNAs for productive miRNA–mRNA interactions and the down-regulation of gene expression. In this article we will: (i consolidate some of our still evolving ideas concerning the role of miRNAs in the CNS in normal aging and in health, and in sporadic Alzheimer’s disease (AD and related forms of chronic neurodegeneration; and (ii highlight certain aspects of the most current work in this research field, with particular emphasis on the findings from our lab of a small pathogenic family of six inducible, pro-inflammatory, NF-κB-regulated miRNAs including miRNA-7, miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. This group of six CNS-abundant miRNAs significantly up-regulated in sporadic AD are emerging as what appear to be key mechanistic contributors to the sporadic AD process and can explain much of the neuropathology of this common, age-related inflammatory neurodegeneration of the human CNS.

MicroRNA (miRNA) Signaling in the Human CNS in Sporadic Alzheimer’s Disease (AD)-Novel and Unique Pathological Features

Science.gov (United States)

Zhao, Yuhai; Pogue, Aileen I.; Lukiw, Walter J.

2015-01-01

Of the approximately ~2.65 × 103 mature microRNAs (miRNAs) so far identified in Homo sapiens, only a surprisingly small but select subset—about 35–40—are highly abundant in the human central nervous system (CNS). This fact alone underscores the extremely high selection pressure for the human CNS to utilize only specific ribonucleotide sequences contained within these single-stranded non-coding RNAs (ncRNAs) for productive miRNA–mRNA interactions and the down-regulation of gene expression. In this article we will: (i) consolidate some of our still evolving ideas concerning the role of miRNAs in the CNS in normal aging and in health, and in sporadic Alzheimer’s disease (AD) and related forms of chronic neurodegeneration; and (ii) highlight certain aspects of the most current work in this research field, with particular emphasis on the findings from our lab of a small pathogenic family of six inducible, pro-inflammatory, NF-κB-regulated miRNAs including miRNA-7, miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. This group of six CNS-abundant miRNAs significantly up-regulated in sporadic AD are emerging as what appear to be key mechanistic contributors to the sporadic AD process and can explain much of the neuropathology of this common, age-related inflammatory neurodegeneration of the human CNS. PMID:26694372

Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer's disease.

Science.gov (United States)

Rorabaugh, Jacki M; Chalermpalanupap, Termpanit; Botz-Zapp, Christian A; Fu, Vanessa M; Lembeck, Natalie A; Cohen, Robert M; Weinshenker, David

2017-11-01

See Grinberg and Heinsen (doi:10.1093/brain/awx261) for a scientific commentary on this article. Clinical evidence suggests that aberrant tau accumulation in the locus coeruleus and noradrenergic dysfunction may be a critical early step in Alzheimer’s disease progression. Yet, an accurate preclinical model of these phenotypes that includes early pretangle tau accrual in the locus coeruleus, loss of locus coeruleus innervation and deficits locus coeruleus/norepinephrine modulated behaviours, does not exist, hampering the identification of underlying mechanisms and the development of locus coeruleus-based therapies. Here, a transgenic rat (TgF344-AD) expressing disease-causing mutant amyloid precursor protein (APPsw) and presenilin-1 (PS1ΔE9) was characterized for histological and behavioural signs of locus coeruleus dysfunction reminiscent of mild cognitive impairment/early Alzheimer’s disease. In TgF344-AD rats, hyperphosphorylated tau was detected in the locus coeruleus prior to accrual in the medial entorhinal cortex or hippocampus, and tau pathology in the locus coeruleus was negatively correlated with noradrenergic innervation in the medial entorhinal cortex. Likewise, TgF344-AD rats displayed progressive loss of hippocampal norepinephrine levels and locus coeruleus fibres in the medial entorhinal cortex and dentate gyrus, with no frank noradrenergic cell body loss. Cultured mouse locus coeruleus neurons expressing hyperphosphorylation-prone mutant human tau had shorter neurites than control neurons, but similar cell viability, suggesting a causal link between pretangle tau accrual and altered locus coeruleus fibre morphology. TgF344-AD rats had impaired reversal learning in the Morris water maze compared to their wild-type littermates, which was rescued by chemogenetic locus coeruleus activation via designer receptors exclusively activated by designer drugs (DREADDs). Our results indicate that TgF344-AD rats uniquely meet several key criteria for a

Factorized tree-level scattering in AdS4 x CP3

International Nuclear Information System (INIS)

Kalousios, Chrysostomos; Vergu, C.; Volovich, Anastasia

2009-01-01

AdS 4 /CFT 3 duality relating IIA string theory on AdS 4 x CP 3 to N = 6 superconformal Chern-Simons theory provides an arena for studying aspects of integrability in a new potentially exactly solvable system. In this paper we explore the tree-level worldsheet scattering for strings on AdS 4 x CP 3 . We compute all bosonic four-, five- and six-point amplitudes in the gauge-fixed action and demonstrate the absence of particle production.

Amyloid β oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis.

Science.gov (United States)

Viola, Kirsten L; Klein, William L

2015-02-01

Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson's and Alzheimer's. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble Aβ oligomers (AβOs), toxins now widely regarded as instigating neuron damage leading to Alzheimer's dementia. Toxic AβOs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. Key experiments using fibril-free AβO solutions demonstrated that while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent. The AD-like cellular pathologies induced by AβOs suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of AβOs into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. AβO binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca(2+) overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of AβOs have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of AβOs has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic AβOs appear early in the disease, they

The DNA Replication Stress Hypothesis of Alzheimer’s Disease

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Yuri B. Yurov

2011-01-01

Full Text Available A well-recognized theory of Alzheimer’s disease (AD pathogenesis suggests ectopic cell cycle events to mediate neurodegeneration. Vulnerable neurons of the AD brain exhibit biomarkers of cell cycle progression and DNA replication suggesting a reentry into the cell cycle. Chromosome reduplication without proper cell cycle completion and mitotic division probably causes neuronal cell dysfunction and death. However, this theory seems to require some inputs in accordance with the generally recognized amyloid cascade theory as well as to explain causes and consequences of genomic instability (aneuploidy in the AD brain. We propose that unscheduled and incomplete DNA replication (replication stress destabilizes (epigenomic landscape in the brain and leads to DNA replication “catastrophe” causing cell death during the S phase (replicative cell death. DNA replication stress can be a key element of the pathogenetic cascade explaining the interplay between ectopic cell cycle events and genetic instabilities in the AD brain. Abnormal cell cycle reentry and somatic genome variations can be used for updating the cell cycle theory introducing replication stress as a missing link between cell genetics and neurobiology of AD.

Depression and Alzheimer's disease: is stress the initiating factor in a common neuropathological cascade?

DEFF Research Database (Denmark)

Aznar, Susana; Knudsen, Gitte M

2011-01-01

The existence of a high co-morbidity between Alzheimer's disease (AD) and depression has been known for a long time. More interesting though are recent studies indicating that depression and number of depressive episodes earlier in life is associated with increased risk of AD development....... This suggests the existence of common neuropathological mechanisms behind depression and AD. Here we propose that the brain changes associated with depressive episodes that compromise the brain's ability to cope with stress may constitute risk factors for development of AD. Furthermore, in individuals...... serotonergic and cholinergic system, hypothalamic-pituitary-adrenal axis and brain derived neurotrophic factor, and discussed in relation to AD....

Shared genetic variants suggest common pathways in allergy and autoimmune diseases

DEFF Research Database (Denmark)

Kreiner-Møller, Eskil; Waage, Johannes; Standl, Marie

2017-01-01

Background: The relationship between allergy and autoimmune disorders is complex and poorly understood. Objective: To investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. Methods: We meta-analyzed two GWAS on self-r...

Autobiographical narratives relate to Alzheimer's disease biomarkers in older adults.

Science.gov (United States)

Buckley, Rachel F; Saling, Michael M; Irish, Muireann; Ames, David; Rowe, Christopher C; Villemagne, Victor L; Lautenschlager, Nicola T; Maruff, Paul; Macaulay, S Lance; Martins, Ralph N; Szoeke, Cassandra; Masters, Colin L; Rainey-Smith, Stephanie R; Rembach, Alan; Savage, Greg; Ellis, Kathryn A

2014-10-01

Autobiographical memory (ABM), personal semantic memory (PSM), and autonoetic consciousness are affected in individuals with mild cognitive impairment (MCI) but their relationship with Alzheimer's disease (AD) biomarkers are unclear. Forty-five participants (healthy controls (HC) = 31, MCI = 14) completed the Episodic ABM Interview and a battery of memory tests. Thirty-one (HC = 22, MCI = 9) underwent β-amyloid positron emission tomography (PET) and magnetic resonance (MR) imaging. Fourteen participants (HC = 9, MCI = 5) underwent one imaging modality. Unlike PSM, ABM differentiated between diagnostic categories but did not relate to AD biomarkers. Personal semantic memory was related to neocortical β-amyloid burden after adjusting for age and apolipoprotein E (APOE) ɛ4. Autonoetic consciousness was not associated with AD biomarkers, and was not impaired in MCI. Autobiographical memory was impaired in MCI participants but was not related to neocortical amyloid burden, suggesting that personal memory systems are impacted by differing disease mechanisms, rather than being uniformly underpinned by β-amyloid. Episodic and semantic ABM impairment represent an important AD prodrome.

Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines

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C. Dirk Keene

2016-06-01

Full Text Available Dozens of transgenic mouse models, generally based on mutations associated with familial Alzheimer's disease (AD, have been developed, in part, for preclinical testing of candidate AD therapies. However, none of these models has successfully predicted the clinical efficacy of drugs for treating AD patients. Therefore, development of more translationally relevant AD mouse models remains a critical unmet need in the field. A concept not previously implemented in AD preclinical drug testing is the use of mouse lines that have been validated for neuropathological features of human AD. Current thinking suggests that amyloid plaque and neurofibrillary tangle deposition is an essential component for accurate modeling of AD. Therefore, the AD translational paradigm would require pathologic Aβ and tau deposition, a disease-relevant distribution of plaques and tangles, and a pattern of disease progression of Aβ and tau isoforms similar to the neuropathological features found in the brains of AD patients. Additional parameters useful to evaluate parallels between AD and animal models would include 1 cerebrospinal fluid (CSF AD biomarker changes with reduced Aβ and increased phospho-tau/tau; 2 structural and functional neuroimaging patterns including MRI hippocampal atrophy, fluorodeoxyglucose (FDG, and amyloid/tau PET alterations in activity and/or patterns of pathologic peptide deposition and distribution; and 3 cognitive impairment with emphasis on spatial learning and memory to distinguish presymptomatic and symptomatic mice at specific ages. A validated AD mouse model for drug testing would likely show tau-related neurofibrillary degeneration following Aβ deposition and demonstrate changes in pathology, CSF analysis, and neuroimaging that mirror human AD. Development of the ideal model would revolutionize the ability to establish the translational value of AD mouse models and serve as a platform for discussions about national phenotyping guidelines

Wilson lines for AdS5 black strings

International Nuclear Information System (INIS)

Hristov, Kiril; Katmadas, Stefanos

2015-01-01

We describe a simple method of extending AdS 5 black string solutions of 5d gauged supergravity in a supersymmetric way by addition of Wilson lines along a circular direction in space. When this direction is chosen along the string, and due to the specific form of 5d supergravity that features Chern-Simons terms, the existence of magnetic charges automatically generates conserved electric charges in a 5d analogue of the Witten effect. Therefore we find a rather generic, model-independent way of adding electric charges to already existing solutions with no backreaction from the geometry or breaking of any symmetry. We use this method to explicitly write down more general versions of the Benini-Bobev black strings (http://dx.doi.org/10.1103/PhysRevLett.110.061601, http://dx.doi.org/10.1007/JHEP06(2013)005) and comment on the implications for the dual field theory and the similarities with generalizations of the Cacciatori-Klemm black holes (http://dx.doi.org/10.1007/JHEP01(2010)085) in AdS 4 .

Is Alzheimer's disease a homogeneous disease entity?

Science.gov (United States)

Korczyn, Amos D

2013-10-01

The epidemic proportions of dementia in old age are a cause of great concern for the medical profession and the society at large. It is customary to consider Alzheimer's disease (AD) as the most common cause of dementia, and vascular dementia (VaD) as being the second. This dichotomous view of a primary neurodegenerative disease as opposed to a disorder where extrinsic factors cause brain damage led to separate lines of research in these two entities. New biomarkers, particularly the introduction of modern neuroimaging and cerebrospinal fluid changes, have, in recent years, helped to identify anatomical and chemical changes of VaD and of AD. Nevertheless, there is a substantial difference between the two entities. While it is clear that VaD is a heterogeneous entity, AD is supposed to be a single disorder. Nobody attempts to use CADASIL as a template to develops treatment for sporadic VaD. On the other hand, early-onset AD is used to develop therapy for sporadic AD. This paper will discuss the problems relating to this false concept and its consequences.

Financial and health literacy predict incident AD dementia and AD pathology

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Yu, Lei; Wilson, Robert S.; Schneider, Julie A.; Bennett, David A.; Boyle, Patricia A.

2017-01-01

Background Domain specific literacy is a multidimensional construct that requires multiple resources including cognitive and non-cognitive factors. Objective We test the hypothesis that domain specific literacy is associated with AD dementia and AD pathology after controlling for cognition. Methods Participants were community based older persons who completed a baseline literacy assessment, underwent annual clinical evaluations for up to 8 years and agreed to organ donation after death. Financial and health literacy was measured using 32 questions and cognition was measured using 19 tests. Annual diagnosis of AD dementia followed standard criteria. AD pathology was examined post-mortem by quantifying plaques and tangles. Cox models examined the association of literacy with incident AD dementia. Performance of model prediction for incident AD dementia was assessed using indices for integrated discrimination improvement and continuous net reclassification improvement. Linear regression models examined the independent association of literacy with AD pathology in autopsied participants. Results All 805 participants were free of dementia at baseline and 102 (12.7%) developed AD dementia during the follow-up. Lower literacy was associated with higher risk for incident AD dementia (pliteracy measure had better predictive performance than the one with demographics and cognition only. Lower literacy also was associated with higher burden of AD pathology after controlling for cognition (β=0.07, p=0.035). Conclusion Literacy predicts incident AD dementia and AD pathology in community-dwelling older persons, and the association is independent of traditional measures of cognition. PMID:28157101

Alzheimer disease therapeutics: focus on the disease and not just plaques and tangles.

Science.gov (United States)

Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

2014-04-15

The bulk of AD research during the last 25 years has been Aβ-centric based on a strong faith in the Amyloid Cascade Hypothesis which is not supported by the data on humans. To date, Aβ-based therapeutic clinical trials on sporadic cases of AD have been negative. Although most likely the major reason for the failure is that Aβ is not an effective therapeutic target for sporadic AD, initiation of the treatment at mild to moderate stages of the disease is blamed as too late to be effective. Clinical trials on presymptomatic familial AD cases have been initiated with the logic that Aβ is a trigger of the disease and hence initiation of the Aβ immunotherapies several years before any clinical symptoms would be effective. There is an urgent need to explore targets other than Aβ. There is now increasing interest in inhibiting tau pathology, which does have a far more compelling rationale than Aβ. AD is multifactorial and over 99% of the cases are the sporadic form of the disease. Understanding of the various etiopathogenic mechanisms of sporadic AD and generation of the disease-relevant animal models are required to develop rational therapeutic targets and therapies. Treatment of AD will require both inhibition of neurodegeneration and regeneration of the brain. Copyright © 2014 Elsevier Inc. All rights reserved.

Development of the Korean version of Alzheimer's Disease Assessment Scale (ADAS-K).

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Youn, J C; Lee, D Y; Kim, K W; Lee, J H; Jhoo, J H; Lee, K U; Ha, J; Woo, J I

2002-09-01

The purpose of this study was the development of the Korean Version of Alzheimer's Disease Assessment Scale (ADAS-K). ADAS-K was administrated to 84 AD patients as well as 105 non-demented control subjects. Three aspects of reliability were tested. To evaluate the validity of ADAS-K, discriminant validity and concurrent validity were tested. To evaluate the sensitivity of ADAS-K to disease severity, all subjects, AD patients and control subjects, were grouped by CDR scale and their mean scores on ADAS-K were compared. ADAS-K demonstrated high levels of reliability. Mean ADAS-K scores for AD patients were significantly different from the control group (p ADAS-K exhibited significant correlations with other tests and scales (range 0.45-0.85, p ADAS-K displayed high diagnostic efficacy and the optimal cut-off point was selected between 18/19. ADAS-K was able to discriminate the degree of AD severity according to CDR classification. Our results suggested that ADAS-K-cog was sensitive to very mild AD. We demonstrated that ADAS-K is a reliable and valid instrument not only for AD diagnosis but also for evaluation of its severity. Copyright 2002 John Wiley & Sons, Ltd.

Effects of Two-Year Treatment with the Cholinesterase Inhibitor Rivastigmine on Behavioural Symptoms in Alzheimer’s Disease

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Michael Rösler

1999-01-01

Full Text Available Alzheimer’s disease (AD is accompanied by prominent behavioural disturbances. They cause significant distress for both caregivers and patients and can play a major role in the decision to institutionalise AD patients. Recent evidence suggests that cholinergic deficiencies not only contribute to the memory and cognitive abnormalities of AD but are also responsible for some behavioural abnormalities seen over the course of the disease. In this study we assessed the ability of rivastigmine, a pseudo-irreversible cholinesterase inhibitor, to improve behavioural and psychopathologic symptoms in AD. The analysis included 34 patients present in the Germanarm of the international study B303 who received and completed long-term treatment with rivastigmine in the open-label study B305. Assessments of behaviour and psychopathological symptoms were performed using the behavioural component of the Clinicians Interview Based Impression of Change Plus (CIBIC-Plus. Results show that long-term treatment with rivastigmine can slow the progression of behavioural and psychopathological symptoms of AD. Behavioural symptoms showing stabilisation included aggressiveness, activity disturbances, hallucinations and paranoid features. Results also suggest that patients treated earlier with rivastigmine may attain a greater benefit compared with patients whose treatment is delayed 6 months. Further studies examining the effects of rivastigmine on behavioural disturbances in AD are therefore warranted.

Mechanical stress as the common denominator between chronic inflammation, cancer and Alzheimer’s disease

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Marcel eLevy Nogueira

2015-09-01

Full Text Available The pathogenesis of common diseases such as Alzheimer’s disease (AD and cancer are currently poorly understood. Inflammation is a common risk factor for cancer and AD. Recent data, provided by our group and from others, demonstrate that increased pressure and inflammation are synonymous. There is a continuous increase in pressure from inflammation to fibrosis and then cancer. This in line with the numerous papers reporting high interstitial pressure in cancer. But most authors focus on the role of pressure in the lack of delivery of chemotherapy in the center of the tumor. Pressure may also be a key factor in carcinogenesis. Increased pressure is responsible for oncogene activation and cytokine secretion. Accumulation of mechanical stress plays a key role in the development of diseases of old age such as cardiomyopathy, atherosclerosis and osteoarthritis. Growing evidence suggest also a possible link between mechanical stress in the pathogenesis of AD. The aim of this review is to describe environmental and endogenous mechanical factors possibly playing a pivotal role in the mechanism of chronic inflammation, AD and cancer.

Unusual Onset of Celiac Disease and Addison's Disease in a 12-Year-Old Boy.

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Miconi, Francesco; Savarese, Emanuela; Miconi, Giovanni; Cabiati, Gabriele; Rapaccini, Valentina; Principi, Nicola; Esposito, Susanna

2017-07-29

Celiac disease (CD) is an autoimmune disorder deriving from an aberrant adaptive immune response against gluten-containing grains in genetically predisposed subjects. In a number of patients, CD is associated with one or more other autoimmune diseases. Primary Addison's disease (AD) and CD may co-exist, although this association is relatively uncommon in children. In addition, it is not precisely defined whether a gluten-free diet influences the course of AD. A case of CD in a 12-year-old boy presenting as acute adrenal insufficiency is described here. A gluten-free diet had a significant therapeutic role in this case, wherein most of the clinical signs and symptoms of AD disappeared in a few days. In addition, the dosage of cortisol acetate, initially administered to treat the AD, was able to be rapidly reduced. This case highlights that CD can be associated with AD in children, and a gluten-free diet seems to positively influence the course of AD.

Thermodynamic and classical instability of AdS black holes in fourth-order gravity

International Nuclear Information System (INIS)

Myung, Yun Soo; Moon, Taeyoon

2014-01-01

We study thermodynamic and classical instability of AdS black holes in fourth-order gravity. These include the BTZ black hole in new massive gravity, Schwarzschild-AdS black hole, and higher-dimensional AdS black holes in fourth-order gravity. All thermodynamic quantities which are computed using the Abbot-Deser-Tekin method are used to study thermodynamic instability of AdS black holes. On the other hand, we investigate the s-mode Gregory-Laflamme instability of the massive graviton propagating around the AdS black holes. We establish the connection between the thermodynamic instability and the GL instability of AdS black holes in fourth-order gravity. This shows that the Gubser-Mitra conjecture holds for AdS black holes found from fourth-order gravity

Winding strings and AdS3 black holes

International Nuclear Information System (INIS)

Troost, Jan

2002-01-01

We start a systematic study of string theory in AdS 3 black hole backgrounds. Firstly, we analyse in detail the geodesic structure of the BTZ black hole, including spacelike geodesics. Secondly, we study the spectrum for massive and massless scalar fields, paying particular attention to the connection between Sl(2,R) subgroups, the theory of special functions and global properties of the BTZ black holes. We construct classical strings that wind the black holes. Finally, we apply the general formalism to the vacuum black hole background, and formulate the boundary spacetime Virasoro algebra in terms of worldsheet operators. We moreover establish the link between a proposal for a ghost free spectrum for Sl(2,R) string propagation and the massless black hole background, thereby claryfing aspects of the AdS 3 /CFT correspondence. (author)

AdS strings with torsion: Noncomplex heterotic compactifications

International Nuclear Information System (INIS)

Frey, Andrew R.; Lippert, Matthew

2005-01-01

Combining the effects of fluxes and gaugino condensation in heterotic supergravity, we use a ten-dimensional approach to find a new class of four-dimensional supersymmetric AdS 4 compactifications on almost-Hermitian manifolds of SU(3) structure. Computation of the torsion allows a classification of the internal geometry, which for a particular combination of fluxes and condensate, is nearly Kaehler. We argue that all moduli are fixed, and we show that the Kaehler potential and superpotential proposed in the literature yield the correct AdS 4 radius. In the nearly Kaehler case, we are able to solve the H Bianchi identity using a nonstandard embedding. Finally, we point out subtleties in deriving the effective superpotential and understanding the heterotic supergravity in the presence of a gaugino condensate

Finger agnosia and cognitive deficits in patients with Alzheimer's disease.

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Davis, Andrew S; Trotter, Jeffrey S; Hertza, Jeremy; Bell, Christopher D; Dean, Raymond S

2012-01-01

The purpose of this study was to examine the presence of finger agnosia in patients with Alzheimer's disease (AD) and to determine if level of finger agnosia was related to cognitive impairment. Finger agnosia is a sensitive measure of cerebral impairment and is associated with neurofunctional areas implicated in AD. Using a standardized and norm-referenced approach, results indicated that patients with AD evidenced significantly decreased performance on tests of bilateral finger agnosia compared with healthy age-matched controls. Finger agnosia was predictive of cognitive dysfunction on four of seven domains, including: Crystallized Language, Fluid Processing, Associative Learning, and Processing Speed. Results suggest that measures of finger agnosia, a short and simple test, may be useful in the early detection of AD.

Contextual advertising using Google AdWords and Google AdSense

OpenAIRE

Mihok, Radovan

2008-01-01

The thesis introduces contextual advertising on internet using Google AdWords. The paper describes individual steps of an ad campaign (product choosing, ad types, keywords), its management and success evaluation (calculation of ROI and modified ROI).

Progranulin mutations as risk factors for Alzheimer disease.

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Perry, David C; Lehmann, Manja; Yokoyama, Jennifer S; Karydas, Anna; Lee, Jason Jiyong; Coppola, Giovanni; Grinberg, Lea T; Geschwind, Dan; Seeley, William W; Miller, Bruce L; Rosen, Howard; Rabinovici, Gil

2013-06-01

Mutations in the progranulin gene are known to cause diverse clinical syndromes, all attributed to frontotemporal lobar degeneration. We describe 2 patients with progranulin gene mutations and evidence of Alzheimer disease (AD) pathology. We also conducted a literature review. This study focused on case reports of 2 unrelated patients with progranulin mutations at the University of California, San Francisco, Memory and Aging Center. One patient presented at age 65 years with a clinical syndrome suggestive of AD and showed evidence of amyloid aggregation on positron emission tomography. Another patient presented at age 54 years with logopenic progressive aphasia and, at autopsy, showed both frontotemporal lobar degeneration with TDP-43 inclusions and AD. In addition to autosomal-dominant frontotemporal lobar degeneration, mutations in the progranulin gene may be a risk factor for AD clinical phenotypes and neuropathology.

Clearance systems in the brain—implications for Alzheimer disease

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Tarasoff-Conway, Jenna M.; Carare, Roxana O.; Osorio, Ricardo S.; Glodzik, Lidia; Butler, Tracy; Fieremans, Els; Axel, Leon; Rusinek, Henry; Nicholson, Charles; Zlokovic, Berislav V.; Frangione, Blas; Blennow, Kaj; Ménard, Joël; Zetterberg, Henrik; Wisniewski, Thomas; de Leon, Mony J.

2015-01-01

Accumulation of toxic protein aggregates—amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles—is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood–brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ. PMID:26195256

Clearance systems in the brain-implications for Alzheimer disease.

Science.gov (United States)

Tarasoff-Conway, Jenna M; Carare, Roxana O; Osorio, Ricardo S; Glodzik, Lidia; Butler, Tracy; Fieremans, Els; Axel, Leon; Rusinek, Henry; Nicholson, Charles; Zlokovic, Berislav V; Frangione, Blas; Blennow, Kaj; Ménard, Joël; Zetterberg, Henrik; Wisniewski, Thomas; de Leon, Mony J

2015-08-01

Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.

Prototype learning and dissociable categorization systems in Alzheimer's disease.

Science.gov (United States)

Heindel, William C; Festa, Elena K; Ott, Brian R; Landy, Kelly M; Salmon, David P

2013-08-01

Recent neuroimaging studies suggest that prototype learning may be mediated by at least two dissociable memory systems depending on the mode of acquisition, with A/Not-A prototype learning dependent upon a perceptual representation system located within posterior visual cortex and A/B prototype learning dependent upon a declarative memory system associated with medial temporal and frontal regions. The degree to which patients with Alzheimer's disease (AD) can acquire new categorical information may therefore critically depend upon the mode of acquisition. The present study examined A/Not-A and A/B prototype learning in AD patients using procedures that allowed direct comparison of learning across tasks. Despite impaired explicit recall of category features in all tasks, patients showed differential patterns of category acquisition across tasks. First, AD patients demonstrated impaired prototype induction along with intact exemplar classification under incidental A/Not-A conditions, suggesting that the loss of functional connectivity within visual cortical areas disrupted the integration processes supporting prototype induction within the perceptual representation system. Second, AD patients demonstrated intact prototype induction but impaired exemplar classification during A/B learning under observational conditions, suggesting that this form of prototype learning is dependent on a declarative memory system that is disrupted in AD. Third, the surprisingly intact classification of both prototypes and exemplars during A/B learning under trial-and-error feedback conditions suggests that AD patients shifted control from their deficient declarative memory system to a feedback-dependent procedural memory system when training conditions allowed. Taken together, these findings serve to not only increase our understanding of category learning in AD, but to also provide new insights into the ways in which different memory systems interact to support the acquisition of

Diagnostic Accuracy of a Combined Analysis of Cerebrospinal Fluid t-PrP, t-tau, p-tau, and Aβ42 in the Differential Diagnosis of Creutzfeldt-Jakob Disease from Alzheimer's Disease with Emphasis on Atypical Disease Variants.

Science.gov (United States)

Abu Rumeileh, Samir; Lattanzio, Francesca; Stanzani Maserati, Michelangelo; Rizzi, Romana; Capellari, Sabina; Parchi, Piero

2017-01-01

According to recent studies, the determination of cerebrospinal fluid (CSF) total tau (t-tau)/phosphorylated tau (p-tau) ratio and total prion protein (t-PrP) levels significantly improves the accuracy of the diagnosis of Alzheimer's disease (AD) in atypical cases with clinical or laboratory features mimicking Creutzfeldt-Jakob disease (CJD). However, this has neither been validated nor tested in series including atypical CJD variants. Furthermore, the added diagnostic value of amyloid-β (Aβ)42 remains unclear. To address these issues, we measured t-PrP, 14-3-3, t-tau, p-tau, and Aβ42 CSF levels in 45 typical and 44 atypical/rapidly progressive AD patients, 54 typical and 54 atypical CJD patients, and 33 controls. CJD patients showed significantly lower CSF t-PrP levels than controls and AD patients. Furthermore, atypical CJD was associated with lower t-PrP levels in comparison to typical CJD. T-tau, 14-3-3, or t-PrP alone yielded, respectively, 80.6, 63.0, and 73.0% sensitivity and 75.3, 92.1, and 75% specificity in distinguishing AD from CJD. On receiver operating characteristic (ROC) curve analyses of biomarker combinations, the (t-tau×Aβ42)/(p-tau×t-PrP) ratio achieved the best accuracy, with 98.1% sensitivity and 97.7% specificity overall, and 96.2% sensitivity and 95.5% specificity for the "atypical" disease groups. Our results show that the combined analysis of CSF t-PrP, t-tau, p-tau, and Aβ42 is clinically useful in the differential diagnosis between CJD and AD. Furthermore, the finding of reduced CSF t-PrP levels in CJD patients suggest that, likewise Aβ42 in AD, CSF t-PrP levels reflect the extent of PrPc conversion into abnormal PrP (PrPSc) and the burden of PrPSc deposition in CJD.

Supersymmetric black holes in AdS4 from very special geometry

International Nuclear Information System (INIS)

Gnecchi, Alessandra; Halmagyi, Nick

2014-01-01

Supersymmetric black holes in AdS spacetime are inherently interesting for the AdS/CFT correspondence. Within a four dimensional gauged supergravity theory coupled to vector multiplets, the only analytic solutions for regular, supersymmetric, static black holes in AdS 4 are those in the STU-model due to Cacciatori and Klemm. We study a class of U(1)-gauged supergravity theories coupled to vector multiplets which have a cubic prepotential, the scalar manifold is then a very special Kähler manifold. When the resulting very special Kähler manifold is a homogeneous space, we find analytic solutions for static, supersymmetric AdS 4 black holes with vanishing axions. The horizon geometries of our solutions are constant curvature Riemann surfaces of arbitrary genus

Prevalence of Comorbidity in Patients With Young-Onset Alzheimer Disease Compared With Late-Onset: A Comparative Cohort Study.

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Gerritsen, Adrie A J; Bakker, Christian; Verhey, Frans R J; de Vugt, Marjolein E; Melis, René J F; Koopmans, Raymond T C M

2016-04-01

.2%) were higher compared with those of patients with LO-AD (4.5%). The cluster analysis revealed a distinctive group of patients with YO-AD with either no comorbidity or with a disease of the nervous system. Endocrine, nutritional, and metabolic diseases and diseases of the circulatory system were present in 34% of the patients with YO-AD. Comorbidity is less common in YO-AD than in LO-AD. However, general practitioners should be aware that approximately one-third of the patients with YO-AD suffer from or have endocrine, nutritional, and metabolic diseases and/or diseases of the circulatory system. Treatment should therefore not only focus on dementia but also on comorbidity. This attention may slow the functional decline in AD. These exploratory analyses suggested a higher prevalence of nervous system diseases in YO-AD compared with LO-AD. However, the finding did not reach statistical significance and in combination with the exploratory nature of the analyses justifies further investigation. If verified, this finding may help to decrease the time to diagnosis of AD and, subsequently, support in young patients with a neurological disease. Further investigation is needed to gain more insight into the association between comorbidity and AD in younger people. Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

Identification of unstable network modules reveals disease modules associated with the progression of Alzheimer's disease.

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Masataka Kikuchi

Full Text Available Alzheimer's disease (AD, the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs, we identified the PINs expressed in three brain regions: the entorhinal cortex (EC, hippocampus (HIP and superior frontal gyrus (SFG. Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system.

Thermodynamic geometry and phase transitions of AdS braneworld black holes

Energy Technology Data Exchange (ETDEWEB)

Chaturvedi, Pankaj, E-mail: cpankaj@iitk.ac.in; Sengupta, Gautam, E-mail: sengupta@iitk.ac.in

2017-02-10

The thermodynamics and phase transitions of charged RN–AdS and rotating Kerr–AdS black holes in a generalized Randall–Sundrum braneworld are investigated in the framework of thermodynamic geometry. A detailed analysis of the thermodynamics, stability and phase structures in the canonical and the grand canonical ensembles for these AdS braneworld black holes are described. The thermodynamic curvatures for both these AdS braneworld black holes are computed and studied as a function of the thermodynamic variables. Through this analysis we illustrate an interesting dependence of the phase structures on the braneworld parameter for these black holes.

Google Advertising Tools Cashing in with AdSense and AdWords

CERN Document Server

Davis, Harold

2010-01-01

With this book, you'll learn how to take full advantage of Google AdWords and AdSense, the sophisticated online advertising tools used by thousands of large and small businesses. This new edition provides a substantially updated guide to advertising on the Web, including how it works in general, and how Google's advertising programs in particular help you make money. You'll find everything you need to work with AdWords, which lets you generate text ads to accompany specific search term results, and AdSense, which automatically delivers precisely targeted text and image ads to your website.

Omega-3 fatty acids: potential role in the management of early Alzheimer’s disease

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Gregory A Jicha

2010-03-01

Full Text Available Gregory A Jicha, William R MarkesberyUniversity of Kentucky Alzheimer’s Disease Center and the Sanders-Brown Center on Aging University of Kentucky College of Medicine, Lexington, KY, USAbstract: Omega-3 fatty acids are essential for brain growth and development. They play an important role throughout life, as critical modulators of neuronal function and regulation of oxidative stress mechanisms, in brain health and disease. Docosahexanoic acid (DHA, the major omega-3 fatty acid found in neurons, has taken on a central role as a target for therapeutic intervention in Alzheimer’s disease (AD. A plethora of in vitro, animal model, and human data, gathered over the past decade, highlight the important role DHA may play in the development of a variety of neurological and psychiatric disorders, including AD. Cross sectional and prospective cohort data have demonstrated that reduced dietary intake or low brain levels of DHA are associated with accelerated cognitive decline or the development of incipient dementia, including AD. Several clinical trials investigating the effects of omega-3 fatty acid supplementation in AD have been completed and all failed to demonstrate its efficacy in the treatment of AD. However, these trials produced intriguing data suggesting that the beneficial effects of omega-3 fatty acid supplementation may depend on the stage of disease, other dietary mediators, and apolipoprotein E status.Keywords: Alzheimer’s disease, omega-3 fatty acids, oxidative stress, clinical studies, treatment

Concurrence of High Fat Diet and APOE Gene Induces Allele Specific Metabolic and Mental Stress Changes in a Mouse Model of Alzheimer's Disease.

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Segev, Yifat; Livne, Adva; Mints, Meshi; Rosenblum, Kobi

2016-01-01

Aging is the main risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). However, evidence indicates that the pathological process begins long before actual cognitive or pathological symptoms are apparent. The long asymptomatic phase and complex integration between genetic, environmental and metabolic factors make it one of the most challenging diseases to understand and cure. In the present study, we asked whether an environmental factor such as high-fat (HF) diet would synergize with a genetic factor to affect the metabolic and cognitive state in the Apolipoprotein E (ApoE4) mouse model of AD. Our data suggest that a HF diet induces diabetes mellitus (DM)-like metabolism in ApoE4 mice, as well as changes in β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) protein levels between the two ApoE strains. Furthermore, HF diet induces anxiety in this AD mouse model. Our results suggest that young ApoE4 carriers are prone to psychological stress and metabolic abnormalities related to AD, which can easily be triggered via HF nutrition.

Anterior-posterior and lateral hemispheric alterations in cortical glucose utilization in Alzheimer's disease

International Nuclear Information System (INIS)

Friedland, T.F.; Budinger, T.F.; Jaqust, W.J.; Yano, Y.; Huesman, R.H.; Knittel, B.; Koss, E.; Ober, B.A.

1984-01-01

The anatomical and chemical features of Alzheimer's disease (AD) are not distributed evenly throughout the brain. However, the nature of this focality has not been well established in vivo. Dynamic studies using the Donner 280-Crystal Positron Tomograph with (F-18)2-fluorodeoxyglucose were performed in 17 subjects meeting current research criteria for AD, and in 7 healthy age-matched control subjects. Glucose metabolic rates in the temporal-parietal cortex are 27% lower in AD than in controls. Ratios of activity density reveal consistently lower metabolic rates in temporal-parietal than frontal cortex in the AD group, while healthy aged subjects have equal metabolic rates in the two areas. Similar findings have been reported by other laboratories. A major finding is a striking lateral asymmetry of cortical metabolism in AD which does not favor either hemisphere. (The asymmetry is 13% in the AD group, 3% in controls, p<.005.) This has not been previously reported in AD. The consistency with which anterior-posterior metabolic differences are found in AD suggests that the focality of the metabolic changes may be used to develop a noninvasive diagnostic test for the disorder. The metabolic asymmetry in AD may be compared to the clinical and pathological asymmetry found in Creutzfeldt-Jakob disease, and may represent an additional link between AD and the subacute spongiform encephalopathies

Increased inflammatory response in cytomegalovirus seropositive patients with Alzheimer's disease.

Directory of Open Access Journals (Sweden)

Gabriel Westman

Full Text Available Alzheimer's disease (AD has been associated with increased local inflammation in the affected brain regions, and in some studies also with elevated levels of proinflammatory cytokines in peripheral blood. Cytomegalovirus (CMV is known to promote a more effector-oriented phenotype in the T-cell compartment, increasing with age. The aim of this study was to investigate the inflammatory response of peripheral blood mononuclear cells (PBMCs from AD patients and non-demented (ND controls. Using a multiplex Luminex xMAP assay targeting GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10 and TNF-α, cytokine profiles from PBMCs were analysed after stimulation with anti-CD3/CD28 beads, CMV pp65 peptide mix or amyloid β (Aβ protofibrils, respectively. CMV seropositive AD subjects presented with higher IFN-γ levels after anti-CD3/CD28 and CMV pp65 but not after Aβ stimulation, compared to CMV seropositive ND controls. When analysing IFN-γ response to anti-CD3/CD28 stimulation on a subgroup level, CMV seropositive AD subjects presented with higher levels compared to both CMV seronegative AD and CMV seropositive ND subjects. Taken together, our data from patients with clinically manifest AD suggest a possible role of CMV as an inflammatory promoter in AD immunology. Further studies of AD patients at earlier stages of disease, could provide better insight into the pathophysiology.

Alzheimer's disease, cerebrovascular dysfunction and the benefits of exercise: from vessels to neurons.

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Lange-Asschenfeldt, Christian; Kojda, Georg

2008-06-01

Exercise training promotes extensive cardiovascular changes and adaptive mechanisms in both the peripheral and cerebral vasculature, such as improved organ blood flow, induction of antioxidant pathways, and enhanced angiogenesis and vascular regeneration. Clinical studies have demonstrated a reduction of morbidity and mortality from cardiovascular disease among exercising individuals. However, evidence from recent large clinical trials also suggests a substantial reduction of dementia risk - particularly regarding Alzheimer's disease (AD) - with regular exercise. Enhanced neurogenesis and improved synaptic plasticity have been implicated in this beneficial effect. However, recent research has revealed that vascular and specifically endothelial dysfunction is essentially involved in the disease process and profoundly aggravates underlying neurodegeneration. Moreover, vascular risk factors (VRFs) are probably determinants of incidence and course of AD. In this review, we emphasize the interconnection between AD and VRFs and the impact of cerebrovascular and endothelial dysfunction on AD pathophysiology. Furthermore, we describe the molecular mechanisms of the beneficial effects of exercise on the vasculature such as activation of the vascular nitric oxide (NO)/endothelial NO synthase (eNOS) pathway, upregulation of antioxidant enzymes, and angiogenesis. Finally, recent prospective clinical studies dealing with the effect of exercise on the risk of incident AD are briefly reviewed. We conclude that, next to upholding neuronal plasticity, regular exercise may counteract AD pathophysiology by building a vascular reserve.

Light-cone gauge formulation for AdS4 x CP3

International Nuclear Information System (INIS)

Uvarov, D.V.

2011-01-01

We review the Type IIA superstring on the AdS 4 x CP 3 background in the k-symmetry light-cone gauge characterized by the choice of the lightlike directions from the D = 3 Minkowski boundary of AdS 4 both in the Lagrangian and Hamiltonian formulations

The Nun study: clinically silent AD, neuronal hypertrophy, and linguistic skills in early life.

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Iacono, D; Markesbery, W R; Gross, M; Pletnikova, O; Rudow, G; Zandi, P; Troncoso, J C

2009-09-01

It is common to find substantial Alzheimer disease (AD) lesions, i.e., neuritic beta-amyloid plaques and neurofibrillary tangles, in the autopsied brains of elderly subjects with normal cognition assessed shortly before death. We have termed this status asymptomatic AD (ASYMAD). We assessed the morphologic substrate of ASYMAD compared to mild cognitive impairment (MCI) in subjects from the Nun Study. In addition, possible correlations between linguistic abilities in early life and the presence of AD pathology with and without clinical manifestations in late life were considered. Design-based stereology was used to measure the volumes of neuronal cell bodies, nuclei, and nucleoli in the CA1 region of hippocampus (CA1). Four groups of subjects were compared: ASYMAD (n = 10), MCI (n = 5), AD (n = 10), and age-matched controls (n = 13). Linguistic ability assessed in early life was compared among all groups. A significant hypertrophy of the cell bodies (+44.9%), nuclei (+59.7%), and nucleoli (+80.2%) in the CA1 neurons was found in ASYMAD compared with MCI. Similar differences were observed with controls. Furthermore, significant higher idea density scores in early life were observed in controls and ASYMAD group compared to MCI and AD groups. 1) Neuronal hypertrophy may constitute an early cellular response to Alzheimer disease (AD) pathology or reflect compensatory mechanisms that prevent cognitive impairment despite substantial AD lesions; 2) higher idea density scores in early life are associated with intact cognition in late life despite the presence of AD lesions.

Clinicopathological correlation of psychosis and brain vascular changes in Alzheimer's disease.

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Ting, Simon Kang Seng; Hao, Ying; Chia, Pei Shi; Tan, Eng-King; Hameed, Shahul

2016-02-12

Psychosis is common in Alzheimer's disease (AD). However, studies on neuropathology in vascular etiology contributing to psychosis in AD is lacking to date. The aim of this study was to investigate neuropathological vascular related changes in Alzheimer's disease with psychosis. Data of patients with AD from the National Alzheimer's Coordinating Center between 2005 to September 2013 was accessed and reviewed. Presence of psychosis was determined based on Neuropsychiatric Inventory Questionnaire taken from the last visit within one year prior to death, and patients were divided into psychosis positive and negative group. Comparison of clinical details and neuropathological vascular changes between the groups was performed using Wilcoxon rank sum test and Chi-square/ Fisher's exact test. Significant variables were further included in a multivariate logistic model. Overall, 145 patients was included. Of these, 50 patients were psychosis positive. Presence of one or more cortical microinfarcts and moderate to severe arteriosclerosis was found to be positively associated with psychosis. Our results suggest vascular changes correlate with psychosis in Alzheimer's disease.

Tau-mediated nuclear depletion and cytoplasmic accumulation of SFPQ in Alzheimer's and Pick's disease.

Directory of Open Access Journals (Sweden)

Yazi D Ke

Full Text Available Tau dysfunction characterizes neurodegenerative diseases such as Alzheimer's disease (AD and frontotemporal lobar degeneration (FTLD. Here, we performed an unbiased SAGE (serial analysis of gene expression of differentially expressed mRNAs in the amygdala of transgenic pR5 mice that express human tau carrying the P301L mutation previously identified in familial cases of FTLD. SAGE identified 29 deregulated transcripts including Sfpq that encodes a nuclear factor implicated in the splicing and regulation of gene expression. To assess the relevance for human disease we analyzed brains from AD, Pick's disease (PiD, a form of FTLD, and control cases. Strikingly, in AD and PiD, both dementias with a tau pathology, affected brain areas showed a virtually complete nuclear depletion of SFPQ in both neurons and astrocytes, along with cytoplasmic accumulation. Accordingly, neurons harboring either AD tangles or Pick bodies were also depleted of SFPQ. Immunoblot analysis of human entorhinal cortex samples revealed reduced SFPQ levels with advanced Braak stages suggesting that the SFPQ pathology may progress together with the tau pathology in AD. To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology. The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. Confocal microscopy revealed that SFPQ was confined to nuclei in non-transfected wild-type cells, whereas in wild-type and P301L tau over-expressing cells, irrespective of the differentiation method, it formed aggregates in the cytoplasm, suggesting that pathogenic tau drives SFPQ pathology in post-mitotic cells. Our findings add SFPQ to a growing list of transcription factors with an altered nucleo-cytoplasmic distribution under neurodegenerative conditions.

Association of GSK3B With Alzheimer Disease and Frontotemporal Dementia

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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