WorldWideScience

Sample records for brain diseases

  1. Brain Diseases

    Science.gov (United States)

    The brain is the control center of the body. It controls thoughts, memory, speech, and movement. It regulates the function of many organs. When the brain is healthy, it works quickly and automatically. However, ...

  2. The cost of brain diseases

    DEFF Research Database (Denmark)

    DiLuca, Monica; Olesen, Jes

    2014-01-01

    Brain diseases represent a considerable social and economic burden in Europe. With yearly costs of about 800 billion euros and an estimated 179 million people afflicted in 2010, brain diseases are an unquestionable emergency and a grand challenge for neuroscientists.......Brain diseases represent a considerable social and economic burden in Europe. With yearly costs of about 800 billion euros and an estimated 179 million people afflicted in 2010, brain diseases are an unquestionable emergency and a grand challenge for neuroscientists....

  3. Brain MRI in Parkinson's disease

    NARCIS (Netherlands)

    Meijer, F.J.A.; Goraj, B.M.

    2014-01-01

    In this review article, conventional brain MRI and advanced MRI techniques in Parkinson`s disease (PD) are discussed, with emphasis on clinical relevance. Conventional brain MRI sequences generally demonstrate limited abnormalities specific for PD and in clinical practice brain MRI is mainly used to

  4. Urinary Biomarkers of Brain Diseases

    Directory of Open Access Journals (Sweden)

    Manxia An

    2015-12-01

    Full Text Available Biomarkers are the measurable changes associated with a physiological or pathophysiological process. Unlike blood, urine is not subject to homeostatic mechanisms. Therefore, greater fluctuations could occur in urine than in blood, better reflecting the changes in human body. The roadmap of urine biomarker era was proposed. Although urine analysis has been attempted for clinical diagnosis, and urine has been monitored during the progression of many diseases, particularly urinary system diseases, whether urine can reflect brain disease status remains uncertain. As some biomarkers of brain diseases can be detected in the body fluids such as cerebrospinal fluid and blood, there is a possibility that urine also contain biomarkers of brain diseases. This review summarizes the clues of brain diseases reflected in the urine proteome and metabolome.

  5. Deep Brain Stimulation for Parkinson's Disease

    Science.gov (United States)

    ... Home » Disorders » All Disorders Deep Brain Stimulation for Parkinson's Disease Information Page Deep Brain Stimulation for Parkinson's Disease Information Page What research is being done? The ...

  6. Inflammatory diseases of the brain

    Energy Technology Data Exchange (ETDEWEB)

    Haehnel, Stefan (ed.) [University of Heidelberg Medical Center (Germany). Div. of Neuroradiology

    2009-07-01

    This book provides a comprehensive overview of inflammatory brain diseases from a neuroradiological point of view. Such diseases may be either infectious (e.g., viral encephalitis and pyogenic brain abscess) or non-infectious (e.g., multiple sclerosis), and many of these entities are becoming increasingly important for differential diagnosis, particularly in immunocompromised persons. Neuroimaging contributes greatly to the differentiation of infectious and noninfectious brain diseases and to the distinction between brain inflammation and other, for instance neoplastic, diseases. In order to ensure a standardized approach throughout the book, each chapter is subdivided into three principal sections: epidemiology, clinical presentation and therapy; imaging; and differential diagnosis. A separate chapter addresses technical and methodological issues and imaging protocols. All of the authors are recognized experts in their fields, and numerous high-quality and informative illustrations are included. This book will be of great value not only to neuroradiologists but also to neurologists, neuropediatricians, and general radiologists. (orig.)

  7. Endothelial cell marker PAL-E reactivity in brain tumor, developing brain, and brain disease

    NARCIS (Netherlands)

    Leenstra, S.; Troost, D.; Das, P. K.; Claessen, N.; Becker, A. E.; Bosch, D. A.

    1993-01-01

    The endothelial cell marker PAL-E is not reactive to vessels in the normal brain. The present study concerns the PAL-E reactivity in brain tumors in contrast to normal brain and nonneoplastic brain disease. A total of 122 specimens were examined: brain tumors (n = 94), nonneoplastic brain disease (n

  8. Brain Diseases in Mesopotamian Societies

    Directory of Open Access Journals (Sweden)

    Piedad Yuste

    2010-04-01

    Full Text Available In ancient Mesopotamia were not practiced neither autopsies nor dissections, so the internal organs of human body were known only from occasional inspections on wounds and injuries. The
    brain was considered as a part of the head and was not related to mental activity. However, Babylonian and Assyrian physicians were able to identify the symptoms of many diseases that affect this organ. We will make here a brief overview of them.

  9. Brain MRI in Parkinson's disease.

    Science.gov (United States)

    Meijer, Frederick J A; Goraj, Bozena

    2014-06-01

    In this review article, conventional brain MRI and advanced MRI techniques in Parkinson`s disease (PD) are discussed, with emphasis on clinical relevance. Conventional brain MRI sequences generally demonstrate limited abnormalities specific for PD and in clinical practice brain MRI is mainly used to exclude other pathology. Possibly, brain MRI at higher magnetic field strengths could provide new diagnostic markers. In recent years, new imaging techniques such as susceptibility weighted imaging (SWI), diffusion (tensor) MRI, magnetization transfer imaging (MTI), and functional MRI (f-MRI) have been applied to patient cohorts with PD to improve understanding of pathophysiologic changes, including functional connectivity. These advanced MRI techniques hold promise to provide additional diagnostic markers for early stage PD, as demonstrated by diffusional changes in the orbital-frontal region in the pre-motor phase of PD. Whether these advanced MRI techniques provide new diagnostic markers for early stage PD, remains a debate. Standardization of scanning protocols and post-processing methods, and validation of diagnostic criteria is crucial for these advanced MRI techniques. For this, well designed prospective clinical cohort studies are needed.

  10. Zinc Signal in Brain Diseases

    Directory of Open Access Journals (Sweden)

    Stuart D. Portbury

    2017-11-01

    Full Text Available The divalent cation zinc is an integral requirement for optimal cellular processes, whereby it contributes to the function of over 300 enzymes, regulates intracellular signal transduction, and contributes to efficient synaptic transmission in the central nervous system. Given the critical role of zinc in a breadth of cellular processes, its cellular distribution and local tissue level concentrations remain tightly regulated via a series of proteins, primarily including zinc transporter and zinc import proteins. A loss of function of these regulatory pathways, or dietary alterations that result in a change in zinc homeostasis in the brain, can all lead to a myriad of pathological conditions with both acute and chronic effects on function. This review aims to highlight the role of zinc signaling in the central nervous system, where it may precipitate or potentiate diverse issues such as age-related cognitive decline, depression, Alzheimer’s disease or negative outcomes following brain injury.

  11. Brain Imaging in Alzheimer Disease

    Science.gov (United States)

    Johnson, Keith A.; Fox, Nick C.; Sperling, Reisa A.; Klunk, William E.

    2012-01-01

    Imaging has played a variety of roles in the study of Alzheimer disease (AD) over the past four decades. Initially, computed tomography (CT) and then magnetic resonance imaging (MRI) were used diagnostically to rule out other causes of dementia. More recently, a variety of imaging modalities including structural and functional MRI and positron emission tomography (PET) studies of cerebral metabolism with fluoro-deoxy-d-glucose (FDG) and amyloid tracers such as Pittsburgh Compound-B (PiB) have shown characteristic changes in the brains of patients with AD, and in prodromal and even presymptomatic states that can help rule-in the AD pathophysiological process. No one imaging modality can serve all purposes as each have unique strengths and weaknesses. These modalities and their particular utilities are discussed in this article. The challenge for the future will be to combine imaging biomarkers to most efficiently facilitate diagnosis, disease staging, and, most importantly, development of effective disease-modifying therapies. PMID:22474610

  12. Methylthioadenosine reverses brain autoimmune disease.

    Science.gov (United States)

    Moreno, Beatriz; Hevia, Henar; Santamaria, Monica; Sepulcre, Jorge; Muñoz, Javier; García-Trevijano, Elena R; Berasain, Carmen; Corrales, Fernando J; Avila, Matias A; Villoslada, Pablo

    2006-09-01

    To assess the immunomodulatory activity of methylthioadenosine (MTA) in rodent experimental autoimmune encephalomyelitis (EAE) and in patients with multiple sclerosis. We studied the effect of intraperitoneal MTA in the acute and chronic EAE model by quantifying clinical and histological scores and by performing immunohistochemistry stains of the brain. We studied the immunomodulatory effect of MTA in lymphocytes from EAE animals and in peripheral blood mononuclear cells from healthy control subjects and multiple sclerosis patients by assessing cell proliferation and cytokine gene expression, by real-time polymerase chain reaction, and by nuclear factor-kappaB modulation by Western blot. We found that MTA prevents acute EAE and, more importantly, reverses chronic-relapsing EAE. MTA treatment markedly inhibited brain inflammation and reduced brain damage. Administration of MTA suppressed T-cell activation in vivo and in vitro, likely through a blockade in T-cell signaling resulting in the prevention of inhibitor of kappa B (IkappaB-alpha) degradation and in the impaired activation transcription factor nuclear factor-kappaB. Indeed, MTA suppressed the production of proinflammatory genes and cytokines (interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase) and increased the production of antiinflammatory cytokines (interleukin-10). MTA has a remarkable immunomodulatory activity and may be beneficial for multiple sclerosis and other autoimmune diseases.

  13. Mental Illness And Brain Disease

    Directory of Open Access Journals (Sweden)

    Bedrick Jeffrey D.

    2014-12-01

    Full Text Available It has become common to say psychiatric illnesses are brain diseases. This reflects a conception of the mental as being biologically based, though it is also thought that thinking of psychiatric illness this way will reduce the stigma attached to psychiatric illness. If psychiatric illnesses are brain diseases, however, it is not clear why psychiatry should not collapse into neurology, and some argue for this course. Others try to maintain a distinction by saying that neurology deals with abnormalities of neural structure while psychiatry deals with specific abnormalities of neural functioning. It is not clear that neurologists would accept this division, nor that they should. I argue that if we take seriously the notion that psychiatric illnesses are mental illnesses we can draw a more defensible boundary between psychiatry and neurology. As mental illnesses, psychiatric illnesses must have symptoms that affect our mental capacities and that the sufferer is capable of being aware of, even if they are not always self-consciously aware of them. Neurological illnesses, such as stroke or multiple sclerosis, may be diagnosed even if they are silent, just as the person may not be aware of having high blood pressure or may suffer a silent myocardial infarction. It does not make sense to speak of panic disorder if the person has never had a panic attack, however, or of bipolar disorder in the absence of mood swings. This does not mean psychiatric illnesses are not biologically based. Mental illnesses are illnesses of persons, whereas other illnesses are illnesses of biological individuals.

  14. Mitochondrial DNA mutations in Parkinson's disease brain

    National Research Council Canada - National Science Library

    David K Simon; Joanne Clark Matott; Janaina Espinosa; Neeta A Abraham

    2017-01-01

    Dear Editors, We read with interest the publication by Wei et al., Mitochondrial DNA Point Mutations and Relative Copy Number in 1363 Disease and Control Human Brains, Acta Neuropathol Commun. 2017; 5: 13 [4...

  15. Alzheimer and vascular brain disease: Senile dementia

    Directory of Open Access Journals (Sweden)

    Eliasz Engelhardt

    Full Text Available Alois Alzheimer is best known for his description of a novel disease, subsequently named after him. However, his wide range of interests also included vascular brain diseases. He described Senile dementia, a highly heterogeneous condition, and was able not only to distinguish it from syphilitic brain disease, but also to discriminate two clinicopathological subtypes, that may be labeled a "arteriosclerotic subtype", comparable to the present clinicopathological continuum of "Vascular cognitive impairment", and another as a "neurodegenerative subtype", characterized by primary [cortical] ganglion cell [nerve cells] degeneration, possibly foreshadowing a peculiar presenile disease that he was to describe some years later and would carry his name. He also considered the possibility of a senile presentation of this disease subtype, which was described by Oskar Fischer a short time later. Considering the clinicopathological overlapping features of the "arteriosclerotic subtype" of Senile dementia with Arteriosclerotic atrophy of the brain, it might be possible to consider that both represent a single condition.

  16. Alzheimer and vascular brain disease: Senile dementia.

    Science.gov (United States)

    Engelhardt, Eliasz; Grinberg, Lea T

    2015-01-01

    Alois Alzheimer is best known for his description of a novel disease, subsequently named after him. However, his wide range of interests also included vascular brain diseases. He described Senile dementia, a highly heterogeneous condition, and was able not only to distinguish it from syphilitic brain disease, but also to discriminate two clinicopathological subtypes, that may be labeled a "arteriosclerotic subtype", comparable to the present clinicopathological continuum of "Vascular cognitive impairment", and another as a "neurodegenerative subtype", characterized by primary [cortical] ganglion cell [nerve cells] degeneration, possibly foreshadowing a peculiar presenile disease that he was to describe some years later and would carry his name. He also considered the possibility of a senile presentation of this disease subtype, which was described by Oskar Fischer a short time later. Considering the clinicopathological overlapping features of the "arteriosclerotic subtype" of Senile dementia with Arteriosclerotic atrophy of the brain, it might be possible to consider that both represent a single condition.

  17. Robust gene dysregulation in Alzheimer's disease brains.

    Science.gov (United States)

    Feng, Xuemei; Bai, Zhouxian; Wang, Jiajia; Xie, Bin; Sun, Jiya; Han, Guangchun; Song, Fuhai; Crack, Peter J; Duan, Yong; Lei, Hongxing

    2014-01-01

    The brain transcriptome of Alzheimer's disease (AD) reflects the prevailing disease mechanism at the gene expression level. However, thousands of genes have been reported to be dysregulated in AD brains in existing studies, and the consistency or discrepancy among these studies has not been thoroughly examined. Toward this end, we conducted a comprehensive survey of the brain transcriptome datasets for AD and other neurological diseases. We first demonstrated that the frequency of observed dysregulation in AD was highly correlated with the reproducibility of the dysregulation. Based on this observation, we selected 100 genes with the highest frequency of dysregulation to illustrate the core perturbation in AD brains. The dysregulation of these genes was validated in several independent datasets for AD. We further identified 12 genes with strong correlation of gene expression with disease progression. The relevance of these genes to disease progression was also validated in an independent dataset. Interestingly, we found a transcriptional "cushion" for these 100 genes in the less vulnerable visual cortex region, which may be a critical component of the protection mechanism for less vulnerable brain regions. To facilitate the research in this field, we have provided the expression information of ~8000 relevant genes on a publicly accessible web server AlzBIG (http://alz.big.ac.cn).

  18. Brain ultrasound in Canavan disease.

    Science.gov (United States)

    Drera, B; Poggiani, C

    2014-09-01

    Canavan disease (MIM 271900) is a rare autosomal recessive leukodystrophy due to mutations in the ASPA gene (MIM 608034) and characterized by a clinical onset at 3-5 months of life, macrocephaly and poor head control, weak cry and suck, development regression and hypotonia. Here, we report cranial ultrasound findings at birth and at 4 months of age in a patient affected with Canavan disease. The comparison of our sonographic data with few other cases in literature allows us to suggest a characteristic pattern in Canavan disease.

  19. Brain Imaging in Alzheimer Disease

    NARCIS (Netherlands)

    Johnson, K.A.; Fox, N.C.; Sperling, R.A.; Klunk, W.E.

    2012-01-01

    Imaging has played a variety of roles in the study of Alzheimer disease (AD) over the past four decades. Initially, computed tomography (CT) and then magnetic resonance imaging (MRI) were used diagnostically to rule out other causes of dementia. More recently, a variety of imaging modalities

  20. Metabolic profiling of Alzheimer's disease brains

    Science.gov (United States)

    Inoue, Koichi; Tsutsui, Haruhito; Akatsu, Hiroyasu; Hashizume, Yoshio; Matsukawa, Noriyuki; Yamamoto, Takayuki; Toyo'Oka, Toshimasa

    2013-08-01

    Alzheimer's disease (AD) is an irreversible, progressive brain disease and can be definitively diagnosed after death through an examination of senile plaques and neurofibrillary tangles in several brain regions. It is to be expected that changes in the concentration and/or localization of low-molecular-weight molecules are linked to the pathological changes that occur in AD, and determining their identity would provide valuable information regarding AD processes. Here, we propose definitive brain metabolic profiling using ultra-performance liquid chromatography coupled with electrospray time-of-flight mass spectrometry analysis. The acquired data were subjected to principal components analysis to differentiate the frontal and parietal lobes of the AD/Control groups. Significant differences in the levels of spermine and spermidine were identified using S-plot, mass spectra, databases and standards. Based on the investigation of the polyamine metabolite pathway, these data establish that the downstream metabolites of ornithine are increased, potentially implicating ornithine decarboxylase activity in AD pathology.

  1. Deep brain stimulation in Parkinson's disease

    OpenAIRE

    Dowsey-Limousin, P.; Fraix, V.; Benabid, A. L.; Pollak, P.

    2001-01-01

    During the last 15 years deep brain stimulation (DBS) has been established as a highly-effective therapy for advanced Parkinson's disease (PD). Patient selection, stereotactic implantation, postoperative stimulator programming and patient care requires a multi-disciplinary team including movement disorders specialists in neurology and functional neurosurgery. To treat medically r...

  2. Computational modeling of neurostimulation in brain diseases.

    Science.gov (United States)

    Wang, Yujiang; Hutchings, Frances; Kaiser, Marcus

    2015-01-01

    Neurostimulation as a therapeutic tool has been developed and used for a range of different diseases such as Parkinson's disease, epilepsy, and migraine. However, it is not known why the efficacy of the stimulation varies dramatically across patients or why some patients suffer from severe side effects. This is largely due to the lack of mechanistic understanding of neurostimulation. Hence, theoretical computational approaches to address this issue are in demand. This chapter provides a review of mechanistic computational modeling of brain stimulation. In particular, we will focus on brain diseases, where mechanistic models (e.g., neural population models or detailed neuronal models) have been used to bridge the gap between cellular-level processes of affected neural circuits and the symptomatic expression of disease dynamics. We show how such models have been, and can be, used to investigate the effects of neurostimulation in the diseased brain. We argue that these models are crucial for the mechanistic understanding of the effect of stimulation, allowing for a rational design of stimulation protocols. Based on mechanistic models, we argue that the development of closed-loop stimulation is essential in order to avoid inference with healthy ongoing brain activity. Furthermore, patient-specific data, such as neuroanatomic information and connectivity profiles obtainable from neuroimaging, can be readily incorporated to address the clinical issue of variability in efficacy between subjects. We conclude that mechanistic computational models can and should play a key role in the rational design of effective, fully integrated, patient-specific therapeutic brain stimulation. © 2015 Elsevier B.V. All rights reserved.

  3. Addiction and the Brain: Development, Not Disease.

    Science.gov (United States)

    Lewis, Marc

    2017-01-01

    I review the brain disease model of addiction promoted by medical, scientific, and clinical authorities in the US and elsewhere. I then show that the disease model is flawed because brain changes in addiction are similar to those generally observed when recurrent, highly motivated goal seeking results in the development of deep habits, Pavlovian learning, and prefrontal disengagement. This analysis relies on concepts of self-organization, neuroplasticity, personality development, and delay discounting. It also highlights neural and behavioral parallels between substance addictions, behavioral addictions, normative compulsive behaviors, and falling in love. I note that the short duration of addictive rewards leads to negative emotions that accelerate the learning cycle, but cortical reconfiguration in recovery should also inform our understanding of addiction. I end by showing that the ethos of the disease model makes it difficult to reconcile with a developmental-learning orientation.

  4. Protecting against vascular disease in brain

    Science.gov (United States)

    2011-01-01

    Endothelial cells exert an enormous influence on blood vessels throughout the circulation, but their impact is particularly pronounced in the brain. New concepts have emerged recently regarding the role of this cell type and mechanisms that contribute to endothelial dysfunction and vascular disease. Activation of the renin-angiotensin system plays a prominent role in producing these abnormalities. Both oxidative stress and local inflammation are key mechanisms that underlie vascular disease of diverse etiology. Endogenous mechanisms of vascular protection are also present, including antioxidants, anti-inflammatory molecules, and peroxisome proliferator-activated receptor-γ. Despite their clear importance, studies of mechanisms that underlie cerebrovascular disease continue to lag behind studies of vascular biology in general. Identification of endogenous molecules and pathways that protect the vasculature may result in targeted approaches to prevent or slow the progression of vascular disease that causes stroke and contributes to the vascular component of dementia and Alzheimer's disease. PMID:21335467

  5. Brain Iron Metabolism Dysfunction in Parkinson's Disease.

    Science.gov (United States)

    Jiang, Hong; Wang, Jun; Rogers, Jack; Xie, Junxia

    2017-05-01

    Dysfunction of iron metabolism, which includes its uptake, storage, and release, plays a key role in neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease, and Huntington's disease. Understanding how iron accumulates in the substantia nigra (SN) and why it specifically targets dopaminergic (DAergic) neurons is particularly warranted for PD, as this knowledge may provide new therapeutic avenues for a more targeted neurotherapeutic strategy for this disease. In this review, we begin with a brief introduction describing brain iron metabolism and its regulation. We then provide a detailed description of how iron accumulates specifically in the SN and why DAergic neurons are especially vulnerable to iron in PD. Furthermore, we focus on the possible mechanisms involved in iron-induced cell death of DAergic neurons in the SN. Finally, we present evidence in support that iron chelation represents a plausable therapeutic strategy for PD.

  6. ADDICTION IS NOT A BRAIN DISEASE

    Directory of Open Access Journals (Sweden)

    Elisardo Becoña

    2016-05-01

    Full Text Available The idea that addiction is a “brain disease” has gradually been consolidated in the medical-psychiatric field over the last years, as it appears in the current DSM-5. In this paper we analyse the way this idea has arisen and been consolidated, as well as the criticisms that it has received, the professional consequences if this model becomes hegemonic, and the underlying interests. The conclusion defends the need to show, as psychologists, our clear contributions to the field of addictions, and the psychological variables that are necessary in order to understand and prevent addictions, as well as the central role of psychological treatment due to its effectiveness. We must also denounce the reductionism that the model of brain disease represents in comparison with a biopsychosocial model of addiction.

  7. Congenital heart disease affects cerebral size but not brain growth.

    Science.gov (United States)

    Ortinau, Cynthia; Inder, Terrie; Lambeth, Jennifer; Wallendorf, Michael; Finucane, Kirsten; Beca, John

    2012-10-01

    Infants with congenital heart disease (CHD) have delayed brain maturation and alterations in brain volume. Brain metrics is a simple measurement technique that can be used to evaluate brain growth. This study used brain metrics to test the hypothesis that alterations in brain size persist at 3 months of age and that infants with CHD have slower rates of brain growth than control infants. Fifty-seven infants with CHD underwent serial brain magnetic resonance imaging (MRI). To evaluate brain growth across the first 3 months of life, brain metrics were undertaken using 19 tissue and fluid spaces shown on MRIs performed before surgery and again at 3 months of age. Before surgery, infants with CHD have smaller frontal, parietal, cerebellar, and brain stem measures (p < 0.001). At 3 months of age, alterations persisted in all measures except the cerebellum. There was no difference between control and CHD infants in brain growth. However, the cerebellum trended toward greater growth in infants with CHD. Somatic growth was the primary factor that related to brain growth. Presence of focal white matter lesions before and after surgery did not relate to alterations in brain size or growth. Although infants with CHD have persistent alterations in brain size at 3 months of age, rates of brain growth are similar to that of healthy term infants. Somatic growth was the primary predictor of brain growth, emphasizing the importance of optimal weight gain in this population.

  8. Prion diseases of the brain; Prionenerkrankung des Gehirns

    Energy Technology Data Exchange (ETDEWEB)

    Lutz, Kira; Urbach, Horst [Universitaetsklinik Freiburg (Germany). Klinik fuer Neuroradiologie

    2015-09-15

    The prion diseases of the brain, especially Creutzfeldt-Jakob disease, are rare fatal neurodegenerative disorders. A definitive CJD diagnosis is currently only possible by a brain biopsy or post mortem autopsy. The diagnosis of Creutzfeldt-Jakob disease is based on clinical signs, pathognomonic EEG, on typical MRI findings and the examination of the cerebrospinal fluid. Using the MRI the diagnosis Creutzfeldt-Jakob disease can be confirmed or excluded with high certainty. The MRI examination should contain diffusion-weighted and FLAIR imaging sequences. This review article provides an overview of the prion diseases of the brain with the corresponding imaging findings.

  9. MRI reveals brain abnormalities in drug-naive Parkinson's disease.

    Science.gov (United States)

    Planetta, Peggy J; McFarland, Nikolaus R; Okun, Michael S; Vaillancourt, David E

    2014-01-01

    Most brain studies of Parkinson's disease (PD) focus on patients who are already taking antiparkinsonian medication. This makes it difficult to isolate the effects of disease from those of treatment. We review magnetic resonance imaging evidence supporting the hypothesis that early-stage untreated PD patients have structural and functional abnormalities in the brain, some of which are related to motor symptoms.

  10. Resting state brain networks and their implications in neurodegenerative disease

    Science.gov (United States)

    Sohn, William S.; Yoo, Kwangsun; Kim, Jinho; Jeong, Yong

    2012-10-01

    Neurons are the basic units of the brain, and form network by connecting via synapses. So far, there have been limited ways to measure the brain networks. Recently, various imaging modalities are widely used for this purpose. In this paper, brain network mapping using resting state fMRI will be introduced with several applications including neurodegenerative disease such as Alzheimer's disease, frontotemporal lobar degeneration and Parkinson's disease. The resting functional connectivity using intrinsic functional connectivity in mouse is useful since we can take advantage of perturbation or stimulation of certain nodes of the network. The study of brain connectivity will open a new era in understanding of brain and diseases thus will be an essential foundation for future research.

  11. Epidemiology of mild traumatic brain injury and neurodegenerative disease

    OpenAIRE

    Gardner, Raquel C.; Yaffe, Kristine

    2015-01-01

    Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion. More severe traumatic brain injury (TBI) is a well-established risk factor for a variety of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Recently, large epidemiological studies have additionally identified MTBI as a risk factor for dementia. The role of MTBI in risk of PD or ALS is less well established. Repet...

  12. Lipidomics of human brain aging and Alzheimer's disease pathology.

    Science.gov (United States)

    Naudí, Alba; Cabré, Rosanna; Jové, Mariona; Ayala, Victoria; Gonzalo, Hugo; Portero-Otín, Manuel; Ferrer, Isidre; Pamplona, Reinald

    2015-01-01

    Lipids stimulated and favored the evolution of the brain. Adult human brain contains a large amount of lipids, and the largest diversity of lipid classes and lipid molecular species. Lipidomics is defined as "the full characterization of lipid molecular species and of their biological roles with respect to expression of proteins involved in lipid metabolism and function, including gene regulation." Therefore, the study of brain lipidomics can help to unravel the diversity and to disclose the specificity of these lipid traits and its alterations in neural (neurons and glial) cells, groups of neural cells, brain, and fluids such as cerebrospinal fluid and plasma, thus helping to uncover potential biomarkers of human brain aging and Alzheimer disease. This review will discuss the lipid composition of the adult human brain. We first consider a brief approach to lipid definition, classification, and tools for analysis from the new point of view that has emerged with lipidomics, and then turn to the lipid profiles in human brain and how lipids affect brain function. Finally, we focus on the current status of lipidomics findings in human brain aging and Alzheimer's disease pathology. Neurolipidomics will increase knowledge about physiological and pathological functions of brain cells and will place the concept of selective neuronal vulnerability in a lipid context. © 2015 Elsevier Inc. All rights reserved.

  13. New progress in brain aging and its related neurological diseases

    Directory of Open Access Journals (Sweden)

    Ming-wei ZHU

    2014-03-01

    Full Text Available Brain aging-related neurological diseases including Alzheimer's disease (AD, Parkinson's disease (PD and cerebral amyloid angiopathy (CAA have become one of the major diseases endangering the health of old people in China. Although the mechanism of brain aging and pathogenesis of its related neurodegenerative diseases remain unclear, protein pathological studies such as tau, α-synuclein (α-Syn, TDP-43 and amyloid-β protein (Aβ based on brain tissue bank and case registration database are opening the door to solve the mystery in the brain aging process and unlock pathogenesis of aging-related neurodegenerative diseases. Research on functional neuroimaging including 11C-PIB PET and 18F-FDDNP PET in Alzheimer's disease and 18F-FDG PET in Parkinson's disease, and biomarkers such as total-tau, phosphorylated-tau, and the 42 amino acid fragment of β-amyloid in cerebrospinal fluid (CSF in the preclinical stages of Alzheimer's disease now become hot topics in the field of elderly dementia and movement disorders. Clinicopathological correlation research of Alzheimer's disease, Parkinson's disease and cerebral amyloid angiopathy is also one of focuses in the geriatric neurological diseases. doi: 10.3969/j.issn.1672-6731.2014.03.004

  14. Aluminium in brain tissue in familial Alzheimer's disease.

    Science.gov (United States)

    Mirza, Ambreen; King, Andrew; Troakes, Claire; Exley, Christopher

    2017-03-01

    The genetic predispositions which describe a diagnosis of familial Alzheimer's disease can be considered as cornerstones of the amyloid cascade hypothesis. Essentially they place the expression and metabolism of the amyloid precursor protein as the main tenet of disease aetiology. However, we do not know the cause of Alzheimer's disease and environmental factors may yet be shown to contribute towards its onset and progression. One such environmental factor is human exposure to aluminium and aluminium has been shown to be present in brain tissue in sporadic Alzheimer's disease. We have made the first ever measurements of aluminium in brain tissue from 12 donors diagnosed with familial Alzheimer's disease. The concentrations of aluminium were extremely high, for example, there were values in excess of 10μg/g tissue dry wt. in 5 of the 12 individuals. Overall, the concentrations were higher than all previous measurements of brain aluminium except cases of known aluminium-induced encephalopathy. We have supported our quantitative analyses using a novel method of aluminium-selective fluorescence microscopy to visualise aluminium in all lobes of every brain investigated. The unique quantitative data and the stunning images of aluminium in familial Alzheimer's disease brain tissue raise the spectre of aluminium's role in this devastating disease. Copyright © 2016 The Authors. Published by Elsevier GmbH.. All rights reserved.

  15. Addiction is not a brain disease (and it matters.

    Directory of Open Access Journals (Sweden)

    Neil eLevy

    2013-04-01

    Full Text Available The claim that addiction is a brain disease is almost universally accepted among scientists who work on addiction. The claim’s attraction rests on two grounds: the fact that addiction seems to be characterized by dysfunction in specific neural pathways and the fact that the claim seems to the compassionate response to people who are suffering. I argue that neural dysfunction is not sufficient for disease: something is a brain disease only when neural dysfunction is sufficient for impairment. I claim that the neural dysfunction that is characteristic of addiction is not sufficient for impairment, because people who suffer from that dysfunction are impaired, sufficiently to count as diseased, only given certain features of their context. Hence addiction is not a brain disease (though it is often a disease, and it may always involve brain dysfunction. I argue that accepting that addiction is not a brain disease does not entail a moralizing attitude toward people who suffer as a result of addiction; if anything, it allows for a more compassionate, and more effective, response to addiction.

  16. Expression of Alzheimer's disease risk genes in ischemic brain degeneration.

    Science.gov (United States)

    Ułamek-Kozioł, Marzena; Pluta, Ryszard; Januszewski, Sławomir; Kocki, Janusz; Bogucka-Kocka, Anna; Czuczwar, Stanisław J

    2016-12-01

    We review the Alzheimer-related expression of genes following brain ischemia as risk factors for late-onset of sporadic Alzheimer's disease and their role in Alzheimer's disease ischemia-reperfusion pathogenesis. More recent advances in understanding ischemic etiology of Alzheimer's disease have revealed dysregulation of Alzheimer-associated genes including amyloid protein precursor, β-secretase, presenilin 1 and 2, autophagy, mitophagy and apoptosis. We review the relationship between these genes dysregulated by brain ischemia and the cellular and neuropathological characteristics of Alzheimer's disease. Here we summarize the latest studies supporting the theory that Alzheimer-related genes play an important role in ischemic brain injury and that ischemia is a needful and leading supplier to the onset and progression of sporadic Alzheimer's disease. Although the exact molecular mechanisms of ischemic dependent neurodegenerative disease and neuronal susceptibility finally are unknown, a downregulated expression of neuronal defense genes like alfa-secretase in the ischemic brain makes the neurons less able to resist injury. The recent challenge is to find ways to raise the adaptive reserve of the brain to overcome such ischemic-associated deficits and support and/or promote neuronal survival. Understanding the mechanisms underlying the association of these genes with risk for Alzheimer's disease will provide the most meaningful targets for therapeutic development to date. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  17. Alois Alzheimer and vascular brain disease: Arteriosclerotic atrophy of the brain

    Directory of Open Access Journals (Sweden)

    Eliasz Engelhardt

    Full Text Available Alois Alzheimer is best known for his description of neurofibrillary changes in brain neurons of a demented patient, identifying a novel disease, soon named after him by Kraepelin. However, the range of his studies was broad, including vascular brain diseases, published between 1894 and 1902. Alzheimer described the clinical picture of Arteriosclerotic atrophy of the brain, differentiating it from other similar disorders. He stated that autopsy allowed pathological distinction between arteriosclerosis and syphilis, thereby achieving some of his objectives of segregating disorders and separating them from syphilis. His studies contributed greatly to establishing the key information on vascular brain diseases, predating the present state of knowledge on the issue, while providing early descriptions of what would be later regarded as the dimensional presentation of the now called "Vascular cognitive impairment", constituted by a spectrum that includes a stage of "Vascular cognitive impairment not dementia" and another of "Vascular dementia".

  18. Loss of brain function - liver disease

    Science.gov (United States)

    ... of chronic liver damage. Common causes of chronic liver disease in the United States are: Chronic hepatitis B ... hepatitis Bile duct disorders Some medicines Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) Once you have ...

  19. Graph Theory and Brain Connectivity in Alzheimer's Disease.

    Science.gov (United States)

    delEtoile, Jon; Adeli, Hojjat

    2017-04-01

    This article presents a review of recent advances in neuroscience research in the specific area of brain connectivity as a potential biomarker of Alzheimer's disease with a focus on the application of graph theory. The review will begin with a brief overview of connectivity and graph theory. Then resent advances in connectivity as a biomarker for Alzheimer's disease will be presented and analyzed.

  20. Blood-brain barrier transport machineries and targeted therapy of brain diseases

    Directory of Open Access Journals (Sweden)

    Jaleh Barar

    2016-12-01

    Full Text Available Introduction: Desired clinical outcome of pharmacotherapy of brain diseases largely depends upon the safe drug delivery into the brain parenchyma. However, due to the robust blockade function of the blood-brain barrier (BBB, drug transport into the brain is selectively controlled by the BBB formed by brain capillary endothelial cells and supported by astrocytes and pericytes. Methods: In the current study, we have reviewed the most recent literature on the subject to provide an insight upon the role and impacts of BBB on brain drug delivery and targeting. Results: All drugs, either small molecules or macromolecules, designated to treat brain diseases must adequately cross the BBB to provide their therapeutic properties on biological targets within the central nervous system (CNS. However, most of these pharmaceuticals do not sufficiently penetrate into CNS, failing to meet the intended therapeutic outcomes. Most lipophilic drugs capable of penetrating BBB are prone to the efflux functionality of BBB. In contrast, all hydrophilic drugs are facing severe infiltration blockage imposed by the tight cellular junctions of the BBB. Hence, a number of strategies have been devised to improve the efficiency of brain drug delivery and targeted therapy of CNS disorders using multimodal nanosystems (NSs. Conclusion: In order to improve the therapeutic outcomes of CNS drug transfer and targeted delivery, the discriminatory permeability of BBB needs to be taken under control. The carrier-mediated transport machineries of brain capillary endothelial cells (BCECs can be exploited for the discovery, development and delivery of small molecules into the brain. Further, the receptor-mediated transport systems can be recruited for the delivery of macromolecular biologics and multimodal NSs into the brain.

  1. Isolation of Borna Disease Virus from Human Brain Tissue

    Science.gov (United States)

    Nakamura, Yurie; Takahashi, Hirokazu; Shoya, Yuko; Nakaya, Takaaki; Watanabe, Makiko; Tomonaga, Keizo; Iwahashi, Kazuhiko; Ameno, Kiyoshi; Momiyama, Noriko; Taniyama, Hiroyuka; Sata, Tetsutaro; Kurata, Takeshi; de la Torre, Juan Carlos; Ikuta, Kazuyoshi

    2000-01-01

    Serological and molecular epidemiological studies indicate that Borna disease virus (BDV) can infect humans and is possibly associated with certain neuropsychiatric disorders. We examined brain tissue collected at autopsy from four schizophrenic patients and two healthy controls for the presence of BDV markers in 12 different brain regions. BDV RNA and antigen was detected in four brain regions of a BDV-seropositive schizophrenic patient (P2) with a very recent (2 years) onset of disease. BDV markers exhibited a regionally localized distribution. BDV RNA was found in newborn Mongolian gerbils intracranially inoculated with homogenates from BDV-positive brain regions of P2. Human oligodendroglia (OL) cells inoculated with brain homogenates from BDV-positive gerbils allowed propagation and isolation of BDVHuP2br, a human brain-derived BDV. Virus isolation was also possible by transfection of Vero cells with ribonucleoprotein complexes prepared from BDV-positive human and gerbil brain tissues. BDVHuP2br was genetically closely related to but distinct from previously reported human- and animal-derived BDV sequences. PMID:10775596

  2. Brain MRI changes in chronic liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Skehan, S. [Department of Diagnostic Imaging, St. Vincent`s Hospital, Elm Park, Dublin 4 (Ireland); Norris, S. [Liver Unit, St. Vincent`s Hospital, Elm Park, Dublin 4 (Ireland); Hegarty, J. [Liver Unit, St. Vincent`s Hospital, Elm Park, Dublin 4 (Ireland); Owens, A. [Department of Diagnostic Imaging, St. Vincent`s Hospital, Elm Park, Dublin 4 (Ireland); MacErlaine, D. [Department of Diagnostic Imaging, St. Vincent`s Hospital, Elm Park, Dublin 4 (Ireland)

    1997-08-01

    Cirrhotic patients are known to have abnormally high signal principally in the globus pallidus on non-contrast T1-weighted MRI. The purpose of this study was to relate MR changes to clinical and pathological features of chronic liver disease. We confirmed abnormally high signal in the globus pallidus on T1-weighted images in 25 of 28 patients with chronic liver disease, showing that it also occurs in patients who have not yet progressed to cirrhosis. Changes were seen in patients both with and without clinical portosystemic shunting. This abnormality is not responsible for hepatic encephalopathy. Cholestatic disease was more likely to produce marked changes than non-cholestatic disease. No statistically significant correlation was demonstrated between the severity of liver disease and the degree of MR abnormality. However, marked improvement in MR appearances was seen after successful liver transplantation. (orig.). With 3 figs., 4 tabs.

  3. The Role of Glucose Transporters in Brain Disease: Diabetes and Alzheimer’s Disease

    Science.gov (United States)

    Shah, Kaushik; DeSilva, Shanal; Abbruscato, Thomas

    2012-01-01

    The occurrence of altered brain glucose metabolism has long been suggested in both diabetes and Alzheimer’s diseases. However, the preceding mechanism to altered glucose metabolism has not been well understood. Glucose enters the brain via glucose transporters primarily present at the blood-brain barrier. Any changes in glucose transporter function and expression dramatically affects brain glucose homeostasis and function. In the brains of both diabetic and Alzheimer’s disease patients, changes in glucose transporter function and expression have been observed, but a possible link between the altered glucose transporter function and disease progress is missing. Future recognition of the role of new glucose transporter isoforms in the brain may provide a better understanding of brain glucose metabolism in normal and disease states. Elucidation of clinical pathological mechanisms related to glucose transport and metabolism may provide common links to the etiology of these two diseases. Considering these facts, in this review we provide a current understanding of the vital roles of a variety of glucose transporters in the normal, diabetic and Alzheimer’s disease brain. PMID:23202918

  4. Alzheimer and vascular brain diseases: Focal and diffuse subforms

    Directory of Open Access Journals (Sweden)

    Eliasz Engelhardt

    Full Text Available Alois Alzheimer is best known for his description of the pre-senile neurodegenerative disease named after him. However, his previous interest in vascular brain diseases, underlying cognitive and behavioral changes, was very strong. Besides describing the Arteriosclerotic atrophy of the brain and the arteriosclerotic subtype of Senile dementia which he viewed as main forms of vascular brain diseases, he also identified and described a series of conditions he considered subforms. These may be divided, as suggested by the authors of the present paper, into 3 groups: gliosis and sclerosis, subcortical atrophies, and apoplectic. The subforms of the three groups present characteristic neuropathological features and clinical, cognitive and behavioral manifestations. These provide the basis, together with part of the main forms, for the contemporary condition known as Vascular Cognitive Impairment.

  5. Cholesterol in brain disease: sometimes determinant and frequently implicated

    Science.gov (United States)

    Martín, Mauricio G; Pfrieger, Frank; Dotti, Carlos G

    2014-01-01

    Cholesterol is essential for neuronal physiology, both during development and in the adult life: as a major component of cell membranes and precursor of steroid hormones, it contributes to the regulation of ion permeability, cell shape, cell–cell interaction, and transmembrane signaling. Consistently, hereditary diseases with mutations in cholesterol-related genes result in impaired brain function during early life. In addition, defects in brain cholesterol metabolism may contribute to neurological syndromes, such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD), and even to the cognitive deficits typical of the old age. In these cases, brain cholesterol defects may be secondary to disease-causing elements and contribute to the functional deficits by altering synaptic functions. In the first part of this review, we will describe hereditary and non-hereditary causes of cholesterol dyshomeostasis and the relationship to brain diseases. In the second part, we will focus on the mechanisms by which perturbation of cholesterol metabolism can affect synaptic function. PMID:25223281

  6. MRI of the brain in muscle-eye-brain (MEB) disease

    Energy Technology Data Exchange (ETDEWEB)

    Valanne, L. (Dept. of Radiology, Children' s Hospital, Univ. of Helsinki (Finland)); Pihko, H. (Dept. of Child Neurology, Children' s Hospital, Univ. of Helsinki (Finland)); Katevuo, K. (Dept. of Radiology, Turku Univ. Hospital (Finland)); Karttunen, P. (Children' s Hospital, Univ. of Kuopio (Finland)); Somer, H. (Dept. of Neurology, Univ. of Helsinki (Finland)); Santavuori, P. (Dept. of Child Neurology, Children' s Hospital, Univ. of Helsinki (Finland))

    1994-08-01

    Muscle-eye-brain (MEB) disease belongs to the spectrum of rare congenital syndromes with migration disorders of the brain and muscular dystrophy, along with the Walker-Warburg syndrome and Fukuyama congenital muscular dystrophy. Their features overlap, and differential diagnosis presents some difficulties. We examined the brain of 10 patients with MEB using high-field MRI and found a uniform pattern consisting of a pachygyria-type cortical migration disorder, septal and corpus callosum defects and severe hypoplasia of the pons in 7 of them. (orig.)

  7. Cognitive and Brain Reserve in Prodromal Huntington Disease

    Science.gov (United States)

    Bonner-Jackson, Aaron; Long, Jeffrey D.; Westervelt, Holly; Tremont, Geoffrey; Aylward, Elizabeth; Paulsen, Jane S.

    2013-01-01

    Background Huntington disease (HD) is associated with decline in cognition and progressive morphological changes in brain structures. Cognitive reserve may represent a mechanism by which disease-related decline may be delayed or slowed. The current study examined the relationship between cognitive reserve and longitudinal change in cognitive functioning and brain volumes among prodromal (gene expansion-positive) HD individuals. Methods Participants were genetically-confirmed individuals with prodromal HD enrolled in the PREDICT-HD study. Cognitive reserve was computed as the composite of performance on a lexical task estimating premorbid intellectual level, occupational status, and years of education. Linear mixed effects regression (LMER) was used to examine longitudinal changes on 4 cognitive measures and 3 brain volumes over approximately 6 years. Results Higher cognitive reserve was significantly associated with a slower rate of change on one cognitive measure (Trail Making Test, Part B) and slower rate of volume loss in two brain structures (caudate, putamen) for those estimated to be closest to motor disease onset. This relationship was not observed among those estimated to be further from motor disease onset. Conclusions Our findings demonstrate a relationship between cognitive reserve and both a measure of executive functioning and integrity of certain brain structures in prodromal HD individuals. PMID:23702309

  8. Drosophila melanogaster as a Model Organism of Brain Diseases

    Directory of Open Access Journals (Sweden)

    Werner Paulus

    2009-02-01

    Full Text Available Drosophila melanogaster has been utilized to model human brain diseases. In most of these invertebrate transgenic models, some aspects of human disease are reproduced. Although investigation of rodent models has been of significant impact, invertebrate models offer a wide variety of experimental tools that can potentially address some of the outstanding questions underlying neurological disease. This review considers what has been gleaned from invertebrate models of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, metabolic diseases such as Leigh disease, Niemann-Pick disease and ceroid lipofuscinoses, tumor syndromes such as neurofibromatosis and tuberous sclerosis, epilepsy as well as CNS injury. It is to be expected that genetic tools in Drosophila will reveal new pathways and interactions, which hopefully will result in molecular based therapy approaches.

  9. Deep brain stimulation and Parkinson's disease

    National Research Council Canada - National Science Library

    Boisson, D

    2008-01-01

    .... The unilateral or bilateral stimulation, adjustable and possibly reversible, led to an exceptional medicosurgical collaboration, within expert dedicated places, based on the control of the Parkinson's disease's (PD) triad...

  10. Regional brain stiffness changes across the Alzheimer's disease spectrum

    Directory of Open Access Journals (Sweden)

    Matthew C. Murphy

    2016-01-01

    Full Text Available Magnetic resonance elastography (MRE is an MRI-based technique to noninvasively measure tissue stiffness. Currently well established for clinical use in the liver, MRE is increasingly being investigated to measure brain stiffness as a novel biomarker of a variety of neurological diseases. The purpose of this work was to apply a recently developed MRE pipeline to measure regional brain stiffness changes in human subjects across the Alzheimer's disease (AD spectrum, and to gain insights into the biological processes underlying those stiffness changes by correlating stiffness with existing biomarkers of AD. The results indicate that stiffness changes occur mostly in the frontal, parietal and temporal lobes, in accordance with the known topography of AD pathology. Furthermore, stiffness in those areas correlates with existing imaging biomarkers of AD including hippocampal volumes and amyloid PET. Additional analysis revealed preliminary but significant evidence that the relationship between brain stiffness and AD severity is nonlinear and non-monotonic. Given that similar relationships have been observed in functional MRI experiments, we used task-free fMRI data to test the hypothesis that brain stiffness was sensitive to structural changes associated with altered functional connectivity. The analysis revealed that brain stiffness is significantly and positively correlated with default mode network connectivity. Therefore, brain stiffness as measured by MRE has potential to provide new and essential insights into the temporal dynamics of AD, as well as the relationship between functional and structural plasticity as it relates to AD pathophysiology.

  11. Disparate effects of training on brain activation in Parkinson disease.

    Science.gov (United States)

    Maidan, Inbal; Rosenberg-Katz, Keren; Jacob, Yael; Giladi, Nir; Hausdorff, Jeffrey M; Mirelman, Anat

    2017-10-24

    To compare the effects of 2 forms of exercise, i.e., a 6-week trial of treadmill training with virtual reality (TT + VR) that targets motor and cognitive aspects of safe ambulation and a 6-week trial of treadmill training alone (TT), on brain activation in patients with Parkinson disease (PD). As part of a randomized controlled trial, patients were randomly assigned to 6 weeks of TT (n = 17, mean age 71.5 ± 1.5 years, disease duration 11.6 ± 1.6 years; 70% men) or TT + VR (n = 17, mean age 71.2 ± 1.7 years, disease duration 7.9 ± 1.4 years; 65% men). A previously validated fMRI imagery paradigm assessed changes in neural activation pretraining and post-training. Participants imagined themselves walking in 2 virtual scenes projected in the fMRI: (1) a clear path and (2) a path with virtual obstacles. Whole brain and region of interest analyses were performed. Brain activation patterns were similar between training arms before the interventions. After training, participants in the TT + VR arm had lower activation than the TT arm in Brodmann area 10 and the inferior frontal gyrus (cluster level familywise error-corrected [FWEcorr] p Exercise modifies brain activation patterns in patients with PD in a mode-specific manner. Motor-cognitive training decreased the reliance on frontal regions, which apparently resulted in improved function, perhaps reflecting increased brain efficiency. © 2017 American Academy of Neurology.

  12. Glucose Transporters in Brain: In Health and in Alzheimer's Disease.

    Science.gov (United States)

    Szablewski, Leszek

    2017-01-01

    Neurons need a continuous supply of glucose, the major source of energy for mammalian brain metabolism. The central nervous system is protected by three main physiological cell barriers. Cell membranes are impermeable for glucose, therefore glucose is transferred across the cell membranes by specific transport proteins: sodium-independent glucose transporters (GLUTs), encoded by SLC2 genes, and sodium-dependent glucose transporters (for example SGLTs), encoded by SLC5 genes. Human brain expresses 10 GLUT proteins and 10 proteins encoded by SLC5 genes. In patients with brain diseases, particularly Alzheimer's (AD) and Huntington's diseases, abnormalities in neuronal glucose metabolism have been showed. The levels of GLUT1 and GLUT3, the major brain glucose transporters, are decreased, especially in the cerebral cortex. Therefore, in AD, hypometabolism of glucose and deficits in energy are observed. Production of ATP from glucose metabolism in sporadic AD declines to 50% and the tendency to decline continues throughout the progression of the disease. This decrease is correlated with O-GlcAcetylation and tau hyperphosphorylation, as the compensatory mechanisms in AD are the utilization of endogenous brain substances and drastic increase in GLUT2 levels. The present review focuses on the changes in the expression of glucose transporters due to AD.

  13. The metabolic syndrome: a brain disease?

    NARCIS (Netherlands)

    Buijs, R.M.; Kreier, F.

    2006-01-01

    The incidence of obesity with, as consequence, a rise in associated diseases such as diabetes, hypertension and dyslipidemia--the metabolic syndrome--is reaching epidemic proportions in industrialized countries. Here, we provide a hypothesis that the biological clock which normally prepares us each

  14. Blood-Brain Glucose Transfer in Alzheimer's disease

    DEFF Research Database (Denmark)

    Gejl, Michael; Brock, Birgitte; Egefjord, Lærke

    2017-01-01

    There are fewer than normal glucose transporters at the blood-brain barrier (BBB) in Alzheimer's disease (AD). When reduced expression of transporters aggravates the symptoms of AD, the transporters become a potential target of therapy. The incretin hormone GLP-1 prevents the decline of cerebral...... metabolic rate for glucose (CMRglc) in AD, and GLP-1 may serve to raise transporter numbers. We hypothesized that the GLP-1 analog liraglutide would prevent the decline of CMRglc in AD by raising blood-brain glucose transfer, depending on the duration of disease. We randomized 38 patients with AD...... to treatment with liraglutide (n = 18) or placebo (n = 20) for 6 months, and determined the blood-brain glucose transfer capacity (Tmax) in the two groups and a healthy age matched control group (n = 6). In both AD groups at baseline, T max estimates correlated inversely with the duration of AD, as did...

  15. Blood-Brain Glucose Transfer in Alzheimer's disease

    DEFF Research Database (Denmark)

    Gejl, Michael; Brock, Birgitte; Egefjord, Lærke

    2017-01-01

    to treatment with liraglutide (n = 18) or placebo (n = 20) for 6 months, and determined the blood-brain glucose transfer capacity (T max) in the two groups and a healthy age matched control group (n = 6). In both AD groups at baseline, T max estimates correlated inversely with the duration of AD, as did......There are fewer than normal glucose transporters at the blood-brain barrier (BBB) in Alzheimer's disease (AD). When reduced expression of transporters aggravates the symptoms of AD, the transporters become a potential target of therapy. The incretin hormone GLP-1 prevents the decline of cerebral...... metabolic rate for glucose (CMRglc) in AD, and GLP-1 may serve to raise transporter numbers. We hypothesized that the GLP-1 analog liraglutide would prevent the decline of CMRglc in AD by raising blood-brain glucose transfer, depending on the duration of disease. We randomized 38 patients with AD...

  16. Insights into brain development and disease from neurogenetic ...

    Indian Academy of Sciences (India)

    2014-07-08

    Jul 8, 2014 ... Insights into brain development and disease from neurogenetic analyses in Drosophila melanogaster. HEINRICH REICHERT. Biozentrum, University of Basel, Basel, Switzerland. (Email, heinrich.reichert@unibas.ch). Groundbreaking work by Obaid Siddiqi has contributed to the powerful genetic toolkit that ...

  17. Schizophrenia as a Brain Disease: Implications for Psychologists and Families.

    Science.gov (United States)

    Johnson, Dale L.

    1989-01-01

    The belief that schizophrenia is a brain disease is the consensus among families of persons with mental illness and is supported by the National Alliance for the Mentally Ill. This article summarizes implications for psychologists from the following standpoints: (1) etiology; (2) vulnerability; (3) treatment; (4) rehabilitation; (5) assessment;…

  18. Abnormalities of Dopamine D Receptor Signaling in the Diseased Brain

    Directory of Open Access Journals (Sweden)

    G Aleph Prieto

    2017-08-01

    Full Text Available Dopamine D 3 receptors (D 3 R modulate neuronal activity in several brain regions including cortex, striatum, cerebellum, and hippocampus. A growing body of evidence suggests that aberrant D 3 R signaling contributes to multiple brain diseases, such as Parkinson’s disease, essential tremor, schizophrenia, and addiction. In line with these findings, D 3 R has emerged as a potential target in the treatment of neurological disorders. However, the mechanisms underlying neuronal D 3 R signaling are poorly understood, either in healthy or diseased brain. Here, I review the molecular mechanisms involved in D 3 R signaling via monomeric D 3 R and heteromeric receptor complexes (e.g., D 3 R-D 1 R, D 3 R-D 2 R, D 3 R-A 2a R, and D 3 R-D 3 nf. I focus on D 3 R signaling pathways that, according to recent reports, contribute to pathological brain states. In particular, I describe evidence on both quantitative (e.g., increased number or affinity and qualitative (e.g., switched signaling changes in D 3 R that has been associated with brain dysfunction. I conclude with a description of basic mechanisms that modulate D 3 R signaling such as desensitization, as disruption of these mechanisms may underlie pathological changes in D 3 R signaling. Because several lines of evidence support the idea that imbalances in D 3 R signaling alter neural function, a better understanding of downstream D 3 R pathways is likely to reveal novel therapeutic strategies toward dopamine-related brain disorders.

  19. Diamox-enhanced brain SPECT in cerebrovascular diseases

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Yun Young [College of Medicine, Hanyang University, Seoul (Korea, Republic of)

    2007-04-15

    Acute event in cerebrovascular disease is the second most common cause of death in Korea following cancer, and it can also cause serious neurologic deficits. Understanding of perfusion status is important for clinical applications in management of patients with cerebrovascular diseases, and then the attacks of ischemic neurologic symptoms and the risk of acute events can be reduced. Therefore, the normal vascular anatomy of brain, various clinical applications of acetazolamide-enhanced brain perfusion SPECT, including meaning and role of assessment of vascular reserve in carotid stenosis before procedure, in pediatric Moyamoya disease before and after operation, in prediction of development of hyperperfusion syndrome before procedure, and in prediction of vasospasm and of prognosis in subarachnoid hemorrhage were reviewed in this paper.

  20. Network analysis of intrinsic functional brain connectivity in Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Kaustubh Supekar

    2008-06-01

    Full Text Available Functional brain networks detected in task-free ("resting-state" functional magnetic resonance imaging (fMRI have a small-world architecture that reflects a robust functional organization of the brain. Here, we examined whether this functional organization is disrupted in Alzheimer's disease (AD. Task-free fMRI data from 21 AD subjects and 18 age-matched controls were obtained. Wavelet analysis was applied to the fMRI data to compute frequency-dependent correlation matrices. Correlation matrices were thresholded to create 90-node undirected-graphs of functional brain networks. Small-world metrics (characteristic path length and clustering coefficient were computed using graph analytical methods. In the low frequency interval 0.01 to 0.05 Hz, functional brain networks in controls showed small-world organization of brain activity, characterized by a high clustering coefficient and a low characteristic path length. In contrast, functional brain networks in AD showed loss of small-world properties, characterized by a significantly lower clustering coefficient (p<0.01, indicative of disrupted local connectivity. Clustering coefficients for the left and right hippocampus were significantly lower (p<0.01 in the AD group compared to the control group. Furthermore, the clustering coefficient distinguished AD participants from the controls with a sensitivity of 72% and specificity of 78%. Our study provides new evidence that there is disrupted organization of functional brain networks in AD. Small-world metrics can characterize the functional organization of the brain in AD, and our findings further suggest that these network measures may be useful as an imaging-based biomarker to distinguish AD from healthy aging.

  1. Dock protein family in brain development and neurological disease.

    Science.gov (United States)

    Shi, Lei

    2013-11-01

    The family of dedicator of cytokinesis (Dock), a protein family that belongs to the atypical Rho guanine nucleotide exchange factors (GEFs) for Rac and/or Cdc42 GTPases, plays pivotal roles in various processes of brain development. To date, 11 members of Docks have been identified in the mammalian system. Emerging evidence has suggested that members of the Dock family are associated with several neurodegenerative and neuropsychiatric diseases, including Alzheimer disease and autism spectrum disorders. This review summarizes recent advances on the understanding of the roles of the Dock protein family in normal and diseased processes in the nervous system. Furthermore, interacting proteins and the molecular regulation of Docks are discussed.

  2. Microbiome, probiotics and neurodegenerative diseases: deciphering the gut brain axis.

    Science.gov (United States)

    Westfall, Susan; Lomis, Nikita; Kahouli, Imen; Dia, Si Yuan; Singh, Surya Pratap; Prakash, Satya

    2017-10-01

    The gut microbiota is essential to health and has recently become a target for live bacterial cell biotherapies for various chronic diseases including metabolic syndrome, diabetes, obesity and neurodegenerative disease. Probiotic biotherapies are known to create a healthy gut environment by balancing bacterial populations and promoting their favorable metabolic action. The microbiota and its respective metabolites communicate to the host through a series of biochemical and functional links thereby affecting host homeostasis and health. In particular, the gastrointestinal tract communicates with the central nervous system through the gut-brain axis to support neuronal development and maintenance while gut dysbiosis manifests in neurological disease. There are three basic mechanisms that mediate the communication between the gut and the brain: direct neuronal communication, endocrine signaling mediators and the immune system. Together, these systems create a highly integrated molecular communication network that link systemic imbalances with the development of neurodegeneration including insulin regulation, fat metabolism, oxidative markers and immune signaling. Age is a common factor in the development of neurodegenerative disease and probiotics prevent many harmful effects of aging such as decreased neurotransmitter levels, chronic inflammation, oxidative stress and apoptosis-all factors that are proven aggravators of neurodegenerative disease. Indeed patients with Parkinson's and Alzheimer's diseases have a high rate of gastrointestinal comorbidities and it has be proposed by some the management of the gut microbiota may prevent or alleviate the symptoms of these chronic diseases.

  3. Disrupted brain network topology in Parkinson's disease: a longitudinal magnetoencephalography study.

    NARCIS (Netherlands)

    Olde Dubbelink, K.T.E.; Hillebrand, A.; Stoffers, D.; Deijen, J.B.; Twisk, J.W.R.; Stam, C.J.; Berendse, H.W.

    2014-01-01

    Although alterations in resting-state functional connectivity between brain regions have previously been reported in Parkinson's disease, the spatial organization of these changes remains largely unknown. Here, we longitudinally studied brain network topology in Parkinson's disease in relation to

  4. Imaging of Brain Connectivity in Dementia: Clinical Implications for Diagnosis of its Underlying Diseases

    NARCIS (Netherlands)

    R. Meijboom (Rozanna)

    2017-01-01

    markdownabstractIn this thesis we investigated the use of advanced magnetic resonance imaging (MRI) techniques in identifying subtle brain abnormalities, associating brain abnormalities with disease symptomatology, and improving early (differential) diagnosis in several diseases underlying dementia.

  5. Psychopathology of Time in Brain Disease and Schizophrenia

    Directory of Open Access Journals (Sweden)

    John Cutting

    1990-01-01

    Full Text Available The literature on disturbance of time-sense in brain disease and schizophrenia is reviewed and the subjective experience of altered time-sense reported by 45 out of 350 personally interviewed schizophrenics is analyzed. A review of the literature on the effect of brain damage revealed that some phenomena (déjà vu, reduplication of time, altered tempo to events were linked with right hemisphere dysfunction, one phenomenon (incorrect sequencing of events was linked with left anterior brain damage, and others (disrupted “biological clock”, disturbed serise of rate of flow of current or past events could arise from subcortical as well as focal cortical damage. The sparse literature on disturbed time-sense in schizophrenia suggested that there was a shared psychopathology in this respect with right hemisphere dysfunction. The phenomena encountered in the 45 schizophrenics are described and classified.

  6. Gluten-induced cognitive impairment ("brain fog") in coeliac disease.

    Science.gov (United States)

    Yelland, Gregory W

    2017-03-01

    Much is known about the serious neurological effects of gluten ingestion in coeliac disease patients, such as sporadic ataxia and peripheral neuropathy, although the causal links to gluten are still under debate. However, such disorders are observed in only a small percentage of coeliac patients. Much less is known about the transient cognitive impairments to memory, attention, executive function, and the speed of cognitive processing reported by the majority of patients with coeliac disease. These mild degradations of cognitive functions, referred to as "brain fog," are yet to be formally recognized as a medical or psychological condition. However, subtle tests of cognitive function are measurable in untreated patients with coeliac disease and improve over the first 12 months' therapy with a gluten-free diet. Such deficits also occur in patients with Crohn's disease, particularly in association with systemic inflammatory activity. Thus, cognitive impairments associated with brain fog are psychologically and neurologically real and improve with adherence to a gluten-free diet. There is not yet sufficient evidence to provide a definitive account of the mechanism by which gluten ingestion causes the impairments to cognitive function associated with brain fog, but current evidence suggests that it is more likely that the causal factor is not directly related to exposure to gluten. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  7. BRAIN IMAGING IN THE STUDY OF ALZHEIMER'S DISEASE

    Science.gov (United States)

    Reiman, Eric M.; Jagust, William J.

    2012-01-01

    Over the last 20 years, there has been extraordinary progress in brain imaging research and its application to the study of Alzheimer's disease (AD). Brain imaging researchers have contributed to the scientific understanding, early detection and tracking of AD. They have set the stage for imaging techniques to play growing roles in the clinical setting, the evaluation of disease-modifying treatments, and the identification of demonstrably effective prevention therapies. They have developed ground-breaking methods, including positron emission tomography (PET) ligands to measure fibrillar amyloid-β (Aβ) deposition, new magnetic resonance imaging (MRI) pulse sequences, and powerful image analysis techniques, to help in these endeavors. Additional work is needed to develop even more powerful imaging methods, to further clarify the relationship and time course of Aβ and other disease processes in the predisposition to AD, to establish the role of brain imaging methods in the clinical setting, and to provide the scientific means and regulatory approval pathway needed to evaluate the range of promising disease-modifying and prevention therapies as quickly as possible. Twenty years from now, AD may not yet be a distant memory, but the best is yet to come. PMID:22173295

  8. Altered resting state brain networks in Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Martin Göttlich

    Full Text Available Parkinson's disease (PD is a neurodegenerative disorder affecting dopaminergic neurons in the substantia nigra leading to dysfunctional cortico-striato-thalamic-cortical loops. In addition to the characteristic motor symptoms, PD patients often show cognitive impairments, affective changes and other non-motor symptoms, suggesting system-wide effects on brain function. Here, we used functional magnetic resonance imaging and graph-theory based analysis methods to investigate altered whole-brain intrinsic functional connectivity in PD patients (n = 37 compared to healthy controls (n = 20. Global network properties indicated less efficient processing in PD. Analysis of brain network modules pointed to increased connectivity within the sensorimotor network, but decreased interaction of the visual network with other brain modules. We found lower connectivity mainly between the cuneus and the ventral caudate, medial orbitofrontal cortex and the temporal lobe. To identify regions of altered connectivity, we mapped the degree of intrinsic functional connectivity both on ROI- and on voxel-level across the brain. Compared to healthy controls, PD patients showed lower connectedness in the medial and middle orbitofrontal cortex. The degree of connectivity was also decreased in the occipital lobe (cuneus and calcarine, but increased in the superior parietal cortex, posterior cingulate gyrus, supramarginal gyrus and supplementary motor area. Our results on global network and module properties indicated that PD manifests as a disconnection syndrome. This was most apparent in the visual network module. The higher connectedness within the sensorimotor module in PD patients may be related to compensation mechanism in order to overcome the functional deficit of the striato-cortical motor loops or to loss of mutual inhibition between brain networks. Abnormal connectivity in the visual network may be related to adaptation and compensation processes as a consequence

  9. Increased White Matter Inflammation in Aging- and Alzheimer's Disease Brain.

    Science.gov (United States)

    Raj, Divya; Yin, Zhuoran; Breur, Marjolein; Doorduin, Janine; Holtman, Inge R; Olah, Marta; Mantingh-Otter, Ietje J; Van Dam, Debby; De Deyn, Peter P; den Dunnen, Wilfred; Eggen, Bart J L; Amor, Sandra; Boddeke, Erik

    2017-01-01

    Chronic neuroinflammation, which is primarily mediated by microglia, plays an essential role in aging and neurodegeneration. It is still unclear whether this microglia-induced neuroinflammation occurs globally or is confined to distinct brain regions. In this study, we investigated microglia activity in various brain regions upon healthy aging and Alzheimer's disease (AD)-related pathology in both human and mouse samples. In purified microglia isolated from aging mouse brains, we found a profound gene expression pattern related to pro-inflammatory processes, phagocytosis, and lipid homeostasis. Particularly in white matter microglia of 24-month-old mice, abundant expression of phagocytic markers including Mac-2, Axl, CD16/32, Dectin1, CD11c, and CD36 was detected. Interestingly, in white matter of human brain tissue the first signs of inflammatory activity were already detected during middle age. Thus quantification of microglial proteins, such as CD68 (commonly associated with phagocytosis) and HLA-DR (associated with antigen presentation), in postmortem human white matter brain tissue showed an age-dependent increase in immunoreactivity already in middle-aged people (53.2 ± 2.0 years). This early inflammation was also detectable by non-invasive positron emission tomography imaging using [11C]-(R)-PK11195, a ligand that binds to activated microglia. Increased microglia activity was also prominently present in the white matter of human postmortem early-onset AD (EOAD) brain tissue. Interestingly, microglia activity in the white matter of late-onset AD (LOAD) CNS was similar to that of the aged clinically silent AD cases. These data indicate that microglia-induced neuroinflammation is predominant in the white matter of aging mice and humans as well as in EOAD brains. This white matter inflammation may contribute to the progression of neurodegeneration, and have prognostic value for detecting the onset and progression of aging and neurodegeneration.

  10. Genetic mouse models of brain ageing and Alzheimer's disease.

    Science.gov (United States)

    Bilkei-Gorzo, Andras

    2014-05-01

    Progression of brain ageing is influenced by a complex interaction of genetic and environmental factors. Analysis of genetically modified animals with uniform genetic backgrounds in a standardised, controlled environment enables the dissection of critical determinants of brain ageing on a molecular level. Human and animal studies suggest that increased load of damaged macromolecules, efficacy of DNA maintenance, mitochondrial activity, and cellular stress defences are critical determinants of brain ageing. Surprisingly, mouse lines with genetic impairment of anti-oxidative capacity generally did not show enhanced cognitive ageing but rather an increased sensitivity to oxidative challenge. Mouse lines with impaired mitochondrial activity had critically short life spans or severe and rapidly progressing neurodegeneration. Strains with impaired clearance in damaged macromolecules or defects in the regulation of cellular stress defences showed alterations in the onset and progression of cognitive decline. Importantly, reduced insulin/insulin-like growth factor signalling generally increased life span but impaired cognitive functions revealing a complex interaction between ageing of the brain and of the body. Brain ageing is accompanied by an increased risk of developing Alzheimer's disease. Transgenic mouse models expressing high levels of mutant human amyloid precursor protein showed a number of symptoms and pathophysiological processes typical for early phase of Alzheimer's disease. Generally, therapeutic strategies effective against Alzheimer's disease in humans were also active in the Tg2576, APP23, APP/PS1 and 5xFAD lines, but a large number of false positive findings were also reported. The 3xtg AD model likely has the highest face and construct validity but further studies are needed. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Brain-gut-microbiota axis in Parkinson's disease.

    Science.gov (United States)

    Mulak, Agata; Bonaz, Bruno

    2015-10-07

    Parkinson's disease (PD) is characterized by alpha-synucleinopathy that affects all levels of the brain-gut axis including the central, autonomic, and enteric nervous systems. Recently, it has been recognized that the brain-gut axis interactions are significantly modulated by the gut microbiota via immunological, neuroendocrine, and direct neural mechanisms. Dysregulation of the brain-gut-microbiota axis in PD may be associated with gastrointestinal manifestations frequently preceding motor symptoms, as well as with the pathogenesis of PD itself, supporting the hypothesis that the pathological process is spread from the gut to the brain. Excessive stimulation of the innate immune system resulting from gut dysbiosis and/or small intestinal bacterial overgrowth and increased intestinal permeability may induce systemic inflammation, while activation of enteric neurons and enteric glial cells may contribute to the initiation of alpha-synuclein misfolding. Additionally, the adaptive immune system may be disturbed by bacterial proteins cross-reacting with human antigens. A better understanding of the brain-gut-microbiota axis interactions should bring a new insight in the pathophysiology of PD and permit an earlier diagnosis with a focus on peripheral biomarkers within the enteric nervous system. Novel therapeutic options aimed at modifying the gut microbiota composition and enhancing the intestinal epithelial barrier integrity in PD patients could influence the initial step of the following cascade of neurodegeneration in PD.

  12. Metabolic resting-state brain networks in health and disease.

    Science.gov (United States)

    Spetsieris, Phoebe G; Ko, Ji Hyun; Tang, Chris C; Nazem, Amir; Sako, Wataru; Peng, Shichun; Ma, Yilong; Dhawan, Vijay; Eidelberg, David

    2015-02-24

    The delineation of resting state networks (RSNs) in the human brain relies on the analysis of temporal fluctuations in functional MRI signal, representing a small fraction of total neuronal activity. Here, we used metabolic PET, which maps nonfluctuating signals related to total activity, to identify and validate reproducible RSN topographies in healthy and disease populations. In healthy subjects, the dominant (first component) metabolic RSN was topographically similar to the default mode network (DMN). In contrast, in Parkinson's disease (PD), this RSN was subordinated to an independent disease-related pattern. Network functionality was assessed by quantifying metabolic RSN expression in cerebral blood flow PET scans acquired at rest and during task performance. Consistent task-related deactivation of the "DMN-like" dominant metabolic RSN was observed in healthy subjects and early PD patients; in contrast, the subordinate RSNs were activated during task performance. Network deactivation was reduced in advanced PD; this abnormality was partially corrected by dopaminergic therapy. Time-course comparisons of DMN loss in longitudinal resting metabolic scans from PD and Alzheimer's disease subjects illustrated that significant reductions appeared later for PD, in parallel with the development of cognitive dysfunction. In contrast, in Alzheimer's disease significant reductions in network expression were already present at diagnosis, progressing over time. Metabolic imaging can directly provide useful information regarding the resting organization of the brain in health and disease.

  13. Circulating exosomes as new biomarkers for brain disease and injury

    Science.gov (United States)

    Graner, Michael W.; Epple, Laura M.; Dusto, Nathaniel L.; Lencioni, Alex M.; Nega, Meheret; Herring, Matthew; Winston, Ben; Madsen, Helen; Bemis, Lynne T.; Anchordoquy, Thomas J.

    2013-05-01

    Brain diseases such as cancers, neurodegenerative disorders, or trauma are frequently diagnosed with imaging modalities and sometimes with intracranial biopsies. Treatment response is similarly monitored, along with clinical indications. While these technologies provide important windows into the disease state, they fail to provide us a detailed molecular portrait of the disease and of the changes taking place during therapy. Exosomes are virus-sized nanovesicles derived from the endosomal system and are released extracellularly from essentially all cell types. Exosomes contain intracellular entities (proteins, nucleic acids, metabolites), membrane proteins and lipids, and even extracellular proteins bound to them. Exosomes may be considered as mini-surrogates of their cells of origin, with some content common to all cells/exosomes, but some of the content would be cell-specific. These vesicles are found in all biofluids in humans, and are thus accessible to "liquid biopsy" with harvest of vesicles from such fluids. Current challenges are to identify disease-related markers or panels of markers to distinguish the disease state. Here we will show examples of brain tumor markers found in/on exosomes from cell culture and patient sera, and we will suggest that aspects of the biology of disease may have a relevant place in the search for biomarkers.

  14. Genetics Home Reference: COL4A1-related brain small-vessel disease

    Science.gov (United States)

    ... Health Conditions COL4A1-related brain small-vessel disease COL4A1-related brain small-vessel disease Printable PDF Open ... Javascript to view the expand/collapse boxes. Description COL4A1 -related brain small-vessel disease is part of ...

  15. A Novel Human Body Area Network for Brain Diseases Analysis.

    Science.gov (United States)

    Lin, Kai; Xu, Tianlang

    2016-10-01

    Development of wireless sensor and mobile communication technology provide an unprecedented opportunity for realizing smart and interactive healthcare systems. Designing such systems aims to remotely monitor the health and diagnose the diseases for users. In this paper, we design a novel human body area network for brain diseases analysis, which is named BABDA. Considering the brain is one of the most complex organs in the human body, the BABDA system provides four function modules to ensure the high quality of the analysis result, which includes initial data collection, data correction, data transmission and comprehensive data analysis. The performance evaluation conducted in a realistic environment with several criteria shows the availability and practicability of the BABDA system.

  16. Extracellular Vesicles in Brain Tumors and Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Federica Ciregia

    2017-08-01

    Full Text Available Extracellular vesicles (EVs can be classified into apoptotic bodies, microvesicles (MVs, and exosomes, based on their origin or size. Exosomes are the smallest and best characterized vesicles which derived from the endosomal system. These vesicles are released from many different cell types including neuronal cells and their functions in the nervous system are investigated. They have been proposed as novel means for intercellular communication, which takes part not only to the normal neuronal physiology but also to the transmission of pathogenic proteins. Indeed, exosomes are fundamental to assemble and transport proteins during development, but they can also transfer neurotoxic misfolded proteins in pathogenesis. The present review will focus on their roles in neurological diseases, specifically brain tumors, such as glioblastoma (GBM, neuroblastoma (NB, medulloblastoma (MB, and metastatic brain tumors and chronic neurodegenerative diseases, such as Alzheimer, Parkinson, multiple sclerosis (MS, amyotrophic lateral sclerosis (ALS, Huntington, and Prion diseseases highlighting their involvement in spreading neurotoxicity, in therapeutics, and in pathogenesis.

  17. Extracellular Vesicles in Brain Tumors and Neurodegenerative Diseases

    Science.gov (United States)

    Ciregia, Federica; Urbani, Andrea; Palmisano, Giuseppe

    2017-01-01

    Extracellular vesicles (EVs) can be classified into apoptotic bodies, microvesicles (MVs), and exosomes, based on their origin or size. Exosomes are the smallest and best characterized vesicles which derived from the endosomal system. These vesicles are released from many different cell types including neuronal cells and their functions in the nervous system are investigated. They have been proposed as novel means for intercellular communication, which takes part not only to the normal neuronal physiology but also to the transmission of pathogenic proteins. Indeed, exosomes are fundamental to assemble and transport proteins during development, but they can also transfer neurotoxic misfolded proteins in pathogenesis. The present review will focus on their roles in neurological diseases, specifically brain tumors, such as glioblastoma (GBM), neuroblastoma (NB), medulloblastoma (MB), and metastatic brain tumors and chronic neurodegenerative diseases, such as Alzheimer, Parkinson, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington, and Prion diseseases highlighting their involvement in spreading neurotoxicity, in therapeutics, and in pathogenesis. PMID:28912682

  18. Deep brain stimulation in Huntington's disease: assessment of potential targets.

    Science.gov (United States)

    Sharma, Mayur; Deogaonkar, Milind

    2015-05-01

    Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder that has very few effective therapeutic interventions. Since the disease has a defined neural circuitry abnormality, neuromodulation could be an option. Case reports, original research, and animal model studies were selected from the databases of Medline and PubMed. All related studies published up to July 2014 were included in this review. The following search terms were used: "Deep brain stimulation," "DBS," "thalamotomy," "pallidal stimulation," and "Huntington's Disease," "HD," "chorea," or "hyperkinetic movement disorders." This review examines potential nodes in the HD circuitry that could be modulated using deep brain stimulation (DBS) therapy. With rapid evolution of imaging and ability to reach difficult targets in the brain with refined DBS technology, some phenotypes of HD could potentially be treated with DBS in the near future. Further clinical studies are warranted to validate the efficacy of neuromodulation and to determine the most optimal target for HD. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. The Choroid Plexus in Healthy and Diseased Brain.

    Science.gov (United States)

    Kaur, Charanjit; Rathnasamy, Gurugirijha; Ling, Eng-Ang

    2016-03-01

    The choroid plexus is composed of epithelial cells resting on a basal lamina. These cells produce the cerebrospinal fluid (CSF), which has many functions including rendering mechanical support, providing a route for some nutrients, removing by-products of metabolism and synaptic activity, and playing a role in hormonal signaling. The choroid plexus synthesizes many growth factors, including insulin-like, fibroblast, and platelet-derived growth factors. The tight junctions located between the apical parts of the choroid plexus epithelial cells form the blood-CSF barrier (BCSFB), which is crucial for the homeostatic regulation of the brain microenvironment along with the blood-brain barrier (BBB). Morphological changes such as atrophy of the epithelial cells and thickening of the basement membrane suggest altered CSF production occurs in aging and in Alzheimer disease. In brain injuries and infections, leukocytes accumulate in the CSF by passing through the choroid plexus. In inflammatory CNS diseases (eg, multiple sclerosis), pathogenic autoreactive T lymphocytes may migrate through the BBB and BCSFB into the CNS. The development of therapeutic strategies to mitigate disruption of the BCSFB may be helpful to curtail the entry of inflammatory cells into the CSF and hence reduce inflammation, thereby overcoming choroid plexus dysfunction in senescence and in various diseases of the CNS. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

  20. Microbiota-Brain-Gut Axis and Neurodegenerative Diseases.

    Science.gov (United States)

    Quigley, Eamonn M M

    2017-10-17

    The purposes of this review were as follows: first, to provide an overview of the gut microbiota and its interactions with the gut and the central nervous system (the microbiota-gut-brain axis) in health, second, to review the relevance of this axis to the pathogenesis of neurodegenerative diseases, such as Parkinson's disease, and, finally, to assess the potential for microbiota-targeted therapies. Work on animal models has established the microbiota-gut-brain axis as a real phenomenon; to date, the evidence for its operation in man has been limited and has been confronted by considerable logistical challenges. Animal and translational models have incriminated a disturbed gut microbiota in a number of CNS disorders, including Parkinson's disease; data from human studies is scanty. While a theoretical basis can be developed for the use of microbiota-directed therapies in neurodegenerative disorders, support is yet to come from high-quality clinical trials. In theory, a role for the microbiota-gut-brain axis is highly plausible; clinical confirmation is awaited.

  1. Interpersonal traits change as a function of disease type and severity in degenerative brain diseases

    Science.gov (United States)

    Sollberger, Marc; Neuhaus, John; Ketelle, Robin; Stanley, Christine M.; Beckman, Victoria; Growdon, Matthew; Jung, Jang; Miller, Bruce L.; Rankin, Katherine P.

    2010-01-01

    Background Different degenerative brain diseases result in distinct personality changes as a result of divergent patterns of brain damage, however, little is known about the natural history of these personality changes throughout the course of each disease. Objective To investigate how interpersonal traits change as a function of degenerative brain disease type and severity. Methods Using the Interpersonal Adjective Scales, informant ratings of retrospective premorbid and current scores for dominance, extraversion, warmth, and ingenuousness were collected annually for one to four years on 188 patients [67 behavioural variant frontotemporal dementia (bvFTD), 40 semantic dementia (SemD), 81 Alzheimer’s disease (AD)] and 65 older healthy controls. Using random coefficient models, interpersonal behaviour scores at very mild, mild, or moderate-to-severe disease stages were compared within and between patient groups. Results Group-level changes from premorbid personality occurred as a function of disease type and severity, and were apparent even at a very mild disease stage (Clinical Dementia Rating=0.5) for all three diseases. Decreases in interpersonal traits associated with emotional affiliation (i.e., extraversion, warmth, and ingenuousness) and more rigid interpersonal behaviour differentiated bvFTD and SemD patients from AD patients. Conclusions Specific changes in affiliative interpersonal traits differentiate degenerative brain diseases even at a very mild disease stage, and patterns of personality change differ across bvFTD, SemD, and AD with advancing disease. This study describes the typical progression of change of interpersonal traits in each disease, improving the ability of clinicians and caregivers to predict and plan for symptom progression. PMID:21172858

  2. Music and the brain. Lessons from brain diseases and some reflections on the "emotional" brain.

    Science.gov (United States)

    Wieser, Heinz Gregor

    2003-11-01

    Studies are reviewed from the perspective of a neurologist and epileptologist interested in "music and the brain." At the neurocognitive level, deficits in pitch discrimination of patients with brain lesions and those during the intracarotid amobarbital test are outlined, because they show that the temporal lobe and, in particular, the right acoustic cortex are crucial. Hallucinations of music during epileptic seizures as well as the analysis of musicogenic epilepsy point to the same gross localization and lateralization. At the esthetic level, music theoretical concepts on the consonance-dissonance dichotomy and related EEG examinations are reported, which illustrate the importance of mesiolimbic temporal lobe structures for the pleasure that we might experience when listening to music. The complex interaction of many neuronal circuits and assemblies of both hemispheres in musical perception and performance is illustrated by musical analysis of a recording by an organ player who experienced a right temporal lobe seizure. This analysis revealed that the seizure-induced errors of the left hand were compensated with the right hand in a musically meaningful way.

  3. Brain activity during complex imagined gait tasks in Parkinson disease.

    Science.gov (United States)

    Peterson, Daniel S; Pickett, Kristen A; Duncan, Ryan P; Perlmutter, Joel S; Earhart, Gammon M

    2014-05-01

    Motor imagery during functional magnetic resonance imaging (fMRI) allows assessment of brain activity during tasks, like walking, that cannot be completed in an MRI scanner. We used gait imagery to assess the neural pathophysiology of locomotion in Parkinson disease (PD). Brain activity was measured in five locomotor regions (supplementary motor area (SMA), globus pallidus (GP), putamen, mesencephalic locomotor region, cerebellar locomotor region) during simple (forward) and complex (backward, turning) gait imagery. Brain activity was correlated to overground walking velocity. Across tasks, PD exhibited reduced activity in the globus pallidus compared to controls. People with PD, but not controls, exhibited more activity in the SMA during imagined turning compared to forward or backward walking. In PD, walking speed was correlated to brain activity in several regions. Altered SMA activity in PD during imagined turning may represent compensatory neural adaptations during complex gait. The lowered activity and positive correlation to locomotor function in GP suggests reduced activity in this region may relate to locomotor dysfunction. This study elucidates changes in neural activity during gait in PD, underscoring the importance of testing simple and complex tasks. Results support a positive relationship between activity in locomotor regions and walking ability. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  4. Directed progression brain networks in Alzheimer's disease: properties and classification.

    Science.gov (United States)

    Friedman, Eric J; Young, Karl; Asif, Danial; Jutla, Inderjit; Liang, Michael; Wilson, Scott; Landsberg, Adam S; Schuff, Norbert

    2014-06-01

    This article introduces a new approach in brain connectomics aimed at characterizing the temporal spread in the brain of pathologies like Alzheimer's disease (AD). The main instrument is the development of "directed progression networks" (DPNets), wherein one constructs directed edges between nodes based on (weakly) inferred directions of the temporal spreading of the pathology. This stands in contrast to many previously studied brain networks where edges represent correlations, physical connections, or functional progressions. In addition, this is one of a few studies showing the value of using directed networks in the study of AD. This article focuses on the construction of DPNets for AD using longitudinal cortical thickness measurements from magnetic resonance imaging data. The network properties are then characterized, providing new insights into AD progression, as well as novel markers for differentiating normal cognition (NC) and AD at the group level. It also demonstrates the important role of nodal variations for network classification (i.e., the significance of standard deviations, not just mean values of nodal properties). Finally, the DPNets are utilized to classify subjects based on their global network measures using a variety of data-mining methodologies. In contrast to most brain networks, these DPNets do not show high clustering and small-world properties.

  5. Structural brain plasticity in Parkinson's disease induced by balance training.

    Science.gov (United States)

    Sehm, Bernhard; Taubert, Marco; Conde, Virginia; Weise, David; Classen, Joseph; Dukart, Juergen; Draganski, Bogdan; Villringer, Arno; Ragert, Patrick

    2014-01-01

    We investigated morphometric brain changes in patients with Parkinson's disease (PD) that are associated with balance training. A total of 20 patients and 16 healthy matched controls learned a balance task over a period of 6 weeks. Balance testing and structural magnetic resonance imaging were performed before and after 2, 4, and 6 training weeks. Balance performance was re-evaluated after ∼20 months. Balance training resulted in performance improvements in both groups. Voxel-based morphometry revealed learning-dependent gray matter changes in the left hippocampus in healthy controls. In PD patients, performance improvements were correlated with gray matter changes in the right anterior precuneus, left inferior parietal cortex, left ventral premotor cortex, bilateral anterior cingulate cortex, and left middle temporal gyrus. Furthermore, a TIME × GROUP interaction analysis revealed time-dependent gray matter changes in the right cerebellum. Our results highlight training-induced balance improvements in PD patients that may be associated with specific patterns of structural brain plasticity. In summary, we provide novel evidence for the capacity of the human brain to undergo learning-related structural plasticity even in a pathophysiological disease state such as in PD. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Sporadic Alzheimer's disease begins as episodes of brain ischemia and ischemically dysregulated Alzheimer's disease genes.

    Science.gov (United States)

    Pluta, Ryszard; Jabłoński, Mirosław; Ułamek-Kozioł, Marzena; Kocki, Janusz; Brzozowska, Judyta; Januszewski, Sławomir; Furmaga-Jabłońska, Wanda; Bogucka-Kocka, Anna; Maciejewski, Ryszard; Czuczwar, Stanisław J

    2013-12-01

    The study of sporadic Alzheimer's disease etiology, now more than ever, needs an infusion of new concepts. Despite ongoing interest in Alzheimer's disease, the basis of this entity is not yet clear. At present, the best-established and accepted "culprit" in Alzheimer's disease pathology by most scientists is the amyloid, as the main molecular factor responsible for neurodegeneration in this disease. Abnormal upregulation of amyloid production or a disturbed clearance mechanism may lead to pathological accumulation of amyloid in brain according to the "amyloid hypothesis." We will critically review these observations and highlight inconsistencies between the predictions of the "amyloid hypothesis" and the published data. There is still controversy over the role of amyloid in the pathological process. A question arises whether amyloid is responsible for the neurodegeneration or if it accumulates because of the neurodegeneration. Recent evidence suggests that the pathophysiology and neuropathology of Alzheimer's disease comprises more than amyloid accumulation, tau protein pathology and finally brain atrophy with dementia. Nowadays, a handful of researchers share a newly emerged view that the ischemic episodes of brain best describe the pathogenic cascade, which eventually leads to neuronal loss, especially in hippocampus, with amyloid accumulation, tau protein pathology and irreversible dementia of Alzheimer type. The most persuasive evidences come from investigations of ischemically damaged brains of patients and from experimental ischemic brain studies that mimic Alzheimer-type dementia. This review attempts to depict what we know and do not know about the triggering factor of the Alzheimer's disease, focusing on the possibility that the initial pathological trigger involves ischemic episodes and ischemia-induced gene dysregulation. The resulting brain ischemia dysregulates additionally expression of amyloid precursor protein and amyloid-processing enzyme genes

  7. The Alzheimer's disease metabolic brain pattern in mild cognitive impairment.

    Science.gov (United States)

    Meles, Sanne K; Pagani, Marco; Arnaldi, Dario; De Carli, Fabrizio; Dessi, Barbara; Morbelli, Silvia; Sambuceti, Gianmario; Jonsson, Cathrine; Leenders, Klaus L; Nobili, Flavio

    2017-12-01

    We investigated the expression of the Alzheimer's disease-related metabolic brain pattern (ADRP) in 18 F-FDG-PET scans of 44 controls, 27 patients with mild cognitive impairment (MCI) who did not convert to Alzheimer's disease (AD) after five or more years of clinical follow-up, 95 MCI patients who did develop AD dementia on clinical follow-up, and 55 patients with mild-to-moderate AD. The ADRP showed good sensitivity (84%) and specificity (86%) for MCI-converters when compared to controls, but limited specificity when compared to MCI non-converters (66%). Assessment of 18 F-FDG-PET scans on a case-by-case basis using the ADRP may be useful for quantifying disease progression.

  8. Resting-state functional brain networks in Parkinson's disease.

    Science.gov (United States)

    Baggio, Hugo C; Segura, Bàrbara; Junque, Carme

    2015-10-01

    The network approach is increasingly being applied to the investigation of normal brain function and its impairment. In the present review, we introduce the main methodological approaches employed for the analysis of resting-state neuroimaging data in Parkinson's disease studies. We then summarize the results of recent studies that used a functional network perspective to evaluate the changes underlying different manifestations of Parkinson's disease, with an emphasis on its cognitive symptoms. Despite the variability reported by many studies, these methods show promise as tools for shedding light on the pathophysiological substrates of different aspects of Parkinson's disease, as well as for differential diagnosis, treatment monitoring and establishment of imaging biomarkers for more severe clinical outcomes. © 2015 John Wiley & Sons Ltd.

  9. Assessment of brain reference genes for RT-qPCR studies in neurodegenerative diseases

    DEFF Research Database (Denmark)

    Rydbirk, Rasmus; Folke, Jonas; Winge, Kristian

    2016-01-01

    . This is especially important in relation to neurodegenerative diseases where disease-related structural changes may affect the most commonly used RGs. We analysed 15 candidate RGs in 98 brain samples from two brain regions from Alzheimer's disease (AD), Parkinson's disease (PD), Multiple System Atrophy...

  10. [Neurosurgical therapy of Parkinson disease. Deep brain stimulation].

    Science.gov (United States)

    Vesper, J; Funk, T; Kern, B C; Klostermann, F; Straschill, M; Brock, M

    2001-05-28

    The introduction of continuous high frequency stimulation (deep brain stimulation) into functional neurosurgery has opened up new avenues in the treatment of Parkinson's disease. This new technique expands the therapeutic possibilities available to those patients in whom, over the years, the effectiveness of drug treatment has deteriorated, or severe side effects developed. In the individual case, the decision as to whether to operate is taken on the basis of interdisciplinary cooperation between the care-providing neurologist and the neurosurgeon specialized in this particular field.

  11. Alzheimer's disease pattern of brain atrophy predicts cognitive decline in Parkinson's disease

    Science.gov (United States)

    Dietz, Nicole; Duda, John E.; Wolk, David A.; Doshi, Jimit; Xie, Sharon X.; Davatzikos, Christos; Clark, Christopher M.; Siderowf, Andrew

    2012-01-01

    Research suggests overlap in brain regions undergoing neurodegeneration in Parkinson's and Alzheimer's disease. To assess the clinical significance of this, we applied a validated Alzheimer's disease-spatial pattern of brain atrophy to patients with Parkinson's disease with a range of cognitive abilities to determine its association with cognitive performance and decline. At baseline, 84 subjects received structural magnetic resonance imaging brain scans and completed the Dementia Rating Scale-2, and new robust and expanded Dementia Rating Scale-2 norms were applied to cognitively classify participants. Fifty-nine non-demented subjects were assessed annually with the Dementia Rating Scale-2 for two additional years. Magnetic resonance imaging scans were quantified using both a region of interest approach and voxel-based morphometry analysis, and a method for quantifying the presence of an Alzheimer's disease spatial pattern of brain atrophy was applied to each scan. In multivariate models, higher Alzheimer's disease pattern of atrophy score was associated with worse global cognitive performance (β = −0.31, P = 0.007), including in non-demented patients (β = −0.28, P = 0.05). In linear mixed model analyses, higher baseline Alzheimer's disease pattern of atrophy score predicted long-term global cognitive decline in non-demented patients [F(1, 110) = 9.72, P = 0.002], remarkably even in those with normal cognition at baseline [F(1, 80) = 4.71, P = 0.03]. In contrast, in cross-sectional and longitudinal analyses there was no association between region of interest brain volumes and cognitive performance in patients with Parkinson's disease with normal cognition. These findings support involvement of the hippocampus and parietal–temporal cortex with cognitive impairment and long-term decline in Parkinson's disease. In addition, an Alzheimer's disease pattern of brain atrophy may be a preclinical biomarker of cognitive decline

  12. The Alzheimer's disease-related glucose metabolic brain pattern.

    Science.gov (United States)

    Teune, Laura K; Strijkert, Fijanne; Renken, Remco J; Izaks, Gerbrand J; de Vries, Jeroen J; Segbers, Marcel; Roerdink, Jos B T M; Dierckx, Rudi A J O; Leenders, Klaus L

    2014-01-01

    [(18)F]fluorodeoxyglucose (FDG) PET imaging of the brain can be used to assist in the differential diagnosis of dementia. Group differences in glucose uptake between patients with dementia and controls are well-known. However, a multivariate analysis technique called scaled subprofile model, principal component analysis (SSM/PCA) aiming at identifying diagnostic neural networks in diseases, have been applied less frequently. We validated an Alzheimer's Disease-related (AD) glucose metabolic brain pattern using the SSM/PCA analysis and applied it prospectively in an independent confirmation cohort. We used FDG-PET scans of 18 healthy controls and 15 AD patients (identification cohort) to identify an AD-related glucose metabolic covariance pattern. In the confirmation cohort (n=15), we investigated the ability to discriminate between probable AD and non-probable AD (possible AD, mild cognitive impairment (MCI) or subjective complaints). The AD-related metabolic covariance pattern was characterized by relatively decreased metabolism in the temporoparietal regions and relatively increased metabolism in the subcortical white matter, cerebellum and sensorimotor cortex. Receiver-operating characteristic (ROC) curves showed at a cut-off value of z=1.23, a sensitivity of 93% and a specificity of 94% for correct AD classification. In the confirmation cohort, subjects with clinically probable AD diagnosis showed a high expression of the AD-related pattern whereas in subjects with a non-probable AD diagnosis a low expression was found. The Alzheimer's disease-related cerebral glucose metabolic covariance pattern identified by SSM/PCA analysis was highly sensitive and specific for Alzheimer's disease. This method is expected to be helpful in the early diagnosis of Alzheimer's disease in clinical practice.

  13. Assessing fibrinogen extravasation into Alzheimer's disease brain using high-content screening of brain tissue microarrays.

    Science.gov (United States)

    Narayan, Pritika J; Kim, Sue-Ling; Lill, Claire; Feng, Sheryl; Faull, Richard L M; Curtis, Maurice A; Dragunow, Michael

    2015-05-30

    Tissue microarrays are commonly used to evaluate disease pathology however methods to automate and quantify pathological changes are limited. This article demonstrates the utility of the VSlide scanner (MetaSystems) for automated image acquisition from immunolabelled tissue microarray slides, and subsequent automated image analysis with MetaXpress (Molecular Devices) software to obtain objective, efficient and reproducible data from immunolabelled tissue microarray sections. Significant increases in fibrinogen immunolabelling were observed in 29 Alzheimer's disease cases compared to 28 control cases analysed from a single tissue microarray slide. Western blot analysis also demonstrated significant increases in fibrinogen immunolabelling in 6 Alzheimer's cases compared to 6 control cases. The observed changes were also validated with gold standard blinded manual H-scoring. VSlide Metafer software offers a 'tissue microarray acquisition' plugin for easy mapping of tissue cores with their original position on the tissue microarray map. High resolution VSlide images are compatible with MetaXpress image analysis software. This article details the coupling of these two technologies to accurately and reproducibly analyse immunolabelled tissue microarrays within minutes, compared to the gold standard method of manual counting using H-scores which is significantly slower and prone to inter-observer variation. Here, we couple brain tissue microarray technology with high-content screening and automated image analysis as a powerful way to address bottle necks in data generation and improve throughput, as well as sensitivity to study biological/pathological changes in brain disease. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Altered brain network centrality in depressed Parkinson's disease patients.

    Science.gov (United States)

    Lou, Yuting; Huang, Peiyu; Li, Dan; Cen, Zhidong; Wang, Bo; Gao, Jixiang; Xuan, Min; Yu, Hualiang; Zhang, Minming; Luo, Wei

    2015-11-01

    Depression is a relatively common and serious nonmotor symptom of Parkinson's disease (PD), which reduces the quality of patients' life. Although disturbances in some related brain networks have been reported, the pathophysiology of depression in PD is still unclear. Here, we aim to investigate whole-brain functional connectivity patterns in depressed PD patients. We recruited 17 PD patients diagnosed with major depressive disorder, 17 PD patients without depression, and 17 healthy control subjects. Resting-state functional MRI and eigenvector centrality mapping were used to identify functional connectivity alterations among these groups. Results showed that depressed PD patients had decreased functional connectivity in the left dorsolateral prefrontal cortex and right superior temporal gyrus and increased functional connectivity in the right posterior cingulate cortex, compared to nondepressed patients. In addition, there was a significant negative correlation between functional connectivity and depression scores in the posterior cingulate cortex. This study suggests that functional connectivity changes in certain nodes of brain networks might contribute to depression in patients with PD. © 2015 International Parkinson and Movement Disorder Society.

  15. Potential Use of Nanomedicine for Drug Delivery Across the Blood-Brain Barrier in Healthy and Diseased Brain.

    Science.gov (United States)

    Ruozi, Barbara; Belletti, Daniela; Pederzoli, Francesca; Forni, Flavio; Vandelli, Maria Angela; Tosi, Giovanni

    2016-01-01

    The research of efficacious non-invasive therapies for the treatment of brain diseases represents a huge challenge, as people affected by disorders of the central nervous system (CNS) will significantly increase. Moreover, the blood-brain barrier is a key factor in hampering a number of effective drugs to reach the CNS. This review is therefore focusing on possible interventions of nanomedicine-based approaches in selected diseases affecting the CNS. A wide overview of the most outstanding results on preclinical evaluations of the potential of nanomedicine in brain diseases (i.e. brain tumor, Alzheimer, Parkinson, epilepsy and others) is given, with highlights on the data with relevant interest and real possibility in translation from bench-to-bedside. Moreover, a critical evaluation on the rationale in planning nanosystems to target specific brain pathologies is described, opening the path to a more structured and pathology-tailored design of nanocarriers.

  16. [Deep brain stimulation for Parkinson's disease: timing and patient selection].

    Science.gov (United States)

    Erasmi, R; Deuschl, G; Witt, K

    2014-02-01

    Deep brain stimulation (DBS) is an effective and evidence-based treatment option for Parkinson's disease. Studies have shown that DBS has good and long-term effects on motor function and quality of life for patients in an advanced stage of the disease and that it is more effective than medical therapy alone. Moreover, a favorable effect of DBS could also be detected at an earlier stage of the disease. On the other hand, possible risks and side effects of the procedure need to be taken into consideration. These can manifest as procedure-related complications, such as bleeding and infections in addition to stimulation-associated phenomena, such as neuropsychiatric disorders and motor side effects. Despite the good effects of DBS important issues still need to be addressed which will be discussed in this article considering the results of several new randomized and controlled clinical studies. For patients with Parkinson's disease with early fluctuations and dyskinesia, DBS has been found to be superior to the best pharmaceutical treatment; therefore, DBS can be considered as a treatment option in the earlier course of the disease. The diagnostic evaluation and the exclusion of contraindications are crucial for patient selection. The choice of the target should be based on the individual symptoms in patients although the subthalamic nucleus (STN) can be considered the standard target. In every case an individual assessment of chances and risks must be conducted and realistic goals and reasonable expectations must be defined.

  17. Brain tissue modifications induced by cholinergic therapy in Alzheimer's disease.

    Science.gov (United States)

    Bozzali, Marco; Parker, Geoff J M; Spanò, Barbara; Serra, Laura; Giulietti, Giovanni; Perri, Roberta; Magnani, Giuseppe; Marra, Camillo; G Vita, Maria; Caltagirone, Carlo; Cercignani, Mara

    2013-12-01

    A previous preliminary investigation based on a novel MRI approach to map anatomical connectivity revealed areas of increased connectivity in Alzheimer's disease (AD) but not in mild cognitive impairment patients. This prompted the hypothesis tested here, that these areas might reflect phenomena of brain plasticity driven by acetylcholinesterase inhibitors (AChEIs). Thirty-eight patients with probable AD (19 under medication with AChEIs and 19 drug-naïve) were recruited together with 11 healthy controls. All subjects had MRI scanning at 3T, including volumetric and diffusion-weighted scans. Probabilistic tractography was used to initiate streamlines from all parenchymal voxels, and anatomical connectivity maps (ACMs) were obtained by counting, among the total number of streamlines initiated, the fraction passing through each brain voxel. After normalization into standard space, ACMs were used to test for between-group comparisons, and for interactions between the exposure to AChEIs and global level of cognition. Patients with AD had reduced ACM values in the fornix, cingulum, and supramarginal gyri. The ACM value was strongly associated with the AChEI dosage-x-duration product in the anterior limb (non-motor pathway) of the internal capsule. Tractography from this region identified the anterior thalamic radiation as the main white matter (WM) tract passing through it. The reduced connectivity in WM bundles connecting the hippocampi with the rest of the brain (fornix/cingulum) suggests a possible mechanism for the spread of AD pathology. An intriguing explanation for the interaction between AChEIs and ACM is related to the mechanisms of brain plasticity, partially driven by neurotrophic properties of acetylcholine replacement. Copyright © 2012 Wiley Periodicals, Inc.

  18. Influence of history of brain disease or brain trauma on psychopathological abnormality in young male in Korea : analysis of multiphasic personal inventory test.

    Science.gov (United States)

    Paik, Ho Kyu; Oh, Chang-Hyun; Choi, Kang; Kim, Chul-Eung; Yoon, Seung Hwan; Chung, Joonho

    2011-08-01

    The purpose of this study is to confirm whether brain disease or brain trauma actually affect psychopathology in young male group in Korea. The authors manually reviewed the result of Korean military multiphasic personal inventory (KMPI) in the examination of conscription in Korea from January 2008 to May 2010. There were total 237 young males in this review. Normal volunteers group (n=150) was composed of those who do not have history of brain disease or brain trauma. Brain disease group (n=33) was consisted of those with history of brain disease. Brain trauma group (n=54) was consisted of those with history of brain trauma. The results of KMPI in each group were compared. Abnormal results of KMPI were found in both brain disease and trauma groups. In the brain disease group, higher tendencies of faking bad response, anxiety, depression, somatization, personality disorder, schizophrenic and paranoid psychopathy was observed and compared to the normal volunteers group. In the brain trauma group, higher tendencies of faking-good, depression, somatization and personality disorder was observed and compared to the normal volunteers group. Young male with history of brain disease or brain trauma may have higher tendencies to have abnormal results of multiphasic personal inventory test compared to young male without history of brain disease or brain trauma, suggesting that damaged brain may cause psychopathology in young male group in Korea.

  19. Brain Region Specific Degeneration with Disease Progression in Late Infantile Neuronal Ceroid Lipofuscinosis (CLN2 Disease)

    Science.gov (United States)

    Dyke, JP; Sondhi, D; Voss, HU; Yohay, K; Hollmann, C; Mancenido, D; Kaminsky, SM; Heier, LA; Rudser, KD; Kosofsky, B; Casey, BJ; Crystal, RG; Ballon, D

    2015-01-01

    Background and Purpose Late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a uniformly fatal lysosomal storage disease resulting from mutations in the CLN2 gene. Our hypothesis was that regional analysis of cortical brain degeneration may identify brain regions that are affected earliest as well as most severely by the disease. Materials and Methods Fifty-two high resolution 3.0 Tesla MRI data sets were prospectively acquired on thirty-eight subjects with CLN2. A retrospective cohort of fifty-two disease free children served as a control population. The FreeSurfer software suite was used for calculation of cortical thickness. Results An increased rate of global cortical thinning in CLN2 versus control subjects was the primary finding in this study. Three distinct patterns were observed across brain regions. In the first, CLN2 subjects exhibited differing rates of cortical thinning versus age. This was true in 22 and 26 of 34 regions in the left and right hemisphere respectively, and was also clearly discernable when considering brain lobes as a whole and Brodmann’s regions. The second pattern exhibited a difference in thickness from normal controls but with no discernable change with age (9 left hemisphere; 5 right hemisphere). In the third pattern there was no difference in either the rate of cortical thinning or the mean cortical thickness between groups (3 left hemisphere; 3 right hemisphere). Conclusions This study demonstrates that CLN2 causes differential rates of degeneration across the brain. Anatomical and functional regions that degenerate sooner and more severely than others compared to normal controls may offer targets for directed therapies. The information gained may also provide neurobiological insights regarding the mechanisms underlying disease progression. PMID:26822727

  20. Alzheimer's disease gene signature says: beware of brain viral infections

    Directory of Open Access Journals (Sweden)

    Ianni Manuela

    2010-12-01

    Full Text Available Abstract Background Recent findings from a genome wide association investigation in a large cohort of patients with Alzheimer's disease (AD and non demented controls (CTR showed that a limited set of genes was in a strong association (p > l0-5 with the disease. Presentation of the hypothesis In this report we suggest that the polymorphism association in 8 of these genes is consistent with a non conventional interpretation of AD etiology. Nectin-2 (NC-2, apolipoprotein E (APOE, glycoprotein carcinoembryonic antigen related cell adhesion molecule- 16 (CEACAM-16, B-cell lymphoma-3 (Bcl-3, translocase of outer mitochondrial membrane 40 homolog (T0MM-40, complement receptor-1 (CR-l, APOJ or clusterin and C-type lectin domain A family-16 member (CLEC-16A result in a genetic signature that might affect individual brain susceptibility to infection by herpes virus family during aging, leading to neuronal loss, inflammation and amyloid deposition. Implications of the hypothesis We hypothesized that such genetic trait may predispose to AD via complex and diverse mechanisms each contributing to an increase of individual susceptibility to brain viral infections

  1. Monoaminergic and histaminergic strategies and treatments in brain diseases

    Directory of Open Access Journals (Sweden)

    Giuseppe Di Giovanni

    2016-11-01

    Full Text Available The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson’s disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable treatments for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity, the identification of monoamines in the diseases processes (Parkinson’s disease, addiction and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer’s disease, stroke. In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in

  2. Case Report of Cardiac Arrest After Succinylcholine in a Child With Muscle-Eye-Brain Disease.

    Science.gov (United States)

    Hackmann, Thomas; Skidmore, David L; MacManus, Brian

    2017-10-15

    Muscle-eye-brain disease is a rare autosomal recessive disorder characterized by congenital muscular dystrophy, ocular abnormalities, and brain malformation. We report an intraoperative hyperkalemic cardiac arrest following the administration of succinylcholine in a child with muscle-eye-brain disease. The disease was diagnosed only after this event. Our experience suggests that preoperative determinations of serum concentrations of lactate and creatine kinase may be useful if clinical signs consistent with myopathy are present.

  3. MR anatomy of deep brain nuclei with special reference to specific diseases and deep brain stimulation localization.

    Science.gov (United States)

    Telford, Ryan; Vattoth, Surjith

    2014-02-01

    Diseases affecting the basal ganglia and deep brain structures vary widely in etiology and include metabolic, infectious, ischemic, and neurodegenerative conditions. Some neurologic diseases, such as Wernicke encephalopathy or pseudohypoparathyroidism, require specific treatments, which if unrecognized could lead to further complications. Other pathologies, such as hypertrophic olivary degeneration, if not properly diagnosed may be mistaken for a primary medullary neoplasm and create unnecessary concern. The deep brain structures are complex and can be difficult to distinguish on routine imaging. It is imperative that radiologists first understand the intrinsic anatomic relationships between the different basal ganglia nuclei and deep brain structures with magnetic resonance (MR) imaging. It is important to understand the "normal" MR signal characteristics, locations, and appearances of these structures. This is essential to recognizing diseases affecting the basal ganglia and deep brain structures, especially since most of these diseases result in symmetrical, and therefore less noticeable, abnormalities. It is also crucial that neurosurgeons correctly identify the deep brain nuclei presurgically for positioning deep brain stimulator leads, the most important being the subthalamic nucleus for Parkinson syndromes and the thalamic ventral intermediate nucleus for essential tremor. Radiologists will be able to better assist clinicians in diagnosis and treatment once they are able to accurately localize specific deep brain structures.

  4. Parkinson's disease rigidity: relation to brain connectivity and motor performance

    Directory of Open Access Journals (Sweden)

    Nazanin eBaradaran

    2013-06-01

    Full Text Available Objective: 1 To determine the brain connectivity pattern associated with clinical rigidity scores in Parkinson's disease (PD and 2 to determine the relation between clinically-assessed rigidity and quantitative metrics of motor performance.Background: Rigidity, the resistance to passive movement, is exacerbated in PD by asking the subject to move the contralateral limb, implying that rigidity involves a distributed brain network. Rigidity mainly affects subjects when they attempt to move; yet the relation between clinical rigidity scores and quantitative aspects of motor performance are unknown.Methods: Ten clinically diagnosed PD patients (off medication and ten controls were recruited to perform an fMRI squeeze-bulb tracking task that included both visually guided and internally guided features. The direct functional connectivity between anatomically defined regions of interest was assessed with Dynamic Bayesian Networks (DBNs. Tracking performance was assessed by fitting Linear Dynamical System (LDS models to the motor performance, and was compared to the clinical rigidity scores. A cross-validated Least Absolute Shrinkage and Selection Operator (LASSO regression method was used to determine the brain connectivity network that best predicted clinical rigidity scores.Results: The damping ratio of the LDS models significantly correlated with clinical rigidity scores (p < 10-4. An fMRI connectivity network in subcortical and primary and premotor cortical regions accurately predicted clinical rigidity scores (p < 10-5. Conclusions: A widely distributed cortical/subcortical network is associated with rigidity observed in PD patients, which reinforces the importance of altered functional connectivity in the pathophysiology of PD. PD subjects with higher rigidity scores tend to have less overshoot in their tracking performance, and damping ratio may represent a robust, quantitative marker of the motoric effects of increasing rigidity.

  5. Candesartan ameliorates brain inflammation associated with Alzheimer's disease.

    Science.gov (United States)

    Torika, Nofar; Asraf, Keren; Apte, Ron N; Fleisher-Berkovich, Sigal

    2018-01-24

    Alzheimer's disease (AD) pathology is associated with brain inflammation involving microglia and astrocytes. The renin-angiotensin system contributes to brain inflammation associated with AD pathology. This study aimed to investigate the role of candesartan, an angiotensin II type 1 receptor blocker, in modulation of glial functions associated with AD. Focusing on the role of candesartan in glial inflammation, we evaluated inflammatory mediators' levels, secreted by lipopolysaccharide-induced microglia following candesartan treatment. Also, short-term intranasal candesartan effects on amyloid burden and microglial activation were investigated in 5 familial AD mice. Candesartan showed anti-inflammatory effects and shifted microglial activation toward a more neuroprotective phenotype. Candesartan decreased the lipopolysaccharide-induced nitric oxide synthase and cyclooxygenase-2 expression levels, which was accompanied by an induction of arginase-1 expression levels and enhanced Aβ1-42 uptake by microglia. Moreover, intranasally administered candesartan to AD mice model significantly reduced the amyloid burden and microglia activation in the hippocampus. These results thus shed light on the neuroprotective role of candesartan in the early stage of AD, which might relate to modulation of microglial activation states. © 2018 John Wiley & Sons Ltd.

  6. Copper pathology in vulnerable brain regions in Parkinson's disease.

    Science.gov (United States)

    Davies, Katherine M; Bohic, Sylvain; Carmona, Asunción; Ortega, Richard; Cottam, Veronica; Hare, Dominic J; Finberg, John P M; Reyes, Stefanie; Halliday, Glenda M; Mercer, Julian F B; Double, Kay L

    2014-04-01

    Synchrotron-based x-ray fluorescence microscopy, immunofluorescence, and Western blotting were used to investigate changes in copper (Cu) and Cu-associated pathways in the vulnerable substantia nigra (SN) and locus coeruleus (LC) and in nondegenerating brain regions in cases of Parkinson's disease (PD) and appropriate healthy and disease controls. In PD and incidental Lewy body disease, levels of Cu and Cu transporter protein 1, were significantly reduced in surviving neurons in the SN and LC. Specific activity of the cuproprotein superoxide dismutase 1 was unchanged in the SN in PD but was enhanced in the parkinsonian anterior cingulate cortex, a region with α-synuclein pathology, normal Cu, and limited cell loss. These data suggest that regions affected by α-synuclein pathology may display enhanced vulnerability and cell loss if Cu-dependent protective mechanisms are compromised. Additional investigation of copper pathology in PD may identify novel targets for the development of protective therapies for this disorder. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Earlier versus later subthalamic deep brain stimulation in Parkinson's disease.

    Science.gov (United States)

    Merola, Aristide; Romagnolo, Alberto; Bernardini, Andrea; Rizzi, Laura; Artusi, Carlo Alberto; Lanotte, Michele; Rizzone, Mario Giorgio; Zibetti, Maurizio; Lopiano, Leonardo

    2015-08-01

    Subthalamic nucleus deep brain stimulation (STN-DBS) has been recently compared to a possible "second therapeutic honeymoon" for Parkinson's disease, as it might prevent the development of severe motor complications and lessen the social adjustment associated to disease progression. This study aims to evaluate whether an early surgical treatment could result in better long-term outcomes, comparing the follow-up evolution of 203 parkinsonian patients, treated at different stages of the disease course. The retrospective allocation to Early- or Late-Stimulated groups was performed in accordance to disease severity at the time of surgery and motor fluctuations duration. Then, the two groups clinical outcomes were compared after more than 8 years of follow-up by means of the Unified Parkinson's Disease Rating Scale, reporting the overall disability experienced by patients during the entire observational period. Subjects receiving an earlier STN-DBS showed a sustained improvement in the activities of daily living and motor complications, never reaching the severe levels of disability reported by Late-Stimulated patients at the time of surgical selection. After ≥8 years of follow-up the Early-Stimulated group still reported a 28.7% lower impairment in activities of daily living and 43.8% lower duration of waking day spent in OFF compared to their pre-surgical basal scores. Although the limitation of a retrospective study design should be considered in the interpretation of data, our findings suggest that an earlier STN-DBS treatment might result in a more precocious stabilization of motor complications, with beneficial effects on the patient's social and professional life autonomy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Deep brain stimulation for psychiatric diseases: what are the risks?

    Science.gov (United States)

    Saleh, Christian; Fontaine, Denys

    2015-05-01

    Despite the application of deep brain stimulation (DBS) as an efficient treatment modality for psychiatric disorders, such as obsessive-compulsive disorder (OCD), Gilles de la Tourette Syndrome (GTS), and treatment refractory major depression (TRD), few patients are operated or included in clinical trials, often for fear of the potential risks of an approach deemed too dangerous. To assess the surgical risks, we conducted an analysis of publications on DBS for psychiatric disorders. A PubMed search was conducted on reports on DBS for OCD, GTS, and TRD. Forty-nine articles were included. Only reports on complications related to DBS were selected and analyzed. Two hundred seventy-two patients with a mean follow-up of 22 months were included in our analysis. Surgical mortality was nil. The overall mortality was 1.1 %: two suicides were unrelated to DBS and one death was reported to be unlikely due to DBS. The majority of complications were transient and related to stimulation. Long-term morbidity occurred in 16.5 % of cases. Three patients had permanent neurological complications due to intracerebral hemorrhage (2.2 %). Complications reported in DBS for psychiatric diseases appear to be similar to those reported for DBS in movement disorders. But class I evidence is lacking. Our analysis was based mainly on small non-randomized studies. A significant number of patients (approximately 150 patients) who were treated with DBS for psychiatric diseases had to be excluded from our analysis as no data on complications was available. The exact prevalence of complications of DBS in psychiatric diseases could not be established. DBS for psychiatric diseases is promising, but remains an experimental technique in need of further evaluation. A close surveillance of patients undergoing DBS for psychiatric diseases is mandatory.

  9. [Brain hemorrhage in a patient with Kawasaki disease].

    Science.gov (United States)

    Yamazaki-Nakashimada, Marco Antonio; Rivas-Larrauri, Francisco; Alcántara-Salinas, Adriana; Hernández-Bautista, Victor; Rodríguez-Lozano, Ana Luisa

    2013-01-01

    Kawasaki disease is an acute, self-limiting vasculitis of unknown origin, characterized by fever, palms and soles edema, cervical lymphadenopathy, strawberry tongue, and non-exudative conjunctivitis. It is a multisystemic vasculitis that affects predominantly infants and young children. The most feared complication is the development of coronary aneurysms that occurs up to 25% of untreated patients; however there are reports of extra coronary involvement. Herein we present the case of a 2 year-old girl who had a severe symptomatology and persistent fever despite intravenous gammaglobulin. Two years later she presented right hemiparesia and headache, with data from CAT and MRI suggestive of brain mass and deviation of the midline, secondary to left frontoparietal haemorrhage that was treated with a craniotomy. She was discharged on prednisone, ASA and rehabilitation.

  10. Deep Brain Stimulation Target Selection for Parkinson's Disease.

    Science.gov (United States)

    Honey, Christopher R; Hamani, Clement; Kalia, Suneil K; Sankar, Tejas; Picillo, Marina; Munhoz, Renato P; Fasano, Alfonso; Panisset, Michel

    2017-01-01

    During the "DBS Canada Day" symposium held in Toronto July 4-5, 2014, the scientific committee invited experts to discuss three main questions on target selection for deep brain stimulation (DBS) of patients with Parkinson's disease (PD). First, is the subthalamic nucleus (STN) or the globus pallidus internus (GPi) the ideal target? In summary, both targets are equally effective in improving the motor symptoms of PD. STN allows a greater medications reduction, while GPi exerts a direct antidyskinetic effect. Second, are there further potential targets? Ventral intermediate nucleus DBS has significant long-term benefit for tremor control but insufficiently addresses other motor features of PD. DBS in the posterior subthalamic area also reduces tremor. The pedunculopontine nucleus remains an investigational target. Third, should DBS for PD be performed unilaterally, bilaterally or staged? Unilateral STN DBS can be proposed to asymmetric patients. There is no evidence that a staged bilateral approach reduces the incidence of DBS-related adverse events.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Effects of deep brain stimulation and levodopa on postural sway in Parkinson's disease

    OpenAIRE

    Rocchi, L.; Chiari, L.; Horak, F

    2002-01-01

    Objective: To quantify postural sway in subjects with Parkinson's disease and elderly controls, and determine the effects of Parkinson's disease, deep brain stimulation, levodopa, and their interactions on postural control during quiet stance.

  13. Brain disease, connectivity, plasticity and cognitive therapy: A neurological view of mental disorders.

    Science.gov (United States)

    Lubrini, G; Martín-Montes, A; Díez-Ascaso, O; Díez-Tejedor, E

    2017-04-25

    Our conception of the mind-brain relationship has evolved from the traditional idea of dualism to current evidence that mental functions result from brain activity. This paradigm shift, combined with recent advances in neuroimaging, has led to a novel definition of brain functioning in terms of structural and functional connectivity. The purpose of this literature review is to describe the relationship between connectivity, brain lesions, cerebral plasticity, and functional recovery. Assuming that brain function results from the organisation of the entire brain in networks, brain dysfunction would be a consequence of altered brain network connectivity. According to this approach, cognitive and behavioural impairment following brain damage result from disrupted functional organisation of brain networks. However, the dynamic and versatile nature of these circuits makes recovering brain function possible. Cerebral plasticity allows for functional reorganisation leading to recovery, whether spontaneous or resulting from cognitive therapy, after brain disease. Current knowledge of brain connectivity and cerebral plasticity provides new insights into normal brain functioning, the mechanisms of brain damage, and functional recovery, which in turn serve as the foundations of cognitive therapy. Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  14. Molecular Mechanism of Adult Neurogenesis and its Association with Human Brain Diseases

    Directory of Open Access Journals (Sweden)

    He Liu

    2016-01-01

    Full Text Available Recent advances in neuroscience challenge the old dogma that neurogenesis occurs only during embryonic development. Mounting evidence suggests that functional neurogenesis occurs throughout adulthood. This review article discusses molecular factors that affect adult neurogenesis, including morphogens, growth factors, neurotransmitters, transcription factors, and epigenetic factors. Furthermore, we summarize and compare current evidence of associations between adult neurogenesis and human brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and brain tumors.

  15. [Deep brain stimulation in Parkinson's disease. Preliminary outcomes].

    Science.gov (United States)

    Pérez-de la Torre, Ramiro Antonio; Calderón-Vallejo, Alejandra; Morales-Briceño, Hugo; Gallardo-Ceja, David; Carrera-Pineda, Raúl; Guinto-Balanzar, Gerardo; Magallón-Barajas, Eduardo; Corlay-Noriega, Irma; Cuevas-García, Carlos

    2016-01-01

    Parkinson's disease justifies the use of deep brain stimulation (DBS) in certain patients who suffer from this condition. We present mid-term and long-term post-surgical outcomes in a cohort of 60 patients, who underwent DBS in the Hospital de Especialidades at Centro Médico Nacional Siglo XXI, in Mexico City. Patients underwent conventional stereotactic surgery with FrameLink software (Medtronics Inc). This technique consisted in the presurgical evaluation, the placement of stereotactic frame, imaging studies, preoperative planning procedure, microrecording, macrostimulation, as well as the placement of electrodes and generators in two phases. The variables were included in a data platform for Excel management. It was also included a variety of measurement instruments for data comparison. As a standard measure, it was used the Unified Parkinson Disease Rating Scale (UPDRS) before the surgery and at 3, 12, and 36 months. 60 patients underwent surgery: 41 men and 19 women, with an average age of 56.5 years (39-70). There were good results in the majority of patients with preoperative UPDRS and at 3, 12 and 36 months of 79.57, 66.85, 65.29 and 58.75, respectively (p Parkinson's patients.

  16. Functional brain networks and cognitive deficits in Parkinson's disease.

    Science.gov (United States)

    Baggio, Hugo-Cesar; Sala-Llonch, Roser; Segura, Bàrbara; Marti, Maria-José; Valldeoriola, Francesc; Compta, Yaroslau; Tolosa, Eduardo; Junqué, Carme

    2014-09-01

    Graph-theoretical analyses of functional networks obtained with resting-state functional magnetic resonance imaging (fMRI) have recently proven to be a useful approach for the study of the substrates underlying cognitive deficits in different diseases. We used this technique to investigate whether cognitive deficits in Parkinson's disease (PD) are associated with changes in global and local network measures. Thirty-six healthy controls (HC) and 66 PD patients matched for age, sex, and education were classified as having mild cognitive impairment (MCI) or not based on performance in the three mainly affected cognitive domains in PD: attention/executive, visuospatial/visuoperceptual (VS/VP), and declarative memory. Resting-state fMRI and graph theory analyses were used to evaluate network measures. We have found that patients with MCI had connectivity reductions predominantly affecting long-range connections as well as increased local interconnectedness manifested as higher measures of clustering, small-worldness, and modularity. The latter measures also tended to correlate negatively with cognitive performance in VS/VP and memory functions. Hub structure was also reorganized: normal hubs displayed reduced centrality and degree in MCI PD patients. Our study indicates that the topological properties of brain networks are changed in PD patients with cognitive deficits. Our findings provide novel data regarding the functional substrate of cognitive impairment in PD, which may prove to have value as a prognostic marker. Copyright © 2014 Wiley Periodicals, Inc.

  17. Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease.

    Science.gov (United States)

    de la Monte, Suzanne M

    2012-01-01

    Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential.

  18. Infectious diseases of the brain: imaging and differential diagnosis; Infektioese Hirnerkrankungen: Bildgebung und differenzialdiagnostische Aspekte

    Energy Technology Data Exchange (ETDEWEB)

    Haehnel, S.; Seitz, A. [Abt. Neuroradiologie, Neurologische Klinik, Universitaetsklinikum Heidelberg (Germany); Storch-Hagenlocher, B. [Abt. Neurologie, Neurologische Klinik, Universitaetsklinikum Heidelberg (Germany)

    2006-09-15

    Infectious diseases of the central nervous system have to be considered in differential diagnosis particularly in immunocompromised persons. Neuro-imaging, specifically advanced techniques such as diffusion weighted MRI and perfusion MRI contribute much to the differentiation of brain infections and for differentiating brain infections from other, for instance, neoplastic diseases. In this review we present the imaging criteria of the most important brains infections in adults and in pediatric patients and discuss differential diagnostic aspects in detail. (orig.)

  19. The usefulness of brain natriuretic peptide in simple congenital heart disease-a systematic review

    NARCIS (Netherlands)

    J.A. Eindhoven (Jannet); A.E. van den Bosch (Annemien); H. Boersma (Eric); J.W. Roos-Hesselink (Jolien)

    2013-01-01

    textabstractBrain natriuretic peptide and N-terminal pro-brain natriuretic peptide are two well-established markers for cardiac failure in acquired heart disease. Nevertheless, the clinical utility of these markers in patients with congenital heart disease remains unclear. Therefore, the aim of this

  20. MRI/MRA evaluation of sickle cell disease of the brain

    Energy Technology Data Exchange (ETDEWEB)

    Zimmerman, Robert A. [Childrens Hospital, Department of Radiology, Philadelphia, PA (United States)

    2005-03-01

    Sickle cell disease is a major cause of pediatric stroke. Understanding the disease that affects the brain as infarctions, both clinically apparent and silent, requires an understanding of how the blood vessels are affected, the way in which both the brain and the blood vessels are imaged by MRI and MRA and the mechanism of injury. (orig.)

  1. MRI reveals brain abnormalities in drug-naïve Parkinson’s disease

    OpenAIRE

    Planetta, Peggy J.; McFarland, Nikolaus R.; Okun, Michael S.; Vaillancourt, David E.

    2014-01-01

    Most brain studies of Parkinson’s disease (PD) focus on patients who are already taking anti-parkinsonian medication. This makes it difficult to isolate the effects of disease from those of treatment. We review MRI evidence supporting the hypothesis that early-stage, untreated PD patients have structural and functional abnormalities in the brain, some of which are related to motor symptoms.

  2. Mid-gestation brain Doppler and head biometry in fetuses with congenital heart disease predict abnormal brain development at birth.

    Science.gov (United States)

    Masoller, N; Sanz-CortéS, M; Crispi, F; Gómez, O; Bennasar, M; Egaña-Ugrinovic, G; Bargalló, N; Martínez, J M; Gratacós, E

    2016-01-01

    Fetuses with congenital heart disease (CHD) show evidence of abnormal brain development before birth, which is thought to contribute to adverse neurodevelopment during childhood. Our aim was to evaluate whether brain development in late pregnancy can be predicted by fetal brain Doppler, head biometry and the clinical form of CHD at the time of diagnosis. This was a prospective cohort study including 58 fetuses with CHD, diagnosed at 20-24 weeks' gestation, and 58 normal control fetuses. At the time of diagnosis, we recorded fetal head circumference (HC), biparietal diameter, middle cerebral artery pulsatility index (MCA-PI), cerebroplacental ratio (CPR) and brain perfusion by fractional moving blood volume. We classified cases into one of two clinical types defined by the expected levels (high or low) of placental (well-oxygenated) blood perfusion, according to the anatomical defect. All fetuses underwent subsequent 3T-magnetic resonance imaging (MRI) at 36-38 weeks' gestation. Abnormal prenatal brain development was defined by a composite score including any of the following findings on MRI: total brain volume type of CHD was not. Fetal brain Doppler and head biometry at the time of CHD diagnosis are independent predictors of abnormal brain development at birth, and could be used in future algorithms to improve counseling and targeted interventions. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

  3. Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases.

    Science.gov (United States)

    Gabathuler, Reinhard

    2010-01-01

    The central nervous system is protected by barriers which control the entry of compounds into the brain, thereby regulating brain homeostasis. The blood-brain barrier, formed by the endothelial cells of the brain capillaries, restricts access to brain cells of blood-borne compounds and facilitates nutrients essential for normal metabolism to reach brain cells. This very tight regulation of the brain homeostasis results in the inability of some small and large therapeutic compounds to cross the blood-brain barrier (BBB). Therefore, various strategies are being developed to enhance the amount and concentration of therapeutic compounds in the brain. In this review, we will address the different approaches used to increase the transport of therapeutics from blood into the brain parenchyma. We will mainly concentrate on the physiologic approach which takes advantage of specific receptors already expressed on the capillary endothelial cells forming the BBB and necessary for the survival of brain cells. Among all the approaches used for increasing brain delivery of therapeutics, the most accepted method is the use of the physiological approach which takes advantage of the transcytosis capacity of specific receptors expressed at the BBB. The low density lipoprotein receptor related protein (LRP) is the most adapted for such use with the engineered peptide compound (EPiC) platform incorporating the Angiopep peptide in new therapeutics the most advanced with promising data in the clinic.

  4. Presence of brain pathology in deceased subjects with and without chronic obstructive pulmonary disease.

    Science.gov (United States)

    Cleutjens, Fiona A H M; Spruit, Martijn A; Beckervordersandforth, Jan; Franssen, Frits M E; Dijkstra, Jeanette B; Ponds, Rudolf W H M; Wouters, Emiel F B; Janssen, Daisy J A

    2015-11-01

    Patients with chronic obstructive pulmonary disease (COPD) have extrapulmonary co-morbidities, such as cardiovascular disease, musculoskeletal wasting and neuropsychological conditions. To date, it remains unknown whether and to what extent COPD is associated with a higher prevalence of brain pathology. Therefore, the aim of this retrospective study was to compare the prevalence of neuropathological brain changes between deceased donors with and without COPD. Brain autopsy reports of age-matched donors with (n = 89) and without COPD (n = 89) from the Netherlands Brain Bank were assessed for demographics, cause of death, co-morbidities and brain pathology. The prevalence of degenerative brain changes was comparable for donors with and without COPD (50.6% vs. 61.8%, p > 0.05). Neoplastic brain changes were reported in a minority of the donors (5.6% vs. 10.1%, p > 0.05). After correction for cerebrovascular accident or cardiac cause of death and Charlson co-morbidity index score, the prevalence of vascular brain changes was higher among control versus COPD donors (27.0% vs. 11.2%, adjusted p = 0.013, odds ratio = 2.98). Brain autopsy reports of donors with and without COPD did not reveal differences in the presence of degenerative or neoplastic brain changes. Vascular brain changes were described more often in controls. Prospective studies including spirometry and structural and functional brain imaging should corroborate our findings. © The Author(s) 2015.

  5. Clinical outcome of deep brain stimulation for Parkinson's disease.

    Science.gov (United States)

    Deuschl, Günther; Paschen, Steffen; Witt, Karsten

    2013-01-01

    Deep brain stimulation is one of the most effective treatments of Parkinson's disease (PD). This report summarizes the state of the art as at January 2013. Stimulation of the subthalamic nucleus is the most commonly used approach. It improves the core motor symptoms better than medication in patients with advanced disease. It also improves the majority of nonmotor symptoms, such as mood, impulse control disorders, sleep, and some autonomic dysfunctions. Quality of life (QoL) is improved significantly more than with medication. Long-term data show that the treatment is effective for up to 10 years, but the late appearance of l-dopa-resistant symptoms is seemingly not influenced. Internal globus pallidus (GPi) stimulation is less well studied but seems to have similar short-term efficacy. Importantly l-dopa use cannot be reduced with GPi DBS, which is a major disadvantage for patients suffering from medication side-effects, although gait may be influenced more positively. Although short-term QoL improvement seems to be similar to that for subthalamic nucleus (STN) DBS - gait and speech may be better improved - long-term data are rare for GPi DBS. Thalamic stimulation in the ventral intermediate nucleus (VIM) is applied only in tremor-dominant elderly patients. The treatment improves the dopa-sensitive symptoms and effectively reduces fluctuations leading to an overall QoL improvement. Although most of the controlled studies have been on advanced PD, the recently published EARLYSTIM study suggests that even patients with a very short duration of their fluctuations and dyskinesia are doing significantly better with neurostimulation in terms of QoL and all major motor outcome parameters. © 2013 Elsevier B.V. All rights reserved.

  6. Computer-Guided Deep Brain Stimulation Programming for Parkinson's Disease.

    Science.gov (United States)

    Heldman, Dustin A; Pulliam, Christopher L; Urrea Mendoza, Enrique; Gartner, Maureen; Giuffrida, Joseph P; Montgomery, Erwin B; Espay, Alberto J; Revilla, Fredy J

    2016-02-01

    Pilot study to evaluate computer-guided deep brain stimulation (DBS) programming designed to optimize stimulation settings using objective motion sensor-based motor assessments. Seven subjects (five males; 54-71 years) with Parkinson's disease (PD) and recently implanted DBS systems participated in this pilot study. Within two months of lead implantation, the subject returned to the clinic to undergo computer-guided programming and parameter selection. A motion sensor was placed on the index finger of the more affected hand. Software guided a monopolar survey during which monopolar stimulation on each contact was iteratively increased followed by an automated assessment of tremor and bradykinesia. After completing assessments at each setting, a software algorithm determined stimulation settings designed to minimize symptom severities, side effects, and battery usage. Optimal DBS settings were chosen based on average severity of motor symptoms measured by the motion sensor. Settings chosen by the software algorithm identified a therapeutic window and improved tremor and bradykinesia by an average of 35.7% compared with baseline in the "off" state (p computer-guided DBS programming identified stimulation parameters that significantly improved tremor and bradykinesia with minimal clinician involvement. Automated motion sensor-based mapping is worthy of further investigation and may one day serve to extend programming to populations without access to specialized DBS centers. © 2015 International Neuromodulation Society.

  7. [Nonmotor symptoms in Parkinson's disease and deep brain stimulation].

    Science.gov (United States)

    Sevillano-García, M D; Manso-Calderón, R

    2010-02-08

    The efficacy of deep brain stimulation (DBS) for the motor symptoms of advanced Parkinson's disease (PD) is well established. However, the effects of DBS on nonmotor symptoms (NMS) are less clear. To review the published literature on nonmotor aspects of DBS for PD. The outcome of NMS after DBS in PD varies across studies. Some symptoms improve -sleep disorders, pain or sensory complaints, obsessive-compulsive disorder- and other aspects decline or appear -word fluency, apathy, body weight gain-. Isolated studies note mild improvements in working memory, visuomotor sequencing and conceptual reasoning, some gastrointestinal, urogenital, sweating and olfactory disturbances; whereas other studies have reported declines in verbal memory (long delay recall), visuospatial memory, processing speed and executive function; orthostatic hypotension remains without changes. The reasons for such a range of symptoms observed is due to the multifactorial etiology of the NMS, including preoperative vulnerability, changes in dopaminergic medications, surgical and stimulation effects, underlying PD-related factors and psychosocial effects. Specific patient subgroups may be at greater risk of cognitive deficits -e.g., those older than 69 years or with cognitive impairment prior to surgery- or depression, mania and suicide -e.g., those ones with preoperative psychiatric symptoms-. Patients who undergo DBS must be well-selected, weighing the risks and benefits, in order to obtain the best results with this treatment. Further multicentre studies are necessary to understand the role of DBS on NMS.

  8. Neuroinflammation and brain functional disconnection in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Francesca eBaglio

    2013-11-01

    Full Text Available Neuroinflammation and brain functional disconnection result from β-amyloid (Aβ accumulation and play fundamental roles in the pathogenesis of Alzheimer’s disease (AD. We investigated possible correlations between these two AD-associated phenomena using DTI-based tractography and immunologic analyses in people with amnestic Mild Cognitive Impairment (aMCI and AD. DTI-Analyses focused on corpus callosum (CC. We found that frontal CC regions were preserved with respect to the posterior ones in aMCI; in these individuals significant correlations were seen between DTI-derived metrics in frontal-parietal CC areas and Aβ42-stimulated BDNF-producing CD4+ T lymphocytes and PDL-1-expressing CD14+ cells. These associations were lost in AD where DTI data involving the same CC areas correlated instead with Aβ42-stimulated IL-21 producing CD4+ T lymphocytes. Higher susceptibility to PDL-1-mediated apoptosis of Aβ42-specific lymphocytes and BDNF-associated survival of existing neurons could contribute to the relative CC structure preservation seen in aMCI. These potentially protective mechanisms are lost in frank AD, when severe alterations in the CC are mirrored in peripheral blood by proinflammatory cytokines-producing T cells. Monitoring of immune cells in peripheral blood could have a prognostic value in AD.

  9. Subthalamic nucleus deep brain stimulation improves deglutition in Parkinson's disease.

    Science.gov (United States)

    Ciucci, Michelle R; Barkmeier-Kraemer, Julie M; Sherman, Scott J

    2008-04-15

    Relatively little is known about the role of the basal ganglia in human deglutition. Deep brain stimulation (DBS) affords us a model for examining deglutition in humans with known impairment of the basal ganglia. The purpose of this study was to examine the effects of subthalamic nuclei (STN) DBS on the oral and pharyngeal stages of deglutition in individuals with Parkinson's Disease (PD). It was hypothesized that DBS would be associated with improved deglutition. Within participant, comparisons were made between DBS in the ON and OFF conditions using the dependent variables: pharyngeal transit time, maximal hyoid bone excursion, oral total composite score, and pharyngeal total composite score. Significant improvement occurred for the pharyngeal composite score and pharyngeal transit time in the DBS ON condition compared with DBS OFF. Stimulation of the STN may excite thalamocortical or brainstem targets to sufficiently overcome the bradykinesia/hypokinesia associated with PD and return some pharyngeal stage motor patterns to performance levels approximating those of "normal" deglutition. However, the degree of hyoid bone excursion and oral stage measures did not improve, suggesting that these motor acts may be under the control of different sensorimotor pathways within the basal ganglia. 2007 Movement Disorder Society

  10. EFFECTIVENESS OF RADIATION TREATMENT IN METASTATIC BRAIN DISEASES

    Directory of Open Access Journals (Sweden)

    Prema

    2016-03-01

    Full Text Available BACKGROUND Brain metastasis are a major cause of mortality and morbidity in cancer patients. Most common primary sites are lung, breast, malignant melanoma and kidney. Whole brain radiation treatment has remained the treatment of choice for brain metastasis. Though it provides early symptomatic relief, survival is limited to 3-6 months. AIM To study the effect of radiation on relief of symptoms and on the survival of patients with brain metastasis, also analysing the incidence of brain metastasis from different primary sites. METHODS This study was conducted in Radiotherapy department of Government Medical College, Calicut during 1997-1999, involving 50 patients with radiologically proven brain metastasis. All patients received whole brain radiation treatment to a dose of 3000 cGY /10 F/2 weeks and were analysed for symptomatic relief and survival. RESULT About ¾th of the patients obtained symptomatic relief within 2 weeks after starting radiation treatment. 72% of patients survived upto 6 months after radiotherapy. CONCLUSION External beam irradiation to whole brain in the dose of 3000 cGY/10F/2 weeks is an effective method of treatment of brain metastasis both in terms of early symptomatic relief and survival.

  11. The Microbiome-Gut-Brain Axis in Health and Disease.

    Science.gov (United States)

    Dinan, Timothy G; Cryan, John F

    2017-03-01

    Gut microbes are capable of producing most neurotransmitters found in the human brain. Evidence is accumulating to support the view that gut microbes influence central neurochemistry and behavior. Irritable bowel syndrome is regarded as the prototypic disorder of the brain-gut-microbiota axis that can be responsive to probiotic therapy. Translational studies indicate that certain bacteria may have an impact on stress responses and cognitive functioning. Manipulating the gut microbiota with psychobiotics, prebiotics, or even antibiotics offers a novel approach to altering brain function and treating gut-brain axis disorders, such as depression and autism. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Brain volumes predict neurodevelopment in adolescents after surgery for congenital heart disease.

    Science.gov (United States)

    von Rhein, Michael; Buchmann, Andreas; Hagmann, Cornelia; Huber, Reto; Klaver, Peter; Knirsch, Walter; Latal, Beatrice

    2014-01-01

    Patients with complex congenital heart disease are at risk for neurodevelopmental impairments. Evidence suggests that brain maturation can be delayed and pre- and postoperative brain injury may occur, and there is limited information on the long-term effect of congenital heart disease on brain development and function in adolescent patients. At a mean age of 13.8 years, 39 adolescent survivors of childhood cardiopulmonary bypass surgery with no structural brain lesions evident through conventional cerebral magnetic resonance imaging and 32 healthy control subjects underwent extensive neurodevelopmental assessment and cerebral magnetic resonance imaging. Cerebral scans were analysed quantitatively using surface-based and voxel-based morphometry. Compared with control subjects, patients had lower total brain (P = 0.003), white matter (P = 0.004) and cortical grey matter (P = 0.005) volumes, whereas cerebrospinal fluid volumes were not different. Regional brain volume reduction ranged from 5.3% (cortical grey matter) to 11% (corpus callosum). Adolescents with cyanotic heart disease showed more brain volume loss than those with acyanotic heart disease, particularly in the white matter, thalami, hippocampi and corpus callosum (all P-values Brain volume reduction correlated significantly with cognitive, motor and executive functions (grey matter: P < 0.05, white matter: P < 0.01). Our findings suggest that there are long-lasting cerebral changes in adolescent survivors of cardiopulmonary bypass surgery for congenital heart disease and that these changes are associated with functional outcome.

  13. Insights into brain development and disease from neurogenetic

    Indian Academy of Sciences (India)

    Studies carried out in this powerful neurogenetic model system during the last decade now provide insight into the molecular mechanisms that operate in neural stem cells during normal brain development and during abnormal brain tumorigenesis. These studies also provide strong support for the notion that conserved ...

  14. Gut-brain and brain-gut axis in Parkinson's disease models : Effects of a uridine and fish oil diet

    NARCIS (Netherlands)

    Perez-Pardo, Paula|info:eu-repo/dai/nl/338040900; Dodiya, Hemraj B.; Broersen, Laus M; Douna, Hidde; van Wijk, Nick; Lopes da Silva, Sofia; Garssen, Johan|info:eu-repo/dai/nl/086369962; Keshavarzian, Ali; Kraneveld, Aletta D|info:eu-repo/dai/nl/126612838

    2017-01-01

    Recent investigations have focused on the potential role of gastrointestinal (GI) abnormalities in the pathogenesis of Parkinson's disease (PD). The 'dual-hit' hypothesis of PD speculates that a putative pathogen enters the brain via two routes: the olfactory system and the GI system. Here, we

  15. The modulatory effect of adaptive deep brain stimulation on beta bursts in Parkinson's disease.

    Science.gov (United States)

    Tinkhauser, Gerd; Pogosyan, Alek; Little, Simon; Beudel, Martijn; Herz, Damian M; Tan, Huiling; Brown, Peter

    2017-04-01

    Adaptive deep brain stimulation uses feedback about the state of neural circuits to control stimulation rather than delivering fixed stimulation all the time, as currently performed. In patients with Parkinson's disease, elevations in beta activity (13-35 Hz) in the subthalamic nucleus have been demonstrated to correlate with clinical impairment and have provided the basis for feedback control in trials of adaptive deep brain stimulation. These pilot studies have suggested that adaptive deep brain stimulation may potentially be more effective, efficient and selective than conventional deep brain stimulation, implying mechanistic differences between the two approaches. Here we test the hypothesis that such differences arise through differential effects on the temporal dynamics of beta activity. The latter is not constantly increased in Parkinson's disease, but comes in bursts of different durations and amplitudes. We demonstrate that the amplitude of beta activity in the subthalamic nucleus increases in proportion to burst duration, consistent with progressively increasing synchronization. Effective adaptive deep brain stimulation truncated long beta bursts shifting the distribution of burst duration away from long duration with large amplitude towards short duration, lower amplitude bursts. Critically, bursts with shorter duration are negatively and bursts with longer duration positively correlated with the motor impairment off stimulation. Conventional deep brain stimulation did not change the distribution of burst durations. Although both adaptive and conventional deep brain stimulation suppressed mean beta activity amplitude compared to the unstimulated state, this was achieved by a selective effect on burst duration during adaptive deep brain stimulation, whereas conventional deep brain stimulation globally suppressed beta activity. We posit that the relatively selective effect of adaptive deep brain stimulation provides a rationale for why this approach could

  16. MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease.

    Science.gov (United States)

    Yoon, Hyejin; Flores, Luis F; Kim, Jungsu

    2016-12-01

    Cholesterol is important for various neuronal functions in the brain. Brain has elaborate regulatory mechanisms to control cholesterol metabolism that are distinct from the mechanisms in periphery. Interestingly, dysregulation of the cholesterol metabolism is strongly associated with a number of neurodegenerative diseases. MicroRNAs are short non-coding RNAs acting as post-transcriptional gene regulators. Recently, several microRNAs are demonstrated to be involved in regulating cholesterol metabolism in the brain. This article reviews the regulatory mechanisms of cellular cholesterol homeostasis in the brain. In addition, we discuss the role of microRNAs in brain cholesterol metabolism and their potential implications for the treatment of Alzheimer's disease. This article is part of a special issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Brain amyloid and cognition in Lewy body diseases.

    Science.gov (United States)

    Gomperts, Stephen N; Locascio, Joseph J; Marquie, Marta; Santarlasci, Andrea L; Rentz, Dorene M; Maye, Jacqueline; Johnson, Keith A; Growdon, John H

    2012-07-01

    Many patients with PD develop PD with dementia (PDD), a syndrome that overlaps clinically and pathologically with dementia with Lewy bodies (DLB); PDD and DLB differ chiefly in the relative timing of dementia and parkinsonism. Brain amyloid deposition is an early feature of DLB and may account, in part, for its early dementia. We sought to confirm this hypothesis and also to determine whether amyloid accumulation contributes to cognitive impairment and dementia in the broad range of parkinsonian diseases. Twenty-nine cognitively healthy PD, 14 PD subjects with mild cognitive impairment (PD-MCI), 18 with DLB, 12 with PDD, and 85 healthy control subjects (HCS) underwent standardized neurologic and neuropsychological examinations and Pittsburgh compound B (PiB) imaging with PET. Apolipoprotein E (ApoE) genotypes were obtained in many patients. PiB retention was expressed as the distribution volume ratio using a cerebellar tissue reference. PiB retention was significantly higher in DLB than in any of the other diagnostic groups. PiB retention did not differ across PDD, PD-MCI, PD, and HCS. Amyloid burden increased with age and with the presence of the ApoE ε4 allele in all patient groups. Only in the DLB group was amyloid deposition associated with impaired cognition. DLB subjects have higher amyloid burden than subjects with PDD, PD-MCI, PD, or HCS; amyloid deposits are linked to cognitive impairment only in DLB. Early amyloid deposits in DLB relative to PDD may account for their difference in the timing of dementia and parkinsonism. Copyright © 2012 Movement Disorder Society.

  18. Deep brain stimulation improves survival in severe Parkinson's disease.

    Science.gov (United States)

    Ngoga, Desire; Mitchell, Rosalind; Kausar, Jamilla; Hodson, James; Harries, Anwen; Pall, Hardev

    2014-01-01

    Levodopa and other dopaminergic treatments have not had the expected effect on survival in Parkinson's disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) has been shown to improve motor function, motor fluctuations, health-related quality of life, and to reduce medication usage and drug-induced dyskinesia in patients with severe PD refractory to medical therapy. Little however, has been described on the impact of STN-DBS on the survival of these patients. We aim in this study to examine the impact of STN-DBS on the survival of patients with severe PD. Patients who were eligible for STN-DBS were given the choice of undergoing surgery or continuing on medical treatment. Those who exercised patient choice and preferred to continue with medical treatment formed a control population. All eligible patients seen in a 10-year period are included in this study. Our primary outcome measure is a difference in mortality between the two groups with a secondary measure of admission rates to residential (nursing home) care. 106 patients underwent STN-DBS, and 41 patients exercised patient choice and declined the procedure. The two groups were matched for age, gender, ethnicity, duration of disease, rates of pre-existing depression and Levodopa equivalent doses of anti-Parkinson's medications taken. Patients undergoing STN-DBS had significantly longer survival and were significantly less likely to be admitted to a residential care home than those managed purely medically. The statistical significance of these findings persisted after adjusting for potential confounding factors (survival: p=0.002, HR 0.29 (0.13 to 0.64) (residential care home admission: OR: 0.1 (95% CI 0.0 to 0.3; padvanced PD. The effect of potential bias factors is examined. The survival advantage may arise for several postulated reasons, ranging from improvement in axial functions, such as swallowing, to some as yet unrecognised benefit of reduction in dopaminergic medication. These

  19. Lymphatic drainage system of the brain: A novel target for intervention of neurological diseases.

    Science.gov (United States)

    Sun, Bao-Liang; Wang, Li-Hua; Yang, Tuo; Sun, Jing-Yi; Mao, Lei-Lei; Yang, Ming-Feng; Yuan, Hui; Colvin, Robert A; Yang, Xiao-Yi

    2017-09-10

    The belief that the vertebrate brain functions normally without classical lymphatic drainage vessels has been held for many decades. On the contrary, new findings show that functional lymphatic drainage does exist in the brain. The brain lymphatic drainage system is composed of basement membrane-based perivascular pathway, a brain-wide glymphatic pathway, and cerebrospinal fluid (CSF) drainage routes including sinus-associated meningeal lymphatic vessels and olfactory/cervical lymphatic routes. The brain lymphatic systems function physiological as a route of drainage for interstitial fluid (ISF) from brain parenchyma to nearby lymph nodes. Brain lymphatic drainage helps maintain water and ion balance of the ISF, waste clearance, and reabsorption of macromolecular solutes. A second physiological function includes communication with the immune system modulating immune surveillance and responses of the brain. These physiological functions are influenced by aging, genetic phenotypes, sleep-wake cycle, and body posture. The impairment and dysfunction of the brain lymphatic system has crucial roles in age-related changes of brain function and the pathogenesis of neurovascular, neurodegenerative, and neuroinflammatory diseases, as well as brain injury and tumors. In this review, we summarize the key component elements (regions, cells, and water transporters) of the brain lymphatic system and their regulators as potential therapeutic targets in the treatment of neurologic diseases and their resulting complications. Finally, we highlight the clinical importance of ependymal route-based targeted gene therapy and intranasal drug administration in the brain by taking advantage of the unique role played by brain lymphatic pathways in the regulation of CSF flow and ISF/CSF exchange. Copyright © 2017. Published by Elsevier Ltd.

  20. The usefulness of brain natriuretic peptide in complex congenital heart disease: A systematic review

    NARCIS (Netherlands)

    J.A. Eindhoven (Jannet); A.E. van den Bosch (Annemien); P.R. Jansen (Philip); H. Boersma (Eric); J.W. Roos-Hesselink (Jolien)

    2012-01-01

    textabstractBrain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are well-established markers for heart failure in the general population. However, the value of BNP as a diagnostic and prognostic marker for patients with structural congenital heart disease (CHD)

  1. Alterations in brain activation during cholinergic enhancement with rivastigmine in Alzheimer's disease

    OpenAIRE

    Rombouts, S.; Barkhof, F; van Meel, C S; Scheltens, P

    2002-01-01

    Background: Rivastigmine enhances cholinergic activity and has been shown in clinical trials to decrease the rate of deterioration in Alzheimer's disease. It remains unclear where in the brain it exerts its effect. Functional magnetic resonance imaging (fMRI) can be used to measure changes in brain function and relate these to cognition.

  2. Diabetes increases atrophy and vascular lesions on brain MRI in patients with symptomatic arterial disease

    NARCIS (Netherlands)

    Tiehuis, Audrey M.; Van der Graaf, Yolanda; Visseren, Frank L.; Vincken, Koen L.; Biessels, Geert Jan; Appelman, Auke P. A.; Kappelle, L. Jaap; Mali, Willem P. T. M.

    Background and Purpose - Diabetes type 2 (DM2) is associated with accelerated cognitive decline and structural brain abnormalities. Macrovascular disease has been described as a determinant for brain MRI changes in DM2, but little is known about the involvement of other DM2-related factors. Methods

  3. Vascular damage: a persisting pathology common to Alzheimer's disease and traumatic brain injury.

    Science.gov (United States)

    Franzblau, Max; Gonzales-Portillo, Chiara; Gonzales-Portillo, Gabriel S; Diamandis, Theo; Borlongan, Mia C; Tajiri, Naoki; Borlongan, Cesar V

    2013-11-01

    Alzheimer's disease (AD) and traumatic brain injury (TBI) are both significant clinical problems characterized by debilitating symptoms with limited available treatments. Interestingly, both neurological diseases are characterized by neurovascular damage. This impaired brain vasculature correlates with the onset of dementia, a symptom associated with hippocampal degeneration seen in both diseases. We posit that vascular damage is a major pathological link between TBI and AD, in that TBI victims are predisposed to AD symptoms due to altered brain vasculature; vice versa, the progression of AD pathology may be accelerated by TBI especially when the brain insult worsens hippocampal degeneration. Our hypothesis is supported by recent data reporting expedited AD pathology in presymptomatic transgenic AD mice subjected to TBI. If our hypothesis is correct, treatments targeted at repairing the vasculature may prove effective at treating both diseases and preventing the evolution of AD symptoms in TBI victims. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. The modulatory effect of adaptive deep brain stimulation on beta bursts in Parkinson’s disease

    Science.gov (United States)

    Tinkhauser, Gerd; Pogosyan, Alek; Little, Simon; Beudel, Martijn; Herz, Damian M.; Tan, Huiling

    2017-01-01

    Abstract Adaptive deep brain stimulation uses feedback about the state of neural circuits to control stimulation rather than delivering fixed stimulation all the time, as currently performed. In patients with Parkinson’s disease, elevations in beta activity (13–35 Hz) in the subthalamic nucleus have been demonstrated to correlate with clinical impairment and have provided the basis for feedback control in trials of adaptive deep brain stimulation. These pilot studies have suggested that adaptive deep brain stimulation may potentially be more effective, efficient and selective than conventional deep brain stimulation, implying mechanistic differences between the two approaches. Here we test the hypothesis that such differences arise through differential effects on the temporal dynamics of beta activity. The latter is not constantly increased in Parkinson’s disease, but comes in bursts of different durations and amplitudes. We demonstrate that the amplitude of beta activity in the subthalamic nucleus increases in proportion to burst duration, consistent with progressively increasing synchronization. Effective adaptive deep brain stimulation truncated long beta bursts shifting the distribution of burst duration away from long duration with large amplitude towards short duration, lower amplitude bursts. Critically, bursts with shorter duration are negatively and bursts with longer duration positively correlated with the motor impairment off stimulation. Conventional deep brain stimulation did not change the distribution of burst durations. Although both adaptive and conventional deep brain stimulation suppressed mean beta activity amplitude compared to the unstimulated state, this was achieved by a selective effect on burst duration during adaptive deep brain stimulation, whereas conventional deep brain stimulation globally suppressed beta activity. We posit that the relatively selective effect of adaptive deep brain stimulation provides a rationale for why this

  5. Corpus callosum thickness on mid-sagittal MRI as a marker of brain volume: a pilot study in children with HIV-related brain disease and controls

    Energy Technology Data Exchange (ETDEWEB)

    Andronikou, Savvas [University of the Witwatersrand, Department of Radiology, Faculty of Health Sciences, Cape Town (South Africa); Ackermann, Christelle [University of Stellenbosch, Department of Radiology, Stellenbosch (South Africa); Laughton, Barbara; Cotton, Mark [Stellenbosch University and Tygerberg Children' s Hospital, Children' s Infectious Diseases Research Unit, Stellenbosch (South Africa); Tomazos, Nicollette [University of Cape Town, Faculty of Commerce, Department of Management Studies, Cape Town (South Africa); Spottiswoode, Bruce [University of Cape Town, MRC/UCT Medical Imaging Research Unit, Department of Human Biology, Cape Town (South Africa); Mauff, Katya [University of Cape Town, Department of Statistical Sciences, Cape Town (South Africa); Pettifor, John M. [University of the Witwatersrand, MRC/Wits Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, Witwatersrand (South Africa)

    2015-07-15

    Corpus callosum thickness measurement on mid-sagittal MRI may be a surrogate marker of brain volume. This is important for evaluation of diseases causing brain volume gain or loss, such as HIV-related brain disease and HIV encephalopathy. To determine if thickness of the corpus callosum on mid-sagittal MRI is a surrogate marker of brain volume in children with HIV-related brain disease and in controls without HIV. A retrospective MRI analysis in children (<5 years old) with HIV-related brain disease and controls used a custom-developed semi-automated tool, which divided the midline corpus callosum and measured its thickness in multiple locations. Brain volume was determined using volumetric analysis. Overall corpus callosum thickness and thickness of segments of the corpus callosum were correlated with overall and segmented (grey and white matter) brain volume. Forty-four children (33 HIV-infected patients and 11 controls) were included. Significant correlations included overall corpus callosum (mean) and total brain volume (P = 0.05); prefrontal corpus callosum maximum with white matter volume (P = 0.02); premotor corpus callosum mean with total brain volume (P = 0.04) and white matter volume (P = 0.02), premotor corpus callosum maximum with white matter volume (P = 0.02) and sensory corpus callosum mean with total brain volume (P = 0.02). Corpus callosum thickness correlates with brain volume both in HIV-infected patients and controls. (orig.)

  6. What does it mean to call chronic pain a brain disease?

    Science.gov (United States)

    Sullivan, Mark D; Cahana, Alex; Derbyshire, Stuart; Loeser, John D

    2013-04-01

    Multiple investigators have recently asked whether neuroimaging has shown that chronic pain is a brain disease. We review the clinical implications of seeing chronic pain as a brain disease. Abnormalities noted on imaging of peripheral structures have previously misled the clinical care of patients with chronic pain. We also cannot assume that the changes associated with chronic pain on neuroimaging are causal. When considering the significance of neuroimaging results, it is important to remember that "disease" is a concept that arises out of clinical medicine, not laboratory science. Following Canguilhem, we believe that disease is best defined as a structural or functional change that causes disvalue to the whole organism. It is important to be cautious in our assertions about chronic pain as a brain disease because these may have negative effects on 1) the therapeutic dialogue between clinicians and patients; 2) the social dialogue about reimbursement for pain treatments and disability due to pain; and 3) the chronic pain research agenda. Considered scientifically, we may be looking for the cause of chronic pain through neuroimaging, but considered clinically, we are in fact often looking to validate pain complaints. We should not yield to the temptation to validate pain with the magnetic resonance imaging scanner (structural or functional). We should not see pain as caused by the brain alone. Pain is not felt by the brain, but by the person. Neuroimaging investigators have argued that brain imaging may demonstrate that chronic pain is a brain disease. We argue that "disease" is a clinical concept and that conceiving of chronic pain as a brain disease can have negative consequences for research and clinical care of patients with chronic pain. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

  7. Genetic Variation Underlying Traumatic Brain injury (TBI) and Late Onset Alzheimer’s Disease (LOAD)

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0588 TITLE: Genetic variation underlying traumatic brain injury (TBI) and Late Onset Alzheimer’s Disease (LOAD...14 Sep 2017 4. TITLE AND SUBTITLE Late-Onset Alzheimer’s Disease (LOAD) 5a. CONTRACT NUMBER Genetic variation underlying traumatic brain injury...accelerating individual’s memory decline and possibly accelerating LOAD like neuro-degeneration. In addition, genetic risk factors including non- coding and

  8. Neuro-Behçet disease mimicking brain tumor: A case report.

    Science.gov (United States)

    Tramontini, Pedro L; Finkelsztejn, Alessandro; Duarte, Juliana Á; Santos, Guilherme T; Roesler, Rafael; Isolan, Gustavo R

    2017-01-01

    Behçet's disease (BD) is an inflammatory multisystem disease with unknown etiology, and consists of a TRIAD comprising recurrent oral ulcers, genital ulcers, and uveitis. In some cases, the disease affects the central nervous system, called Neuro-Behçet Disease (NBD). Few cases of NBD simulating a brain tumor have been previously reported. Here, we describe the case of a 46-year-old male patient with a previous diagnosis of brain tumor who was later diagnosed for BD. This case highlights the importance of differential diagnosis of lesions with tumoral features. Checking for the possibility of NBD may help avoiding biopsy in these types of cases.

  9. GLP-1 analog raises glucose transport capacity of blood-brain barrier in Alzheimer's disease

    DEFF Research Database (Denmark)

    Gejl, M.; Brock, B.; Egefjord, L.

    2017-01-01

    claim that the GLP-1 analog liraglutide may prevent the decline of blood-brain glucose transfer in AD. Methods: In this 26-week test of the hypothesis, we randomized 38 patients with AD to treatment with the GLP-1 analog liraglutide (n = 18) or placebo (n = 20). We determined blood-brain glucose......Objectives: Glucose enters the brain tissue from plasma by facilitated diffusion across the two membranes of the endothelium of the blood-brain barrier (BBB), mediated by the glucose transporter 1 (GLUT1). There is evidence in Alzheimer's disease (AD) of reduction of glucose transport across...... and degeneration. Hypothesis: The incretin hormone GLP-1 prevents the decline of the cerebral metabolic rate of glucose that signifies cognitive impairment, synaptic dysfunction, and disease evolution in AD, and GLP-1 may directly activate GLUT1 transport in brain capillary endothelium. For this reason, we here...

  10. An unusual presentation of muscle-eye-brain disease: severe eye abnormalities with mild muscle and brain involvement.

    Science.gov (United States)

    Demir, Ercan; Gucuyener, Kivilcim; Akturk, Aysima; Talim, Beril; Konus, Oznur; Del Bo, Roberto; Ghezzi, Serena; Comi, Giacomo P

    2009-10-01

    Muscle-eye-brain disease (MEB) is characterised by congenital muscular dystrophy, structural brain malformations and eye abnormalities. We report a MEB case whose presenting sign was congenital blindness. She was investigated primarily for eye abnormalities at onset. She had bilateral retinal detachment and microphthalmia. Mild axial hypotonia and motor retardation were attributed to cerebral disorder in another center. Muscle biopsy showed mild myopathic changes and significant alpha-dystroglycan deficiency. Analysis of the POMGnT1 showed a novel homozygous mutation 1814G>C, causing p.Arg605Pro change. This case expands the clinical spectrum of MEB with unusually severe eye abnormalities compared to mild skeletal muscle and brain involvement.

  11. The Brain in Congenital Heart Disease across the Lifespan: The Cumulative Burden of Injury

    Science.gov (United States)

    Marelli, Ariane; Miller, Steven P.; Marino, Bradley Scott; Jefferson, Angela L.; Newburger, Jane W.

    2017-01-01

    The number of patients surviving with congenital heart disease (CHD) has soared over the last three decades. Adults constitute the fastest growing segment of the CHD population, now outnumbering children. Research to date on the heart-brain intersection in this population has largely been focused on neurodevelopmental outcomes in childhood and adolescence. Mutations in genes that are highly expressed in heart and brain may cause cerebral dysgenesis. Together with altered cerebral perfusion in utero, these factors are associated with abnormalities of brain structure and brain immaturity in a significant portion of neonates with critical CHD even before they undergo cardiac surgery. In infancy and childhood, the brain may be affected by risk factors related to heart disease itself or to its interventional treatments. As children with CHD become adults, they increasingly develop heart failure, atrial fibrillation, hypertension, diabetes and coronary disease. These acquired cardiovascular comorbidities can be expected to have effects similar to those in the general population on cerebral blood flow, brain volumes, and dementia. In both children and adults, cardiovascular disease may have adverse effects on achievement, executive function, memory, language, social interactions, and quality of life. In summary, against the backdrop of shifting demographics, risk factors for brain injury in the CHD population are cumulative and synergistic. As neurodevelopmental sequelae in children with CHD evolve to cognitive decline or dementia during adulthood, a growing population of CHD can be expected to require support services. We highlight evidence gaps and future research directions. PMID:27185022

  12. Neural Plasticity in Human Brain Connectivity: The Effects of Long Term Deep Brain Stimulation of the Subthalamic Nucleus in Parkinson's Disease

    OpenAIRE

    van Hartevelt, Tim J; Joana Cabral; Gustavo Deco; Arne Møller; Green, Alexander L.; Aziz, Tipu Z.; Morten L Kringelbach

    2014-01-01

    Background: Positive clinical outcomes are now well established for deep brain stimulation, but little is known about the effects of long-term deep brain stimulation on brain structural and functional connectivity. Here, we used the rare opportunity to acquire pre- and postoperative diffusion tensor imaging in a patient undergoing deep brain stimulation in bilateral subthalamic nuclei for Parkinson’s Disease. This allowed us to analyse the differences in structural connectivity before and aft...

  13. Novel Noninvasive Brain Disease Detection System Using a Facial Image Sensor

    Directory of Open Access Journals (Sweden)

    Ting Shu

    2017-12-01

    Full Text Available Brain disease including any conditions or disabilities that affect the brain is fast becoming a leading cause of death. The traditional diagnostic methods of brain disease are time-consuming, inconvenient and non-patient friendly. As more and more individuals undergo examinations to determine if they suffer from any form of brain disease, developing noninvasive, efficient, and patient friendly detection systems will be beneficial. Therefore, in this paper, we propose a novel noninvasive brain disease detection system based on the analysis of facial colors. The system consists of four components. A facial image is first captured through a specialized sensor, where four facial key blocks are next located automatically from the various facial regions. Color features are extracted from each block to form a feature vector for classification via the Probabilistic Collaborative based Classifier. To thoroughly test the system and its performance, seven facial key block combinations were experimented. The best result was achieved using the second facial key block, where it showed that the Probabilistic Collaborative based Classifier is the most suitable. The overall performance of the proposed system achieves an accuracy −95%, a sensitivity −94.33%, a specificity −95.67%, and an average processing time (for one sample of <1 min at brain disease detection.

  14. A brain mass in a patient with Behcet's disease: a case report.

    Science.gov (United States)

    Alfedaghi, Ahmad S; Masters, Y; Mourou, M; Eshak, O

    2015-09-30

    This case report describes an uncommon presentation of Behcet's disease which manifested as neuro-Behcet's disease. Although it is not the first reported case in the medical literature, it is a possible differential in a patient presenting with a brain tumor. Since the diagnosis of neuro-Behcet's disease depends largely on the clinical picture and medical history, it should be considered prior to opting for invasive diagnostic methods. Our patient is a 36-year-old white man from Kuwait. He presented with acute onset of headache, vomiting, and right-sided weakness. Magnetic resonance imaging of his brain showed a mass in the brain stem. He then revealed that he had a history of recurrent painful oral and genital ulcers for the past 10 years, which suggested a diagnosis of Behcet's disease. A brain biopsy was recommended by a neurosurgeon at the time, but the patient refused the procedure. After initiating steroid therapy, the mass began to regress and, eventually, was undetectable on subsequent imaging of his brain. This case of neuro-Behcet's disease reflects the need to consider this diagnosis in a patient of less than 40 years of age presenting with a suspected brain tumor. This may delay the need for invasive diagnostic methods, especially if such methods are not desired by the patient. In the management of suspected neuro-Behcet's disease, initiating steroid therapy and measuring the response is a reasonable option before seeking a definitive diagnosis via brain biopsy. If the response to steroids is minimal then a brain biopsy should be performed.

  15. The Alzheimer's Disease-Related Glucose Metabolic Brain Pattern

    NARCIS (Netherlands)

    Teune, Laura K.; Strijkert, Fijanne; Renken, Remco J.; Izaks, Gerbrand J.; de Vries, Jeroen J.; Segbers, Marcel; Roerdink, Jos B. T. M.; Dierckx, Rudi A. J. O.; Leenders, Klaus L.

    2014-01-01

    Purpose: [F-18] fluorodeoxyglucose (FDG) PET imaging of the brain can be used to assist in the differential diagnosis of dementia. Group differences in glucose uptake between patients with dementia and controls are well-known. However, a multivariate analysis technique called scaled subprofile

  16. The imaging of HIV-related brain disease : clinical: imaging

    African Journals Online (AJOL)

    Furthermore, a correlation between declining cognitive function and the loss of ... and highly active antiretroviral therapy (HAART) is an important aspect of managing these conditions effec- tively.2 In ... sult in damage to white matter tracts in the brain.6 Once damage is established and related cognitive disorders ensue, the ...

  17. Disease association and inter-connectivity analysis of human brain specific co-expressed functional modules.

    Science.gov (United States)

    Oh, Kimin; Hwang, Taeho; Cha, Kihoon; Yi, Gwan-Su

    2015-12-16

    In the recent studies, it is suggested that the analysis of transcriptomic change of functional modules instead of individual genes would be more effective for system-wide identification of cellular functions. This could also provide a new possibility for the better understanding of difference between human and chimpanzee. In this study, we analyzed to find molecular characteristics of human brain functions from the difference of transcriptome between human and chimpanzee's brain using the functional module-centric co-expression analysis. We performed analysis of brain disease association and systems-level connectivity of species-specific co-expressed functional modules. Throughout the analyses, we found human-specific functional modules and significant overlap between their genes in known brain disease genes, suggesting that human brain disorder could be mediated by the perturbation of modular activities emerged in human brain specialization. In addition, the human-specific modules having neurobiological functions exhibited higher networking than other functional modules. This finding suggests that the expression of neural functions are more connected than other functions, and the resulting high-order brain functions could be identified as a result of consolidated inter-modular gene activities. Our result also showed that the functional module based transcriptome analysis has a potential to expand molecular understanding of high-order complex functions like cognitive abilities and brain disorders.

  18. Regulatory factor X4 variant 3: a transcription factor involved in brain development and disease.

    Science.gov (United States)

    Zhang, Donghui; Zeldin, Darryl C; Blackshear, Perry J

    2007-12-01

    Regulatory factor X4 variant 3 (RFX4_v3) is a recently identified transcription factor specifically expressed in the brain. Gene disruption in mice demonstrated that interruption of a single allele (heterozygous, +/-) prevented formation of the subcommissural organ (SCO), resulting in congenital hydrocephalus, whereas interruption of two alleles (homozygous, -/-) caused fatal failure of dorsal midline brain structure formation. These mutagenesis studies implicated RFX4_v3 in early brain development as well as the genesis of the SCO. Rfx4_v3 deficiency presumably causes abnormalities in brain by altering the expression levels of many genes that are crucial for brain morphogenesis, such as the signaling components in the Wnt, bone morphogenetic protein, and retinoic acid pathways. RFX4_v3 might affect these critical signaling pathways in brain development. Cx3cl1, a chemokine gene highly expressed in brain, was identified as a direct target for RFX4_v3, indicating that RFX4_v3 possesses trans-acting activity to stimulate gene expression. Rfx4_v3 is highly expressed in the suprachiasmatic nucleus and might be involved in regulating the circadian clock. One haplotype in RFX4_v3 gene is linked to a higher risk of bipolar disorder, suggesting that this protein might contribute to the pathogenesis of the disease. This Mini-Review describes our current knowledge about RFX4_v3, an important protein that appears to be involved in many aspects of brain development and disease. (c) 2007 Wiley-Liss, Inc.

  19. Deep-brain-stimulation does not impair deglutition in Parkinson's disease.

    Science.gov (United States)

    Lengerer, Sabrina; Kipping, Judy; Rommel, Natalie; Weiss, Daniel; Breit, Sorin; Gasser, Thomas; Plewnia, Christian; Krüger, Rejko; Wächter, Tobias

    2012-08-01

    A large proportion of patients with Parkinson's disease develop dysphagia during the course of the disease. Dysphagia in Parkinson's disease affects different phases of deglutition, has a strong impact on quality of life and may cause severe complications, i.e., aspirational pneumonia. So far, little is known on how deep-brain-stimulation of the subthalamic nucleus influences deglutition in PD. Videofluoroscopic swallowing studies on 18 patients with Parkinson's disease, which had been performed preoperatively, and postoperatively with deep-brain-stimulation-on and deep-brain-stimulation-off, were analyzed retrospectively. The patients were examined in each condition with three consistencies (viscous, fluid and solid). The 'New Zealand index for multidisciplinary evaluation of swallowing (NZIMES) Subscale One' for qualitative and 'Logemann-MBS-Parameters' for quantitative evaluation were assessed. Preoperatively, none of the patients presented with clinically relevant signs of dysphagia. While postoperatively, the mean daily levodopa equivalent dosage was reduced by 50% and deep-brain-stimulation led to a 50% improvement in motor symptoms measured by the UPDRS III, no clinically relevant influence of deep-brain-stimulation-on swallowing was observed using qualitative parameters (NZIMES). However quantitative parameters (Logemann scale) found significant changes of pharyngeal parameters with deep-brain-stimulation-on as compared to preoperative condition and deep-brain-stimulation-off mostly with fluid consistency. In Parkinson patients without dysphagia deep-brain-stimulation of the subthalamic nucleus modulates the pharyngeal deglutition phase but has no clinically relevant influence on deglutition. Further studies are needed to test if deep-brain-stimulation is a therapeutic option for patients with swallowing disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. ADAM10 as a therapeutic target for brain diseases: from developmental disorders to Alzheimer's disease.

    Science.gov (United States)

    Marcello, Elena; Borroni, Barbara; Pelucchi, Silvia; Gardoni, Fabrizio; Di Luca, Monica

    2017-11-01

    In the central nervous system a disintegrin and metalloproteinase 10 (ADAM10) controls several functions such as neurodevelopment, synaptic plasticity and dendritic spine morphology thanks to its activity towards a high number of substrates, including the synaptic cell adhesion molecules as the Amyloid Precursor Protein, N-cadherin, Notch and Ephrins. In particular, ADAM10 plays a key role in the modulation of the molecular mechanisms responsible for dendritic spine formation, maturation and stabilization and in the regulation of the molecular organization of the glutamatergic synapse. Consequently, an alteration of ADAM10 activity is strictly correlated to the onset of different types of synaptopathies, ranging from neurodevelopmental disorders, i.e. autism spectrum disorders, to neurodegenerative diseases, i.e. Alzheimer's Disease. Areas covered: We describe the most recent discoveries in understanding of the role of ADAM10 activity at the glutamatergic excitatory synapse and its involvement in the onset of neurodevelopmental and neurodegenerative disorders. Expert opinion: A progress in the understanding of the molecular mechanisms driving ADAM10 activity at synapses and its alterations in brain disorders is the first step before designing a specific drug able to modulate ADAM10 activity.

  1. Positron Emission Tomography and Magnetic Resonance Imaging of the Brain in Fabry Disease

    DEFF Research Database (Denmark)

    Korsholm, Kirsten; Feldt-Rasmussen, Ulla; Granqvist, Henrik

    2015-01-01

    risk of cerebrovascular disease at a young age in addition to heart and kidney failure. OBJECTIVE: The objective of this study was to assess brain function and structure in the Danish cohort of patients with Fabry disease in a prospective way using 18-fluoro-deoxyglucose (F-18 FDG) positron emission...

  2. PIXE analysis of low concentration aluminum in brain tissues of an Alzheimer's disease patient

    Science.gov (United States)

    Ishihara, R.; Hanaichi, T.; Takeuchi, T.; Ektessabi, A. M.

    1999-06-01

    An excess accumulation and presence of metal ions may significantly alter a brain cell's normal functions. There have been increasing efforts in recent years to measure and quantify the density and distribution of excessive accumulations of constituent elements (such as Fe, Zn, Cu, and Ca) in the brain, as well as the presence and distribution of contaminating elements (such as Al). This is particularly important in cases of neuropathological disorders such as Alzheimer's disease, Parkinson's disease and ALS. The aim of this paper was to measure the Al present in the temporal cortex of the brain of an Alzheimer's disease patient. The specimens were taken from an unfixed autopsy brain which has been preserved for a period of 4 years in the deep freezer at -80 °C. Proton Induced X-ray Emission Spectroscopy was used for the measurement of Al concentration in this brain tissue. A tandem accelerator with 2 MeV of energy was also used. In order to increase the sensitivity of the signals in the low energy region of the spectra, the absorbers were removed. The results show that the peak height depends on the measurement site. However, in certain cases an extremely high concentration of Al was observed in the PIXE spectra, with an intensity higher than those in the other major elements of the brain's matrix element. Samples from tissues affected by the same disease were analyzed using the EDX analyzer. The results are quantitatively in very good agreement with those of the PIXE analysis.

  3. Impaired topological architecture of brain structural networks in idiopathic Parkinson's disease: a DTI study.

    Science.gov (United States)

    Li, Changhong; Huang, Biao; Zhang, Ruibin; Ma, Qing; Yang, Wanqun; Wang, Lijuan; Wang, Limin; Xu, Qin; Feng, Jieying; Liu, Liqing; Zhang, Yuhu; Huang, Ruiwang

    2017-02-01

    Parkinson's disease (PD) is considered as a neurodegenerative disorder of the brain central nervous system. But, to date, few studies adopted the network model to reveal topological changes in brain structural networks in PD patients. Additionally, although the concept of rich club organization has been widely used to study brain networks in various brain disorders, there is no study to report the changed rich club organization of brain networks in PD patients. Thus, we collected diffusion tensor imaging (DTI) data from 35 PD patients and 26 healthy controls and adopted deterministic tractography to construct brain structural networks. During the network analysis, we calculated their topological properties, and built the rich club organization of brain structural networks for both subject groups. By comparing the between-group differences in topological properties and rich club organizations, we found that the connectivity strength of the feeder and local connections are lower in PD patients compared to those of the healthy controls. Furthermore, using a network-based statistic (NBS) approach, we identified uniformly significantly decreased connections in two modules, the limbic/paralimbic/subcortical module and the cognitive control/attention module, in patients compared to controls. In addition, for the topological properties of brain network topology in the PD patients, we found statistically increased shortest path length and decreased global efficiency. Statistical comparisons of nodal properties were also widespread in the frontal and parietal regions for the PD patients. These findings may provide useful information to better understand the abnormalities of brain structural networks in PD patients.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Brain-Gut-Microbe Communication in Health and Disease

    Directory of Open Access Journals (Sweden)

    Sue eGrenham

    2011-12-01

    Full Text Available Bidirectional signalling between the gastrointestinal tract and the brain is regulated at neural, hormonal and immunological levels. This construct is known as the brain-gut axis and is vital for maintaining homeostasis. Bacterial colonisation of the intestine plays a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS signalling. Recent research advances have seen a tremendous improvement in our understanding of the scale, diversity and importance of the gut microbiome. This has been reflected in the form of a revised nomenclature to the more inclusive brain-gut-enteric microbiota axis and a sustained research effort to establish how communication along this axis contributes to both normal and pathological conditions. In this review, we will briefly discuss the critical components of this axis and the methodological challenges that have been presented in attempts to define what constitutes a normal microbiota and chart its temporal development. Emphasis is placed on the new research narrative that confirms the critical influence of the microbiota on mood and behaviour. Mechanistic insights are provided with examples of both neural and humoral routes through which these effects can be mediated. The evidence supporting a role for the enteric flora in brain-gut axis disorders is explored with the spotlight on the clinical relevance for irritable bowel syndrome (IBS, a stress-related functional gastrointestinal disorder. We also critically evaluate the therapeutic opportunities arising from this research and consider in particular whether targeting the microbiome might represent a valid strategy for the management of CNS disorders and ponder the pitfalls inherent in such an approach. Despite the considerable challenges that lie ahead, this is an exciting area of research and one that is destined to remain the centre of focus for some

  6. Tau, Amyloid Beta and Deep Brain Stimulation: Aiming to Restore Cognitive Deficit in Alzheimer's Disease.

    Science.gov (United States)

    Mondragón-Rodríguez, Siddhartha; Perry, George; Pena-Ortega, Fernando; Williams, Sylvain

    2017-01-01

    The last two decades have seen a great advance in the data that supports the two current hypotheses in Alzheimer`s disease field, the amyloid beta hypothesis and the tau hypothesis. Not surprisingly, Aβ and tau proteins are currently the major therapeutic research targets for AD treatment. Unfortunately, nothing but moderate success has emerged from such therapeutic approaches. With this in mind, we will discuss deep brain stimulation as a promising therapeutic strategy that aims to restore brain activity. Lastly, in the scope of cognitive deficit restoration, we will discuss the relevance of the limbic formation as a promising neuroanatomical target for deep brain stimulation. Immunohistochemistry for modified tau (phosphorylated at Ser199-202-Thr205 labelled by the antibody AT8) was performed on paraffin-embedded human brain sections providing a detailed characterization of NFT pathology. Abnormally phosphorylated tau protein is the key common marker in several brain diseases such as Alzheimer's disease, Parkinson`s disease, Pick Disease, Down syndrome and frontotemporal dementia and is capable of affecting synaptic events that are critical for memory formation. With this in mind, therapeutic strategies aiming to restore synaptic events could offer better outcomes. The humble success of current therapeutic strategies along with the lack of basic knowledge of the brain disease mechanisms calls for alternatives that benefit patients in the present moment. One of particular interest is the neurostimulation strategy that is already a well-established treatment for several movement disorders and when compared to current Alzheimer`s therapeutic strategies, deep brain stimulation does not directly interfere with the normal protein function, therefore increasing the probability of success.

  7. The choroid plexus in health and in disease: dialogues into and out of the brain.

    Science.gov (United States)

    Marques, Fernanda; Sousa, João Carlos; Brito, Maria Alexandra; Pahnke, Jens; Santos, Cecilia; Correia-Neves, Margarida; Palha, Joana Almeida

    2017-11-01

    This article brings the choroid plexus into the context of health and disease. It is remarkable that the choroid plexus, composed by a monolayer of epithelial cells that lie in a highly vascularized stroma, floating within the brain ventricles, gets so little attention in major physiology and medicine text books and in the scientific literature in general. Consider that it is responsible for producing most of the about 150mL of cerebrospinal fluid that fills the brain ventricles and the subarachnoid space and surrounds the spinal cord in the adult human central nervous system, which is renewed approximately 2-3 times daily. As such, its activity influences brain metabolism and function, which will be addressed. Reflect that it contains an impressive number of receptors and transporters, both in the apical and basolateral sides of the epithelial cells, and as such is a key structure for the communication between the brain and the periphery. This will be highlighted in the context of neonatal jaundice, multiple sclerosis and Alzheimer's disease. Realize that the capillaries that irrigate the choroid plexus stroma do not possess tight junctions and that the blood flow to the choroid plexus is five times higher than that in the brain parenchyma, allowing for a rapid sensing system and delivery of molecules such as nutrients and metals as will be revised. Recognize that certain drugs reach the brain parenchyma solely through the choroid plexus epithelia, which has potential to be manipulated in diseases such as neonatal jaundice and Alzheimer's disease as will be discussed. Without further notice, it must be now clear that understanding the choroid plexus is necessary for comprehending the brain and how the brain is modulated and modulates all other systems, in health and in disease. This review article intends to address current knowledge on the choroid plexus, and to motivate the scientific community to consider it when studying normal brain physiology and diseases of

  8. Brain Sex Matters: estrogen in cognition and Alzheimer’s disease

    Science.gov (United States)

    Li, Rena; Cui, Jie; Shen, Yong

    2014-01-01

    Estrogens are the primary female sex hormones and play important roles in both reproductive and non-reproductive systems. Estrogens can be synthesized in non-reproductive tissues such as liver, heart, muscle, bone and the brain. During the past decade, increasing evidence suggests that brain estrogen can not only be synthesized by neurons, but also by astrocytes. Brain estrogen also works locally at the site of synthesis in paracrine and/or intracrine fashion to maintain important tissue-specific functions. Here, we will focus on the biology of brain estrogen and its impact on cognitive function and Alzheimer’s disease. This comprehensive review provides new insights into brain estrogens by presenting a better understanding of the tissue-specific estrogen effects and their roles in healthy ageing and cognitive function. PMID:24418360

  9. Exploring the Virchow-Robin spaces function: A unified theory of brain diseases.

    Science.gov (United States)

    Cherian, Iype; Beltran, Margarita; Kasper, Ekkehard M; Bhattarai, Binod; Munokami, Sunil; Grasso, Giovanni

    2016-01-01

    Cerebrospinal fluid (CSF) transport across the central nervous system (CNS) is no longer believed to be on the conventional lines. The Virchow-Robin space (VRS) that facilitates CSF transport from the basal cisterns into the brain interstitial fluid (ISF) has gained interest in a whole new array of studies. Moreover, new line of evidence suggests that VRS may be involved in different pathological mechanisms of brain diseases. Here, we review emerging studies proving the feasible role of VRS in sleep, Alzheimer's disease, chronic traumatic encephalopathy, and traumatic brain injury (TBI). In this study, we have outlined the possible role of VRS in different pathological conditions. The new insights into the physiology of the CSF circulation may have important clinical relevance for understanding the mechanisms underlying brain pathologies and their cure.

  10. Exploring the Virchow–Robin spaces function: A unified theory of brain diseases

    Science.gov (United States)

    Cherian, Iype; Beltran, Margarita; Kasper, Ekkehard M.; Bhattarai, Binod; Munokami, Sunil; Grasso, Giovanni

    2016-01-01

    Background: Cerebrospinal fluid (CSF) transport across the central nervous system (CNS) is no longer believed to be on the conventional lines. The Virchow–Robin space (VRS) that facilitates CSF transport from the basal cisterns into the brain interstitial fluid (ISF) has gained interest in a whole new array of studies. Moreover, new line of evidence suggests that VRS may be involved in different pathological mechanisms of brain diseases. Methods: Here, we review emerging studies proving the feasible role of VRS in sleep, Alzheimer's disease, chronic traumatic encephalopathy, and traumatic brain injury (TBI). Results: In this study, we have outlined the possible role of VRS in different pathological conditions. Conclusion: The new insights into the physiology of the CSF circulation may have important clinical relevance for understanding the mechanisms underlying brain pathologies and their cure. PMID:27857861

  11. Periodontal disease associates with higher brain amyloid load in normal elderly

    Science.gov (United States)

    Kamer, Angela R.; Pirraglia, Elizabeth; Tsui, Wai; Rusinek, Henry; Vallabhajosula, Shankar; Mosconi, Lisa; Yi, Li; McHugh, Pauline; Craig, Ronald G.; Svetcov, Spencer; Linker, Ross; Shi, Chen; Glodzik, Lidia; Williams, Schantel; Corby, Patricia; Saxena, Deepak; de Leon, Mony J.

    2015-01-01

    Background The accumulation of amyloid β plaques (Aβ) is a central feature of Alzheimer’s disease (AD). First reported in animal models, it remains uncertain if peripheral inflammatory/infectious conditions in humans can promote Aβ brain accumulation. Periodontal disease, a common chronic infection, has been previously reported to be associated with AD. Methods Thirty-eight cognitively normal, healthy, community residing elderly (mean age 61; 68% female) were examined in an Alzheimer’s Disease research center and a University-based Dental School. Linear regression models (adjusted for age, ApoE and smoking) were used to test the hypothesis that periodontal disease assessed by clinical attachment loss was associated with brain Aβ load using 11C-PIB PET imaging. Results After adjusting for confounders, clinical attachment loss (≥ 3mm), representing a history of periodontal inflammatory/infectious burden, was associated with increased 11C-PIB uptake in Aβ vulnerable brain regions (p=0.002). Conclusion We show for the first time in humans an association between periodontal disease and brain Aβ load. These data are consistent with prior animal studies showing that peripheral inflammation/infections are sufficient to produce brain Aβ accumulations. PMID:25491073

  12. Microprobe PIXE analysis and EDX analysis on the brain of patients with Alzheimer`s disease

    Energy Technology Data Exchange (ETDEWEB)

    Yumoto, S. [Tokyo Univ. (Japan). Faculty of Medicine; Horino, Y.; Mokuno, Y.; Fujii, K.; Kakimi, S.; Mizutani, T.; Matsushima, H.; Ishikawa, A.

    1996-12-31

    To investigate the cause of Alzheimer`s disease (senile dementia of Alzheimer`s disease type), we examined aluminium (Al) in the brain (hippocampus) of patients with Alzheimer`s disease using heavy ion (5 MeV Si{sup 3+}) microprobe particle-induced X-ray emission (PIXE) analysis. Heavy ion microprobes (3 MeV Si{sup 2+}) have several times higher sensitivity for Al detection than 2 MeV proton microprobes. We also examined Al in the brain of these patients by energy dispersive X-ray spectroscopy (EDX). (1) Al was detected in the cell nuclei isolated from the brain of patients with Alzheimer`s disease using 5 MeV Si{sup 3+} microprobe PIXE analysis, and EDX analysis. (2) EDX analysis demonstrated high levels of Al in the nucleolus of nerve cells in frozen sections prepared from the brain of these patients. Our results support the theory that Alzheimer`s disease is caused by accumulation of Al in the nuclei of brain cells. (author)

  13. Periodontal disease associates with higher brain amyloid load in normal elderly.

    Science.gov (United States)

    Kamer, Angela R; Pirraglia, Elizabeth; Tsui, Wai; Rusinek, Henry; Vallabhajosula, Shankar; Mosconi, Lisa; Yi, Li; McHugh, Pauline; Craig, Ronald G; Svetcov, Spencer; Linker, Ross; Shi, Chen; Glodzik, Lidia; Williams, Schantel; Corby, Patricia; Saxena, Deepak; de Leon, Mony J

    2015-02-01

    The accumulation of amyloid-β (Aβ) plaques is a central feature of Alzheimer's disease (AD). First reported in animal models, it remains uncertain if peripheral inflammatory and/or infectious conditions in humans can promote Aβ brain accumulation. Periodontal disease, a common chronic infection, has been previously reported to be associated with AD. Thirty-eight cognitively normal, healthy, and community-residing elderly (mean age, 61 and 68% female) were examined in an Alzheimer's Disease Research Center and a University-Based Dental School. Linear regression models (adjusted for age, apolipoprotein E, and smoking) were used to test the hypothesis that periodontal disease assessed by clinical attachment loss was associated with brain Aβ load using (11)C-Pittsburgh compound B (PIB) positron emission tomography imaging. After adjusting for confounders, clinical attachment loss (≥3 mm), representing a history of periodontal inflammatory/infectious burden, was associated with increased PIB uptake in Aβ vulnerable brain regions (p = 0.002). We show for the first time in humans an association between periodontal disease and brain Aβ load. These data are consistent with the previous animal studies showing that peripheral inflammation/infections are sufficient to produce brain Aβ accumulations. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Blood brain barrier and Alzheimer's disease: Similarity and dissimilarity of molecular alerts.

    Science.gov (United States)

    Toropova, Alla P; Toropov, Andrey A; Begum, S; Achary, P G R

    2017-10-16

    Blood brain barrier and Alzheimer's disease are interrelated. This interrelation is detected by physicochemical methods, pharmacological and electrophysiological analyses. Nature of the phenomenon is extremely complex. The description of this interrelation in mathematical terms is very important task. The systematization of facts, which are described in the literature and related to interaction between processes, which influence on Alzheimer's disease and blood brain barrier is object of this work. In addition, the establishing of correlations between molecular features and endpoints, which are related to treatment of Alzheimer's disease and blood brain barrier using the CORAL software are objects study in this work. The logically structural analysis of information available in the literature; and building up quantitative structure - activity relationships (QSARs) by the Monte Carlo method has been used to solve the task of systematization of facts related to "treatment Alzheimer's disease vs. blood brain barrier". Comparison of agreements and disagreements of available published papers together with the statistical quality of built up QSARs are results of this work. The facts from published papers; and technical details of QSAR built up in this study give possibility to formulate the following rules: (i) there are molecular alerts, which are promoters of increase of blood brain barrier and therapeutic activity of anti-Alzheimer disease agents; (ii) there are molecular alerts, which contradict each other. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  15. Histamine Induces Alzheimer's Disease-Like Blood Brain Barrier Breach and Local Cellular Responses in Mouse Brain Organotypic Cultures

    Science.gov (United States)

    Sedeyn, Jonathan C.; Wu, Hao; Hobbs, Reilly D.; Levin, Eli C.; Nagele, Robert G.; Venkataraman, Venkat

    2015-01-01

    Among the top ten causes of death in the United States, Alzheimer's disease (AD) is the only one that cannot be cured, prevented, or even slowed down at present. Significant efforts have been exerted in generating model systems to delineate the mechanism as well as establishing platforms for drug screening. In this study, a promising candidate model utilizing primary mouse brain organotypic (MBO) cultures is reported. For the first time, we have demonstrated that the MBO cultures exhibit increased blood brain barrier (BBB) permeability as shown by IgG leakage into the brain parenchyma, astrocyte activation as evidenced by increased expression of glial fibrillary acidic protein (GFAP), and neuronal damage-response as suggested by increased vimentin-positive neurons occur upon histamine treatment. Identical responses—a breakdown of the BBB, astrocyte activation, and neuronal expression of vimentin—were then demonstrated in brains from AD patients compared to age-matched controls, consistent with other reports. Thus, the histamine-treated MBO culture system may provide a valuable tool in combating AD. PMID:26697497

  16. Temporal Loss of Tsc1: Neural Development and Brain Disease in Tuberous Sclerosis

    Science.gov (United States)

    2013-06-01

    brain development causes neurological disease in Tuberous Sclerosis". Honorary Lecturer at 8th Annual Pharmacology Graduate Students’ Symposium...Orthopedics and Surgery at Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, RI 02903, USA *Correspondence...analysis, five thalamic regions from five medial-to-lateral brain sections were assessed. The measure function (Voloc- ity) was used to calculate the

  17. Relating Education, Brain Structure, and Cognition: The Role of Cardiovascular Disease Risk Factors

    OpenAIRE

    Mortby, Moyra E.; Richard Burns; Janke, Andrew L.; Sachdev, Perminder S.; Anstey, Kaarin J.; Nicolas Cherbuin

    2014-01-01

    The protective effect of education on cognitive and brain health is well established. While the direct effects of individual cardiovascular disease (CVD) risk factors (i.e., hypertension, smoking, diabetes, and obesity) on cerebral structure have been investigated, little is understood about the possible interaction between the protective effect of education and the deleterious effects of CVD risk factors in predicting brain ageing and cognition. Using data from the PATH Through Life study (N...

  18. Multimodal neuroimaging of male and female brain structure in health and disease across the life span.

    Science.gov (United States)

    Jahanshad, Neda; Thompson, Paul M

    2017-01-02

    Sex differences in brain development and aging are important to identify, as they may help to understand risk factors and outcomes in brain disorders that are more prevalent in one sex compared with the other. Brain imaging techniques have advanced rapidly in recent years, yielding detailed structural and functional maps of the living brain. Even so, studies are often limited in sample size, and inconsistent findings emerge, one example being varying findings regarding sex differences in the size of the corpus callosum. More recently, large-scale neuroimaging consortia such as the Enhancing Neuro Imaging Genetics through Meta Analysis Consortium have formed, pooling together expertise, data, and resources from hundreds of institutions around the world to ensure adequate power and reproducibility. These initiatives are helping us to better understand how brain structure is affected by development, disease, and potential modulators of these effects, including sex. This review highlights some established and disputed sex differences in brain structure across the life span, as well as pitfalls related to interpreting sex differences in health and disease. We also describe sex-related findings from the ENIGMA consortium, and ongoing efforts to better understand sex differences in brain circuitry. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

  19. Increased Selenoprotein P in Choroid Plexus and Cerebrospinal Fluid in Alzheimer’s Disease Brain

    OpenAIRE

    Rueli, Rachel H.L.H.; Parubrub, Arlene C.; Dewing, Andrea S.T.; Hashimoto, Ann C.; Bellinger, Miyoko T.; Weeber, Edwin J.; Uyehara-Lock, Jane H.; White, Lon R.; Berry, Marla J.; Bellinger, Frederick P.

    2015-01-01

    Subjects with Alzheimer’s disease (AD) have elevated brain levels of the selenium transporter selenoprotein P (Sepp1). We investigated if this elevation results from increased release of Sepp1 from the choroid plexus (CP). Sepp1 is significantly increased in CP from AD brains in comparison to non-AD brains. Sepp1 localizes to the trans-Golgi network within CP epithelia, where it is processed for secretion. The cerebrospinal fluid from AD subjects also contains increased levels Sepp1 in compar...

  20. Copper pathology in vulnerable brain regions in Parkinson's disease. : Copper pathology in PD

    OpenAIRE

    Davies, Katherine,; Bohic, Sylvain; Carmona, Asunción; Ortega, Richard; Cottam, Veronica; Hare, Dominic,; Finberg, John,; Reyes, Stefanie; Halliday, Glenda; Mercer, Julian,; Double, Kay,

    2014-01-01

    International audience; Synchrotron-based x-ray fluorescence microscopy, immunofluorescence, and Western blotting were used to investigate changes in copper (Cu) and Cu-associated pathways in the vulnerable substantia nigra (SN) and locus coeruleus (LC) and in nondegenerating brain regions in cases of Parkinson's disease (PD) and appropriate healthy and disease controls. In PD and incidental Lewy body disease, levels of Cu and Cu transporter protein 1, were significantly reduced in surviving ...

  1. Pathways of Polyunsaturated Fatty Acid Utilization: Implications for Brain Function in Neuropsychiatric Health and Disease

    Science.gov (United States)

    Liu, Joanne J.; Green, Pnina; Mann, J. John; Rapoport, Stanley I.; Sublette, M. Elizabeth

    2014-01-01

    Essential polyunsaturated fatty acids (PUFAs) have profound effects on brain development and function. Abnormalities of PUFA status have been implicated in neuropsychiatric diseases such as major depression, bipolar disorder, schizophrenia, Alzheimer’s disease, and attention deficit hyperactivity disorder. Pathophysiologic mechanisms could involve not only suboptimal PUFA intake, but also metabolic and genetic abnormalities, defective hepatic metabolism, and problems with diffusion and transport. This article provides an overview of physiologic factors regulating PUFA utilization, highlighting their relevance to neuropsychiatric disease. PMID:25498862

  2. Brain expression genome-wide association study (eGWAS identifies human disease-associated variants.

    Directory of Open Access Journals (Sweden)

    Fanggeng Zou

    Full Text Available Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202 and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197. We conducted an expression genome-wide association study (eGWAS using 213,528 cisSNPs within ± 100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs significant in both ADs and non-ADs (q<0.05, p=7.70 × 10(-5-1.67 × 10(-82. Of these, 2,089 were also significant in the temporal cortex (p=1.85 × 10(-5-1.70 × 10(-141. The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10(-6. We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9-3.3 fold enrichment (p<10(-6 of significant cisSNPs with suggestive AD-risk association (p<10(-3 in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS and non-CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings

  3. Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Jean E. Vance

    2012-11-01

    Full Text Available Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer’s disease (AD, Huntington’s disease (HD, Parkinson’s disease (PD, Niemann-Pick type C (NPC disease and Smith-Lemli Opitz syndrome (SLOS. However, the molecular mechanisms underlying the correlation between altered cholesterol metabolism and the neurological deficits are, for the most part, not clear. NPC disease and SLOS are caused by mutations in genes involved in the biosynthesis or intracellular trafficking of cholesterol, respectively. However, the types of neurological impairments, and the areas of the brain that are most affected, differ between these diseases. Some, but not all, studies indicate that high levels of plasma cholesterol correlate with increased risk of developing AD. Moreover, inheritance of the E4 isoform of apolipoprotein E (APOE, a cholesterol-carrying protein, markedly increases the risk of developing AD. Whether or not treatment of AD with statins is beneficial remains controversial, and any benefit of statin treatment might be due to anti-inflammatory properties of the drug. Cholesterol balance is also altered in HD and PD, although no causal link between dysregulated cholesterol homeostasis and neurodegeneration has been established. Some important considerations for treatment of neurodegenerative diseases are the impermeability of the blood-brain barrier to many therapeutic agents and difficulties in reversing brain damage that has already occurred. This article focuses on how cholesterol balance in the brain is altered in several neurodegenerative diseases, and discusses some commonalities and differences among the diseases.

  4. Detection of Alzheimer’s disease amyloid-beta plaque deposition by deep brain impedance profiling

    Science.gov (United States)

    Béduer, Amélie; Joris, Pierre; Mosser, Sébastien; Fraering, Patrick C.; Renaud, Philippe

    2015-04-01

    Objective. Alzheimer disease (AD) is the most common form of neurodegenerative disease in elderly people. Toxic brain amyloid-beta (Aß) aggregates and ensuing cell death are believed to play a central role in the pathogenesis of the disease. In this study, we investigated if we could monitor the presence of these aggregates by performing in situ electrical impedance spectroscopy measurements in AD model mice brains. Approach. In this study, electrical impedance spectroscopy measurements were performed post-mortem in APPPS1 transgenic mice brains. This transgenic model is commonly used to study amyloidogenesis, a pathological hallmark of AD. We used flexible probes with embedded micrometric electrodes array to demonstrate the feasibility of detecting senile plaques composed of Aß peptides by localized impedance measurements. Main results. We particularly focused on deep brain structures, such as the hippocampus. Ex vivo experiments using brains from young and old APPPS1 mice lead us to show that impedance measurements clearly correlate with the percentage of Aβ plaque load in the brain tissues. We could monitor the effects of aging in the AD APPPS1 mice model. Significance. We demonstrated that a localized electrical impedance measurement constitutes a valuable technique to monitor the presence of Aβ-plaques, which is complementary with existing imaging techniques. This method does not require prior Aβ staining, precluding the risk of variations in tissue uptake of dyes or tracers, and consequently ensuring reproducible data collection.

  5. Neural Plasticity in Human Brain Connectivity: The Effects of Long Term Deep Brain Stimulation of the Subthalamic Nucleus in Parkinson’s Disease

    Science.gov (United States)

    van Hartevelt, Tim J.; Cabral, Joana; Deco, Gustavo; Møller, Arne; Green, Alexander L.; Aziz, Tipu Z.; Kringelbach, Morten L.

    2014-01-01

    Background Positive clinical outcomes are now well established for deep brain stimulation, but little is known about the effects of long-term deep brain stimulation on brain structural and functional connectivity. Here, we used the rare opportunity to acquire pre- and postoperative diffusion tensor imaging in a patient undergoing deep brain stimulation in bilateral subthalamic nuclei for Parkinson’s Disease. This allowed us to analyse the differences in structural connectivity before and after deep brain stimulation. Further, a computational model of spontaneous brain activity was used to estimate the changes in functional connectivity arising from the specific changes in structural connectivity. Results We found significant localised structural changes as a result of long-term deep brain stimulation. These changes were found in sensory-motor, prefrontal/limbic, and olfactory brain regions which are known to be affected in Parkinson’s Disease. The nature of these changes was an increase of nodal efficiency in most areas and a decrease of nodal efficiency in the precentral sensory-motor area. Importantly, the computational model clearly shows the impact of deep brain stimulation-induced structural alterations on functional brain changes, which is to shift the neural dynamics back towards a healthy regime. The results demonstrate that deep brain stimulation in Parkinson’s Disease leads to a topological reorganisation towards healthy bifurcation of the functional networks measured in controls, which suggests a potential neural mechanism for the alleviation of symptoms. Conclusions The findings suggest that long-term deep brain stimulation has not only restorative effects on the structural connectivity, but also affects the functional connectivity at a global level. Overall, our results support causal changes in human neural plasticity after long-term deep brain stimulation and may help to identify the underlying mechanisms of deep brain stimulation. PMID

  6. Neural plasticity in human brain connectivity: the effects of long term deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

    Science.gov (United States)

    van Hartevelt, Tim J; Cabral, Joana; Deco, Gustavo; Møller, Arne; Green, Alexander L; Aziz, Tipu Z; Kringelbach, Morten L

    2014-01-01

    Positive clinical outcomes are now well established for deep brain stimulation, but little is known about the effects of long-term deep brain stimulation on brain structural and functional connectivity. Here, we used the rare opportunity to acquire pre- and postoperative diffusion tensor imaging in a patient undergoing deep brain stimulation in bilateral subthalamic nuclei for Parkinson's Disease. This allowed us to analyse the differences in structural connectivity before and after deep brain stimulation. Further, a computational model of spontaneous brain activity was used to estimate the changes in functional connectivity arising from the specific changes in structural connectivity. We found significant localised structural changes as a result of long-term deep brain stimulation. These changes were found in sensory-motor, prefrontal/limbic, and olfactory brain regions which are known to be affected in Parkinson's Disease. The nature of these changes was an increase of nodal efficiency in most areas and a decrease of nodal efficiency in the precentral sensory-motor area. Importantly, the computational model clearly shows the impact of deep brain stimulation-induced structural alterations on functional brain changes, which is to shift the neural dynamics back towards a healthy regime. The results demonstrate that deep brain stimulation in Parkinson's Disease leads to a topological reorganisation towards healthy bifurcation of the functional networks measured in controls, which suggests a potential neural mechanism for the alleviation of symptoms. The findings suggest that long-term deep brain stimulation has not only restorative effects on the structural connectivity, but also affects the functional connectivity at a global level. Overall, our results support causal changes in human neural plasticity after long-term deep brain stimulation and may help to identify the underlying mechanisms of deep brain stimulation.

  7. Neuroenhancement: enhancing brain and mind in health and in disease.

    Science.gov (United States)

    Clark, Vincent P; Parasuraman, Raja

    2014-01-15

    Humans have long used cognitive enhancement methods to expand the proficiency and range of the various mental activities that they engage in, including writing to store and retrieve information, and computers that allow them to perform myriad activities that are now commonplace in the internet age. Neuroenhancement describes the use of neuroscience-based techniques for enhancing cognitive function by acting directly on the human brain and nervous system, altering its properties to increase performance. Cognitive neuroscience has now reached the point where it may begin to put theory derived from years of experimentation into practice. This special issue includes 16 articles that employ or examine a variety of neuroenhancement methods currently being developed to increase cognition in healthy people and in patients with neurological or psychiatric illness. This includes transcranial electromagnetic stimulation methods, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), along with deep brain stimulation, neurofeedback, behavioral training techniques, and these and other techniques in conjunction with neuroimaging. These methods can be used to improve attention, perception, memory and other forms of cognition in healthy individuals, leading to better performance in many aspects of everyday life. They may also reduce the cost, duration and overall impact of brain and mental illness in patients with neurological and psychiatric illness. Potential disadvantages of these techniques are also discussed. Given that the benefits of neuroenhancement outweigh the potential costs, these methods could potentially reduce suffering and improve quality of life for everyone, while further increasing our knowledge about the mechanisms of human cognition. © 2013. Published by Elsevier Inc. All rights reserved.

  8. Training-related brain plasticity in subjects at risk of developing Alzheimer's disease.

    Science.gov (United States)

    Belleville, Sylvie; Clément, Francis; Mellah, Samira; Gilbert, Brigitte; Fontaine, Francine; Gauthier, Serge

    2011-06-01

    Subjects with mild cognitive impairment are at risk of developing Alzheimer's disease. Cognitive stimulation is an emerging intervention in the field of neurology and allied sciences, having already been shown to improve cognition in subjects with mild cognitive impairment. Yet no studies have attempted to unravel the brain mechanisms that support such improvement. This study uses functional magnetic resonance imaging to measure the effect of memory training on brain activation in older adults with mild cognitive impairment and to assess whether it can reverse the brain changes associated with mild cognitive impairment. Brain activation associated with verbal encoding and retrieval was recorded twice prior to training and once after training. In subjects with mild cognitive impairment, increased activation was found after training within a large network that included the frontal, temporal and parietal areas. Healthy controls showed mostly areas of decreased activation following training. Comparison with pre-training indicated that subjects with mild cognitive impairment used a combination of specialized areas; that is, areas activated prior to training and new alternative areas activated following training. However, only activation of the right inferior parietal lobule, a new area of activation, correlated with performance. Furthermore, the differences between the brain activation patterns of subjects with mild cognitive impairment and those of healthy controls were attenuated by training in a number of brain regions. These results indicate that memory training can result in significant neural changes that are measurable with brain imaging. They also show that the brains of people with mild cognitive impairment remain highly plastic.

  9. Lymphatic drainage of the brain and the pathophysiology of neurological disease.

    Science.gov (United States)

    Weller, Roy O; Djuanda, Effie; Yow, Hong-Yeen; Carare, Roxana O

    2009-01-01

    There are no conventional lymphatics in the brain but physiological studies have revealed a substantial and immunologically significant lymphatic drainage from brain to cervical lymph nodes. Cerebrospinal fluid drains via the cribriform plate and nasal mucosa to cervical lymph nodes in rats and sheep and to a lesser extent in humans. More significant for a range of human neurological disorders is the lymphatic drainage of interstitial fluid (ISF) and solutes from brain parenchyma along capillary and artery walls. Tracers injected into grey matter, drain out of the brain along basement membranes in the walls of capillaries and cerebral arteries. Lymphatic drainage of antigens from the brain by this route may play a significant role in the immune response in virus infections, experimental autoimmune encephalomyelitis and multiple sclerosis. Neither antigen-presenting cells nor lymphocytes drain to lymph nodes by the perivascular route and this may be a factor in immunological privilege of the brain. Vessel pulsations appear to be the driving force for the lymphatic drainage along artery walls, and as vessels stiffen with age, amyloid peptides deposit in the drainage pathways as cerebral amyloid angiopathy (CAA). Blockage of lymphatic drainage of ISF and solutes from the brain by CAA may result in loss of homeostasis of the neuronal environment that may contribute to neuronal malfunction and dementia. Facilitating perivascular lymphatic drainage of amyloid-beta (Abeta) in the elderly may prevent the accumulation of Abeta in the brain, maintain homeostasis and provide a therapeutic strategy to help avert cognitive decline in Alzheimer's disease.

  10. Impact of congenital heart disease on brain development in newborn infants

    Directory of Open Access Journals (Sweden)

    Moustafa M Abdel Raheem

    2012-01-01

    Full Text Available Objective: To assess brain development and brain injury in neonates with cyanotic and acyanotic congenital heart disease (CHD. Methods: The study included 52 term infants with CHD who were divided into two groups: Cyanotic (n=21 and acyanotic (n=31. Fifteen healthy neonates of matched age and sex were enrolled in the study as controls. Three-dimensional proton magnetic resonance spectroscopic imaging and diffusion tensor imaging were used to assess brain development and injury. We calculated the ratio of N-acetylaspartate (NAA to choline (which increases with maturation, average diffusivity (which decreases with maturation, fractional anisotropy of white matter (which increases with maturation, and the ratio of lactate to choline (which increases with brain injury. Results: As compared with control neonates, those with CHD had significant decrease in NAA/choline ratio (P<0.001, significant increase in lactate/choline ratio (P<0.0001, significant increase in average diffusivity (P<0.0001, and significant decrease of white matter fractional anisotropy (P<0.001. Neonates with cyanotic CHD had significant less brain development and more brain injury than those with acyanotic CHD (P<0.05. Conclusions: Newborn infants with cyanotic and acyanotic CHD are at high risk of brain injury and impaired brain maturity.

  11. LIS1 and DCX: Implications for Brain Development and Human Disease in Relation to Microtubules

    Directory of Open Access Journals (Sweden)

    Orly Reiner

    2013-01-01

    Full Text Available Proper lamination of the cerebral cortex requires the orchestrated motility of neurons from their place of birth to their final destination. Improper neuronal migration may result in a wide range of diseases, including brain malformations, such as lissencephaly, mental retardation, schizophrenia, and autism. Ours and other studies have implicated that microtubules and microtubule-associated proteins play an important role in the regulation of neuronal polarization and neuronal migration. Here, we will review normal processes of brain development and neuronal migration, describe neuronal migration diseases, and will focus on the microtubule-associated functions of LIS1 and DCX, which participate in the regulation of neuronal migration and are involved in the human developmental brain disease, lissencephaly.

  12. Atrophy-specific MRI brain template for Alzheimer's disease and mild cognitive impairment

    DEFF Research Database (Denmark)

    Fonov, Vladimir; Coupe, Pierrick; Eskildsen, Simon Fristed

    and MCI makes use of a single disease-specific template challenging. We propose a novel approach to generate a continuous four-dimensional template, where the 4th dimension is a surrogate measure of overall brain atrophy. Methods We used MRI scans obtained from the ADNI database (www......Background Rapid brain loss is characteristic for the patients with mild cognitive impairment (MCI) and Alzheimer disease (AD) [1]. Increase of the lateral ventricular volume is strongly correlated with the progression of the disease. High variability in the degree of atrophy for subjects with AD.......loni.ucla.edu/ADNI). Automated methods to estimate intracranial capacity (ICC) and lateral ventricles volume (LVV) [2] was applied to all available datasets at base line. The ratio between LVV and ICC (RLVV) was used as a surrogate measure of overall brain atrophy with mean(standard deviation) value of 2.46(0.87)%. Subsets from...

  13. The effect of aging on brain barriers and the consequences for Alzheimer's disease development.

    Science.gov (United States)

    Gorlé, Nina; Van Cauwenberghe, Caroline; Libert, Claude; Vandenbroucke, Roosmarijn E

    2016-08-01

    Life expectancy has increased in most developed countries, which has led to an increase in the proportion of elderly people in the world's population. However, this increase in life expectancy is not accompanied by a lengthening of the health span since aging is characterized with progressive deterioration in cellular and organ functions. The brain is particularly vulnerable to disease, and this is reflected in the onset of age-related neurodegenerative diseases such as Alzheimer's disease. Research shows that dysfunction of two barriers in the central nervous system (CNS), the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB), plays an important role in the progression of these neurodegenerative diseases. The BBB is formed by the endothelial cells of the blood capillaries, whereas the BCSFB is formed by the epithelial cells of the choroid plexus (CP), both of which are affected during aging. Here, we give an overview of how these barriers undergo changes during aging and in Alzheimer's disease, thereby disturbing brain homeostasis. Studying these changes is needed in order to gain a better understanding of the mechanisms of aging at the brain barriers, which might lead to the development of new therapies to lengthen the health span (including mental health) and reduce the chances of developing Alzheimer's disease.

  14. Is art therapy a reliable tool for rehabilitating people suffering from brain/mental diseases?

    Science.gov (United States)

    Mirabella, Giovanni

    2015-04-01

    Whether art therapy can be an effective rehabilitative treatment for people with brain or mental diseases (e.g., dementia, Alzheimer's disease, Parkinson's disease, autism, schizophrenia) is a long-standing and highly debated issue. On the one hand, several observational studies and anecdotal evidence enthusiastically support the effectiveness of arts-based therapy. On the other hand, few rigorous clinical investigations have been performed, and there is too little empirical evidence to allow a full assessment of the risks and benefits of this intervention. Nevertheless, there is a progressively increasing demand for the development of appropriate complementary therapies to improve the personal and social lives of patients with neurodegenerative diseases. This is because conventional medical treatments are aimed at alleviating symptoms but cannot arrest or reverse the degenerative process. Thus, as disease progresses and adverse effects emerge, patients' quality of life dramatically decreases; when this occurs patients seek different forms of intervention. Art therapy is a potentially appealing treatment because of its more holistic approach to healthcare. However, as with any medicine, its effects must be tested by using standard, rigorous scientific approaches. This report describes the current state of research into art therapy and outlines many key factors that future research should consider, all of which are directly or indirectly related to the neural mechanism underlying behavioral changes: brain plasticity. Artistic performance could promote some form of brain plasticity that, to some extent, might compensate for the brain damage caused by the disease.

  15. Brain atrophy rates in Parkinson's disease with and without dementia using serial magnetic resonance imaging.

    Science.gov (United States)

    Burton, Emma J; McKeith, Ian G; Burn, David J; O'Brien, John T

    2005-12-01

    Increased rates of brain atrophy are seen in Alzheimer's disease, but whether rates are similarly increased in other dementias such as Parkinson's disease dementia (PDD) has not been well examined. We determined the rates of brain atrophy using serial magnetic resonance imaging (MRI) in PDD and compared this finding to rates seen in cognitively intact Parkinson's disease (PD) patients and age-matched control subjects. Thirty-one patients (PD = 18, PDD = 13) and 24 age-matched controls underwent serial volumetric 1.5 T MRI scans, approximately 1 year apart. Baseline and repeat scans were registered and quantification of the brain boundary shift integral was used to determine whole-brain atrophy rates. Rates of brain atrophy were significantly increased in PDD (1.12 +/- 0.98%/year) compared to PD (0.31 +/- 0.69%/year; P = 0.018) and control subjects (0.34 +/- 0.76%/year; P = 0.015). There were no differences in atrophy rates between controls and PD (P = 0.79). No correlations between increased atrophy rates and age or dementia severity (Mini-Mental State Examination score) were observed. Serial MRI may be a useful tool for monitoring disease progression in PDD and further studies should investigate its utility for early diagnosis.

  16. Blood N-terminal Pro-brain Natriuretic Peptide and Interleukin-17 for Distinguishing Incomplete Kawasaki Disease from Infectious Diseases.

    Science.gov (United States)

    Wu, Ling; Chen, Yuanling; Zhong, Shiling; Li, Yunyan; Dai, Xiahua; Di, Yazhen

    2015-06-01

    To explore the diagnostic value of blood N-terminal pro-brain natriuretic peptide (NT-proBNP) and interleukin-17(IL-17) for incomplete Kawasaki disease. Patients with Kawasaki disease, Incomplete Kawasaki disease and unclear infectious fever were included in this retrospective study. Their clinical features, and laboratory test results of blood NT-proBNP and IL-17 were collected and compared. 766 patients with complete clinical information were recruited, consisting of 291 cases of Kawasaki disease, 74 cases of incomplete Kawasaki disease, and 401 cases of unclear infectious diseases. When the consistency with indicator 2 and 3 in Kawasaki disease diagnosis criteria was assessed with blood IL-17 ?11.55 pg/mL and blood NT-proBNP ? 225.5 pg/dL as the criteria, the sensitivity and specificity for distinguishing incomplete Kawasaki disease and infectious diseases reached 86.5% and 94.8%, respectively. When we chose the consistency with indicator 1 and 2 in Kawasaki disease diagnosis criteria, the appearance of decrustation and/or the BCG erythema, blood IL-17 ?11.55 pg/mL and blood NT-Pro BNP ?225.5 pg/dL as the criteria, the sensitivity and specificity for distinguishing incomplete Kawasaki disease and infectious diseases was 43.2% and 100%, respectively. Blood NT-proBNP and IL-17 are useful laboratory indicators for distinguishing incomplete Kawasaki disease and infectious diseases at the early stage.

  17. Delta opioid receptors in brain function and diseases.

    Science.gov (United States)

    Chu Sin Chung, Paul; Kieffer, Brigitte L

    2013-10-01

    Evidence that the delta opioid receptor (DOR) is an attractive target for the treatment of brain disorders has strengthened in recent years. This receptor is broadly expressed in the brain, binds endogenous opioid peptides, and shows as functional profile highly distinct from those of mu and kappa opioid receptors. Our knowledge of DOR function has enormously progressed from in vivo studies using pharmacological tools and genetic approaches. The important role of this receptor in reducing chronic pain has been extensively overviewed; therefore this review focuses on facets of delta receptor activity relevant to psychiatric and other neurological disorders. Beneficial effects of DOR agonists are now well established in the context of emotional responses and mood disorders. DOR activation also regulates drug reward, inhibitory controls and learning processes, but whether delta compounds may represent useful drugs in the treatment of drug abuse remains open. Epileptogenic and locomotor-stimulating effects of delta agonists appear drug-dependent, and the possibility of biased agonism at DOR for these effects is worthwhile further investigations to increase benefit/risk ratio of delta therapies. Neuroprotective effects of DOR activity represent a forthcoming research area. Future developments in DOR research will benefit from in-depth investigations of DOR function at cellular and circuit levels. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies

    Science.gov (United States)

    Head, Elizabeth; Schmitt, Frederick A.; Davis, Paulina R.; Neltner, Janna H.; Jicha, Gregory A.; Abner, Erin L.; Smith, Charles D.; Van Eldik, Linda J.; Kryscio, Richard J.; Scheff, Stephen W.

    2011-01-01

    Human studies are reviewed concerning whether “aging”-related mechanisms contribute to Alzheimer’s disease (AD) pathogenesis. AD is defined by specific neuropathology: neuritic amyloid plaques and neocortical neurofibrillary tangles. AD pathology is driven by genetic factors related not to aging per se, but instead to the amyloid precursor protein (APP). In contrast to genes involved in APP-related mechanisms, there is no firm connection between genes implicated in human “accelerated aging” diseases (progerias) and AD. The epidemiology of AD in advanced age is highly relevant but deceptively challenging to address given the low autopsy rates in most countries. In extreme old age, brain diseases other than AD approximate AD prevalence while the impact of AD pathology appears to peak by age 95 and decline thereafter. Many distinct brain diseases other than AD afflict older human brains and contribute to cognitive impairment. Additional prevalent pathologies include cerebrovascular disease and hippocampal sclerosis, both high-morbidity brain diseases that appear to peak in incidence later than AD chronologically. Because of these common brain diseases of extreme old age, the epidemiology differs between clinical “dementia” and the subset of dementia cases with AD pathology. Additional aging-associated mechanisms for cognitive decline such as diabetes and synapse loss have been linked to AD and these hypotheses are discussed. Criteria are proposed to define an “aging-linked” disease, and AD fails all of these criteria. In conclusion, it may be most fruitful to focus attention on specific pathways involved in AD rather than attributing it to an inevitable consequence of aging. PMID:21516511

  19. Autosomal dominant polycystic kidney disease and the heart and brain.

    Science.gov (United States)

    Krishnappa, Vinod; Vinod, Poornima; Deverakonda, Divya; Raina, Rupesh

    2017-06-01

    Autosomal dominant polycystic kidney disease (ADPKD) has numerous systemic manifestations and complications. This article gives an overview of hypertension, cardiac complications, and intracranial aneurysms in ADPKD, their pathophysiology, and recent developments in their management. Copyright © 2017 Cleveland Clinic.

  20. Brain-water diffusion coefficients reflect the severity of inherited prion disease

    Science.gov (United States)

    Hyare, H.; Wroe, S.; Siddique, D.; Webb, T.; Fox, N. C.; Stevens, J.; Collinge, J.; Yousry, T.; Thornton, J. S.

    2010-01-01

    Objective: Inherited prion diseases are progressive neurodegenerative conditions, characterized by cerebral spongiosis, gliosis, and neuronal loss, caused by mutations within the prion protein (PRNP) gene. We wished to assess the potential of diffusion-weighted MRI as a biomarker of disease severity in inherited prion diseases. Methods: Twenty-five subjects (mean age 45.2 years) with a known PRNP mutation including 19 symptomatic patients, 6 gene-positive asymptomatic subjects, and 7 controls (mean age 54.1 years) underwent conventional and diffusion-weighted MRI. An index of normalized brain volume (NBV) and region of interest (ROI) mean apparent diffusion coefficient (ADC) for the head of caudate, putamen, and pulvinar nuclei were recorded. ADC histograms were computed for whole brain (WB) and gray matter (GM) tissue fractions. Clinical assessment utilized standardized clinical scores. Mann-Whitney U test and regression analyses were performed. Results: Symptomatic patients exhibited an increased WB mean ADC (p = 0.006) and GM mean ADC (p = 0.024) compared to controls. Decreased NBV and increased mean ADC measures significantly correlated with clinical measures of disease severity. Using a stepwise multivariate regression procedure, GM mean ADC was an independent predictor of Clinician's Dementia Rating score (p = 0.001), Barthel Index of activities of daily living (p = 0.001), and Rankin disability score (p = 0.019). Conclusions: Brain volume loss in inherited prion diseases is accompanied by increased cerebral apparent diffusion coefficient (ADC), correlating with increased disease severity. The association between gray matter ADC and clinical neurologic status suggests this measure may prove a useful biomarker of disease activity in inherited prion diseases. GLOSSARY ADAS-Cog = Alzheimer's Disease Assessment Scale–Cognitive subscale; ADC = apparent diffusion coefficient; ADL = Barthel Activities of Daily Living scale; BET = brain extraction tool; BPRS

  1. Nicotinamide phosphoribosyltransferase may be involved in age-related brain diseases.

    Directory of Open Access Journals (Sweden)

    Li-Ying Liu

    Full Text Available Nicotinamide phosphoribosyltransferase (NAMPT is a key enzyme for nicotinamide adenine dinucleotide (NAD biosynthesis, and can be found either intracellularly (iNAMPT or extracellularly (eNAMPT. Studies have shown that both iNAMPT and eNAMPT are implicated in aging and age-related diseases/disorders in the peripheral system. However, their functional roles in aged brain remain to be established. Here we showed that upon aging, NAMPT level increased in serum but decreased in brain, decreased in cortex and hippocampus but remained unchanged in cerebellum and striatum in brain, and increased in microglia but likely decreased in neuron. Accordingly, total NAD (tNAD level significantly decreased in hippocampus, cerebellum and striatum in aged brain. Application of recombinant NAMPT, mimicking the elevated serum NAMPT level, enhanced the susceptibility of cerebral endothelial cells to ischemic injury, while inhibition of iNAMPT by FK866, a specific inhibitor, reduced intracellular NAD level and induced neuronal death. Taken together, we have revealed a region- and cell-specific change of NAMPT level in brain and serum upon aging, deduced its potential consequences, which suggests that NAMPT is a regulatory factor in aging and age-related brain diseases.

  2. Automatic detection of the hippocampal region associated with Alzheimer's disease from microscopic images of mice brain

    Science.gov (United States)

    Albaidhani, Tahseen; Hawkes, Cheryl; Jassim, Sabah; Al-Assam, Hisham

    2016-05-01

    The hippocampus is the region of the brain that is primarily associated with memory and spatial navigation. It is one of the first brain regions to be damaged when a person suffers from Alzheimer's disease. Recent research in this field has focussed on the assessment of damage to different blood vessels within the hippocampal region from a high throughput brain microscopic images. The ultimate aim of our research is the creation of an automatic system to count and classify different blood vessels such as capillaries, veins, and arteries in the hippocampus region. This work should provide biologists with efficient and accurate tools in their investigation of the causes of Alzheimer's disease. Locating the boundary of the Region of Interest in the hippocampus from microscopic images of mice brain is the first essential stage towards developing such a system. This task benefits from the variation in colour channels and texture between the two sides of the hippocampus and the boundary region. Accordingly, the developed initial step of our research to locating the hippocampus edge uses a colour-based segmentation of the brain image followed by Hough transforms on the colour channel that isolate the hippocampus region. The output is then used to split the brain image into two sides of the detected section of the boundary: the inside region and the outside region. Experimental results on a sufficiently number of microscopic images demonstrate the effectiveness of the developed solution.

  3. Quantifying structural alterations in Alzheimer's disease brains using quantitative phase imaging (Conference Presentation)

    Science.gov (United States)

    Lee, Moosung; Lee, Eeksung; Jung, JaeHwang; Yu, Hyeonseung; Kim, Kyoohyun; Yoon, Jonghee; Lee, Shinhwa; Jeong, Yong; Park, YongKeun

    2017-02-01

    Imaging brain tissues is an essential part of neuroscience because understanding brain structure provides relevant information about brain functions and alterations associated with diseases. Magnetic resonance imaging and positron emission tomography exemplify conventional brain imaging tools, but these techniques suffer from low spatial resolution around 100 μm. As a complementary method, histopathology has been utilized with the development of optical microscopy. The traditional method provides the structural information about biological tissues to cellular scales, but relies on labor-intensive staining procedures. With the advances of illumination sources, label-free imaging techniques based on nonlinear interactions, such as multiphoton excitations and Raman scattering, have been applied to molecule-specific histopathology. Nevertheless, these techniques provide limited qualitative information and require a pulsed laser, which is difficult to use for pathologists with no laser training. Here, we present a label-free optical imaging of mouse brain tissues for addressing structural alteration in Alzheimer's disease. To achieve the mesoscopic, unlabeled tissue images with high contrast and sub-micrometer lateral resolution, we employed holographic microscopy and an automated scanning platform. From the acquired hologram of the brain tissues, we could retrieve scattering coefficients and anisotropies according to the modified scattering-phase theorem. This label-free imaging technique enabled direct access to structural information throughout the tissues with a sub-micrometer lateral resolution and presented a unique means to investigate the structural changes in the optical properties of biological tissues.

  4. A Search for Mitochondrial Damage in Alzheimer's Disease Using Isolated Rat Brain Mitochondria.

    Science.gov (United States)

    Faizi, Mehrdad; Seydi, Enayatollah; Abarghuyi, Sadegh; Salimi, Ahmad; Nasoohi, Sanaz; Pourahmad, Jalal

    2016-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects regions of the brain that control cognition, memory, language, speech and awareness to one's physical surroundings. The pathological initiation and progression of AD is highly complex and its prevalence is on the rise. In his study, Alzheimer's disease was induced with single injection of amyloid-β (Aβ) peptides (30ng, by stereotaxy) in each hemisphere of the Wistar rat brain. Then memory dysfunction, oxidative stress and apoptosis induced by Aβ peptide were investigated on isolated brain mitochondria obtained from infected rat. Our results showed memory impairment in rats after receiving an Aβ peptide. We also found significant rise (Pmitochondrial membrane depolarization, mitochondria swelling, cytochrome c release and significant decrease in ATP/ADP ratio on mitochondria isolated from brain of these memory impaired rats compared with those of untreated control rat group. Activation of caspase-3 the final mediator of apoptosis in the brain homogenate of the memory impaired rats was another justification for occurrence of neuron loss in the experimental model of AD. Our results suggest that oxidative stress and mitochondria mediated apoptosis in brain neurons play very important role in initiation of AD.

  5. Exercise Regulation of Cognitive Function and Neuroplasticity in the Healthy and Diseased Brain.

    Science.gov (United States)

    Hamilton, Gilian F; Rhodes, Justin S

    2015-01-01

    Regular exercise broadly enhances physical and mental health throughout the lifespan. Animal models have provided us with the tools to gain a better understanding of the underlying biochemical, physiological, and morphological mechanisms through which exercise exerts its beneficial cognitive effects. One brain region in particular, the hippocampus, is especially responsive to exercise. It is critically involved in learning and memory and is one of two regions in the mammalian brain that continues to generate new neurons throughout life. Exercise prevents the decline of the hippocampus from aging and ameliorates many neurodegenerative diseases, in part by increasing adult hippocampal neurogenesis but also by activating a multitude of molecular mechanisms that promote brain health. In this chapter, we first describe some rodent models used to study effects of exercise on the brain. Then we review the rodent work focusing on the mechanisms behind which exercise improves cognition and brain health in both the normal and the diseased brain, with emphasis on the hippocampus. © 2015 Elsevier Inc. All rights reserved.

  6. Gut-brain and brain-gut axis in Parkinson's disease models: Effects of a uridine and fish oil diet.

    Science.gov (United States)

    Perez-Pardo, Paula; Dodiya, Hemraj B; Broersen, Laus M; Douna, Hidde; van Wijk, Nick; Lopes da Silva, Sofia; Garssen, Johan; Keshavarzian, Ali; Kraneveld, Aletta D

    2017-03-09

    Recent investigations have focused on the potential role of gastrointestinal (GI) abnormalities in the pathogenesis of Parkinson's disease (PD). The 'dual-hit' hypothesis of PD speculates that a putative pathogen enters the brain via two routes: the olfactory system and the GI system. Here, we investigated (1) whether local exposures of the neurotoxin rotenone in the gut or the brain of mice could induce PD-like neurological and GI phenotypes as well as a characteristic neuropathology in accordance with this 'dual-hit hypothesis' and (2) the effects of a diet containing uridine and fish oil providing docosahexaenoic acid (DHA), in both models. Mice were given rotenone either orally or by an injection in the striatum. Dietary interventions were started 1 week before rotenone exposures. We found that (1) both oral and intrastriatal administration of rotenone induced similar PD-like motor deficits, dopaminergic cell loss, delayed intestinal transit, inflammation, and alpha-synuclein accumulation in the colon; (2) the uridine and DHA containing diet prevented rotenone-induced motor and GI dysfunctions in both models. The models suggest possible bidirectional communication between the gut and the brain for the genesis of PD-like phenotype and pathology. The dietary intervention may provide benefits in the prevention of motor and non-motor symptoms in PD.

  7. Brain copper, iron, magnesium, zinc, calcium, sulfur and phosphorus storage in Wilson's disease.

    Science.gov (United States)

    Faa, G; Lisci, M; Caria, M P; Ambu, R; Sciot, R; Nurchi, V M; Silvagni, R; Diaz, A; Crisponi, G

    2001-01-01

    Wilson's disease (WD) is an inherited disorder of copper metabolism characterised by juvenile liver cirrhosis and by neurological symptoms. Copper levels in brain in WD have been reported to be 10 to 15 fold normal values, depending on the different brain regions. Being very few data on copper distribution in central nervous system in WD available, it seemed of interest to study the concentration of copper and of other trace elements (Zn, P, Mg, Ca, Fe and S) in the brain of a patient died for WD. a 56 year old woman affected by WD was admitted to our hospital with signs of hepatic failure and died few days later. At autopsy, a brain slice extending from the left to the right hemisphere was divided in 28 samples. On each sample Copper, Iron, Magnesium, Phosphorus, Sulphur, Zinc and Calcium were determined by Induced Coupled Plasma Atomic Emission Spectroscopy. the mean concentration of copper, ranging from 88 to 158 microg/g of dry tissue in all the brain specimens was higher than literature reference values, while that of the other tested elements was considerably lower. 1) In the brain of WD patient examined the status of trace elements was extensively altered. Further studies are necessary to correlate the concentration of trace elements with pathological lesions and with clinical pictures. 2) The elements considered in our study showed an uneven distribution in different brain areas.

  8. Natural distribution of environmental radon daughters in the different brain areas of an Alzheimer Disease victim

    Directory of Open Access Journals (Sweden)

    Momčilović Berislav

    2006-09-01

    Full Text Available Abstract Background Radon is a ubiquitous noble gas in the environment and a primary source of harmful radiation exposure for humans; it decays in a cascade of daughters (RAD by releasing the cell damaging high energy alpha particles. Results We studied natural distribution of RAD 210Po and 210Bi in the different parts of the postmortem brain of 86-year-old woman who had suffered from Alzheimer's disease (AD. A distinct brain map emerged, since RAD distribution was different among the analyzed brain areas. The highest RAD irradiation (mSv·year-1 occurred in the decreasing order of magnitude: amygdale (Amy >> hippocampus (Hip > temporal lobe (Tem ~ frontal lobe (Fro > occipital lobe (Occ ~ parietal lobe (Par > substantia nigra (SN >> locus ceruleus (LC ~ nucleus basalis (NB; generally more RAD accumulated in the proteins than lipids of gray and white (gray > white brain matter. Amy and Hip are particularly vulnerable brain structure targets to significant RAD internal radiation damage in AD (5.98 and 1.82 mSv·year-1, respectively. Next, naturally occurring RAD radiation for Tem and Fro, then Occ and Par, and SN was an order of magnitude higher than that in LC and NB; the later was within RAD we observed previously in the healthy control brains. Conclusion Naturally occurring environmental RAD exposure may dramatically enhance AD deterioration by selectively targeting brain areas of emotions (Amy and memory (Hip.

  9. Integrating Health Promotion Into Physical Therapy Practice to Improve Brain Health and Prevent Alzheimer Disease.

    Science.gov (United States)

    McGough, Ellen; Kirk-Sanchez, Neva; Liu-Ambrose, Teresa

    2017-07-01

    Alzheimer disease is the most common cause of dementia, and brain pathology appears years before symptoms are evident. Primary prevention through health promotion can incorporate lifestyle improvement across the lifespan. Risk factor assessment and identifying markers of disease might also trigger preventive measures needed for high-risk individuals and groups. Many potential risk factors are modifiable through exercise, and may be responsive to early intervention strategies to reduce the downward slope toward disability. Through the use of common clinical tests to identify cognitive and noncognitive functional markers of disease, detection and intervention can occur at earlier stages, including preclinical stages of disease. Physical activity and exercise interventions to address modifiable risk factors and impairments can play a pivotal role in the prevention and delay of functional decline, ultimately reducing the incidence of dementia. This article discusses prevention, prediction, plasticity, and participation in the context of preserving brain health and preventing Alzheimer disease and related dementias in aging adults. Rehabilitation professionals have opportunities to slow disease progression through research, practice, and education initiatives. From a clinical perspective, interventions that target brain health through lifestyle changes and exercise interventions show promise for preventing stroke and associated neurovascular diseases in addition to dementia. Physical therapists are well positioned to integrate primary health promotion into practice for the prevention of dementia and other neurological conditions in older adults.

  10. Nano-enabled drug delivery systems for brain cancer and Alzheimer's disease: research patterns and opportunities.

    Science.gov (United States)

    Ma, Jing; Porter, Alan L; Aminabhavi, Tejraj M; Zhu, Donghua

    2015-10-01

    "Tech mining" applies bibliometric and text analytic methods to scientific literature of a target field. In this study, we compare the evolution of nano-enabled drug delivery (NEDD) systems for two different applications - viz., brain cancer (BC) and Alzheimer's disease (AD) - using this approach. In this process, we derive research intelligence from papers indexed in MEDLINE. Review by domain specialists helps understand the macro-level disease problems and pathologies to identify commonalities and differences between BC and AD. Results provide a fresh perspective on the developmental pathways for NEDD approaches that have been used in the treatment of BC and AD. Results also point toward finding future solutions to drug delivery issues that are critical to medical practitioners and pharmaceutical scientists addressing the brain. Drug delivery to brain cells has been very challenging due to the presence of the blood-brain barrier (BBB). Suitable and effective nano-enabled drug delivery (NEDD) system is urgently needed. In this study, the authors utilized "tech-mining" tools to describe and compare various choices of delivery system available for the diagnosis, as well as treatment, of brain cancer and Alzheimer's disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Gut-brain actions underlying comorbid anxiety and depression associated with inflammatory bowel disease.

    Science.gov (United States)

    Abautret-Daly, Áine; Dempsey, Elaine; Parra-Blanco, Adolfo; Medina, Carlos; Harkin, Andrew

    2017-03-08

    Introduction Inflammatory bowel disease (IBD) is a chronic relapsing and remitting disorder characterised by inflammation of the gastrointestinal tract. There is a growing consensus that IBD is associated with anxiety- and depression-related symptoms. Psychological symptoms appear to be more prevalent during active disease states with no difference in prevalence between Crohn's disease and ulcerative colitis. Behavioural disturbances including anxiety- and depression-like symptoms have also been observed in animal models of IBD. The likely mechanisms underlying the association are discussed with particular reference to communication between the gut and brain. The close bidirectional relationship known as the gut-brain axis includes neural, hormonal and immune communication links. Evidence is provided for a number of interacting factors including activation of the inflammatory response system in the brain, the hypothalamic-pituitary-adrenal axis, and brain areas implicated in altered behaviours, changes in blood brain barrier integrity, and an emerging role for gut microbiota and response to probiotics in IBD. Discussion The impact of psychological stress in models of IBD remains somewhat conflicted, however, it is weighted in favour of stress or early stressful life events as risk factors in the development of IBD, stress-induced exacerbation of inflammation and relapse. It is recommended that patients with IBD be screened for psychological disturbance and treated accordingly as intervention can improve quality of life and may reduce relapse rates.

  12. Increased Selenoprotein P in Choroid Plexus and Cerebrospinal Fluid in Alzheimer’s Disease Brain

    Science.gov (United States)

    Rueli, Rachel H.L.H.; Parubrub, Arlene C.; Dewing, Andrea S.T.; Hashimoto, Ann C.; Bellinger, Miyoko T.; Weeber, Edwin J.; Uyehara-Lock, Jane H.; White, Lon R.; Berry, Marla J.; Bellinger, Frederick P.

    2015-01-01

    Subjects with Alzheimer’s disease (AD) have elevated brain levels of the selenium transporter selenoprotein P (Sepp1). We investigated if this elevation results from increased release of Sepp1 from the choroid plexus (CP). Sepp1 is significantly increased in CP from AD brains in comparison to non-AD brains. Sepp1 localizes to the trans-Golgi network within CP epithelia, where it is processed for secretion. The cerebrospinal fluid from AD subjects also contains increased levels Sepp1 in comparison to non-AD subjects. These findings suggest that AD pathology induces increased levels of Sepp1 within CP epithelia for release into the cerebrospinal fluid to ultimately increase brain selenium. PMID:25298198

  13. Demyelinating and ischemic brain diseases: detection algorithm through regular magnetic resonance images

    Science.gov (United States)

    Castillo, D.; Samaniego, René; Jiménez, Y.; Cuenca, L.; Vivanco, O.; Rodríguez-Álvarez, M. J.

    2017-09-01

    This work presents the advance to development of an algorithm for automatic detection of demyelinating lesions and cerebral ischemia through magnetic resonance images, which have contributed in paramount importance in the diagnosis of brain diseases. The sequences of images to be used are T1, T2, and FLAIR. Brain demyelination lesions occur due to damage of the myelin layer of nerve fibers; and therefore this deterioration is the cause of serious pathologies such as multiple sclerosis (MS), leukodystrophy, disseminated acute encephalomyelitis. Cerebral or cerebrovascular ischemia is the interruption of the blood supply to the brain, thus interrupting; the flow of oxygen and nutrients needed to maintain the functioning of brain cells. The algorithm allows the differentiation between these lesions.

  14. Foundation for PSP/CBD and Related Brain Diseases

    Science.gov (United States)

    ... Care Where It Counts When disease leads to disability, patients and their caregivers can become painfully isolated. Homebound patients without access to the expert care that can offer both symptomatic relief and psychosocial support tend to be much more frequently hospitalized ...

  15. Targeting the Gut-Brain axis in Parkinson's disease

    NARCIS (Netherlands)

    Perez Pardo, P.|info:eu-repo/dai/nl/338040900

    2017-01-01

    Parkinson’s disease (PD) is the most common progressive movement disorder, with increasing age being the greatest risk factor for its development. PD is hallmarked by the progressive degeneration of dopaminergic nigrostriatal neurons, with reductions in striatal dopamine levels resulting in the

  16. Altered subcellular localization of ornithine decarboxylase in Alzheimer's disease brain

    DEFF Research Database (Denmark)

    Nilsson, Tatjana; Bogdanovic, Nenad; Volkman, Inga

    2006-01-01

    The amyloid precursor protein can through ligand-mimicking induce expression of ornithine decarboxylase (ODC), the initial and rate-limiting enzyme in polyamine biosynthesis. We report here the regional distribution and cellular localization of ODC immunoreactivity in Alzheimer's disease (AD...

  17. Parkinson's disease progression at 30 years: a study of subthalamic deep brain-stimulated patients.

    Science.gov (United States)

    Merola, Aristide; Zibetti, Maurizio; Angrisano, Serena; Rizzi, Laura; Ricchi, Valeria; Artusi, Carlo A; Lanotte, Michele; Rizzone, Mario G; Lopiano, Leonardo

    2011-07-01

    Clinical findings in Parkinson's disease suggest that most patients progressively develop disabling non-levodopa-responsive symptoms during the course of the disease. Nevertheless, several heterogeneous factors, such as clinical phenotype, age at onset and genetic aspects may influence the long-term clinical picture. In order to investigate the main features of long-term Parkinson's disease progression, we studied a cohort of 19 subjects treated with subthalamic nucleus deep brain stimulation after >20 years of disease, reporting clinical and neuropsychological data up to a mean of 30 years from disease onset. This group of patients was characterized by an early onset of disease, with a mean age of 38.63 years at Parkinson's disease onset, which was significantly lower than in the other long-term subthalamic nucleus deep brain stimulation follow-up cohorts reported in the literature. All subjects were regularly evaluated by a complete Unified Parkinson's Disease Rating Scale, a battery of neuropsychological tests and a clinical interview, intended to assess the rate of non-levodopa-responsive symptom progression. Clinical data were available for all patients at presurgical baseline and at 1, 3 and 5 years from the subthalamic nucleus deep brain stimulation surgical procedure, while follow-up data after >7 years were additionally reported in a subgroup of 14 patients. The clinical and neuropsychological performance progressively worsened during the course of follow-up; 64% of patients gradually developed falls, 86% dysphagia, 57% urinary incontinence and 43% dementia. A progressive worsening of motor symptoms was observed both in 'medication-ON' condition and in 'stimulation-ON' condition, with a parallel reduction in the synergistic effect of 'medication-ON/stimulation-ON' condition. Neuropsychological data also showed a gradual decline in the performances of all main cognitive domains, with an initial involvement of executive functions, followed by the impairment

  18. Midbrain morphology reflects extent of brain damage in Krabbe disease

    Energy Technology Data Exchange (ETDEWEB)

    Zuccoli, Giulio; Narayanan, Srikala; Panigrahy, Ashok [Children' s Hospital of Pittsburgh of University of Pittsburgh Medical Center, Section of Neuroradiology, Pittsburgh, PA (United States); Poe, Michele D.; Escolar, Maria L. [University of Pittsburgh, Program for the Study of Neurodevelopment in Rare Disorders, Children' s Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA (United States)

    2015-07-15

    To study the relationships between midbrain morphology, Loes score, gross motor function, and cognitive function in infantile Krabbe disease. Magnetic resonance imaging (MRI) scans were evaluated by two neuroradiologists blinded to clinical status and neurodevelopmental function of children with early or late infantile Krabbe disease. A simplified qualitative 3-point scoring system based on midbrain morphology on midsagittal MRI was used. A score of 0 represented normal convex morphology of the midbrain, a score of 1 represented flattening of the midbrain, and a score of 3 represented concave morphology of the midbrain (hummingbird sign). Spearman correlations were estimated between this simplified MRI scoring system and the Loes score, gross motor score, and cognitive score. Forty-two MRIs of 27 subjects were reviewed. Analysis of the 42 scans showed normal midbrain morphology in 3 (7.1 %) scans, midbrain flattening in 11 (26.2 %) scans, and concave midbrain morphology (hummingbird sign) in 28 (66.7 %) scans. Midbrain morphology scores were positively correlated with the Loes score (r = 0.81, p < 0.001) and negatively correlated with both gross motor and cognitive scores (r = -.84, p < 0.001; r = -0.87, p < 0.001, respectively). The inter-rater reliability for the midbrain morphology scale was κ =.95 (95 % CI: 0.86-1.0), and the inter-rater reliability for the Loes scale was κ =.58 (95 % CI: 0.42-0.73). Midbrain morphology scores of midsagittal MRI images correlates with cognition and gross motor function in children with Krabbe disease. This MRI scoring system represents a simple but reliable method to assess disease progression in patients with infantile Krabbe disease. (orig.)

  19. The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease.

    Science.gov (United States)

    Sundman, Mark H; Chen, Nan-Kuei; Subbian, Vignesh; Chou, Ying-Hui

    2017-11-01

    As head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral

  20. Whole-brain atrophy differences between progressive supranuclear palsy and idiopathic Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Carlos Guevara

    2016-09-01

    Full Text Available Background: The absence of markers for ante-mortem diagnosis of progressive supranuclear palsy (PSP results in this disorder’s being commonly mistaken for other conditions, such as idiopathic Parkinson's disease (IPD. Such mistakes occur particularly in the initial stages, when ‘plus syndrome’ has not yet clinically emerged.Objective. To investigate global brain volume and tissue loss in patients with PSP relative to patients with IPD and healthy controls and correlations between clinical parameters and magnetic resonance imaging (MRI-derived brain volume estimates.Methods: T1-weighted images were obtained from three groups of Chilean Latin American adults: 21 patients with IPD, 18 patients with PSP and 14 healthy controls. We used Structural Imaging Evaluation with Normalization of Atrophy (SIENAX to assess white matter, gray matter and whole-brain volumes (normalized to cranial volume. Imaging data were used to analyze putative correlations with the clinical status of PSP and IPD patients using the Unified Parkinson’s Disease Rating Scale Part III, Hoehn and Yahr, the Clinical Global Impression for Disease Severity Scale and the Frontal Assessment Battery.Results: PSP patients had significantly lower whole brain volume than both IPD patients and controls. Whole brain volume reduction in PSP patients was primarily attributable to gray matter volume reduction. We found a significant correlation between brain volume reduction and clinical status in the PSP group.Conclusions: At the group level, whole brain and gray matter volumes differentiated patients with PSP from patients with IPD. There was also significant clinical-imaging correlations with motor disturbances in PSP.

  1. Brain region's relative proximity as marker for Alzheimer's disease based on structural MRI

    DEFF Research Database (Denmark)

    Erleben, Lene Lillemark; Sørensen, Lauge Emil; Pai, Akshay Sadananda Uppinakudru

    2014-01-01

    brain structures like hippocampus, this paper investigates the relationship and proximity between regions in the brain and uses this information as a novel way of classifying normal control (NC), mild cognitive impaired (MCI), and AD subjects.METHODS:A longitudinal cohort of 528 subjects (170 NC, 240......BACKGROUND:Alzheimer's disease (AD) is a progressive, incurable neurodegenerative disease and the most common type of dementia. It cannot be prevented, cured or drastically slowed, even though AD research has increased in the past 5-10 years. Instead of focusing on the brain volume or on the single...... MCI, and 114 AD) from ADNI at baseline and month 12 was studied. We investigated a marker based on Procrustes aligned center of masses and the percentile surface connectivity between regions. These markers were classified using a linear discriminant analysis in a cross validation setting and compared...

  2. Eyes-closed task-free electroencephalography in clinical trials for Alzheimer's disease: an emerging method based upon brain dynamics

    NARCIS (Netherlands)

    van Straaten, E.C.W.; Scheltens, P.; Gouw, A.A.; Stam, C.J.

    2014-01-01

    Electroencephalography (EEG) is a longstanding technique to measure electrical brain activity and thereby an indirect measure of synaptic activity. Synaptic dysfunction accompanies Alzheimer's disease (AD) and EEG can be regarded as a potentially useful biomarker in this disease. Lately, emerging

  3. Evidence for enhanced aluminum concentration in brain tissue from Alzheimer's disease patients using PIXE

    Science.gov (United States)

    Debray, M. E.; Kreiner, A. J.; Buhler, M.; Cardona, M. A.; Hojman, D.; Kesque, J. M.; Levinton, G.; Menéndez, J. J.; Naab, F.; Ozafrán, M. J.; Somacal, H.; Vázquez, M. E.; Grahmann, H.; Davidson, M.; Davidson, J.; Levin, M. E.; Mangone, C. A.; Caccuri, R. L.; Tokuda, A.; Eurnekian, A. A.; González, D.; López, C.; Roses, O. E.

    1997-02-01

    The Particle Induced X-Ray Emission (PIXE) analytical technique with 16O ion beams (18 MeV) was applied to the study of elemental composition at different brain regions of patients with a confirmed post-mortem diagnosis of Alzheimer's disease and in samples from control subjects. The results obtained in the actual study show a clear correlation between occurrence of Alzheimer's disease and the presence and increased concentration of aluminum (Al).

  4. Asymptomatic Brain Lesions on Cranial Magnetic Resonance Imaging in Inflammatory Bowel Disease

    OpenAIRE

    Dolapcioglu, Can; Guleryuzlu, Yuksel; Uygur-Bayramicli, Oya; Ahishali, Emel; Dabak, Resat

    2013-01-01

    Background/Aims This study aimed to examine the frequency and type of asymptomatic neurological involvement in inflammatory bowel disease (IBD) using cranial magnetic resonance imaging (MRI). Methods Fifty-one IBD patients with no known neurological diseases or symptoms and 30 controls with unspecified headaches without neurological origins were included. Patients and controls underwent cranial MRI assessments for white matter lesions, sinusitis, otitis-mastoiditis, and other brain parenchyma...

  5. Amyloid-β Annular Protofibrils Evade Fibrillar Fate in Alzheimer Disease Brain*♦

    OpenAIRE

    Lasagna-Reeves, Cristian A; Charles G Glabe; Kayed, Rakez

    2011-01-01

    Annular protofibrils (APFs) represent a new and distinct class of amyloid structures formed by disease-associated proteins. In vitro, these pore-like structures have been implicated in membrane permeabilization and ion homeostasis via pore formation. Still, evidence for their formation and relevance in vivo is lacking. Herein, we report that APFs are in a distinct pathway from fibril formation in vitro and in vivo. In human Alzheimer disease brain samples, amyloid-β APFs were associated with ...

  6. Decreased alternative splicing of estrogen receptor-α mRNA in the Alzheimer's disease brain

    NARCIS (Netherlands)

    Ishunina, Tatjana A.; Swaab, Dick F.

    2012-01-01

    In this study we identified 62 estrogen receptor alpha (ERα) mRNA splice variants in different human brain areas of Alzheimer's disease (AD) and control cases and classified them into 12 groups. Forty-eight of these splice forms were identified for the first time. The distribution of alternatively

  7. The modulatory effect of adaptive deep brain stimulation on beta bursts in Parkinson's disease

    NARCIS (Netherlands)

    Tinkhauser, Gerd; Pogosyan, Alek; Little, Simon; Beudel, Martijn; Herz, Damian M.; Tan, Huiling; Brown, Peter

    Adaptive deep brain stimulation uses feedback about the state of neural circuits to control stimulation rather than delivering fixed stimulation all the time, as currently performed. In patients with Parkinson's disease, elevations in beta activity (13-35 Hz) in the subthalamic nucleus have been

  8. Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting state networks in Parkinson's disease

    NARCIS (Netherlands)

    Oswal, Ashwini; Beudel, Martijn; Zrinzo, Ludvic; Limousin, Patricia; Hariz, Marwan; Foltynie, Tom; Litvak, Vladimir; Brown, Peter

    2016-01-01

    Oswal et al. characterise the effect of deep brain stimulation (DBS) on STN-cortical synchronisation in Parkinson-s disease. They propose that cortical driving of the STN in beta frequencies is subdivided anatomically and spectrally, corresponding to the hyperdirect and indirect pathways. DBS

  9. Slowing of oscillatory brain activity is a stable characteristic of Parkinson's disease without dementia

    NARCIS (Netherlands)

    Stoffers, D.; Bosboom, JL; Deijen, J.B.; Wolters, E.C.M.J.; Berendse, H.W.; Stam, L.

    2007-01-01

    Extensive changes in resting-state oscillatory brain activity have recently been demonstrated using magnetoencephalography (MEG) in moderately advanced, non-demented Parkinson's disease patients relative to age-matched controls. The aim of the present study was to determine the onset and evolution

  10. Propranolol in the treatment of assaultive patients with organic brain disease.

    Science.gov (United States)

    Greendyke, R M; Schuster, D B; Wooton, J A

    1984-10-01

    Propranolol in doses up to 520 mg/day was administered to eight patients with organic brain disease characterized by violent and assaultive behavior refractory to conventional treatment. Improvement was demonstrated in the seven patients able to tolerate adequate drug dosages. Hypotension, bradycardia, and interactions with other medications constituted complications.

  11. Brain Injury and Neurodevelopmental Outcome in Congenital Heart Disease : A Systematic Review

    NARCIS (Netherlands)

    Mebius, Mirthe J.; Kool, Elisabeth M. W.; Bilardo, Catherina M.; Bos, Arend F.

    2017-01-01

    CONTEXT: Brain injury during prenatal and preoperative postnatal life might play a major role in neurodevelopmental impairment in infants with congenital heart disease (CIID) who require corrective or palliative surgery during infancy. A systematic review of cerebral findings during this period in

  12. Pedunculopontine Nucleus Region Deep Brain Stimulation in Parkinson Disease: Surgical Techniques, Side Effects, and Postoperative Imaging

    NARCIS (Netherlands)

    Hamani, C.; Lozano, A.M.; Mazzone, P.A.; Moro, E.; Hutchison, W.; Silburn, P.A.; Zrinzo, L.; Alam, M.; Goetz, L.; Pereira, E.; Rughani, A.; Thevathasan, W.; Aziz, T.; Bloem, B.R.; Brown, P.; Chabardes, S.; Coyne, T.; Foote, K.; Garcia-Rill, E.; Hirsch, E.C.; Okun, M.S.; Krauss, J.K.

    2016-01-01

    The pedunculopontine nucleus (PPN) region has received considerable attention in clinical studies as a target for deep brain stimulation (DBS) in Parkinson disease. These studies have yielded variable results with an overall impression of improvement in falls and freezing in many but not all

  13. Brain Serotonin Transporter Binding In a Minipig Model of Parkinson's Disease

    DEFF Research Database (Denmark)

    Lillethorup, Thea Pinholt; Glud, Andreas Nørgaard; Sørensen, Jens Christian Hedemann

    Objectives: Some of the debilitating non-motor aspects of Parkinson’s disease (PD) are related to the serotonin system1. To investigate the involvement of the brain serotonergic system in a PD animal model, we measured the in vivo binding of [11C]-DASB to the serotonin transporter (SERT...

  14. Rest and action tremor in Parkinson's disease: effects of Deep Brain Stimulation

    NARCIS (Netherlands)

    Heida, Tjitske; Wentink, E.C.

    2010-01-01

    One of the cardinal symptoms of Parkinson’s disease is rest tremor. While rest tremor generally disappears during sleep and voluntary movement, action tremor may be triggered by voluntary movement, and may even be more disabling than rest tremor. Deep brain stimulation (DBS) in the subthalamic

  15. Microbes Tickling Your Tummy : the Importance of the Gut-Brain Axis in Parkinson's Disease

    NARCIS (Netherlands)

    Perez-Pardo, Paula|info:eu-repo/dai/nl/338040900; Hartog, Mitch; Garssen, Johan|info:eu-repo/dai/nl/086369962; Kraneveld, Aletta D|info:eu-repo/dai/nl/126612838

    2017-01-01

    Purpose of Review: Patients suffering from Parkinson's disease (PD) are known to experience gastrointestinal dysfunction that might precede the onset of motor symptoms by several years. Evidence suggests an important role of the gut-brain axis in PD pathogenesis. These interactions might be

  16. Patterns of regional brain hypometabolism associated with knowledge of semantic features and categories in alzheimer's disease

    DEFF Research Database (Denmark)

    Zahn, R.; Garrard, P.; Talazko, J.

    2006-01-01

    The study of semantic memory in patients with Alzheimer's disease (AD) has raised important questions about the representation of conceptual knowledge in the human brain. It is still unknown whether semantic memory impairments are caused by localized damage to specialized regions or by diffuse da...

  17. Subthalamic Nucleus Deep Brain Stimulation Changes Velopharyngeal Control in Parkinson's Disease

    Science.gov (United States)

    Hammer, Michael J.; Barlow, Steven M.; Lyons, Kelly E.; Pahwa, Rajesh

    2011-01-01

    Purpose: Adequate velopharyngeal control is essential for speech, but may be impaired in Parkinson's disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on velopharyngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of velopharyngeal…

  18. The imaging of HIV-related brain disease | Hoare | Southern African ...

    African Journals Online (AJOL)

    ... matter tracts in the brain.6 Once damage is established and related cognitive disorders ensue, the ability of HAART to reverse existing dysfunction is probably limited.7 Earlier treatment with HAART in at-risk or minimally symptomatic patients may prevent further decline in cognition and delay the course of HIV disease.

  19. Brain stem and cerebellum volumetric analysis of Machado Joseph disease patients

    Directory of Open Access Journals (Sweden)

    S T Camargos

    2011-01-01

    Full Text Available Machado-Joseph disease, or spinocerebellar ataxia type 3(MJD/SCA3, is the most frequent late onset spinocerebellar ataxia and results from a CAG repeat expansion in the ataxin-3 gene. Previous studies have found correlation between atrophy of cerebellum and brainstem with age and CAG repeats, although no such correlation has been found with disease duration and clinical manifestations. In this study we test the hypothesis that atrophy of cerebellum and brainstem in MJD/SCA3 is related to clinical severity, disease duration and CAG repeat length as well as to other variables such as age and ICARS (International Cooperative Ataxia Rating Scale. Whole brain high resolution MRI and volumetric measurement with cranial volume normalization were obtained from 15 MJD/SCA3 patients and 15 normal, age and sex-matchedcontrols. We applied ICARS and compared the score with volumes and CAG number, disease duration and age. We found significant correlation of both brain stem and cerebellar atrophy with CAG repeat length, age, disease duration and degree of disability. The Spearman rank correlation was stronger with volumetric reduction of the cerebellum than with brain stem. Our data allow us to conclude that volumetric analysis might reveal progressive degeneration after disease onset, which in turn is linked to both age and number of CAG repeat expansions in SCA 3.

  20. Cerebrospinal Fluid Markers of Neurodegeneration and Rates of Brain Atrophy in Early Alzheimer Disease.

    Science.gov (United States)

    Tarawneh, Rawan; Head, Denise; Allison, Samantha; Buckles, Virginia; Fagan, Anne M; Ladenson, Jack H; Morris, John C; Holtzman, David M

    2015-06-01

    Measures of neuronal loss are likely good surrogates for clinical and radiological disease progression in Alzheimer disease (AD). Cerebrospinal fluid (CSF) markers of neuronal injury or neurodegeneration may offer usefulness in predicting disease progression and guiding outcome assessments and prognostic decisions in clinical trials of disease-modifying therapies. Visinin-like protein 1 (VILIP-1) has demonstrated potential usefulness as a marker of neuronal injury in AD. To investigate the usefulness of CSF VILIP-1, tau, p-tau181, and Aβ42 levels in predicting rates of whole-brain and regional atrophy in early AD and cognitively normal control subjects over time. Longitudinal observational study of brain atrophy in participants with early AD and cognitively normal controls. Study participants had baseline CSF biomarker measurements and longitudinal magnetic resonance imaging assessments for a mean follow-up period of 2 to 3 years. Mixed linear models assessed the ability of standardized baseline CSF biomarker measures to predict rates of whole-brain and regional atrophy over the follow-up period. The setting was The Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St Louis. Participants (mean age, 72.6 years) were individuals with a clinical diagnosis of very mild AD (n = 23) and cognitively normal controls (n = 64) who were enrolled in longitudinal studies of healthy aging and dementia. The study dates were 2000 to 2010. Correlations between baseline CSF biomarker measures and rates of whole-brain or regional atrophy in the AD and control cohorts over the follow-up period. Baseline CSF VILIP-1, tau, and p-tau181 levels (but not Aβ42 levels) predicted rates of whole-brain and regional atrophy in AD over the follow-up period. Baseline CSF VILIP-1 levels predicted whole-brain (P = .006), hippocampal (P = .01), and entorhinal (P = .001) atrophy rates at least as well as tau and p-tau181 in early AD

  1. Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Alana M. Horowitz

    2017-08-01

    Full Text Available Neurodegenerative diseases are a devastating group of conditions that cause progressive loss of neuronal integrity, affecting cognitive and motor functioning in an ever-increasing number of older individuals. Attempts to slow neurodegenerative disease advancement have met with little success in the clinic; however, a new therapeutic approach may stem from classic interventions, such as caloric restriction, exercise, and parabiosis. For decades, researchers have reported that these systemic-level manipulations can promote major functional changes that extend organismal lifespan and healthspan. Only recently, however, have the functional effects of these interventions on the brain begun to be appreciated at a molecular and cellular level. The potential to counteract the effects of aging in the brain, in effect rejuvenating the aged brain, could offer broad therapeutic potential to combat dementia-related neurodegenerative disease in the elderly. In particular, results from heterochronic parabiosis and young plasma administration studies indicate that pro-aging and rejuvenating factors exist in the circulation that can independently promote or reverse age-related phenotypes. The recent demonstration that human umbilical cord blood similarly functions to rejuvenate the aged brain further advances this work to clinical translation. In this review, we focus on these blood-based rejuvenation strategies and their capacity to delay age-related molecular and functional decline in the aging brain. We discuss new findings that extend the beneficial effects of young blood to neurodegenerative disease models. Lastly, we explore the translational potential of blood-based interventions, highlighting current clinical trials aimed at addressing therapeutic applications for the treatment of dementia-related neurodegenerative disease in humans.

  2. Brain changes detected by functional magnetic resonance imaging and spectroscopy in patients with Crohn's disease.

    Science.gov (United States)

    Lv, Kun; Fan, Yi-Hong; Xu, Li; Xu, Mao-Sheng

    2017-05-28

    Crohn's disease (CD) is a chronic, non-specific granulomatous inflammatory disorder that commonly affects the small intestine and is a phenotype of inflammatory bowel disease (IBD). CD is prone to relapse, and its incidence displays a persistent increase in developing countries. However, the pathogenesis of CD is poorly understood, with some studies emphasizing the link between CD and the intestinal microbiota. Specifically, studies point to the brain-gut-enteric microbiota axis as a key player in the occurrence and development of CD. Furthermore, investigations have shown white-matter lesions and neurologic deficits in patients with IBD. Based on these findings, brain activity changes in CD patients have been detected by blood oxygenation level dependent functional magnetic resonance imaging (BOLD-fMRI). BOLD-fMRI functions by detecting a local increase in relative blood oxygenation that results from neurotransmitter activity and thus reflects local neuronal firing rates. Therefore, biochemical concentrations of neurotransmitters or metabolites may change in corresponding brain regions of CD patients. To further study this phenomenon, brain changes of CD patients can be detected non-invasively, effectively and accurately by BOLD-fMRI combined with magnetic resonance spectroscopy (MRS). This approach can further shed light on the mechanisms of the occurrence and development of neurological CD. Overall, this paper reviews the current status and prospects on fMRI and MRS for evaluation of patients with CD based on the brain-gut-enteric microbiota axis.

  3. The role of ceramides in selected brain pathologies: ischemia/hypoxia, Alzheimer disease

    Directory of Open Access Journals (Sweden)

    Halina Car

    2012-05-01

    Full Text Available  Ceramides, members of the sphingolipids, are produced in the central nervous system by de novo synthesis, sphingomyelin hydrolysis or the so-called salvage pathway. They are engaged in formation of lipid rafts that are essential in regulation and transduction of signals coming to the cell from the environment. Ceramides represent the major transmitters of the sphingomyelin pathway of signal transduction. They regulate proliferation, differentiation, programmed cell death and senescence. Ceramide overexpression, mainly as a result of sphingomyelin hydrolysis, is a component of brain damage caused by ischemia and early reperfusion. Their high concentrations induce mitochondria-dependent neuronal apoptosis, exacerbate the synthesis of reactive oxygen species, decrease ATP level, inhibit electron transport and release cytochrome c, and activate caspase-3. Reduced ceramide accumulation in the brain, dependent mainly on ceramide synthesized de novo, may exert an anti-apoptotic effect after pre-conditioning. The increase of ceramide content in the brain was observed in Alzheimer disease and its animal models. Enhanced ceramide concentration in this pathology is an effect of their synthesis de novo or sphingomyelin metabolism augmentation. The ceramide pathway can directly stimulate biochemical changes in the brain noted at the onset of disease: tau overphosphorylation and β-amyloid peptide accumulation. The higher concentration of ceramides in blood in the pre-clinical phase of the illness may mark early brain changes.

  4. Classification of Alzheimer's disease using regional saliency maps from brain MR volumes

    Science.gov (United States)

    Pulido, Andrea; Rueda, Andrea; Romero, Eduardo

    2013-02-01

    Accurate diagnosis of Alzheimer's disease (AD) from structural Magnetic Resonance (MR) images is difficult due to the complex alteration of patterns in brain anatomy that could indicate the presence or absence of the pathology. Currently, an effective approach that allows to interpret the disease in terms of global and local changes is not available in the clinical practice. In this paper, we propose an approach for classification of brain MR images, based on finding pathology-related patterns through the identification of regional structural changes. The approach combines a probabilistic Latent Semantic Analysis (pLSA) technique, which allows to identify image regions through latent topics inferred from the brain MR slices, with a bottom-up Graph-Based Visual Saliency (GBVS) model, which calculates maps of relevant information per region. Regional saliency maps are finally combined into a single map on each slice, obtaining a master saliency map of each brain volume. The proposed approach includes a one-to-one comparison of the saliency maps which feeds a Support Vector Machine (SVM) classifier, to group test subjects into normal or probable AD subjects. A set of 156 brain MR images from healthy (76) and pathological (80) subjects, splitted into a training set (10 non-demented and 10 demented subjects) and one testing set (136 subjects), was used to evaluate the performance of the proposed approach. Preliminary results show that the proposed method reaches a maximum classification accuracy of 87.21%.

  5. Cognitive profiles in dementia: Alzheimer disease vs healthy brain aging.

    Science.gov (United States)

    Johnson, D K; Storandt, M; Morris, J C; Langford, Z D; Galvin, J E

    2008-11-25

    To re-examine proposed models of cognitive test performance that concluded separate factor structures were required for people with Alzheimer disease (AD) and older adults without dementia. Five models of cognitive test performance were compared using multistep confirmatory factor analysis in 115 individuals with autopsy-confirmed AD and 191 research participants without clinical dementia from longitudinal studies at the Washington University AD Research Center. The models were then cross-validated using independent samples of 323 people with clinically diagnosed dementia of the Alzheimer type and 212 cognitively healthy older adults. After controlling for Alzheimer-specific changes in episodic memory, performance on the battery of tests used here was best represented in people both with and without dementia by a single model of one general factor and three specific factors (verbal memory, visuospatial ability, and working memory). Performance by people with dementia was lower on the general factor than it was by those without dementia. Larger variances associated with the specific factors in the group with dementia indicated greater individual differences in the pattern of cognitive deficits in the stage of AD. A hybrid model of general and specific cognitive domains simplifies cognitive research by allowing direct comparison of normal aging and Alzheimer disease performance. The presence of a general factor maximizes detection of the dementia, whereas the specific factors reveal the heterogeneity of dementia's associated cognitive deficits.

  6. Sex differences in metabolic aging of the brain: insights into female susceptibility to Alzheimer's disease.

    Science.gov (United States)

    Zhao, Liqin; Mao, Zisu; Woody, Sarah K; Brinton, Roberta D

    2016-06-01

    Despite recent advances in the understanding of clinical aspects of sex differences in Alzheimer's disease (AD), the underlying mechanisms, for instance, how sex modifies AD risk and why the female brain is more susceptible to AD, are not clear. The purpose of this study is to elucidate sex disparities in brain aging profiles focusing on 2 major areas-energy and amyloid metabolism-that are most significantly affected in preclinical development of AD. Total RNA isolated from hippocampal tissues of both female and male 129/C57BL/6 mice at ages of 6, 9, 12, or 15 months were comparatively analyzed by custom-designed Taqman low-density arrays for quantitative real-time polymerase chain reaction detection of a total of 182 genes involved in a broad spectrum of biological processes modulating energy production and amyloid homeostasis. Gene expression profiles revealed substantial differences in the trajectory of aging changes between female and male brains. In female brains, 44.2% of genes were significantly changed from 6 months to 9 months and two-thirds showed downregulation. In contrast, in male brains, only 5.4% of genes were significantly altered at this age transition. Subsequent changes in female brains were at a much smaller magnitude, including 10.9% from 9 months to 12 months and 6.1% from 12 months to 15 months. In male brains, most changes occurred from 12 months to 15 months and the majority were upregulated. Furthermore, gene network analysis revealed that clusterin appeared to serve as a link between the overall decreased bioenergetic metabolism and increased amyloid dyshomeostasis associated with the earliest transition in female brains. Together, results from this study indicate that: (1) female and male brains follow profoundly dissimilar trajectories as they age; (2) female brains undergo age-related changes much earlier than male brains; (3) early changes in female brains signal the onset of a hypometabolic phenotype at risk for AD. These

  7. Rapid and Quantitative Assay of Amyloid-Seeding Activity in Human Brains Affected with Prion Diseases.

    Directory of Open Access Journals (Sweden)

    Hanae Takatsuki

    Full Text Available The infectious agents of the transmissible spongiform encephalopathies are composed of amyloidogenic prion protein, PrPSc. Real-time quaking-induced conversion can amplify very small amounts of PrPSc seeds in tissues/body fluids of patients or animals. Using this in vitro PrP-amyloid amplification assay, we quantitated the seeding activity of affected human brains. End-point assay using serially diluted brain homogenates of sporadic Creutzfeldt-Jakob disease patients demonstrated that 50% seeding dose (SD50 is reached approximately 10(10/g brain (values varies 10(8.79-10.63/g. A genetic case (GSS-P102L yielded a similar level of seeding activity in an autopsy brain sample. The range of PrPSc concentrations in the samples, determined by dot-blot assay, was 0.6-5.4 μg/g brain; therefore, we estimated that 1 SD50 unit was equivalent to 0.06-0.27 fg of PrPSc. The SD50 values of the affected brains dropped more than three orders of magnitude after autoclaving at 121°C. This new method for quantitation of human prion activity provides a new way to reduce the risk of iatrogenic prion transmission.

  8. Disrupted small-world brain networks in moderate Alzheimer's disease: a resting-state FMRI study.

    Directory of Open Access Journals (Sweden)

    Xiaohu Zhao

    Full Text Available The small-world organization has been hypothesized to reflect a balance between local processing and global integration in the human brain. Previous multimodal imaging studies have consistently demonstrated that the topological architecture of the brain network is disrupted in Alzheimer's disease (AD. However, these studies have reported inconsistent results regarding the topological properties of brain alterations in AD. One potential explanation for these inconsistent results lies with the diverse homogeneity and distinct progressive stages of the AD involved in these studies, which are thought to be critical factors that might affect the results. We investigated the topological properties of brain functional networks derived from resting functional magnetic resonance imaging (fMRI of carefully selected moderate AD patients and normal controls (NCs. Our results showed that the topological properties were found to be disrupted in AD patients, which showing increased local efficiency but decreased global efficiency. We found that the altered brain regions are mainly located in the default mode network, the temporal lobe and certain subcortical regions that are closely associated with the neuropathological changes in AD. Of note, our exploratory study revealed that the ApoE genotype modulates brain network properties, especially in AD patients.

  9. A putative Alzheimer's disease risk allele in PCK1 influences brain atrophy in multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Zongqi Xia

    2010-11-01

    Full Text Available Brain atrophy and cognitive dysfunction are neurodegenerative features of Multiple Sclerosis (MS. We used a candidate gene approach to address whether genetic variants implicated in susceptibility to late onset Alzheimer's Disease (AD influence brain volume and cognition in MS patients.MS subjects were genotyped for five single nucleotide polymorphisms (snps associated with susceptibility to AD: PICALM, CR1, CLU, PCK1, and ZNF224. We assessed brain volume using Brain Parenchymal Fraction (BPF measurements obtained from Magnetic Resonance Imaging (MRI data and cognitive function using the Symbol Digit Modalities Test (SDMT. Genotypes were correlated with cross-sectional BPF and SDMT scores using linear regression after adjusting for sex, age at symptom onset, and disease duration. 722 MS patients with a mean (±SD age at enrollment of 41 (±10 years were followed for 44 (±28 months. The AD risk-associated allele of a non-synonymous SNP in the PCK1 locus (rs8192708G is associated with a smaller average brain volume (P=0.0047 at the baseline MRI, but it does not impact our baseline estimate of cognition. PCK1 is additionally associated with higher baseline T2-hyperintense lesion volume (P=0.0088. Finally, we provide technical validation of our observation in a subset of 641 subjects that have more than one MRI study, demonstrating the same association between PCK1 and smaller average brain volume (P=0.0089 at the last MRI visit.Our study provides suggestive evidence for greater brain atrophy in MS patients bearing the PCK1 allele associated with AD-susceptibility, yielding new insights into potentially shared neurodegenerative process between MS and late onset AD.

  10. Docosahexaenoic acid (DHA): An essential nutrient and a nutraceutical for brain health and diseases.

    Science.gov (United States)

    Sun, Grace Y; Simonyi, Agnes; Fritsche, Kevin L; Chuang, Dennis Y; Hannink, Mark; Gu, Zezong; Greenlief, C Michael; Yao, Jeffrey K; Lee, James C; Beversdorf, David Q

    2017-03-10

    Docosahexaenoic acid (DHA), a polyunsaturated fatty acid (PUFA) enriched in phospholipids in the brain and retina, is known to play multi-functional roles in brain health and diseases. While arachidonic acid (AA) is released from membrane phospholipids by cytosolic phospholipase A2 (cPLA2), DHA is linked to action of the Ca2+-independent iPLA2. DHA undergoes enzymatic conversion by 15-lipoxygenase (Alox 15) to form oxylipins including resolvins and neuroprotectins, which are powerful lipid mediators. DHA can also undergo non-enzymatic conversion by reacting with oxygen free radicals (ROS), which cause the production of 4-hydoxyhexenal (4-HHE), an aldehyde derivative which can form adducts with DNA, proteins and lipids. In studies with both animal models and humans, there is evidence that inadequate intake of maternal n-3 PUFA may lead to aberrant development and function of the central nervous system (CNS). What is less certain is whether consumption of n-3 PUFA is important in maintaining brain health throughout one's life span. Evidence mostly from non-human studies suggests that DHA intake above normal nutritional requirements might modify the risk/course of a number of diseases of the brain. This concept has fueled much of the present interest in DHA research, in particular, in attempts to delineate mechanisms whereby DHA may serve as a nutraceutical and confer neuroprotective effects. Current studies have revealed ability for the oxylipins to regulation of cell redox homeostasis through the Nuclear factor (erythroid-derived 2)-like 2/Antioxidant response element (Nrf2/ARE) anti-oxidant pathway, and impact signaling pathways associated with neurotransmitters, and modulation of neuronal functions involving brain-derived neurotropic factor (BDNF). This review is aimed at describing recent studies elaborating these mechanisms with special regard to aging and Alzheimer's disease, autism spectrum disorder, schizophrenia, traumatic brain injury, and stroke. Copyright

  11. Oxidative stress-mediated brain dehydroepiandrosterone (DHEA formation in Alzheimer’s disease diagnosis

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    Geogres eRammouz

    2011-11-01

    Full Text Available Neurosteroids are steroids made by brain cells independently of peripheral steroidogenic sources. The biosynthesis of most neurosteroids is mediated by proteins and enzymes similar to those identified in the steroidogenic pathway of adrenal and gonadal cells. Dehydroepiandrosterone (DHEA is a major neurosteroid identified in the brain. Over the years we have reported that, unlike other neurosteroids, DHEA biosynthesis in rat, bovine, and human brain is mediated by an oxidative stress-mediated mechanism, independent of the cytochrome P450 17a-hydroxylase/17,20-lyase (CYP17A1 enzyme activity found in the periphery. This alternative pathway is induced by pro-oxidant agents, such as Fe2+ and b-amyloid peptide. Neurosteroids are involved in many aspects of brain function, and as such, are involved in various neuropathologies, including Alzheimer’s disease (AD. AD is a progressive, yet irreversible neurodegenerative disease for which there are limited means for ante-mortem diagnosis. Using brain tissue specimens from control and AD patients, we provided evidence that DHEA is formed in the AD brain by the oxidative stress-mediated metabolism of an unidentified precursor, thus depleting levels of the precursor in the blood stream. We tested for the presence of this DHEA precursor in human serum using a Fe2+-based reaction and determined the amounts of DHEA formed. Fe2+ treatment of the serum resulted in a dramatic increase in DHEA levels in control patients, whereas only a moderate or no increase was observed in AD patients. The DHEA variation after oxidation correlated with the patients’ cognitive and mental status. In this review, we present the cumulative evidence for oxidative stress as a natural regulator of DHEA formation and the use of this concept to develop a blood-based diagnostic tool for neurodegenerative diseases linked to oxidative stress, such as AD.

  12. Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer's disease brain tissue.

    Science.gov (United States)

    Poole, Sophie; Singhrao, Sim K; Kesavalu, Lakshmyya; Curtis, Michael A; Crean, StJohn

    2013-01-01

    The aim of this study was to establish a link between periodontal disease and Alzheimer's disease (AD) with a view to identifying the major periodontal disease bacteria (Treponema denticola, Tannerella forsythia, and Porphyromonas gingivalis) and/or bacterial components in brain tissue from 12 h postmortem delay. Our request matched 10 AD cases for tissue from Brains for Dementia Research alongside 10 non-AD age-related controls with similar or greater postmortem interval. We exposed SVGp12, an astrocyte cell line, to culture supernatant containing lipopolysaccharide (LPS) from the putative periodontal bacteria P. gingivalis. The challenged SVGp12 cells and cryosections from AD and control brains were immunolabeled and immunoblotted using a battery of antibodies including the anti-P. gingivalis-specific monoclonal antibody. Immunofluorescence labeling demonstrated the SVGp12 cell line was able to adsorb LPS from culture supernatant on its surface membrane; similar labeling was observed in four out of 10 AD cases. Immunoblotting demonstrated bands corresponding to LPS from P. gingivalis in the SVGp12 cell lysate and in the same four AD brain specimens which were positive when screened by immunofluorescence. All controls remained negative throughout while the same four cases were consistently positive for P. gingivalis LPS (p = 0.029). This study confirms that LPS from periodontal bacteria can access the AD brain during life as labeling in the corresponding controls, with equivalent/longer postmortem interval, was absent. Demonstration of a known chronic oral-pathogen-related virulence factor reaching the human brains suggests an inflammatory role in the existing AD pathology.

  13. Abnormalities of Dopamine D3 Receptor Signaling in the Diseased Brain

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    Prieto, G Aleph

    2017-01-01

    Dopamine D3 receptors (D3R) modulate neuronal activity in several brain regions including cortex, striatum, cerebellum, and hippocampus. A growing body of evidence suggests that aberrant D3R signaling contributes to multiple brain diseases, such as Parkinson’s disease, essential tremor, schizophrenia, and addiction. In line with these findings, D3R has emerged as a potential target in the treatment of neurological disorders. However, the mechanisms underlying neuronal D3R signaling are poorly understood, either in healthy or diseased brain. Here, I review the molecular mechanisms involved in D3R signaling via monomeric D3R and heteromeric receptor complexes (e.g., D3R-D1R, D3R-D2R, D3R-A2aR, and D3R-D3nf). I focus on D3R signaling pathways that, according to recent reports, contribute to pathological brain states. In particular, I describe evidence on both quantitative (e.g., increased number or affinity) and qualitative (e.g., switched signaling) changes in D3R that has been associated with brain dysfunction. I conclude with a description of basic mechanisms that modulate D3R signaling such as desensitization, as disruption of these mechanisms may underlie pathological changes in D3R signaling. Because several lines of evidence support the idea that imbalances in D3R signaling alter neural function, a better understanding of downstream D3R pathways is likely to reveal novel therapeutic strategies toward dopamine-related brain disorders. PMID:28855798

  14. Longitudinal evaluation of early Alzheimer's disease using brain perfusion SPECT.

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    Kogure, D; Matsuda, H; Ohnishi, T; Asada, T; Uno, M; Kunihiro, T; Nakano, S; Takasaki, M

    2000-07-01

    The aim of this SPECT study was to determine the initial abnormality and longitudinal changes in regional cerebral blood flow (rCBF) in early Alzheimer's disease (AD) using statistical parametric mapping (SPM). rCBF was noninvasively measured using (99m)Tc-ethyl cysteinate dimer SPECT in 32 patients complaining of mild cognitive impairment, with a Mini-Mental State Examination score more than 24 at the initial study, and 45 age-matched healthy volunteers. All patients satisfied the diagnostic criteria of AD during the follow-up period of at least 2 y. Follow-up SPECT studies were performed on the patients at a mean interval of 15 mo. We used the raw data (absolute rCBF parametric maps) and the adjusted rCBF images of relative flow distribution (normalization of global cerebral blood flow [CBF] for each subject to 50 mL/100 g/min with proportional scaling) to compare these groups with SPM. In the baseline study, the adjusted rCBF was significantly and bilaterally decreased in the posterior cingulate gyri and precunei of patients compared with healthy volunteers. In the follow-up study, selected reduction of the adjusted rCBF was observed in the left hippocampus and parahippocampal gyrus. These areas showed the most prominent reduction in absolute rCBF on each occasion. Moreover, further decline of the absolute rCBF was longitudinally observed in extensive areas of the cerebral association cortex. SPM analysis showed the characteristic early-AD rCBF pattern of selective decrease and longitudinal decline, which may be overlooked by a conventional region-of-interest technique with observer a priori choice and hypothesis. This alteration in rCBF may closely relate to the pathophysiologic process of this disease.

  15. Nanoparticle technology for treatment of Parkinson's disease: the role of surface phenomena in reaching the brain.

    Science.gov (United States)

    Leyva-Gómez, Gerardo; Cortés, Hernán; Magaña, Jonathan J; Leyva-García, Norberto; Quintanar-Guerrero, David; Florán, Benjamín

    2015-07-01

    The absence of a definitive treatment for Parkinson's disease has driven the emerging investigation in the search for novel therapeutic alternatives. At present, the formulation of different drugs on nanoparticles has represented several advantages over conventional treatments. This type of multifunctional carrier, owing to its size and composition, has different interactions in biological systems that can lead to a decrease in ability to cross the blood-brain barrier. Therefore, this review focuses on the latest advances in obtaining nanoparticles for Parkinson's disease and provides an overview of technical aspects in the design of brain drug delivery of nanoparticles and an analysis of surface phenomena, a key aspect in the development of functional nanoparticles for Parkinson's disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Circadian clock gene expression in brain regions of Alzheimer 's disease patients and control subjects.

    Science.gov (United States)

    Cermakian, Nicolas; Lamont, Elaine Waddington; Boudreau, Philippe; Boivin, Diane B

    2011-04-01

    Circadian oscillators have been observed throughout the rodent brain. In the human brain, rhythmic expression of clock genes has been reported only in the pineal gland, and little is known about their expression in other regions. The investigators sought to determine whether clock gene expression could be detected and whether it varies as a function of time of day in the bed nucleus of the stria terminalis (BNST) and cingulate cortex, areas known to be involved in decision making and motivated behaviors, as well as in the pineal gland, in the brains of Alzheimer's disease (AD) patients and aged controls. Relative expression levels of PERIOD1 (PER1 ), PERIOD2 (PER2), and Brain and muscle Arnt-like protein-1 (BMAL1) were detected by quantitative PCR in all 3 brain regions. A harmonic regression model revealed significant 24-h rhythms of PER1 in the BNST of AD subjects. A significant rhythm of PER2 was found in the cingulate cortex and BNST of control subjects and in all 3 regions of AD patients. In controls, BMAL1 did not show a diurnal rhythm in the cingulate cortex but significantly varied with time of death in the pineal and BNST and in all 3 regions for AD patients. Notable differences in the phase of clock gene rhythms and phase relationships between genes and regions were observed in the brains of AD compared to those of controls. These results indicate the presence of multiple circadian oscillators in the human brain and suggest altered synchronization among these oscillators in the brain of AD patients. © 2011 Sage Publications

  17. Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting state networks in Parkinson's disease.

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    Oswal, Ashwini; Beudel, Martijn; Zrinzo, Ludvic; Limousin, Patricia; Hariz, Marwan; Foltynie, Tom; Litvak, Vladimir; Brown, Peter

    2016-05-01

    Chronic dopamine depletion in Parkinson's disease leads to progressive motor and cognitive impairment, which is associated with the emergence of characteristic patterns of synchronous oscillatory activity within cortico-basal-ganglia circuits. Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson's disease, but its influence on synchronous activity in cortico-basal-ganglia loops remains to be fully characterized. Here, we demonstrate that deep brain stimulation selectively suppresses certain spatially and spectrally segregated resting state subthalamic nucleus-cortical networks. To this end we used a validated and novel approach for performing simultaneous recordings of the subthalamic nucleus and cortex using magnetoencephalography (during concurrent subthalamic nucleus deep brain stimulation). Our results highlight that clinically effective subthalamic nucleus deep brain stimulation suppresses synchrony locally within the subthalamic nucleus in the low beta oscillatory range and furthermore that the degree of this suppression correlates with clinical motor improvement. Moreover, deep brain stimulation relatively selectively suppressed synchronization of activity between the subthalamic nucleus and mesial premotor regions, including the supplementary motor areas. These mesial premotor regions were predominantly coupled to the subthalamic nucleus in the high beta frequency range, but the degree of deep brain stimulation-associated suppression in their coupling to the subthalamic nucleus was not found to correlate with motor improvement. Beta band coupling between the subthalamic nucleus and lateral motor areas was not influenced by deep brain stimulation. Motor cortical coupling with subthalamic nucleus predominantly involved driving of the subthalamic nucleus, with those drives in the higher beta frequency band having much shorter net delays to subthalamic nucleus than those in the lower beta band. These observations raise the

  18. White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease

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    Lauren P. Klosinski

    2015-12-01

    Full Text Available White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer's. Age remains the greatest risk factor for Alzheimer's and the prevalence of age-related late onset Alzheimer's is greatest in females. We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer's risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A2 sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its chronologically phased activation, links mitochondrial dysfunction early in aging with later age development of white matter degeneration. The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. Elucidation of the initiating factors and the mechanistic pathway leading to white matter catabolism in the aging female brain provides potential therapeutic targets to prevent and treat demyelinating diseases such as Alzheimer's and multiple sclerosis. Targeting stages of disease and associated mechanisms will be critical.

  19. Bilingualism as a contributor to cognitive reserve: evidence from brain atrophy in Alzheimer's disease.

    Science.gov (United States)

    Schweizer, Tom A; Ware, Jenna; Fischer, Corinne E; Craik, Fergus I M; Bialystok, Ellen

    2012-09-01

    Much of the research on delaying the onset of symptoms of Alzheimer's disease (AD) has focused on pharmacotherapy, but environmental factors have also been acknowledged to play a significant role. Bilingualism may be one factor contributing to 'cognitive reserve' (CR) and therefore to a delay in symptom onset. If bilingualism is protective, then the brains of bilinguals should show greater atrophy in relevant areas, since their enhanced CR enables them to function at a higher level than would be predicted from their level of disease. We analyzed a number of linear measurements of brain atrophy from the computed tomography (CT) scans of monolingual and bilingual patients diagnosed with probable AD who were matched on level of cognitive performance and years of education. Bilingual patients with AD exhibited substantially greater amounts of brain atrophy than monolingual patients in areas traditionally used to distinguish AD patients from healthy controls, specifically, the radial width of the temporal horn and the temporal horn ratio. Other measures of brain atrophy were comparable for the two groups. Bilingualism appears to contribute to increased CR, thereby delaying the onset of AD and requiring the presence of greater amounts of neuropathology before the disease is manifest. Copyright © 2011 Elsevier Srl. All rights reserved.

  20. Chitinase expression in Alzheimer's disease and non-demented brains regions.

    Science.gov (United States)

    Sanfilippo, C; Malaguarnera, L; Di Rosa, M

    2016-10-15

    Alzheimer disease is the most typical form of dementia. The causes of AD are not yet completely understood, but they include a combination of genetic, environmental and lifestyle factors that influence ja person's risk for developing the disease. New biomarkers related to these processes could be important for the diagnosis and follow-up of AD patients. The intent of this study was to weigh the expression levels of chitinases genes in brain regions of late-onset AD (LOAD) patients. We analysed three microarray datasets obtained from the NCBI in order to verify the expression levels of chitinase genes family in brain biopsies (CR, DLPFC and VC) of LOAD patients compared to healthy subjects. We also divided the sample in function of sex difference and ages. The analysis showed that all chitinases genes were modulated in LOAD brain regions compared to healthy subjects. Furthermore positively correlation was identified between chitinases gene expression and healthy age's subjects. Moreover, it has been shown that CHI3L1 and CHI3L2 were regulated differently in healthy and LOAD brain depending on the sex. It is possible to conclude that all chitinases could be considered new potential markers for LOAD disease. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Brain Microstructural Abnormalities Are Related to Physiological Alterations in End-Stage Renal Disease.

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    Zhigang Bai

    Full Text Available To study whole-brain microstructural alterations in patients with end-stage renal disease (ESRD and examine the relationship between brain microstructure and physiological indictors in the disease.Diffusion tensor imaging data were collected from 35 patients with ESRD (28 men, 18-61 years and 40 age- and gender-matched healthy controls (HCs, 32 men, 22-58 years. A voxel-wise analysis was then used to identify microstructural alterations over the whole brain in the ESRD patients compared with the HCs. Multiple biochemical measures of renal metabolin, vascular risk factors, general cognitive ability and dialysis duration were correlated with microstructural integrity for the patients.Compared to the HCs, the ESRD patients exhibited disrupted microstructural integrity in not only white matter (WM but also gray matter (GM regions, as characterized by decreased fractional anisotropy (FA and increased mean diffusivity (MD, axial diffusivity (AD and radial diffusivity (RD. Further correlation analyses revealed that the in MD, AD and RD values showed significantly positive correlations with the blood urea nitrogen in the left superior temporal gyrus and significantly negative correlations with the calcium levels in the left superior frontal gyrus (orbital part in the patients.Our findings suggest that ESRD is associated with widespread diffusion abnormalities in both WM and GM regions in the brain, and microstructural integrity of several GM regions are related to biochemical alterations in the disease.

  2. White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease.

    Science.gov (United States)

    Klosinski, Lauren P; Yao, Jia; Yin, Fei; Fonteh, Alfred N; Harrington, Michael G; Christensen, Trace A; Trushina, Eugenia; Brinton, Roberta Diaz

    2015-12-01

    White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer's. Age remains the greatest risk factor for Alzheimer's and the prevalence of age-related late onset Alzheimer's is greatest in females. We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer's risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A2 sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its chronologically phased activation, links mitochondrial dysfunction early in aging with later age development of white matter degeneration. The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. Elucidation of the initiating factors and the mechanistic pathway leading to white matter catabolism in the aging female brain provides potential therapeutic targets to prevent and treat demyelinating diseases such as Alzheimer's and multiple sclerosis. Targeting stages of disease and associated mechanisms will be critical.

  3. Subthalamic deep brain stimulation can improve gastric emptying in Parkinson's disease.

    Science.gov (United States)

    Arai, Eiji; Arai, Makoto; Uchiyama, Tomoyuki; Higuchi, Yoshinori; Aoyagi, Kyoko; Yamanaka, Yoshitaka; Yamamoto, Tatsuya; Nagano, Osamu; Shiina, Akihiro; Maruoka, Daisuke; Matsumura, Tomoaki; Nakagawa, Tomoo; Katsuno, Tatsuro; Imazeki, Fumio; Saeki, Naokatsu; Kuwabara, Satoshi; Yokosuka, Osamu

    2012-05-01

    It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinson's disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of (13)CO(2) excretion (T(max)) in the (13)C-acetate breath test and was assessed in patients with and without administration of 100-150 mg levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months post-surgery. The pattern of (13)CO(2) excretion curve was analysed. To evaluate potential factors related to the effect of subthalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of (13)CO(2) excretion (T(max)) values for gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6 ± 22.7 min and 42.5 ± 13.6 min, respectively (P = not significant), thus demonstrating levodopa resistance. The peak time of (13)CO(2) excretion (T(max)) values without and with subthalamic deep brain stimulation after surgery were 44.0 ± 17.5 min and 30.0 ± 12.5 min (P deep brain stimulation was effective. Simultaneously, the pattern of the (13)CO(2) excretion curve was also significantly improved relative to surgery with no stimulation (P = 0.002), although the difference with and without levodopa/decarboxylase inhibitor was not significant. The difference in peak time of (13)CO(2) excretion (T(max)) values without levodopa/decarboxylase inhibitor before surgery and without levodopa/decarboxylase inhibitor and subthalamic deep

  4. Memory with emotional content, brain amygdala and Alzheimer's disease.

    Science.gov (United States)

    Schultz, R R; de Castro, C C; Bertolucci, P H F

    2009-08-01

    A highly adaptive aspect of human memory is the enhancement of explicit, consciously accessible memory by emotional stimuli. We studied the performance of Alzheimer's disease (AD) patients and elderly controls using a memory battery with emotional content, and we correlated these results with the amygdala and hippocampus volume. Twenty controls and 20 early AD patients were subjected to the International Affective Picture System (IAPS) and to magnetic resonance imaging-based volumetric measurements of the medial temporal lobe structures. The results show that excluding control group subjects with 5 or more years of schooling, both groups showed improvement with pleasant or unpleasant figures for the IAPS in an immediate free recall test. Likewise, in a delayed free recall test, both the controls and the AD group showed improvement for pleasant pictures, when education factor was not controlled. The AD group showed improvement in the immediate and delayed free recall test proportional to the medial temporal lobe structures, with no significant clinical correlation between affective valence and amygdala volume. AD patients can correctly identify emotions, at least at this early stage, but this does not improve their memory performance.

  5. Parsing brain activity associated with acupuncture treatment in Parkinson's diseases.

    Science.gov (United States)

    Chae, Younbyoung; Lee, Hyejung; Kim, Hackjin; Kim, Chang-Hwan; Chang, Dae-Il; Kim, Kyung-Mi; Park, Hi-Joon

    2009-09-15

    Acupuncture, a common treatment modality within complementary and alternative medicine, has been widely used for Parkinson's disease (PD). Using functional magnetic resonance imaging (fMRI), we explored the neural mechanisms underlying the effect of specific and genuine acupuncture treatment on the motor function in patients with PD. Three fMRI scans were performed in random order in a block design, one for verum acupuncture (VA) treatment, another one for a covert placebo (CP), and the third one for an overt placebo (OP) at the motor function implicated acupoint GB34 on the left foot of 10 patients with PD. We calculated the contrast that subtracts the blood-oxygen-level dependent (BOLD) response for the acupuncture effect (VA vs. CP) and the placebo effect (CP vs. OP). We found a significant improvement in the motor function of the affected hand after acupuncture treatment. The putamen and the primary motor cortex were activated when patients with PD received the acupuncture treatment (VA vs. CP) and these activations correlated with individual enhanced motor function. Expectation towards acupuncture modality (CP vs. OP) elicited activation over the anterior cingulate gyrus, the superior frontal gyrus, and the superior temporal gyrus. These findings suggest that acupuncture treatment might facilitate improvement in the motor functioning of patients with PD via the basal ganglia-thalamocortical circuit.

  6. Brain metabolic dysfunction at the core of Alzheimer’s disease

    Science.gov (United States)

    de la Monte, Suzanne M.; Tong, Ming

    2015-01-01

    Growing evidence supports the concept that Alzheimer’s disease (AD) is fundamentally a metabolic disease with molecular and biochemical features that correspond with diabetes mellitus and other peripheral insulin resistance disorders. Brain insulin/IGF resistance and its consequences can readily account for most of the structural and functional abnormalities in AD. However, disease pathogenesis is complicated by the fact that AD can occur as a separate disease process, or arise in association with systemic insulin resistance diseases, including diabetes, obesity, and non-alcoholic fatty liver disease. Whether primary or secondary in origin, brain insulin/IGF resistance initiates a cascade of neurodegeneration that is propagated by metabolic dysfunction, increased oxidative and ER stress, neuro-inflammation, impaired cell survival, and dysregulated lipid metabolism. These injurious processes compromise neuronal and glial functions, reduce neurotransmitter homeostasis, and cause toxic oligomeric pTau and (amyloid beta peptide of amyloid beta precursor protein) AβPP-Aβ fibrils and insoluble aggregates (neurofibrillary tangles and plaques) to accumulate in brain. AD progresses due to: (1) activation of a harmful positive feedback loop that progressively worsens the effects of insulin resistance; and (2) the formation of ROS- and RNS-related lipid, protein, and DNA adducts that permanently damage basic cellular and molecular functions. Epidemiologic data suggest that insulin resistance diseases, including AD, are exposure-related in etiology. Furthermore, experimental and lifestyle trend data suggest chronic low-level nitrosamine exposures are responsible. These concepts offer opportunities to discover and implement new treatments and devise preventive measures to conquer the AD and other insulin resistance disease epidemics. PMID:24380887

  7. Effects of traumatic brain injury on reactive astrogliosis and seizures in mouse models of Alexander disease.

    Science.gov (United States)

    Cotrina, Maria Luisa; Chen, Michael; Han, Xiaoning; Iliff, Jeffrey; Ren, Zeguang; Sun, Wei; Hagemann, Tracy; Goldman, James; Messing, Albee; Nedergaard, Maiken

    2014-09-25

    Alexander disease (AxD) is the only known human pathology caused by mutations in an astrocyte-specific gene, glial fibrillary acidic protein (GFAP). These mutations result in abnormal GFAP accumulations that promote seizures, motor delays and, ultimately, death. The exact contribution of increased, abnormal levels of astrocytic mutant GFAP in the development and progression of the epileptic phenotype is not clear, and we addressed this question using two mouse models of AxD. Comparison of brain seizure activity spontaneously and after traumatic brain injury (TBI), an effective way to trigger seizures, revealed that abnormal GFAP accumulation contributes to anomalous brain activity (increased non-convulsive hyperactivity) but is not a risk factor for the development of epilepsy after TBI. These data highlight the need to further explore the complex and heterogeneous response of astrocytes towards injury and the involvement of GFAP in the progression of AxD. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. The treatment of Parkinson′s disease with deep brain stimulation: current issues

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    Alexia-Sabine Moldovan

    2015-01-01

    Full Text Available Deep brain stimulation has become a well-established symptomatic treatment for Parkinson′s disease during the last 25 years. Besides improving motor symptoms and long-term motor complications, positive effects on patients′ mobility, activities of daily living, emotional well-being and health-related quality of life have been recognized. Apart from that, numerous clinical trials analyzed effects on non-motor symptoms and side effects of deep brain stimulation. Several technical issues and stimulation paradigms have been and are still being developed to optimize the therapeutic effects, minimize the side effects and facilitate handling. This review summarizes current therapeutic issues, i.e., patient and target selection, surgical procedure and programming paradigms. In addition it focuses on neuropsychological effects and side effects of deep brain stimulation.

  9. On the Central Role of Brain Connectivity in Neurodegenerative Disease Progression

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    Yasser eIturria Medina

    2015-05-01

    Full Text Available Increased brain connectivity, in all its variants, is often considered an evolutionary advantage by mediating complex sensorimotor function and higher cognitive faculties. Interaction among components at all spatial scales, including genes, proteins, neurons, local neuronal circuits and macroscopic brain regions, are indispensable for such vital functions. However, a growing body of evidence suggests that, from the microscopic to the macroscopic levels, such connections might also be a conduit for in intra-brain disease spreading. For instance, cell-to-cell misfolded proteins transmission and neuronal toxicity are prominent connectivity-mediated factors in aging and neurodegeneration. This article offers an overview of connectivity dysfunctions associated with neurodegeneration, with a specific focus on how these may be central to both normal aging and the neuropathologic degenerative progression.

  10. The neurological effects of ghrelin in brain diseases: Beyond metabolic functions.

    Science.gov (United States)

    Jiao, Qian; Du, Xixun; Li, Yong; Gong, Bing; Shi, Limin; Tang, Tingting; Jiang, Hong

    2017-02-01

    Ghrelin, a peptide released by the stomach that plays a major role in regulating energy metabolism, has recently been shown to have effects on neurobiological behaviors. Ghrelin enhances neuronal survival by reducing apoptosis, alleviating inflammation and oxidative stress, and accordingly improving mitochondrial function. Ghrelin also stimulates the proliferation, differentiation and migration of neural stem/progenitor cells (NS/PCs). Additionally, the ghrelin is benefit for the recovery of memory, mood and cognitive dysfunction after stroke or traumatic brain injury. Because of its neuroprotective and neurogenic roles, ghrelin may be used as a therapeutic agent in the brain to combat neurodegenerative disease. In this review, we highlight the pre-clinical evidence and the proposed mechanisms underlying the role of ghrelin in physiological and pathological brain function. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Landmark-based deep multi-instance learning for brain disease diagnosis.

    Science.gov (United States)

    Liu, Mingxia; Zhang, Jun; Adeli, Ehsan; Shen, Dinggang

    2018-01-01

    In conventional Magnetic Resonance (MR) image based methods, two stages are often involved to capture brain structural information for disease diagnosis, i.e., 1) manually partitioning each MR image into a number of regions-of-interest (ROIs), and 2) extracting pre-defined features from each ROI for diagnosis with a certain classifier. However, these pre-defined features often limit the performance of the diagnosis, due to challenges in 1) defining the ROIs and 2) extracting effective disease-related features. In this paper, we propose a landmark-based deep multi-instance learning (LDMIL) framework for brain disease diagnosis. Specifically, we first adopt a data-driven learning approach to discover disease-related anatomical landmarks in the brain MR images, along with their nearby image patches. Then, our LDMIL framework learns an end-to-end MR image classifier for capturing both the local structural information conveyed by image patches located by landmarks and the global structural information derived from all detected landmarks. We have evaluated our proposed framework on 1526 subjects from three public datasets (i.e., ADNI-1, ADNI-2, and MIRIAD), and the experimental results show that our framework can achieve superior performance over state-of-the-art approaches. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Functional Brain Connectome and Its Relation to Hoehn and Yahr Stage in Parkinson Disease.

    Science.gov (United States)

    Suo, Xueling; Lei, Du; Li, Nannan; Cheng, Lan; Chen, Fuqin; Wang, Meiyun; Kemp, Graham J; Peng, Rong; Gong, Qiyong

    2017-09-04

    Purpose To use resting-state functional magnetic resonance (MR) imaging and graph theory approaches to investigate the brain functional connectome and its potential relation to disease severity in Parkinson disease (PD). Materials and Methods This case-control study was approved by the local research ethics committee, and all participants provided informed consent. There were 153 right-handed patients with PD and 81 healthy control participants recruited who were matched for age, sex, and handedness to undergo a 3-T resting-state functional MR examination. The whole-brain functional connectome was constructed by thresholding the Pearson correlation matrices of 90 brain regions, and the topologic properties were analyzed by using graph theory approaches. Nonparametric permutation tests were used to compare topologic properties, and their relationship to disease severity was assessed. Results The functional connectome in PD showed abnormalities at the global level (ie, decrease in clustering coefficient, global efficiency, and local efficiency, and increase in characteristic path length) and at the nodal level (decreased nodal centralities in the sensorimotor cortex, default mode, and temporal-occipital regions; P Scale III score (P = .038, false discovery rate corrected, r = -0.198; and P = .009, false discovery rate corrected, r = -0.270, respectively) and decreased with increasing Hoehn and Yahr stage in patients with PD. Conclusion The configurations of brain functional connectome in patients with PD were perturbed and correlated with disease severity, notably with those responsible for motor functions. These results provide topologic insights into understanding the neural functional changes in relation to disease severity of PD. (©) RSNA, 2017 Online supplemental material is available for this article.

  13. Deep brain stimulation for psychiatric diseases: a pooled analysis of published studies employing disease-specific standardized outcome scales.

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    Nangunoori, Raj; Tomycz, Nestor D; Quigley, Matthew; Oh, Michael Y; Whiting, Donald M

    2013-01-01

    Deep brain stimulation (DBS) has emerged in recent years as a novel therapy in the treatment of refractory psychiatric disease, including major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). Standardized outcome scales were crucial in establishing that DBS was an effective therapy for movement disorders. In order to better characterize the evidence supporting DBS for various psychiatric diseases, we performed a pooled analysis of those studies which incorporated specific standardized rating scales. A Medline search was conducted to identify all studies reporting DBS for MDD, OCD, and TS. The search yielded a total of 49 articles, of which 24 were included: 4 related to MDD (n = 48), 10 to OCD (n = 64), and 10 to TS (n = 46). A meta-analysis of DBS for MDD, OCD, and TS in studies employing disease-specific standardized outcome scales showed that the outcome scales all improved in a statistically significant fashion for these psychiatric diseases. Our pooled analysis suggests that DBS for TS has the highest efficacy amongst the psychiatric diseases currently being treated with DBS, followed by OCD and MDD. DBS for psychiatric diseases remains investigational; however, even when studies failing to incorporate standardized outcome scales are excluded, there is statistically significant evidence that DBS can improve symptoms in MDD, OCD, and TS. Standardized disease-specific outcome scales facilitate pooled analysis and should be a required metric in future studies of DBS for psychiatric disease.

  14. Brain stem and cerebellar atrophy in chronic progressive neuro-Behçet's disease

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    Kanoto, Masafumi, E-mail: mkanoto@med.id.yamagata-u.ac.jp [Department of Diagnostic Radiology, Faculty of Medicine, Yamagata University, Iida-Nishi 2-2-2, 990-9585 Yamagata (Japan); Hosoya, Takaaki, E-mail: thosoya@med.id.yamagata-u.ac.jp [Department of Diagnostic Radiology, Faculty of Medicine, Yamagata University, Iida-Nishi 2-2-2, 990-9585 Yamagata (Japan); Toyoguchi, Yuuki, E-mail: c-elegans_0201g@mail.goo.ne.jp [Department of Diagnostic Radiology, Faculty of Medicine, Yamagata University, Iida-Nishi 2-2-2, 990-9585 Yamagata (Japan); Oda, Atsuko, E-mail: a.oda@med.id.yamagata-u.ac.jp [Department of Diagnostic Radiology, Faculty of Medicine, Yamagata University, Iida-Nishi 2-2-2, 990-9585 Yamagata (Japan)

    2013-01-15

    Purpose: Chronic progressive neuro-Behçet's disease (CPNBD) resembles multiple sclerosis (MS) on patient background and image findings, and therefore is difficult to diagnose. The purpose is to identify the characteristic magnetic resonance imaging (MRI) findings of CPNBD and to clarify the differences between the MRI findings of CPNBD and those of MS. Materials and methods: The subjects consist of a CPNBD group (n = 4; 1 male and 3 females; mean age, 51 y.o.), a MS group (n = 19; 3 males and 16 females; mean age, 45 y.o.) and a normal control group (n = 23; 10 males and 13 females; mean age, 45 y.o.). Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were retrospectively evaluated in each subjects. In middle sagittal brain MR images, the prepontine distance was measured as an indirect index of brain stem and cerebellar atrophy and the pontine and mesencephalic distance was measured as a direct index of brain stem atrophy. These indexes were statistically analyzed. Results: Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were seen in all CPNBD cases. Prepontine distance was significantly different between the CPNBD group and the MS group (p < 0.05), and between the CPNBD group and the normal control group (p < 0.001). Pontine and mesencephalic distance were significantly different between the CPNBD group and the MS group (p < 0.001, p < 0.01 respectively), and between the CPNBD group and the normal control group (p < 0.001). Conclusions: Chronic progressive neuro-Behçet's disease should be considered in patients with brain stem and cerebellar atrophy in addition to leukoencephalopathy similar to that seen in multiple sclerosis.

  15. Graph analysis of structural brain networks in Alzheimer's disease: beyond small world properties.

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    John, Majnu; Ikuta, Toshikazu; Ferbinteanu, Janina

    2017-03-01

    Changes in brain connectivity in patients with early Alzheimer's disease (AD) have been investigated using graph analysis. However, these studies were based on small data sets, explored a limited range of network parameters, and did not focus on more restricted sub-networks, where neurodegenerative processes may introduce more prominent alterations. In this study, we constructed structural brain networks out of 87 regions using data from 135 healthy elders and 100 early AD patients selected from the Open Access Series of Imaging Studies (OASIS) database. We evaluated the graph properties of these networks by investigating metrics of network efficiency, small world properties, segregation, product measures of complexity, and entropy. Because degenerative processes take place at different rates in different brain areas, analysis restricted to sub-networks may reveal changes otherwise undetected. Therefore, we first analyzed the graph properties of a network encompassing all brain areas considered together, and then repeated the analysis after dividing the brain areas into two sub-networks constructed by applying a clustering algorithm. At the level of large scale network, the analysis did not reveal differences between AD patients and controls. In contrast, the same analysis performed on the two sub-networks revealed that small worldness diminished with AD only in the sub-network containing the areas of medial temporal lobe known to be heaviest and earliest affected. The second sub-network, which did not present significant AD-induced modifications of 'classical' small world parameters, nonetheless showed a trend towards an increase in small world propensity, a novel metric that unbiasedly quantifies small world structure. Beyond small world properties, complexity and entropy measures indicated that the intricacy of connection patterns and structural diversity decreased in both sub-networks. These results show that neurodegenerative processes impact volumetric

  16. Microbiome-Derived Lipopolysaccharide Enriched in the Perinuclear Region of Alzheimer’s Disease Brain

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    Yuhai Zhao

    2017-09-01

    Full Text Available Abundant clinical, epidemiological, imaging, genetic, molecular, and pathophysiological data together indicate that there occur an unusual inflammatory reaction and a disruption of the innate-immune signaling system in Alzheimer’s disease (AD brain. Despite many years of intense study, the origin and molecular mechanics of these AD-relevant pathogenic signals are still not well understood. Here, we provide evidence that an intensely pro-inflammatory bacterial lipopolysaccharide (LPS, part of a complex mixture of pro-inflammatory neurotoxins arising from abundant Gram-negative bacilli of the human gastrointestinal (GI tract, are abundant in AD-affected brain neocortex and hippocampus. For the first time, we provide evidence that LPS immunohistochemical signals appear to aggregate in clumps in the parenchyma in control brains, and in AD, about 75% of anti-LPS signals were clustered around the periphery of DAPI-stained nuclei. As LPS is an abundant secretory product of Gram-negative bacilli resident in the human GI-tract, these observations suggest (i that a major source of pro-inflammatory signals in AD brain may originate from internally derived noxious exudates of the GI-tract microbiome; (ii that due to aging, vascular deficits or degenerative disease these neurotoxic molecules may “leak” into the systemic circulation, cerebral vasculature, and on into the brain; and (iii that this internal source of microbiome-derived neurotoxins may play a particularly strong role in shaping the human immune system and contributing to neural degeneration, particularly in the aging CNS. This “Perspectives” paper will further highlight some very recent developments that implicate GI-tract microbiome-derived LPS as an important contributor to inflammatory-neurodegeneration in the AD brain.

  17. Differential pharmacological effects on brain reactivity and plasticity in Alzheimer’s Disease

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    Anna-Katharine eBrem

    2013-10-01

    Full Text Available Acetylcholinesterase inhibitors (AChEI are the most commonly prescribed monotherapeutic medications for Alzheimer’s disease (AD. However, their underlying neurophysiological effects remain largely unknown.We investigated the effects of monotherapy (AChEI and combination therapy (AChEI and memantine on brain reactivity and plasticity. Patients treated with monotherapy (AChEI (N=7 were compared to patients receiving combination therapy (COM (N=9 and a group of age-matched, healthy controls (HC (N=13. Cortical reactivity and plasticity of the motor cortex (MC were examined using transcranial magnetic stimulation (TMS. Cognitive functions were assessed with the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog, activities of daily living with the ADCS-ADL. In addition we assessed the degree of brain atrophy by measuring brain-scalp distances in seven different brain areas.Patient groups differed in resting motor threshold and brain atrophy, with COM showing a lower motor threshold but less atrophy than AChEI. COM showed similar plasticity effects as the HC group, while plasticity was reduced in AChEI. Long-interval intracortical inhibition (LICI was impaired in both patient groups when compared to HC. ADAS-Cog scores were positively correlated with LICI measures and with brain atrophy, specifically in the left IPL.AD patients treated with mono- or combination therapy show distinct neurophysiological patterns. Further studies should investigate whether these measures might serve as biomarkers of treatment response and whether they could guide other therapeutic interventions.

  18. Framingham coronary heart disease risk score can be predicted from structural brain images in elderly subjects.

    Directory of Open Access Journals (Sweden)

    Jane Maryam Rondina

    2014-12-01

    Full Text Available Recent literature has presented evidence that cardiovascular risk factors (CVRF play an important role on cognitive performance in elderly individuals, both those who are asymptomatic and those who suffer from symptoms of neurodegenerative disorders. Findings from studies applying neuroimaging methods have increasingly reinforced such notion. Studies addressing the impact of CVRF on brain anatomy changes have gained increasing importance, as recent papers have reported gray matter loss predominantly in regions traditionally affected in Alzheimer’s disease (AD and vascular dementia in the presence of a high degree of cardiovascular risk. In the present paper, we explore the association between CVRF and brain changes using pattern recognition techniques applied to structural MRI and the Framingham score (a composite measure of cardiovascular risk largely used in epidemiological studies in a sample of healthy elderly individuals. We aim to answer the following questions: Is it possible to decode (i.e., to learn information regarding cardiovascular risk from structural brain images enabling individual predictions? Among clinical measures comprising the Framingham score, are there particular risk factors that stand as more predictable from patterns of brain changes? Our main findings are threefold: i we verified that structural changes in spatially distributed patterns in the brain enable statistically significant prediction of Framingham scores. This result is still significant when controlling for the presence of the APOE 4 allele (an important genetic risk factor for both AD and cardiovascular disease. ii When considering each risk factor singly, we found different levels of correlation between real and predicted factors; however, single factors were not significantly predictable from brain images when considering APOE4 allele presence as covariate. iii We found important gender differences, and the possible causes of that finding are discussed.

  19. Whole-brain functional networks in cognitively normal, mild cognitive impairment, and Alzheimer's disease.

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    Eun Hyun Seo

    Full Text Available The conceptual significance of understanding functional brain alterations and cognitive deficits associated with Alzheimer's disease (AD process has been widely established. However, the whole-brain functional networks of AD and its prodromal stage, mild cognitive impairment (MCI, are not well clarified yet. In this study, we compared the characteristics of the whole-brain functional networks among cognitively normal (CN, MCI, and AD individuals by applying graph theoretical analyses to [(18F] fluorodeoxyglucose positron emission tomography (FDG-PET data. Ninety-four CN elderly, 183 with MCI, and 216 with AD underwent clinical evaluation and FDG-PET scan. The overall small-world property as seen in the CN whole-brain network was preserved in MCI and AD. In contrast, individual parameters of the network were altered with the following patterns of changes: local clustering of networks was lower in both MCI and AD compared to CN, while path length was not different among the three groups. Then, MCI had a lower level of local clustering than AD. Subgroup analyses for AD also revealed that very mild AD had lower local clustering and shorter path length compared to mild AD. Regarding the local properties of the whole-brain networks, MCI and AD had significantly decreased normalized betweenness centrality in several hubs regionally associated with the default mode network compared to CN. Our results suggest that the functional integration in whole-brain network progressively declines due to the AD process. On the other hand, functional relatedness between neighboring brain regions may not gradually decrease, but be the most severely altered in MCI stage and gradually re-increase in clinical AD stages.

  20. Increased White Matter Inflammation in Aging- and Alzheimer’s Disease Brain

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    Divya Raj

    2017-06-01

    Full Text Available Chronic neuroinflammation, which is primarily mediated by microglia, plays an essential role in aging and neurodegeneration. It is still unclear whether this microglia-induced neuroinflammation occurs globally or is confined to distinct brain regions. In this study, we investigated microglia activity in various brain regions upon healthy aging and Alzheimer’s disease (AD-related pathology in both human and mouse samples. In purified microglia isolated from aging mouse brains, we found a profound gene expression pattern related to pro-inflammatory processes, phagocytosis, and lipid homeostasis. Particularly in white matter microglia of 24-month-old mice, abundant expression of phagocytic markers including Mac-2, Axl, CD16/32, Dectin1, CD11c, and CD36 was detected. Interestingly, in white matter of human brain tissue the first signs of inflammatory activity were already detected during middle age. Thus quantification of microglial proteins, such as CD68 (commonly associated with phagocytosis and HLA-DR (associated with antigen presentation, in postmortem human white matter brain tissue showed an age-dependent increase in immunoreactivity already in middle-aged people (53.2 ± 2.0 years. This early inflammation was also detectable by non-invasive positron emission tomography imaging using [11C]-(R-PK11195, a ligand that binds to activated microglia. Increased microglia activity was also prominently present in the white matter of human postmortem early-onset AD (EOAD brain tissue. Interestingly, microglia activity in the white matter of late-onset AD (LOAD CNS was similar to that of the aged clinically silent AD cases. These data indicate that microglia-induced neuroinflammation is predominant in the white matter of aging mice and humans as well as in EOAD brains. This white matter inflammation may contribute to the progression of neurodegeneration, and have prognostic value for detecting the onset and progression of aging and neurodegeneration.

  1. Brain Atrophy of Secondary REM-Sleep Behavior Disorder in Neurodegenerative Disease.

    Science.gov (United States)

    Kim, Hee-Jin; Im, Hyung Kyun; Kim, Juhan; Han, Jee-Young; de Leon, Mony; Deshpande, Anup; Moon, Won-Jin

    2016-04-05

    Rapid eye movement sleep behavior disorder (RBD) may present as an early manifestation of an evolving neurodegenerative disorder with alpha-synucleinopathy. We investigated that dementia with RBD might show distinctive cortical atrophic patterns. A total of 31 patients with idiopathic Parkinson's disease (IPD), 23 with clinically probable Alzheimer's disease (AD), and 36 healthy controls participated in this study. Patients with AD and IPD were divided into two groups according to results of polysomnography and rated with a validated Korean version of the RBD screening questionnaire (RBDSQ-K), which covers the clinical features of RBD. Voxel-based morphometry was adapted for detection of regional brain atrophy among groups of subjects. Scores on RBDSQ-K were higher in the IPD group (3.54 ± 2.8) than in any other group (AD, 2.94 ± 2.4; healthy controls, 2.31 ± 1.9). Atrophic changes according to RBDSQ-K scores were characteristically in the posterior part of the brain and brain stem, including the hypothalamus and posterior temporal region including the hippocampus and bilateral occipital lobe. AD patients with RBD showed more specialized atrophic patterns distributed in the posterior and inferior parts of the brain including the bilateral temporal and occipital cortices compared to groups without RBD. The IPD group with RBD showed right temporal cortical atrophic changes. The group of patients with neurodegenerative diseases and RBD showed distinctive brain atrophy patterns, especially in the posterior and inferior cortices. These results suggest that patients diagnosed with clinically probable AD or IPD might have mixed pathologies including α-synucleinopathy.

  2. Parkinson's disease and brain mitochondrial dysfunction: a functional phosphorus magnetic resonance spectroscopy study.

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    Rango, Mario; Bonifati, Cristiana; Bresolin, Nereo

    2006-02-01

    In spite of several evidences for a mitochondrial impairment in Parkinson's disease (PD), so far it has not been possible to show in vivo mitochondrial dysfunction in the human brain of PD patients. The authors used the high temporal and spatial resolution 31 phosphorus magnetic resonance spectroscopy (31P MRS) technique, which they have previously developed in normal subjects and in patients with mitochondrial diseases to study mitochondrial function by observing high-energy phosphates (HEPs) and intracellular pH (pH) in the visual cortex of 20 patients with PD and 20 normal subjects at rest, during, and after visual activation. In normal subjects, HEPs remained unchanged during activation, but rose significantly (by 16%) during recovery, and pH increased during visual activation with a slow return to rest values. In PD patients, HEPs were within the normal range at rest and did not change during activation, but fell significantly (by 36%) in the recovery period; pH did not reveal a homogeneous pattern with a wide spread of values. Energy unbalance under increased oxidative metabolism requirements, that is, the postactivation phase, discloses a mitochondrial dysfunction that is present in the brain of patients with PD even in the absence of overt clinical manifestations, as in the visual cortex. This is in agreement with our previous findings in patients with mitochondrial disease without clinical central nervous system (CNS) involvement. The heterogeneity of the physicochemical environment (i.e., pH) suggests various degrees of subclinical brain involvement in PD. The combined use of MRS and brain activation is fundamental for the study of brain energetics in patients with PD and may prove an important tool for diagnostic purposes and, possibly, to monitor therapeutic interventions.

  3. Comparison of neuropathology in Parkinson's disease subjects with and without deep brain stimulation.

    Science.gov (United States)

    Pal, Gian D; Ouyang, Bichun; Serrano, Geidy; Shill, Holly A; Goetz, Christopher; Stebbins, Glenn; Metman, Leo Verhagen; Driver-Dunckley, Erika; Mehta, Shyamal H; Caviness, John N; Sabbagh, Marwan N; Adler, Charles H; Beach, Thomas G

    2017-02-01

    The aim of this postmortem study was to compare, in Parkinson's disease subjects with and without bilateral subthalamic nucleus deep brain stimulation (STN-DBS), the loss of pigmented neurons within the substantia nigra and pathological alpha-synuclein density within the SN and other brain regions. PD subjects were identified from the Arizona Study of Aging and Neurodegenerative Disorders database (STN-DBS = 11, non-DBS = 156). Pigmented neuron loss scores within the substantia nigra as well as alpha-synuclein density scores within the substantia nigra and 9 other brain regions were compared, the latter individually and in summary as the Lewy body brain load score. DBS subjects had higher alpha-synuclein density scores within the substantia nigra, olfactory bulb, and locus ceruleus, as well as higher total Lewy body brain load scores when compared with non-DBS subjects. No differences in substantia nigra pigmented neuron loss scores were found. STN-DBS subjects tend to have higher alpha-synuclein density scores, but do not have a differential loss of substantia nigra pigmented neurons. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

  4. Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer's disease

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    Jiao, S-S; Shen, L-L; Zhu, C; Bu, X-L; Liu, Y-H; Liu, C-H; Yao, X-Q; Zhang, L-L; Zhou, H-D; Walker, D G; Tan, J; Götz, J; Zhou, X-F; Wang, Y-J

    2016-01-01

    Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aβ-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established. Here, we found that the BDNF level was reduced in the serum and brain of AD patients and P301L transgenic mice (a mouse model of tauopathy). Intralateral ventricle injection of adeno-associated virus carrying the gene encoding human BDNF (AAV-BDNF) achieved stable expression of BDNF gene and restored the BDNF level in the brains of P301L mice. Restoration of the BDNF level attenuated behavioral deficits, prevented neuron loss, alleviated synaptic degeneration and reduced neuronal abnormality, but did not affect tau hyperphosphorylation level in the brains of P301L mice. Long-term expression of AAV-BDNF in the brain was well tolerated by the mice. These findings suggest that the gene delivery of BDNF is a promising treatment for tau-related neurodegeneration for AD and other neurodegenerative disorders with tauopathy. PMID:27701410

  5. Molecular pathophysiology of impaired glucose metabolism, mitochondrial dysfunction, and oxidative DNA damage in Alzheimer's disease brain.

    Science.gov (United States)

    Abolhassani, Nona; Leon, Julio; Sheng, Zijing; Oka, Sugako; Hamasaki, Hideomi; Iwaki, Toru; Nakabeppu, Yusaku

    2017-01-01

    In normal brain, neurons in the cortex and hippocampus produce insulin, which modulates glucose metabolism and cognitive functions. It has been shown that insulin resistance impairs glucose metabolism and mitochondrial function, thus increasing production of reactive oxygen species. Recent progress in Alzheimer's disease (AD) research revealed that insulin production and signaling are severely impaired in AD brain, thereby resulting in mitochondrial dysfunction and increased oxidative stress. Among possible oxidative DNA lesions, 8-oxoguanine (8-oxoG) is highly accumulated in the brain of AD patients. Previously we have shown that incorporating 8-oxoG in nuclear and mitochondrial DNA promotes MUTYH (adenine DNA glycosylase) dependent neurodegeneration. Moreover, cortical neurons prepared from MTH1 (8-oxo-dGTPase)/OGG1 (8-oxoG DNA glycosylase)-double deficient adult mouse brains is shown to exhibit significantly poor neuritogenesis in vitro with increased 8-oxoG accumulation in mitochondrial DNA in the absence of antioxidants. Therefore, 8-oxoG can be considered involved in the neurodegenerative process in AD brain. In mild cognitive impairment, mitochondrial dysfunction and oxidative damage may induce synaptic dysfunction due to energy failures in neurons thus resulting in impaired cognitive function. If such abnormality lasts long, it can lead to vicious cycles of oxidative damage, which may then trigger the neurodegenerative process seen in Alzheimer type dementia. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Cognitive rehabilitation changes memory-related brain activity in people with Alzheimer disease.

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    van Paasschen, Jorien; Clare, Linda; Yuen, Kenneth S L; Woods, Robert T; Evans, Suzannah J; Parkinson, Caroline H; Rugg, Michael D; Linden, David E J

    2013-06-01

    People with Alzheimer disease (AD) are capable of new learning when cognitive support is provided, suggesting that there is plasticity even in a degenerating brain. However, it is unclear how a cognition-focused intervention operates on a neural level. The present study examined the effects of cognitive rehabilitation (CR) on memory-related brain activation in people with early-stage AD, as measured by functional magnetic resonance imaging (fMRI). A total of 19 participants either received 8 weeks of CR treatment (n = 7) or formed a control group (n = 12). We scanned participants pretreatment and posttreatment while they learned and recognized unfamiliar face-name pairs. Following treatment, the CR group showed higher brain activation during recognition of face-name pairs in the left middle and inferior frontal gyri, the left insula, and 2s regions in the right medial parietal cortex. The control group showed decreased activation in these areas during recognition after the intervention period. Neither group showed an activation change during encoding. Behavioral performance on face-name learning did not improve for either group. We suggest that CR may have operated on the process of recognition through partial restoration of function in frontal brain areas that are less compromised in early-stage AD and that physiological markers may be more sensitive indicators of brain plasticity than behavioral performance.

  7. Brain ischemia with Alzheimer phenotype dysregulates Alzheimer's disease-related proteins.

    Science.gov (United States)

    Ułamek-Kozioł, Marzena; Pluta, Ryszard; Bogucka-Kocka, Anna; Januszewski, Sławomir; Kocki, Janusz; Czuczwar, Stanisław J

    2016-06-01

    There are evidences for the influence of Alzheimer's proteins on postischemic brain injury. We present here an overview of the published evidence underpinning the relationships between β-amyloid peptide, hyperphosphorylated tau protein, presenilins, apolipoproteins, secretases and neuronal survival/death decisions after ischemia and development of postischemic dementia. The interactions of above molecules and their influence and contribution to final ischemic brain degeneration resulting in dementia of Alzheimer phenotype are reviewed. Generation and deposition of β-amyloid peptide and tau protein pathology are essential factors involved in Alzheimer's disease development as well as in postischemic brain dementia. Postischemic injuries demonstrate that ischemia may stimulate pathological amyloid precursor protein processing by upregulation of β- and γ-secretases and therefore are capable of establishing a vicious cycle. Functional postischemic brain recovery is always delayed and incomplete by an injury-related increase in the amount of the neurotoxic C-terminal of amyloid precursor protein and β-amyloid peptide. Finally, we present here the concept that Alzheimer's proteins can contribute to and/or precipitate postischemic brain neurodegeneration including dementia with Alzheimer's phenotype. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  8. Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer's disease.

    Science.gov (United States)

    Jiao, S-S; Shen, L-L; Zhu, C; Bu, X-L; Liu, Y-H; Liu, C-H; Yao, X-Q; Zhang, L-L; Zhou, H-D; Walker, D G; Tan, J; Götz, J; Zhou, X-F; Wang, Y-J

    2016-10-04

    Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aβ-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established. Here, we found that the BDNF level was reduced in the serum and brain of AD patients and P301L transgenic mice (a mouse model of tauopathy). Intralateral ventricle injection of adeno-associated virus carrying the gene encoding human BDNF (AAV-BDNF) achieved stable expression of BDNF gene and restored the BDNF level in the brains of P301L mice. Restoration of the BDNF level attenuated behavioral deficits, prevented neuron loss, alleviated synaptic degeneration and reduced neuronal abnormality, but did not affect tau hyperphosphorylation level in the brains of P301L mice. Long-term expression of AAV-BDNF in the brain was well tolerated by the mice. These findings suggest that the gene delivery of BDNF is a promising treatment for tau-related neurodegeneration for AD and other neurodegenerative disorders with tauopathy.

  9. Impact of small vessel disease in the brain on gait and balance.

    Science.gov (United States)

    Pinter, Daniela; Ritchie, Stuart J; Doubal, Fergus; Gattringer, Thomas; Morris, Zoe; Bastin, Mark E; Del C Valdés Hernández, Maria; Royle, Natalie A; Corley, Janie; Muñoz Maniega, Susana; Pattie, Alison; Dickie, David A; Staals, Julie; Gow, Alan J; Starr, John M; Deary, Ian J; Enzinger, Christian; Fazekas, Franz; Wardlaw, Joanna

    2017-01-30

    Gait and balance impairment is highly prevalent in older people. We aimed to assess whether and how single markers of small vessel disease (SVD) or a combination thereof explain gait and balance function in the elderly. We analysed 678 community-dwelling healthy subjects from the Lothian Birth Cohort 1936 at the age of 71-74 years who had undergone comprehensive risk factor assessment, gait and balance assessment as well as brain MRI. We investigated the impact of individual SVD markers (white matter hyperintensity - WMH, microbleeds, lacunes, enlarged perivascular spaces, brain atrophy) as seen on structural brain MRI and of a global SVD score on the patients' performance. A regression model revealed that age, sex, and hypertension significantly explained gait speed. Among SVD markers white matter hyperintensity (WMH) score or volume were additional significant and independent predictors of gait speed in the regression model. A similar association was seen with the global SVD score. Our study confirms a negative impact of SVD-related morphologic brain changes on gait speed in addition to age, sex and hypertension independent from brain atrophy. The presence of WMH seems to be the major driving force for SVD on gait impairment in healthy elderly subjects.

  10. Testosterone effect on brain metabolism in elderly patients with Alzheimer's disease: comparing two cases at different disease stages.

    Science.gov (United States)

    Tan, R S

    2013-06-01

    To describe the effect of testosterone replacement therapy (TRT) on the brain activity of two demented, hypogonadal male patients with early and late-stage Alzheimer's disease (AD), respectively. We describe the clinical and positron emission tomography (PET) findings for two individuals, one with early stage and the other with late-stage Alzheimer's disease, before and after treatment with a topical testosterone gel. Both patients were hypogonadal at baseline. We assessed cerebral glucose metabolism (CGM) via (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET). We investigated whether there are testosterone-susceptible areas within cerebral structures in patients with Alzheimer's disease. Under testosterone replacement therapy, changes in cerebral glucose metabolism were observed in both patients. Improvement in glucose uptake was observed most consistently in the parietal lobe and brainstem; decreased glucose metabolism was observed in the temporal lobe, the limbic system and the insula for these two subjects. These case reports demonstrate the potential for PET scanning to detect changes in cerebral glucose metabolism in hypogonadal men with Alzheimer's disease who are treated with testosterone. Further study will be needed to investigate the consistency and significance of these changes in terms of magnitude and brain region, and the correlation with functional changes.

  11. Bilateral Deep Brain Stimulation vs Best Medical Therapy for Patients With Advanced Parkinson Disease

    Science.gov (United States)

    Weaver, Frances M.; Follett, Kenneth; Stern, Matthew; Hur, Kwan; Harris, Crystal; Marks, William J.; Rothlind, Johannes; Sagher, Oren; Reda, Domenic; Moy, Claudia S.; Pahwa, Rajesh; Burchiel, Kim; Hogarth, Penelope; Lai, Eugene C.; Duda, John E.; Holloway, Kathryn; Samii, Ali; Horn, Stacy; Bronstein, Jeff; Stoner, Gatana; Heemskerk, Jill; Huang, Grant D.

    2010-01-01

    Context Deep brain stimulation is an accepted treatment for advanced Parkinson disease (PD), although there are few randomized trials comparing treatments, and most studies exclude older patients. Objective To compare 6-month outcomes for patients with PD who received deep brain stimulation or best medical therapy. Design, Setting, and Patients Randomized controlled trial of patients who received either deep brain stimulation or best medical therapy, stratified by study site and patient age (managed by movement disorder neurologists. Main Outcome Measures The primary outcome was time spent in the “on” state (good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries. Other outcomes included motor function, quality of life, neurocognitive function, and adverse events. Results Patients who received deep brain stimulation gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95% CI, 3.7-5.4 h/d]; P<.001). Motor function improved significantly (P<.001) with deep brain stimulation vs best medical therapy, such that 71% of deep brain stimulation patients and 32% of best medical therapy patients experienced clinically meaningful motor function improvements (≥5 points). Compared with the best medical therapy group, the deep brain stimulation group experienced significant improvements in the summary measure of quality of life and on 7 of 8 PD quality-of-life scores (P<.001). Neurocognitive testing revealed small decrements in some areas of information processing for patients receiving deep brain stimulation vs best medical therapy. At least 1 serious adverse event occurred in 49 deep brain stimulation patients and 15 best medical therapy patients (P<.001), including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage. Conclusion In this randomized controlled trial of

  12. Group-Level Progressive Alterations in Brain Connectivity Patterns Revealed by Diffusion-Tensor Brain Networks across Severity Stages in Alzheimer's Disease.

    Science.gov (United States)

    Rasero, Javier; Alonso-Montes, Carmen; Diez, Ibai; Olabarrieta-Landa, Laiene; Remaki, Lakhdar; Escudero, Iñaki; Mateos, Beatriz; Bonifazi, Paolo; Fernandez, Manuel; Arango-Lasprilla, Juan Carlos; Stramaglia, Sebastiano; Cortes, Jesus M

    2017-01-01

    Alzheimer's disease (AD) is a chronically progressive neurodegenerative disease highly correlated to aging. Whether AD originates by targeting a localized brain area and propagates to the rest of the brain across disease-severity progression is a question with an unknown answer. Here, we aim to provide an answer to this question at the group-level by looking at differences in diffusion-tensor brain networks. In particular, making use of data from Alzheimer's Disease Neuroimaging Initiative (ADNI), four different groups were defined (all of them matched by age, sex and education level): G1 (N1 = 36, healthy control subjects, Control), G2 (N2 = 36, early mild cognitive impairment, EMCI), G3 (N3 = 36, late mild cognitive impairment, LMCI) and G4 (N4 = 36, AD). Diffusion-tensor brain networks were compared across three disease stages: stage I (Control vs. EMCI), stage II (Control vs. LMCI) and stage III (Control vs. AD). The group comparison was performed using the multivariate distance matrix regression analysis, a technique that was born in genomics and was recently proposed to handle brain functional networks, but here applied to diffusion-tensor data. The results were threefold: First, no significant differences were found in stage I. Second, significant differences were found in stage II in the connectivity pattern of a subnetwork strongly associated to memory function (including part of the hippocampus, amygdala, entorhinal cortex, fusiform gyrus, inferior and middle temporal gyrus, parahippocampal gyrus and temporal pole). Third, a widespread disconnection across the entire AD brain was found in stage III, affecting more strongly the same memory subnetwork appearing in stage II, plus the other new subnetworks, including the default mode network, medial visual network, frontoparietal regions and striatum. Our results are consistent with a scenario where progressive alterations of connectivity arise as the disease severity increases and provide the brain areas

  13. Recent Developments in Understanding Brain Aging: Implications for Alzheimer's Disease and Vascular Cognitive Impairment.

    Science.gov (United States)

    Deak, Ferenc; Freeman, Willard M; Ungvari, Zoltan; Csiszar, Anna; Sonntag, William E

    2016-01-01

    As the population of the Western world is aging, there is increasing awareness of age-related impairments in cognitive function and a rising interest in finding novel approaches to preserve cerebral health. A special collection of articles in The Journals of Gerontology: Biological Sciences and Medical Sciences brings together information of different aspects of brain aging, from latest developments in the field of neurodegenerative disorders to cerebral microvascular mechanisms of cognitive decline. It is emphasized that although the cellular changes that occur within aging neurons have been widely studied, more research is required as new signaling pathways are discovered that can potentially protect cells. New avenues for research targeting cellular senescence, epigenetics, and endocrine mechanisms of brain aging are also discussed. Based on the current literature it is clear that understanding brain aging and reducing risk for neurological disease with age requires searching for mechanisms and treatment options beyond the age-related changes in neuronal function. Thus, comprehensive approaches need to be developed that address the multiple, interrelated mechanisms of brain aging. Attention is brought to the importance of maintenance of cerebromicrovascular health, restoring neuroendocrine balance, and the pressing need for funding more innovative research into the interactions of neuronal, neuroendocrine, inflammatory and microvascular mechanisms of cognitive impairment, and Alzheimer's disease. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. ROS and Brain Diseases: The Good, the Bad, and the Ugly

    Directory of Open Access Journals (Sweden)

    Aurel Popa-Wagner

    2013-01-01

    Full Text Available The brain is a major metabolizer of oxygen and yet has relatively feeble protective antioxidant mechanisms. This paper reviews the Janus-faced properties of reactive oxygen species. It will describe the positive aspects of moderately induced ROS but it will also outline recent research findings concerning the impact of oxidative and nitrooxidative stress on neuronal structure and function in neuropsychiatric diseases, including major depression. A common denominator of all neuropsychiatric diseases including schizophrenia and ADHD is an increased inflammatory response of the brain caused either by an exposure to proinflammatory agents during development or an accumulation of degenerated neurons, oxidized proteins, glycated products, or lipid peroxidation in the adult brain. Therefore, modulation of the prooxidant-antioxidant balance provides a therapeutic option which can be used to improve neuroprotection in response to oxidative stress. We also discuss the neuroprotective role of the nuclear factor erythroid 2-related factor (Nrf2 in the aged brain in response to oxidative stressors and nanoparticle-mediated delivery of ROS-scavenging drugs. The antioxidant therapy is a novel therapeutic strategy. However, the available drugs have pleiotropic actions and are not fully characterized in the clinic. Additional clinical trials are needed to assess the risks and benefits of antioxidant therapies for neuropsychiatric disorders.

  15. Automated diagnosis of Alzheimer's disease with multi-atlas based whole brain segmentations

    Science.gov (United States)

    Luo, Yuan; Tang, Xiaoying

    2017-03-01

    Voxel-based analysis is widely used in quantitative analysis of structural brain magnetic resonance imaging (MRI) and automated disease detection, such as Alzheimer's disease (AD). However, noise at the voxel level may cause low sensitivity to AD-induced structural abnormalities. This can be addressed with the use of a whole brain structural segmentation approach which greatly reduces the dimension of features (the number of voxels). In this paper, we propose an automatic AD diagnosis system that combines such whole brain segmen- tations with advanced machine learning methods. We used a multi-atlas segmentation technique to parcellate T1-weighted images into 54 distinct brain regions and extract their structural volumes to serve as the features for principal-component-analysis-based dimension reduction and support-vector-machine-based classification. The relationship between the number of retained principal components (PCs) and the diagnosis accuracy was systematically evaluated, in a leave-one-out fashion, based on 28 AD subjects and 23 age-matched healthy subjects. Our approach yielded pretty good classification results with 96.08% overall accuracy being achieved using the three foremost PCs. In addition, our approach yielded 96.43% specificity, 100% sensitivity, and 0.9891 area under the receiver operating characteristic curve.

  16. Gene expression of the TGF-beta family in rat brain infected with Borna disease virus.

    Science.gov (United States)

    Nishino, Yoshii; Ooishi, Ryo; Kurokawa, Sachiko; Fujino, Kan; Murakami, Masaru; Madarame, Hiroo; Hashimoto, Osamu; Sugiyama, Kazutoshi; Funaba, Masayuki

    2009-01-01

    CRNP5, a variant of Borna disease virus (BDV), has stronger pathogenesis in rats than the related variant CRP3, although only 4 amino acids in the whole genome are different. As a first step to clarify the differential pathogenesis between the variants, the present study focused on examining the expression of the transforming growth factor (TGF)-beta family in the brain of rats infected with BDV. The main results were as follows. (1) BDV infection, irrespective of the variant, up-regulates TGF-beta1 expression in the brain, (2) the expressions of signal receptors for TGF-beta1 are also increased, (3) the expression of brain inhibin/activin betaE is up-regulated by BDV infection, and (4) the expression of brain inhibin/activin betaC tends to be higher in rats exhibiting severe Borna disease. These results indicate that members of the TGF-beta family are involved in neuronal disorders induced by BDV infection in a ligand-dependent manner. In particular, up-regulation of inhibin/activin betaC may be a key event responsible for induction of the stronger pathogenesis of the CRNP5 variant of BDV.

  17. Cannabinoid Signaling and Neuroinflammatory Diseases: A Melting pot for the Regulation of Brain Immune Responses.

    Science.gov (United States)

    Chiurchiù, Valerio; Leuti, Alessandro; Maccarrone, Mauro

    2015-06-01

    The concept of the central nervous system (CNS) as an immune-privileged site, essentially due to the presence of the blood brain barrier, appears to be overly simplistic. Indeed, within healthy CNS immune activities are permitted and are required for neuronal function and host defense, not only due to the presence of the resident innate immune cells of the brain, but also by virtue of a complex cross-talk of the CNS with peripheral immune cells. Nonetheless, long-standing and persisting neuroinflammatory responses are most often detrimental and characterize several neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease and amyotrophic lateral sclerosis. A growing body of evidence suggests that Cannabis sativa-derived phytocannabinoids, as well as synthetic cannabinoids, are endowed with significant immunoregulatory and anti-inflammatory properties, both in peripheral tissues and in the CNS, through the activation of cannabinoid receptors. In this review, the immunomodulatory effects of cannabinoid signaling on the most relevant brain immune cells will be discussed. In addition, the impact of cannabinoid regulation on the overall integration of the manifold brain immune responses will also be highlighted, along with the implication of these compounds as potential agents for the management of neuroinflammatory disorders.

  18. GM-CSF is not essential for experimental autoimmune encephalomyelitis but promotes brain-targeted disease.

    Science.gov (United States)

    Pierson, Emily R; Goverman, Joan M

    2017-04-06

    Experimental autoimmune encephalomyelitis (EAE) has been used as an animal model of multiple sclerosis to identify pathogenic cytokines that could be therapeutic targets. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is the only cytokine reported to be essential for EAE. We investigated the role of GM-CSF in EAE in C3HeB/FeJ mice that uniquely exhibit extensive brain and spinal cord inflammation. Unexpectedly, GM-CSF-deficient C3HeB/FeJ mice were fully susceptible to EAE because IL-17 activity compensated for the loss of GM-CSF during induction of spinal cord-targeted disease. In contrast, both GM-CSF and IL-17 were needed to fully overcome the inhibitory influence of IFN-γ on the induction of inflammation in the brain. Both GM-CSF and IL-17 independently promoted neutrophil accumulation in the brain, which was essential for brain-targeted disease. These results identify a GM-CSF/IL-17/IFN-γ axis that regulates inflammation in the central nervous system and suggest that a combination of cytokine-neutralizing therapies may be needed to dampen central nervous system autoimmunity.

  19. Differential Changes in Postsynaptic Density Proteins in Postmortem Huntington’s Disease and Parkinson’s Disease Human Brains

    Directory of Open Access Journals (Sweden)

    C. Fourie

    2014-01-01

    Full Text Available NMDA and AMPA-type glutamate receptors and their bound membrane-associated guanylate kinases (MAGUKs are critical for synapse development and plasticity. We hypothesised that these proteins may play a role in the changes in synapse function that occur in Huntington’s disease (HD and Parkinson’s disease (PD. We performed immunohistochemical analysis of human postmortem brain tissue to examine changes in the expression of SAP97, PSD-95, GluA2 and GluN1 in human control, and HD- and PD-affected hippocampus and striatum. Significant increases in SAP97 and PSD-95 were observed in the HD and PD hippocampus, and PSD95 was downregulated in HD striatum. We observed a significant increase in GluN1 in the HD hippocampus and a decrease in GluA2 in HD and PD striatum. Parallel immunohistochemistry experiments in the YAC128 mouse model of HD showed no change in the expression levels of these synaptic proteins. Our human data show that major but different changes occur in glutamatergic proteins in HD versus PD human brains. Moreover, the changes in human HD brains differ from those occurring in the YAC128 HD mouse model, suggesting that unique changes occur at a subcellular level in the HD human hippocampus.

  20. A novel method for evaluating brain function and microstructural changes in Parkinson′s disease

    Directory of Open Access Journals (Sweden)

    Ming-fang Jiang

    2015-01-01

    Full Text Available In this study, microstructural brain damage in Parkinson′s disease patients was examined using diffusion tensor imaging and tract-based spatial statistics. The analyses revealed the presence of neuronal damage in the substantia nigra and putamen in the Parkinson′s disease patients. Moreover, disease symptoms worsened with increasing damage to the substantia nigra, confirming that the substantia nigra and basal ganglia are the main structures affected in Parkinson′s disease. We also found that microstructural damage to the putamen, caudate nucleus and frontal lobe positively correlated with depression. Based on the tract-based spatial statistics, various white matter tracts appeared to have microstructural damage, and this correlated with cognitive disorder and depression. Taken together, our results suggest that diffusion tensor imaging and tract-based spatial statistics can be used to effectively study brain function and microstructural changes in patients with Parkinson′s disease. Our novel findings should contribute to our understanding of the histopathological basis of cognitive dysfunction and depression in Parkinson′s disease.

  1. Hallmarks of Alzheimer's Disease in Stem-Cell-Derived Human Neurons Transplanted into Mouse Brain.

    Science.gov (United States)

    Espuny-Camacho, Ira; Arranz, Amaia M; Fiers, Mark; Snellinx, An; Ando, Kunie; Munck, Sebastian; Bonnefont, Jerome; Lambot, Laurie; Corthout, Nikky; Omodho, Lorna; Vanden Eynden, Elke; Radaelli, Enrico; Tesseur, Ina; Wray, Selina; Ebneth, Andreas; Hardy, John; Leroy, Karelle; Brion, Jean-Pierre; Vanderhaeghen, Pierre; De Strooper, Bart

    2017-03-08

    Human pluripotent stem cells (PSCs) provide a unique entry to study species-specific aspects of human disorders such as Alzheimer's disease (AD). However, in vitro culture of neurons deprives them of their natural environment. Here we transplanted human PSC-derived cortical neuronal precursors into the brain of a murine AD model. Human neurons differentiate and integrate into the brain, express 3R/4R Tau splice forms, show abnormal phosphorylation and conformational Tau changes, and undergo neurodegeneration. Remarkably, cell death was dissociated from tangle formation in this natural 3D model of AD. Using genome-wide expression analysis, we observed upregulation of genes involved in myelination and downregulation of genes related to memory and cognition, synaptic transmission, and neuron projection. This novel chimeric model for AD displays human-specific pathological features and allows the analysis of different genetic backgrounds and mutations during the course of the disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. A Culture-Brain Link: Negative Age Stereotypes Predict Alzheimer’s-disease Biomarkers

    Science.gov (United States)

    Levy, Becca R.; Ferrucci, Luigi; Zonderman, Alan B.; Slade, Martin D.; Troncoso, Juan; Resnick, Susan M.

    2016-01-01

    Although negative age stereotypes have been found to predict adverse outcomes among older individuals, it was unknown whether the influence of stereotypes extends to brain changes associated with Alzheimer’s disease. To consider this possibility, we drew on the age stereotypes of dementia-free participants in the Baltimore Longitudinal Study of Aging that had been measured decades before yearly MRIs and brain autopsies were performed. Those with more negative age stereotypes earlier in life had significantly steeper hippocampal-volume loss, and significantly greater accumulation of neurofibrillary tangles and amyloid plaques at autopsy, adjusting for relevant covariates. These findings suggest a new pathway to identifying mechanisms and potential interventions related to the neuropathology of Alzheimer’s disease. PMID:26641877

  3. Soluble Amyloid-beta Aggregates from Human Alzheimer’s Disease Brains

    Science.gov (United States)

    Esparza, Thomas J.; Wildburger, Norelle C.; Jiang, Hao; Gangolli, Mihika; Cairns, Nigel J.; Bateman, Randall J.; Brody, David L.

    2016-01-01

    Soluble amyloid-beta (Aβ) aggregates likely contribute substantially to the dementia that characterizes Alzheimer’s disease. However, despite intensive study of in vitro preparations and animal models, little is known about the characteristics of soluble Aβ aggregates in the human Alzheimer’s disease brain. Here we present a new method for extracting soluble Aβ aggregates from human brains, separating them from insoluble aggregates and Aβ monomers using differential ultracentrifugation, and purifying them >6000 fold by dual antibody immunoprecipitation. The method resulted in soluble aggregate sizes. By immunoelectron microscopy, soluble Aβ aggregates typically appear as clusters of 10–20 nanometer diameter ovoid structures with 2-3 amino-terminal Aβ antibody binding sites, distinct from previously characterized structures. This approach may facilitate investigation into the characteristics of native soluble Aβ aggregates, and deepen our understanding of Alzheimer’s dementia. PMID:27917876

  4. Mild traumatic brain injury is associated with reduced cortical thickness in those at risk for Alzheimer's disease.

    Science.gov (United States)

    Hayes, Jasmeet P; Logue, Mark W; Sadeh, Naomi; Spielberg, Jeffrey M; Verfaellie, Mieke; Hayes, Scott M; Reagan, Andrew; Salat, David H; Wolf, Erika J; McGlinchey, Regina E; Milberg, William P; Stone, Annjanette; Schichman, Steven A; Miller, Mark W

    2017-03-01

    Moderate-to-severe traumatic brain injury is one of the strongest environmental risk factors for the development of neurodegenerative diseases such as late-onset Alzheimer's disease, although it is unclear whether mild traumatic brain injury, or concussion, also confers risk. This study examined mild traumatic brain injury and genetic risk as predictors of reduced cortical thickness in brain regions previously associated with early Alzheimer's disease, and their relationship with episodic memory. Participants were 160 Iraq and Afghanistan War veterans between the ages of 19 and 58, many of whom carried mild traumatic brain injury and post-traumatic stress disorder diagnoses. Whole-genome polygenic risk scores for the development of Alzheimer's disease were calculated using summary statistics from the largest Alzheimer's disease genome-wide association study to date. Results showed that mild traumatic brain injury moderated the relationship between genetic risk for Alzheimer's disease and cortical thickness, such that individuals with mild traumatic brain injury and high genetic risk showed reduced cortical thickness in Alzheimer's disease-vulnerable regions. Among males with mild traumatic brain injury, high genetic risk for Alzheimer's disease was associated with cortical thinning as a function of time since injury. A moderated mediation analysis showed that mild traumatic brain injury and high genetic risk indirectly influenced episodic memory performance through cortical thickness, suggesting that cortical thinning in Alzheimer's disease-vulnerable brain regions is a mechanism for reduced memory performance. Finally, analyses that examined the apolipoprotein E4 allele, post-traumatic stress disorder, and genetic risk for schizophrenia and depression confirmed the specificity of the Alzheimer's disease polygenic risk finding. These results provide evidence that mild traumatic brain injury is associated with greater neurodegeneration and reduced memory performance

  5. Aggravated stuttering following subthalamic deep brain stimulation in Parkinson's disease - two cases

    OpenAIRE

    Dietrichs Espen; Toft Mathias

    2011-01-01

    Abstract Stuttering is a speech disorder with disruption of verbal fluency which is occasionally present in patients with Parkinson's disease (PD). Long-term medical management of PD is frequently complicated by fluctuating motor functions and dyskinesias. High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment of motor fluctuations and is the most common surgical procedure in PD. Here we report the re-occurrence and aggravation of stuttering fol...

  6. Selecting deep brain stimulation or infusion therapies in advanced Parkinson's disease: an evidence-based review

    OpenAIRE

    Volkmann, Jens; Albanese, Alberto; Antonini, Angelo; Chaudhuri, K. Ray; Clarke, Carl E.; de Bie, Rob M.A.; Deuschl, Günther; Eggert, Karla; Houeto, Jean-Luc; Kulisevsky, Jaime; Nyholm, Dag; Odin, Per; Østergaard, Karen; Poewe, Werner; Pollak, Pierre

    2013-01-01

    Motor complications in Parkinson’s disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness,...

  7. Deep brain stimulation of the subthalamic nucleus modulates sensitivity to decision outcome value in Parkinson's disease.

    OpenAIRE

    Seymour, Benjamin John; Barbe, M; Dayan, P; Shiner, T.; Dolan, R.; Fink, GR

    2016-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson's disease is known to cause a subtle but important adverse impact on behaviour, with impulsivity its most widely reported manifestation. However, precisely which computational components of the decision process are modulated is not fully understood. Here we probe a number of distinct subprocesses, including temporal discount, outcome utility, instrumental learning rate, instrumental outcome sensitivity, reward-loss trade-off...

  8. Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer's disease

    OpenAIRE

    Jiao, S-S; Shen, L-L; C. Zhu; Bu, X-L; Liu, Y-H; Liu, C-H; Yao, X-Q; Zhang, L-L; Zhou, H-D; Walker, D. G.; J. Tan; G?tz, J; Zhou, X-F; Wang, Y-J

    2016-01-01

    Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (A?) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against A?-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy ...

  9. Lower brain and blood nutrient status in Alzheimer's disease: Results from meta-analyses

    OpenAIRE

    de Wilde, Martijn C.; Vellas, Bruno; Girault, Elodie; Yavuz, Aysun Cetinyurek; Sijben, John W.

    2017-01-01

    Introduction Alzheimer's disease (AD) patients are at risk of nutritional insufficiencies because of physiological and psychological factors. Recently, we showed the results of the meta-analyses indicating lower plasma levels of vitamins A, B12, C, E, and folate in AD patients compared with cognitively intact elderly controls (controls). Now, additional and more extensive literature searches were performed selecting studies which compare blood and brain/cerebrospinal fluid (CSF) levels of vit...

  10. Cerebral hemodynamics of the aging brain: risk of Alzheimer disease and benefit of aerobic exercise

    Directory of Open Access Journals (Sweden)

    Takashi eTarumi

    2014-01-01

    Full Text Available Alzheimer disease (AD and cerebrovascular disease often coexist with advanced age. Mounting evidence indicates that the presence of vascular disease and its risk factors increase the risk of AD, suggesting a potential overlap of the underlying pathophysiological mechanisms. In particular, atherosclerosis, endothelial dysfunction, and stiffening of central elastic arteries have been shown to associate with AD. Currently, there are no effective treatments for the cure and prevention of AD. Vascular risk factors are modifiable via either pharmacological or lifestyle intervention. In this regard, habitual aerobic exercise is increasingly recognized for its benefits on brain structure and cognitive function. Considering the well-established benefits of regular aerobic exercise on vascular health, exercise-related improvements in brain structure and cognitive function may be mediated by vascular adaptations. In this review, we will present the current evidence for the physiological mechanisms by which vascular health alters the structural and functional integrity of the aging brain and how improvements in vascular health, via regular aerobic exercise, potentially benefits cognitive function.

  11. Fluorescent nanodiamond tracking reveals intraneuronal transport abnormalities induced by brain-disease-related genetic risk factors

    Science.gov (United States)

    Haziza, Simon; Mohan, Nitin; Loe-Mie, Yann; Lepagnol-Bestel, Aude-Marie; Massou, Sophie; Adam, Marie-Pierre; Le, Xuan Loc; Viard, Julia; Plancon, Christine; Daudin, Rachel; Koebel, Pascale; Dorard, Emilie; Rose, Christiane; Hsieh, Feng-Jen; Wu, Chih-Che; Potier, Brigitte; Herault, Yann; Sala, Carlo; Corvin, Aiden; Allinquant, Bernadette; Chang, Huan-Cheng; Treussart, François; Simonneau, Michel

    2017-05-01

    Brain diseases such as autism and Alzheimer's disease (each inflicting >1% of the world population) involve a large network of genes displaying subtle changes in their expression. Abnormalities in intraneuronal transport have been linked to genetic risk factors found in patients, suggesting the relevance of measuring this key biological process. However, current techniques are not sensitive enough to detect minor abnormalities. Here we report a sensitive method to measure the changes in intraneuronal transport induced by brain-disease-related genetic risk factors using fluorescent nanodiamonds (FNDs). We show that the high brightness, photostability and absence of cytotoxicity allow FNDs to be tracked inside the branches of dissociated neurons with a spatial resolution of 12 nm and a temporal resolution of 50 ms. As proof of principle, we applied the FND tracking assay on two transgenic mouse lines that mimic the slight changes in protein concentration (∼30%) found in the brains of patients. In both cases, we show that the FND assay is sufficiently sensitive to detect these changes.

  12. Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation?

    Science.gov (United States)

    Faden, Alan I; Loane, David J

    2015-01-01

    It has long been suggested that prior traumatic brain injury (TBI) increases the subsequent incidence of chronic neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis. Among these, the association with Alzheimer disease has the strongest support. There is also a long-recognized association between repeated concussive insults and progressive cognitive decline or other neuropsychiatric abnormalities. The latter was first described in boxers as dementia pugilistica, and has received widespread recent attention in contact sports such as professional American football. The term chronic traumatic encephalopathy was coined to attempt to define a "specific" entity marked by neurobehavioral changes and the extensive deposition of phosphorylated tau protein. Nearly lost in the discussions of post-traumatic neurodegeneration after traumatic brain injury has been the role of sustained neuroinflammation, even though this association has been well established pathologically since the 1950s, and is strongly supported by subsequent preclinical and clinical studies. Manifested by extensive microglial and astroglial activation, such chronic traumatic brain inflammation may be the most important cause of post-traumatic neurodegeneration in terms of prevalence. Critically, emerging preclinical studies indicate that persistent neuroinflammation and associated neurodegeneration may be treatable long after the initiating insult(s).

  13. Recent advances in basic neurosciences and brain disease: from synapses to behavior

    Directory of Open Access Journals (Sweden)

    Salter Michael W

    2006-12-01

    Full Text Available Abstract Understanding basic neuronal mechanisms hold the hope for future treatment of brain disease. The 1st international conference on synapse, memory, drug addiction and pain was held in beautiful downtown Toronto, Canada on August 21–23, 2006. Unlike other traditional conferences, this new meeting focused on three major aims: (1 to promote new and cutting edge research in neuroscience; (2 to encourage international information exchange and scientific collaborations; and (3 to provide a platform for active scientists to discuss new findings. Up to 64 investigators presented their recent discoveries, from basic synaptic mechanisms to genes related to human brain disease. This meeting was in part sponsored by Molecular Pain, together with University of Toronto (Faculty of Medicine, Department of Physiology as well as Center for the Study of Pain. Our goal for this meeting is to promote future active scientific collaborations and improve human health through fundamental basic neuroscience researches. The second international meeting on Neurons and Brain Disease will be held in Toronto (August 29–31, 2007.

  14. Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation

    Directory of Open Access Journals (Sweden)

    Luissint Anny-Claude

    2012-11-01

    Full Text Available Abstract The Blood–brain barrier (BBB, present at the level of the endothelium of cerebral blood vessels, selectively restricts the blood-to-brain paracellular diffusion of compounds; it is mandatory for cerebral homeostasis and proper neuronal function. The barrier properties of these specialized endothelial cells notably depend on tight junctions (TJs between adjacent cells: TJs are dynamic structures consisting of a number of transmembrane and membrane-associated cytoplasmic proteins, which are assembled in a multimolecular complex and acting as a platform for intracellular signaling. Although the structural composition of these complexes has been well described in the recent years, our knowledge about their functional regulation still remains fragmentary. Importantly, pericytes, embedded in the vascular basement membrane, and perivascular microglial cells, astrocytes and neurons contribute to the regulation of endothelial TJs and BBB function, altogether constituting the so-called neurovascular unit. The present review summarizes our current understanding of the structure and functional regulation of endothelial TJs at the BBB. Accumulating evidence points to a correlation between BBB dysfunction, alteration of TJ complexes and progression of a variety of CNS diseases, such as stroke, multiple sclerosis and brain tumors, as well as neurodegenerative diseases like Parkinson’s and Alzheimer’s diseases. Understanding how TJ integrity is controlled may thus help improve drug delivery across the BBB and the design of therapeutic strategies for neurological disorders.

  15. Cerebral hemodynamics of the aging brain: risk of Alzheimer disease and benefit of aerobic exercise

    Science.gov (United States)

    Tarumi, Takashi; Zhang, Rong

    2014-01-01

    Alzheimer disease (AD) and cerebrovascular disease often coexist with advanced age. Mounting evidence indicates that the presence of vascular disease and its risk factors increase the risk of AD, suggesting a potential overlap of the underlying pathophysiological mechanisms. In particular, atherosclerosis, endothelial dysfunction, and stiffening of central elastic arteries have been shown to associate with AD. Currently, there are no effective treatments for the cure and prevention of AD. Vascular risk factors are modifiable via either pharmacological or lifestyle intervention. In this regard, habitual aerobic exercise is increasingly recognized for its benefits on brain structure and cognitive function. Considering the well-established benefits of regular aerobic exercise on vascular health, exercise-related improvements in brain structure and cognitive function may be mediated by vascular adaptations. In this review, we will present the current evidence for the physiological mechanisms by which vascular health alters the structural and functional integrity of the aging brain and how improvements in vascular health, via regular aerobic exercise, potentially benefits cognitive function. PMID:24478719

  16. Compartment analysis of {sup 123}I-iomazenil brain SPECT in patients with moyamoya disease

    Energy Technology Data Exchange (ETDEWEB)

    Kaneta, Tomohiro; Yamazaki, Tetsuro; Takahashi, Shoki; Yamada, Shogo [Tohoku Univ., Sendai (Japan). School of Medicine; Maruoka, Shin; Abe, Yoetsu

    1999-12-01

    We investigated 11 patients with moyamoya disease about {sup 123}I-Iomazenil kinetics in the brain using three-compartment, two-parameter model. The transition rate constant (K1) from the blood to the brain and the binding potential (BP) of the benzodiazepine to the receptors were calculated for every ROI (right and left side of cerebellum, frontal lobe, parietal lobe, occipital lobe and temporal lobe; 10 ROIs a case). The K1 value correlated with BP value significantly, but not so closely (r=0.639). And there is no significant difference in BP valued among low-K1 group (mean (of K1)-S.D.{<=}K1{<=}mean) and high-K1 group (meandisease patients. And we showed a case with IMP/IMZ discrepancy. The nerve cell in the hypoperfused area which has almost normal BP value is ischemic but viable. IMZ-SPECT presents an important information about the viability of the hypoperfused area in moyamoya disease patients' brain. (author)

  17. Brain PET and technetium-99m-ECD SPECT imaging in Lhermitte-Duclos disease

    Energy Technology Data Exchange (ETDEWEB)

    Ogasawara, K.; Yasuda, S.; Beppu, T.; Kobayashi, M.; Doi, M.; Kuroda, K.; Ogawa, A. [Dept. of Neurosurgery, Iwate Medical Univ., Morioka (Japan)

    2001-11-01

    Two patients with Lhermitte-Duclos disease were evaluated by brain positron emission tomography (PET) and technetium-99m-ethyl cysteinate dimer ({sup 99m}Tc-ECD) single-photon emission computed tomography (SPECT). In the lesions in both patients, hyperperfusion was detected on cerebral blood flow images obtained by PET, and hyperactivity by standard {sup 99m}Tc-ECD SPECT. Dynamic {sup 99m}Tc-ECD SPECT images demonstrated a plateau of activity in each lesion. These findings suggest that lesions in Lhermitte-Duclos disease have a retention mechanism for {sup 99m}Tc-ECD equivalent to that of normal neural tissue. (orig.)

  18. Characteristics of Brain Perfusion in Patients of Parkinson's Disease

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Young Jin; Park, Min Jung; Kim, Jae Woo; Kang, Young Kang [Dong-A University College of Medicine, Busan (Korea, Republic of)

    2008-02-15

    It was well known that cerebral blood perfusion is normal or diffusely decreased in the majority of patients with Parkinson's disease (PD). Actually we interpreted brain perfusion SPECT images of PD patients in the clinical situation, we observed various cerebral perfusion patterns in patients with PD. So we performed brain perfusion SPECT to know the brain perfusion patterns of PD patients and the difference of perfusion patterns according to the sex and the age. Also we classified PD patients into small groups based on the brain perfusion pattern. Two hundred nineteen patients (M: 70, F: 149, mean age: 62.9{+-}6.9 y/o) who were diagnosed as PD without dementia clinically and 55 patients (M: 15, F: 40, mean age: 61.4{+-}9.2 y/o) as normal controls who had no past illness history were performed {sup 99m}Tc-HMPAO brain perfusion SPECT and neuropsychological test. At first, we compared all patients with PD and normal controls. Brain perfusion in left inferior frontal gyrus, left insula, left transverse temporal gyrus, left inferior parietal lobule, left superior parietal lobule, right precuneus, right caudate tail were lower in patients with PD than normal controls. Secondly, we compared male and female patients with PD and normal controls, respectively. Brain perfusion SPECT showed more decreased cerebral perfusion in left hemisphere than right side in both male and female patients compared to normal controls. And there was larger hypoperfusion area in female patients compared with male. Thirdly, we classified patients with PD and normal controls into 4 groups according to the age and compared brain perfusion respectively. In patient below fifties, brain perfusion in both occipitoparietal and left temporal lobe were lower in PD group. As the patients with PD grew older, hypoperfusion area were shown in both frontal, temporal and limbic lobes. Fourthly, We were able to divide patients into small groups based on cerebral perfusion pattern. There was normal

  19. Diagnostic usefulness of 3 tesla MRI of the brain for cushing disease in a child.

    Science.gov (United States)

    Ono, Erina; Ozawa, Ayako; Matoba, Kaori; Motoki, Takanori; Tajima, Asako; Miyata, Ichiro; Ito, Junko; Inoshita, Naoko; Yamada, Syozo; Ida, Hiroyuki

    2011-10-01

    It is sometimes difficult to confirm the location of a microadenoma in Cushing disease. Recently, we experienced an 11-yr-old female case of Cushing disease with hyperprolactinemia. She was referred to our hospital because of decrease of height velocity with body weight gain. On admission, she had typical symptoms of Cushing syndrome. Although no pituitary microadenomas were detected on 1.5 Tesla MRI of the brain, endocrinological examinations including IPS and CS sampling were consistent with Cushing disease with hyperprolactinemia. Oral administration of methyrapone instead of neurosurgery was started after discharge, but subsequent 3 Tesla MRI of the brain clearly demonstrated a 3-mm less-enhanced lesion in the left side of the pituitary gland. Finally, transsphenoidal surgery was performed, and a 3.5-mm left-sided microadenoma was resected. Compared with 1.5 Tesla MRI, 3 Tesla MRI offers the advantage of a higher signal to noise ratio (SNR), which provides higher resolution and proper image quality. Therefore, 3 Tesla MRI is a very useful tool to localize microadenomas in Cushing disease in children as well as in adults. It will be the first choice of radiological examinations in suspected cases of Cushing disease.

  20. Patients' expectations in subthalamic nucleus deep brain stimulation surgery for Parkinson disease.

    Science.gov (United States)

    Hasegawa, Harutomo; Samuel, Michael; Douiri, Abdel; Ashkan, Keyoumars

    2014-12-01

    Subthalamic nucleus (STN) deep brain stimulation (DBS) is an established treatment for patients with advanced Parkinson disease. However, some patients feel less satisfied with the outcome of surgery. We sought to study the relationship between expectations, satisfaction, and outcome in STN DBS for Parkinson disease. Twenty-two consecutive patients undergoing STN DBS completed a modified 39-item Parkinson disease questionnaire (PDQ-39) preoperatively and 6 months postoperatively. A satisfaction questionnaire accompanied the postoperative questionnaire. Patients expected a significant improvement from surgery preoperatively: preoperative score (median PDQ-39 summary score [interquartile range]): 37.0 (9.5), expected postoperative score: 13.0 (8.0), P Parkinson disease. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy

    Directory of Open Access Journals (Sweden)

    Kevin A. Clayton

    2017-12-01

    Full Text Available Brain aging is central to late-onset Alzheimer's disease (LOAD, although the mechanisms by which it occurs at protein or cellular levels are not fully understood. Alzheimer's disease is the most common proteopathy and is characterized by two unique pathologies: senile plaques and neurofibrillary tangles, the former accumulating earlier than the latter. Aging alters the proteostasis of amyloid-β peptides and microtubule-associated protein tau, which are regulated in both autonomous and non-autonomous manners. Microglia, the resident phagocytes of the central nervous system, play a major role in the non-autonomous clearance of protein aggregates. Their function is significantly altered by aging and neurodegeneration. This is genetically supported by the association of microglia-specific genes, TREM2 and CD33, and late onset Alzheimer's disease. Here, we propose that the functional characterization of microglia, and their contribution to proteopathy, will lead to a new therapeutic direction in Alzheimer's disease research.

  2. Astrocytes contain amyloid-β annular protofibrils in Alzheimer's disease brains.

    Science.gov (United States)

    Lasagna-Reeves, Cristian A; Kayed, Rakez

    2011-10-03

    Annular protofibrils (APFs) represent a newly described and distinct class of amyloid structures formed by disease-associated proteins. In vitro, these pore-like structures have been implicated in membrane permeabilization and ion homeostasis via pore formation. Still, their formation and relevance in vivo are poorly understood. Herein, we report that APFs are in human Alzheimer's disease brain samples and that amyloid-β APFs were associated with activated astrocytes. Moreover, we show that amyloid-β APFs in astrocytes adopt a conformation in which the N-terminal region is buried inside the wall of the pore. Our results together with previous studies suggest that the formation of amyloid-β APFs in astrocytes could be a relevant event in the pathogenesis of Alzheimer's disease and validate this amyloidogenic structure as a target for the prevention of the disease. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  3. Selenotranscriptomic Analyses Identify Signature Selenoproteins in Brain Regions in a Mouse Model of Parkinson's Disease.

    Directory of Open Access Journals (Sweden)

    Xiong Zhang

    Full Text Available Genes of selenoproteome have been increasingly implicated in various aspects of neurobiology and neurological disorders, but remain largely elusive in Parkinson's disease (PD. In this study, we investigated the selenotranscriptome (24 selenoproteins in total in five brain regions (cerebellum, substantia nigra, cortex, pons and hippocampus by real time qPCR in a two-phase manner using a mouse model of chronic PD. A wide range of changes in selenotranscriptome was observed in a manner depending on selenoproteins and brain regions. While Selv mRNA was not detectable and Dio1& 3 mRNA levels were not affected, 1, 11 and 9 selenoproteins displayed patterns of increase only, decrease only, and mixed response, respectively, in these brain regions of PD mice. In particular, the mRNA expression of Gpx1-4 showed only a decreased trend in the PD mouse brains. In substantia nigra, levels of 17 selenoprotein mRNAs were significantly decreased whereas no selenoprotein was up-regulated in the PD mice. In contrast, the majority of selenotranscriptome did not change and a few selenoprotein mRNAs that respond displayed a mixed pattern of up- and down-regulation in cerebellum, cortex, hippocampus, and/or pons of the PD mice. Gpx4, Sep15, Selm, Sepw1, and Sepp1 mRNAs were most abundant across all these five brain regions. Our results showed differential responses of selenoproteins in various brain regions of the PD mouse model, providing critical selenotranscriptomic profiling for future functional investigation of individual selenoprotein in PD etiology.

  4. Wilson's disease: two treatment modalities. Correlations to pretreatment and posttreatment brain MRI

    Energy Technology Data Exchange (ETDEWEB)

    Leiros da Costa, Maria do Desterro [Federal University of Paraiba, Movement Disorders Unit, Paraiba (Brazil); Spitz, Mariana; Bacheschi, Luiz Alberto; Barbosa, Egberto Reis [University of Sao Paulo, Movement Disorders Unit, Sao Paulo (Brazil); Leite, Claudia Costa; Lucato, Leandro Tavares [University of Sao Paulo, Department of Radiology, Sao Paulo (Brazil)

    2009-10-15

    Brain magnetic resonance imaging (MRI) studies on Wilson's disease (WD) show lack of correlations between neurological and neuroimaging features. Long-term follow-up reports with sequential brain MRI in patients with neurological WD comparing different modalities of treatment are scarce. Eighteen patients with neurological WD underwent pretreatment and posttreatment brain MRI scans to evaluate the range of abnormalities and the evolution along these different periods. All patients underwent at least two MRI scans at different intervals, up to 11 years after the beginning of treatment. MRI findings were correlated with clinical picture, clinical severity, duration of neurological symptoms, and treatment with two different drugs. Patients were divided into two groups according to treatment: d-penicillamine (D-P), zinc (Zn), and Zn after the onset of severe intolerance to D-P. MRI scans before treatment showed, in all patients, hypersignal intensity lesions on T2- and proton-density-weighted images bilaterally and symmetrically at basal nuclei, thalamus, brain stem, cerebellum, brain cortex, and brain white matter. The most common neurological symptoms were: dysarthria, parkinsonism, dystonia, tremor, psychiatric disturbances, dysphagia, risus sardonicus, ataxia, chorea, and athetosis. From the neurological point of view, there was no difference on the evolution between the group treated exclusively with D-P and the one treated with Zn. Analysis of MRI scans with longer intervals after the beginning of treatment depicted a trend for neuroimaging worsening, without neurological correspondence, among patients treated with Zn. Neuroimaging pattern of evolution was more favorable for the group that received exclusively D-P. (orig.)

  5. Patient-derived stem cells: pathways to drug discovery for brain diseases

    Directory of Open Access Journals (Sweden)

    Alan eMackay-Sim

    2013-03-01

    Full Text Available The concept of drug discovery through stem cell biology is based on technological developments whose genesis is now coincident. The first is automated cell microscopy with concurrent advances in image acquisition and analysis, known as high content screening (HCS. The second is patient-derived stem cells for modelling the cell biology of brain diseases. HCS has developed from the requirements of the pharmaceutical industry for high throughput assays to screen thousands of chemical compounds in the search for new drugs. HCS combines new fluorescent probes with automated microscopy and computational power to quantify the effects of compounds on cell functions. Stem cell biology has advanced greatly since the discovery of genetic reprogramming of somatic cells into induced pluripotent stem cells (iPSCs. There is now a rush of papers describing their generation from patients with various diseases of the nervous system. Although the majority of these have been genetic diseases, iPSCs have been generated from patients with complex diseases (schizophrenia and sporadic Parkinson’s disease. Some genetic diseases are also modelled in embryonic stem cells generated from blastocysts rejected during in vitro fertilisation. Neural stem cells have been isolated from post-mortem brain of Alzheimer’s patients and neural stem cells generated from biopsies of the olfactory organ of patients is another approach. These olfactory neurosphere-derived cells demonstrate robust disease-specific phenotypes in patients with schizophrenia and Parkinson’s disease. High content screening is already in use to find small molecules for the generation and differentiation of embryonic stem cells and induced pluripotent stem cells. The challenges for using stem cells for drug discovery are to develop robust stem cell culture methods that meet the rigorous requirements for repeatable, consistent quantities of defined cell types at the industrial scale necessary for high

  6. Predicting Alzheimer's disease by classifying 3D-Brain MRI images using SVM and other well-defined classifiers

    Science.gov (United States)

    Matoug, S.; Abdel-Dayem, A.; Passi, K.; Gross, W.; Alqarni, M.

    2012-02-01

    Alzheimer's disease (AD) is the most common form of dementia affecting seniors age 65 and over. When AD is suspected, the diagnosis is usually confirmed with behavioural assessments and cognitive tests, often followed by a brain scan. Advanced medical imaging and pattern recognition techniques are good tools to create a learning database in the first step and to predict the class label of incoming data in order to assess the development of the disease, i.e., the conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease, which is the most critical brain disease for the senior population. Advanced medical imaging such as the volumetric MRI can detect changes in the size of brain regions due to the loss of the brain tissues. Measuring regions that atrophy during the progress of Alzheimer's disease can help neurologists in detecting and staging the disease. In the present investigation, we present a pseudo-automatic scheme that reads volumetric MRI, extracts the middle slices of the brain region, performs segmentation in order to detect the region of brain's ventricle, generates a feature vector that characterizes this region, creates an SQL database that contains the generated data, and finally classifies the images based on the extracted features. For our results, we have used the MRI data sets from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.

  7. Network science and the human brain: Using graph theory to understand the brain and one of its hubs, the amygdala, in health and disease.

    Science.gov (United States)

    Mears, David; Pollard, Harvey B

    2016-06-01

    Over the past 15 years, the emerging field of network science has revealed the key features of brain networks, which include small-world topology, the presence of highly connected hubs, and hierarchical modularity. The value of network studies of the brain is underscored by the range of network alterations that have been identified in neurological and psychiatric disorders, including epilepsy, depression, Alzheimer's disease, schizophrenia, and many others. Here we briefly summarize the concepts of graph theory that are used to quantify network properties and describe common experimental approaches for analysis of brain networks of structural and functional connectivity. These range from tract tracing to functional magnetic resonance imaging, diffusion tensor imaging, electroencephalography, and magnetoencephalography. We then summarize the major findings from the application of graph theory to nervous systems ranging from Caenorhabditis elegans to more complex primate brains, including man. Focusing, then, on studies involving the amygdala, a brain region that has attracted intense interest as a center for emotional processing, fear, and motivation, we discuss the features of the amygdala in brain networks for fear conditioning and emotional perception. Finally, to highlight the utility of graph theory for studying dysfunction of the amygdala in mental illness, we review data with regard to changes in the hub properties of the amygdala in brain networks of patients with depression. We suggest that network studies of the human brain may serve to focus attention on regions and connections that act as principal drivers and controllers of brain function in health and disease. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  8. Brain SPECT can differentiate between essential tremor and early-stage tremor-dominant Parkinson's disease.

    Science.gov (United States)

    Song, In-Uk; Park, Jeong-Wook; Chung, Sung-Woo; Chung, Yong-An

    2014-09-01

    There are no confirmatory or diagnostic tests or tools to differentiate between essential tremor (ET) and tremor in idiopathic Parkinson's disease (PD). Although a number of imaging studies have indicated that there are differences between ET and PD, the functional imaging study findings are controversial. Therefore, we analyzed regional cerebral blood flow (CBF) by perfusion brain single-photon emission computed tomography (SPECT) to identify differences between ET and tremor-dominant Parkinson's disease (TPD). We recruited 33 patients with TPD, 16 patients with ET, and 33 healthy controls. We compared the severity of tremor symptoms by comparing the Fahn-Tolosa-Marin rating scale (FTM) score and the tremor score from Unified Parkinson's Disease Rating Scale (UPDRS) between TPD and ET patients. Subjects were evaluated by neuropsychological assessments, MRI and perfusion SPECT of the brain. Total FTM score was significantly higher in ET patients than TPD patients. However, there was no significant difference in FTM Part A scores between the two patient groups, while the scores for FTM Part B and C were significantly higher in ET patients than TPD patients. Brain SPECT analysis of the TPD group demonstrated significant hypoperfusion of both the lentiform nucleus and thalamus compared to the ET group. Brain perfusion SPECT may be a useful clinical method to differentiate between TPD and ET even during early-phase PD, because the lentiform nucleus and thalamus show differences in regional perfusion between these two groups during this time period. Additionally, we found evidence of cerebellar dysfunction in both TPT and ET. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Leptomeningeal disease following stereotactic radiosurgery for brain metastases from breast cancer.

    Science.gov (United States)

    Trifiletti, Daniel M; Romano, Kara D; Xu, Zhiyuan; Reardon, Kelli A; Sheehan, Jason

    2015-09-01

    Leptomeningeal disease (LMD) is a highly aggressive and usually rapidly fatal condition. The purpose of this study is to identify clinical factors that can serve to predict for LMD at the time of stereotactic radiosurgery (SRS) for brain metastases from breast carcinoma. We conducted a retrospective review of patients with brain metastases from breast cancer treated with SRS from 1995 to 2014 at our institution. Clinical, radiographic, and dosimetric data were collected. LMD was diagnosed by cerebrospinal fluid (CSF) cytology or MRI demonstrating CSF seeding. Comparative statistical analyses were conducted using Cox proportional hazards regression, binary logistic regression, and/or log-rank test. 126 patients met inclusion criteria. Eighteen patients (14 %) developed LMD following SRS. From the time of SRS, the actuarial rate of LMD at 12 months from diagnosis of brain metastasis was 9 % (11 patients). Active disease in the chest at the time of SRS was associated with development of LMD (p = 0.038). Factors including receptor status, tumor size, number of intra-axial tumors, cystic tumor morphology, prior WBRT, active bone metastases, and active liver metastases were not significantly associated with the development of LMD. In patients with brain metastasis from breast cancer that undergo SRS, there is a relatively low rate of LMD. We found that while tumor hormonal status, bone metastases, and hepatic metastases were not associated with the development of LMD, active lung metastases at SRS was associated with LMD. Further research may help to delineate a causative relationship between metastatic lung disease and LMD.

  10. Toxoplasma gondii-A Gastrointestinal Pathogen Associated with Human Brain Diseases.

    Science.gov (United States)

    Severance, E G; Xiao, J; Jones-Brando, L; Sabunciyan, S; Li, Y; Pletnikov, M; Prandovszky, E; Yolken, R

    2016-01-01

    Serious psychiatric disorders such as schizophrenia, bipolar disorder, and major depression are important causes of mortality and morbidity worldwide. While these are primarily diseases involving altered brain functioning, numerous studies have documented increased rates of gastrointestinal inflammation and dysfunction in many individuals with these disorders. Toxoplasma gondii is an apicomplexan protozoan intracellular parasite with a widespread distribution in both developed and developing countries. Toxoplasma organisms enter the ecosystem through the shedding of oocysts by Toxoplasma-infected felines. In almost all cases of postnatal human infection, Toxoplasma enters its hosts through the intestinal tract either by the ingestion of oocysts or by the consumption of meat from food animals which themselves were infected by Toxoplasma oocysts. It had previously been thought that most cases of Toxoplasma infection in immune competent children and adults were inapparent and asymptomatic. However, recent studies cast doubt on this concept as exposure to Toxoplasma has been associated with a range of acute and chronic symptoms. Of particular note has been the finding of an increased rate of a range of neurological and psychiatric disorders associated with serological evidence of Toxoplasma exposure. A role of Toxoplasma infection in brain diseases is also supported by the consistent finding of altered cognition and behavior in animal models of infections. Much of the attention relating to the role of Toxoplasma infection in neuropsychiatric disorders has focused on the brain, where Toxoplasma tissue cysts can persist for extended periods of time. However, recent discoveries relating to the role of the gastrointestinal tract in cognition and behavior suggest that Toxoplasma may also increase susceptibility to human brain diseases through immune activation, particularly involving the gastrointestinal mucosa. The study of the pathways relating to the pathobiology and

  11. Alzheimer Disease Alters the Relationship of Cardiorespiratory Fitness With Brain Activity During the Stroop Task

    Science.gov (United States)

    Gayed, Matthew R.; Honea, Robyn A.; Savage, Cary R.; Hobbs, Derek; Burns, Jeffrey M.

    2013-01-01

    Background Despite mounting evidence that physical activity has positive benefits for brain and cognitive health, there has been little characterization of the relationship between cardiorespiratory (CR) fitness and cognition-associated brain activity as measured by functional magnetic resonance imaging (fMRI). The lack of evidence is particularly glaring for diseases such as Alzheimer disease (AD) that degrade cognitive and functional performance. Objective The aim of this study was to describe the relationship between regional brain activity during cognitive tasks and CR fitness level in people with and without AD. Design A case-control, single-observation study design was used. Methods Thirty-four individuals (18 without dementia and 16 in the earliest stages of AD) completed maximal exercise testing and performed a Stroop task during fMRI. Results Cardiorespiratory fitness was inversely associated with anterior cingulate activity in the participants without dementia (r=−.48, P=.05) and unassociated with activation in those with AD (P>.7). Weak associations of CR fitness and middle frontal cortex were noted. Limitations The wide age range and the use of a single task in fMRI rather than multiple tasks challenging different cognitive capacities were limitations of the study. Conclusions The results offer further support of the relationship between CR fitness and regional brain activity. However, this relationship may be attenuated by disease. Future work in this area may provide clinicians and researchers with interpretable and dependable regional fMRI biomarker signatures responsive to exercise intervention. It also may shed light on mechanisms by which exercise can support cognitive function. PMID:23559521

  12. The Effect of Souvenaid on Functional Brain Network Organisation in Patients with Mild Alzheimer's Disease: A Randomised Controlled Study

    NARCIS (Netherlands)

    de Waal, H.; Stam, C.J.; Lansbergen, M.M.; Wieggers, R.L.; Kamphuis, P.J.G.H.; Scheltens, P.; Maestu, F.; van Straaten, E.C.W.

    2014-01-01

    Background: Synaptic loss is a major hallmark of Alzheimer's disease (AD). Disturbed organisation of large-scale functional brain networks in AD might reflect synaptic loss and disrupted neuronal communication. The medical food Souvenaid, containing the specific nutrient combination Fortasyn

  13. Marek's Disease Virus Infection in the Brain: Virus Replication, Cellular Infiltration, and Major Histocompatibility Complex Antigen Expression

    National Research Council Canada - National Science Library

    Gimeno, I. M; Witter, R. L; Hunt, H. D; Lee, L. F; Reddy, S. M; Neumann, U

    2001-01-01

    Marek's disease virus (MDV) infection in the brain was studied chronologically after inoculating 3-week-old chickens of two genetic lines with two strains of serotype 1 MDV representing two pathotypes (v and vv...

  14. Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson's disease (NSTAPS study) : a randomised controlled trial

    NARCIS (Netherlands)

    Odekerken, Vincent J J; van Laar, Teus; Staal, Michiel J; Mosch, Arne; Hoffmann, Carel F E; Nijssen, Peter C G; Beute, Guus N; van Vugt, Jeroen P P; Lenders, Mathieu W P M; Contarino, M Fiorella; Mink, Marieke S J; Bour, Lo J; van den Munckhof, Pepijn; Schmand, Ben A; de Haan, Rob J; Schuurman, P Richard; de Bie, Rob M A

    Background Patients with advanced Parkinson's disease often have rapid swings between mobility and immobility, and many respond unsatisfactorily to adjustments in pharmacological treatment. We assessed whether globus pallidus pars interna (GPi) deep brain stimulation (DBS) gives greater functional

  15. Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson's disease (NSTAPS study): a randomised controlled trial

    NARCIS (Netherlands)

    Odekerken, V.J.J.; van Laar, T.; Staal, M.J.; Mosch, A.; Hoffmann, C.F.E.; Nijssen, P.C.G.; Beute, G.N.; Vugt, J.P.P.; Lenders, M.W.P.M.; Contarino, M.F.; Mink, M.S.J.; Bour, L.J.; van den Munckhof, P.; Schmand, B.A.; de Haan, R.J.; Schuurman, P.R.; de Bie, R.M.A.

    2013-01-01

    Background: Patients with advanced Parkinson's disease often have rapid swings between mobility and immobility, and many respond unsatisfactorily to adjustments in pharmacological treatment. We assessed whether globus pallidus pars interna (GPi) deep brain stimulation (DBS) gives greater functional

  16. Cognitive decline in Parkinson’s disease is associated with slowing of resting-state brain activity: a longitudinal study

    NARCIS (Netherlands)

    Olde Dubbelink, K.T.E.; Stoffers, D.; Deijen, J.B.; Twisk, J.W.R.; Stam, C.J.; Berendse, H.W.

    2013-01-01

    The pathophysiological mechanisms of Parkinson's disease (PD)-related dementia (PDD) are still poorly understood. Previous studies using electroencephalography (EEG) and magnetoencephalography (MEG) have demonstrated widespread slowing of oscillatory brain activity as a neurophysiological

  17. Altered brain mechanisms of emotion processing in pre-manifest Huntington's disease.

    Science.gov (United States)

    Novak, Marianne J U; Warren, Jason D; Henley, Susie M D; Draganski, Bogdan; Frackowiak, Richard S; Tabrizi, Sarah J

    2012-04-01

    Huntington's disease is an inherited neurodegenerative disease that causes motor, cognitive and psychiatric impairment, including an early decline in ability to recognize emotional states in others. The pathophysiology underlying the earliest manifestations of the disease is not fully understood; the objective of our study was to clarify this. We used functional magnetic resonance imaging to investigate changes in brain mechanisms of emotion recognition in pre-manifest carriers of the abnormal Huntington's disease gene (subjects with pre-manifest Huntington's disease): 16 subjects with pre-manifest Huntington's disease and 14 control subjects underwent 1.5 tesla magnetic resonance scanning while viewing pictures of facial expressions from the Ekman and Friesen series. Disgust, anger and happiness were chosen as emotions of interest. Disgust is the emotion in which recognition deficits have most commonly been detected in Huntington's disease; anger is the emotion in which impaired recognition was detected in the largest behavioural study of emotion recognition in pre-manifest Huntington's disease to date; and happiness is a positive emotion to contrast with disgust and anger. Ekman facial expressions were also used to quantify emotion recognition accuracy outside the scanner and structural magnetic resonance imaging with voxel-based morphometry was used to assess the relationship between emotion recognition accuracy and regional grey matter volume. Emotion processing in pre-manifest Huntington's disease was associated with reduced neural activity for all three emotions in partially separable functional networks. Furthermore, the Huntington's disease-associated modulation of disgust and happiness processing was negatively correlated with genetic markers of pre-manifest disease progression in distributed, largely extrastriatal networks. The modulated disgust network included insulae, cingulate cortices, pre- and postcentral gyri, precunei, cunei, bilateral putamena

  18. Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains.

    Science.gov (United States)

    Zeppenfeld, Douglas M; Simon, Matthew; Haswell, J Douglas; D'Abreo, Daryl; Murchison, Charles; Quinn, Joseph F; Grafe, Marjorie R; Woltjer, Randall L; Kaye, Jeffrey; Iliff, Jeffrey J

    2017-01-01

    Cognitive impairment and dementia, including Alzheimer disease (AD), are common within the aging population, yet the factors that render the aging brain vulnerable to these processes are unknown. Perivascular localization of aquaporin-4 (AQP4) facilitates the clearance of interstitial solutes, including amyloid-β, through the brainwide network of perivascular pathways termed the glymphatic system, which may be compromised in the aging brain. To determine whether alterations in AQP4 expression or loss of perivascular AQP4 localization are features of the aging human brain and to define their association with AD pathology. Expression of AQP4 was analyzed in postmortem frontal cortex of cognitively healthy and histopathologically confirmed individuals with AD by Western blot or immunofluorescence for AQP4, amyloid-β 1-42, and glial fibrillary acidic protein. Postmortem tissue and clinical data were provided by the Oregon Health and Science University Layton Aging and Alzheimer Disease Center and Oregon Brain Bank. Postmortem tissue from 79 individuals was evaluated, including cognitively intact "young" individuals aged younger than 60 years (range, 33-57 years), cognitively intact "aged" individuals aged older than 60 years (range, 61-96 years) with no known neurological disease, and individuals older than 60 years (range, 61-105 years) of age with a clinical history of AD confirmed by histopathological evaluation. Forty-eight patient samples (10 young, 20 aged, and 18 with AD) underwent histological analysis. Sixty patient samples underwent Western blot analysis (15 young, 24 aged, and 21 with AD). Expression of AQP4 protein, AQP4 immunoreactivity, and perivascular AQP4 localization in the frontal cortex were evaluated. Expression of AQP4 was associated with advancing age among all individuals (R2 = 0.17; P = .003). Perivascular AQP4 localization was significantly associated with AD status independent of age (OR, 11.7 per 10% increase in localization; z

  19. Computation of an MRI brain atlas from a population of Parkinson’s disease patients

    Science.gov (United States)

    Angelidakis, L.; Papageorgiou, I. E.; Damianou, C.; Psychogios, M. N.; Lingor, P.; von Eckardstein, K.; Hadjidemetriou, S.

    2017-11-01

    Parkinson’s Disease (PD) is a degenerative disorder of the brain. This study presents an MRI-based brain atlas of PD to characterize associated alterations for diagnostic and interventional purposes. The atlas standardizes primarily the implicated subcortical regions such as the globus pallidus (GP), substantia nigra (SN), subthalamic nucleus (STN), caudate nucleus (CN), thalamus (TH), putamen (PUT), and red nucleus (RN). The data were 3.0 T MRI brain images from 16 PD patients and 10 matched controls. The images used were T1-weighted (T 1 w), T2-weighted (T 2 w) images, and Susceptibility Weighted Images (SWI). The T1w images were the reference for the inter-subject non-rigid registration available from 3DSlicer. Anatomic labeling was achieved with BrainSuite and regions were refined with the level sets segmentation of ITK-Snap. The subcortical centers were analyzed for their volume and signal intensity. Comparison with an age-matched control group unravels a significant PD-related T1w signal loss in the striatum (CN and PUT) centers, but approximately a constant volume. The results in this study improve MRI based PD localization and can lead to the development of novel biomarkers.

  20. Brain targeted delivery of mucoadhesive thermosensitive nasal gel of selegiline hydrochloride for treatment of Parkinson's disease.

    Science.gov (United States)

    Sridhar, Vinay; Wairkar, Sarika; Gaud, Ram; Bajaj, Amrita; Meshram, Pramod

    2017-07-18

    Selegiline hydrochloride (SL), is an anti-Parkinson's agent, has low-oral bioavailability due to its high first pass metabolism and scarce oral absorption. In the present study, SL mucoadhesive nasal thermosensitive gel (SNT-gel) was prepared to enhance the bioavailability and subsequently, its concentration in the brain. The SNT-gel was prepared using Poloxamer 407-Chitosan combination and optimised formulation was further evaluated for physicochemical parameters. The comparative pharmacodynamic studies including behavioural studies, biochemical testing and histopathology of the brain was carried out in rats for SNT-gel, SL-nasal solution and SL Marketed Tablets. The optimised SNT-gel formulation (SNT-V) revealed sol-gel transition at 33-34°C. In-vitro diffusion study of SNT-V showed 102.37 ± 2.1% diffusion at 12 h which reduced to 89.64 ± 1.2% in Ex-vivo diffusion. Comparative results of behavioural studies indicated an improved score of photoactometer and reduced motor deficit (catalepsy score) in SNT-gel treatment group as compared with other groups. Similarly, a significant increase in brain dopamine, reduction in monoamine oxidase B level, increase in catalase activity and level of reduced glutathione upon treatment with SNT-gel indicated its effectiveness which was also supported by histopathology results. Therefore, nasal thermosensitive gel holds better potential for brain targeting in Parkinson's disease over the conventional nasal or oral formulations.

  1. The Implication of the Brain Insulin Receptor in Late Onset Alzheimer’s Disease Dementia

    Directory of Open Access Journals (Sweden)

    Jaume Folch

    2018-01-01

    Full Text Available Alzheimer’s disease (AD is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid β peptide (Aβ, which form senile plaques, neurofibrillary tangles (NFT and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM and this pathology, being one of the risk factors for the development of AD pathogenesis. Information as it is, it would point out that, impairment in insulin signalling and glucose metabolism, in central as well as peripheral systems, would be one of the reasons for the cognitive decline. Brain insulin resistance, also known as Type 3 diabetes, leads to the increase of Aβ production and TAU phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, and cognitive impairment, which are all hallmarks of AD. Moreover, given the complexity of interlocking mechanisms found in late onset AD (LOAD pathogenesis, more data is being obtained. Recent evidence showed that Aβ42 generated in the brain would impact negatively on the hypothalamus, accelerating the “peripheral” symptomatology of AD. In this situation, Aβ42 production would induce hypothalamic dysfunction that would favour peripheral hyperglycaemia due to down regulation of the liver insulin receptor. The objective of this review is to discuss the existing evidence supporting the concept that brain insulin resistance and altered glucose metabolism play an important role in pathogenesis of LOAD. Furthermore, we discuss AD treatment approaches targeting insulin signalling using anti-diabetic drugs and mTOR inhibitors.

  2. Brain Injury and Neurodevelopmental Outcome in Congenital Heart Disease: A Systematic Review.

    Science.gov (United States)

    Mebius, Mirthe J; Kooi, Elisabeth M W; Bilardo, Catherina M; Bos, Arend F

    2017-07-01

    Brain injury during prenatal and preoperative postnatal life might play a major role in neurodevelopmental impairment in infants with congenital heart disease (CHD) who require corrective or palliative surgery during infancy. A systematic review of cerebral findings during this period in relation to neurodevelopmental outcome (NDO), however, is lacking. To assess the association between prenatal and postnatal preoperative cerebral findings and NDO in infants with CHD who require corrective or palliative surgery during infancy. PubMed, Embase, reference lists. We conducted 3 different searches for English literature between 2000 and 2016; 1 for prenatal cerebral findings, 1 for postnatal preoperative cerebral findings, and 1 for the association between brain injury and NDO. Two reviewers independently screened sources and extracted data on cerebral findings and neurodevelopmental outcome. Quality of studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. Abnormal cerebral findings are common during the prenatal and postnatal preoperative periods. Prenatally, a delay of cerebral development was most common; postnatally, white matter injury, periventricular leukomalacia, and stroke were frequently observed. Abnormal Doppler measurements, brain immaturity, cerebral oxygenation, and abnormal EEG or amplitude-integrated EEG were all associated with NDO. Observational studies, different types of CHD with different pathophysiological effects, and different reference values. Prenatal and postnatal preoperative abnormal cerebral findings might play an important role in neurodevelopmental impairment in infants with CHD. Increased awareness of the vulnerability of the young developing brain of an infant with CHD among caregivers is essential. Copyright © 2017 by the American Academy of Pediatrics.

  3. Brain perfusion SPECT correlates with CSF biomarkers in Alzheimer's disease

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    Habert, Marie-Odile [UMR-S 678, Universite Pierre et Marie Curie-Paris 6, INSERM, Paris (France); CHU Pitie-Salpetriere, AP-HP, Department of Nuclear Medicine, Paris (France); Hopital Pitie-Salpetriere, Department of Nuclear Medicine, Paris (France); Souza, Leonardo Cruz de; Dubois, Bruno; Sarazin, Marie [CHU Pitie-Salpetriere, AP-HP, Research and Resource Memory Centre and INSERM U610, Paris (France); Lamari, Foudil; Jardel, Claude [CHU Pitie-Salpetriere, AP-HP, Department of Metabolic Biochemistry, Paris (France); Daragon, Nelle; Desarnaud, Serge [CHU Pitie-Salpetriere, AP-HP, Department of Nuclear Medicine, Paris (France)

    2010-03-15

    Our aim was to study the correlations between cerebrospinal fluid (CSF) biomarker levels such as {beta}-amyloid 42 (A{beta}{sub 42}), total and phosphorylated tau protein (T-tau and P-tau) and brain perfusion SPECT in Alzheimer's disease (AD) using a voxel-based methodology. Patients (n = 31) with clinical features of AD (n = 25) or amnestic mild cognitive impairment (aMCI) (n = 6) were retrospectively included. All subjects underwent the same clinical, neuropsychological and neuroimaging tests. They had a lumbar puncture and a brain perfusion ({sup 99m}Tc-ECD) SPECT within a time interval of 10 ({+-}26) days. Correlations between CSF biomarker concentrations and perfusion were studied using SPM2 software. Individual normalised regional activity values were extracted from the eligible clusters for calculation of correlation coefficients. No significant correlation was found between A{beta}{sub 42} concentrations and brain perfusion. A significant correlation (p < 0.01, corrected) was found between T-tau or P-tau concentrations and perfusion in the left parietal cortex. Our results suggest a strong correlation between T-tau and P-tau levels and decreased brain perfusion in regions typically affected by neuropathological changes in AD. (orig.)

  4. No disease in the brain of a 115-year-old woman.

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    den Dunnen, Wilfred F A; Brouwer, Wiebo H; Bijlard, Eveline; Kamphuis, Jeanine; van Linschoten, Klaas; Eggens-Meijer, Ellie; Holstege, Gert

    2008-08-01

    Are there limits to the duration of high quality of life? Are there limits to healthy life for a human brain? We have had the opportunity to evaluate the performance of a 112-113-year-old woman and perform full pathological examination of her body immediately after death at the age of 115. The psychological tests revealed that her general performance was above average of healthy adults of 60-75 years. The pathological observations revealed almost no atherosclerotic changes throughout the body. In the brain almost no beta-amyloid plaques or vascular changes were found and only slight accumulation of hyperphosphorylated tau protein with a Braak-stage 2. Counts of the number of locus coeruleus neurons corresponded with the number of neurons found in the brains of healthy people of 60-80 years old. Our observations indicate that the limits of human cognitive function extends far beyond the range that is currently enjoyed by most individuals and that brain disease, even in supercentanarians, is not inevitable.

  5. The nuclear receptor PPARγ as a therapeutic target for cerebrovascular and brain dysfunction in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Nektaria Nicolakakis

    2010-05-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are ligand-activated nuclear transcription factors that regulate peripheral lipid and glucose metabolism. Three subtypes make up the PPAR family (α, γ, β/δ, and synthetic ligands for PPARα (fibrates and PPARγ (Thiazolidinediones, TZDs are currently prescribed for the respective management of dyslipidemia and type 2 diabetes. In contrast to the well characterized action of PPARs in the periphery, little was known about the presence or function of these receptors in the brain and cerebral vasculature, until fairly recently. Indeed, research in the last decade has uncovered these receptors in most brain cell types, and has shown that their activation, particularly that of PPARγ, is implicated in normal brain and cerebrovascular physiology, and confers protection under pathological conditions. Notably, accumulating evidence has highlighted the therapeutic potential of PPARγ ligands in the treatment of brain disorders such as Alzheimer’s disease (AD, leading to the testing of the TZDs pioglitazone and rosiglitazone in AD clinical trials. This review will focus on the benefits of PPARγ agonists for vascular, neuronal and glial networks, and assess the value of these compounds as future AD therapeutics in light of evidence from transgenic mouse models and recent clinical trials.

  6. The impact of cognitive reserve on brain functional connectivity in Alzheimer's disease.

    Science.gov (United States)

    Bozzali, Marco; Dowling, Claire; Serra, Laura; Spanò, Barbara; Torso, Mario; Marra, Camillo; Castelli, Diana; Dowell, Nicholas G; Koch, Giacomo; Caltagirone, Carlo; Cercignani, Mara

    2015-01-01

    One factor believed to impact brain resilience to the pathological damage of Alzheimer's disease (AD) is the so-called "cognitive reserve" (CR). A critical issue that still needs to be fully understood is the mechanism by which environmental enrichment interacts with brain plasticity to determine resilience to AD pathology. Previous work using PET suggests that increased brain connectivity might be at the origin of the compensatory mechanisms implicated in this process. This study aims to further clarify this issue using resting-state functional MRI. Resting-state functional MRI was collected for 11 patients with AD, 18 with mild cognitive impairment (MCI), and 16 healthy controls, and analyzed to isolate the default mode network (DMN). A quantitative score of CR was obtained by combining information about number of years of education and type of schools attended. Consistent with previous reports, education was found to modulate functional connectivity in the posterior cingulate cortex, whose disconnection with the temporal lobes is known to be critical for the conversion from MCI to AD. This effect was highly significant in AD patients, less so in patients with MCI, and absent in healthy subjects. These findings show the potential neural mechanisms underlying the individual's ability to cope with brain damage, although they should be treated with some caution based on small numbers.

  7. Statistical quantifiers of memory for an analysis of human brain and neuro-system diseases

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    Demin, S. A.; Yulmetyev, R. M.; Panischev, O. Yu.; Hänggi, Peter

    2008-03-01

    On the basis of a memory function formalism for correlation functions of time series we investigate statistical memory effects by the use of appropriate spectral and relaxation parameters of measured stochastic data for neuro-system diseases. In particular, we study the dynamics of the walk of a patient who suffers from Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and compare against the data of healthy people (CO - control group). We employ an analytical method which is able to characterize the stochastic properties of stride-to-stride variations of gait cycle timing. Our results allow us to estimate quantitatively a few human locomotion function abnormalities occurring in the human brain and in the central nervous system (CNS). Particularly, the patient's gait dynamics are characterized by an increased memory behavior together with sizable fluctuations as compared with the locomotion dynamics of healthy patients. Moreover, we complement our findings with peculiar features as detected in phase-space portraits and spectral characteristics for the different data sets (PD, HD, ALS and healthy people). The evaluation of statistical quantifiers of the memory function is shown to provide a useful toolkit which can be put to work to identify various abnormalities of locomotion dynamics. Moreover, it allows one to diagnose qualitatively and quantitatively serious brain and central nervous system diseases.

  8. Subcellular compartmentalisation of copper, iron, manganese, and zinc in the Parkinson's disease brain.

    Science.gov (United States)

    Genoud, Sian; Roberts, Blaine R; Gunn, Adam P; Halliday, Glenda M; Lewis, Simon J G; Ball, Helen J; Hare, Dominic J; Double, Kay L

    2017-10-18

    Elevated iron and decreased copper levels are cardinal features of the degenerating substantia nigra pars compacta in the Parkinson's disease brain. Both of these redox-active metals, and fellow transition metals manganese and zinc, are found at high concentrations within the midbrain and participate in a range of unique biological reactions. We examined the total metal content and cellular compartmentalisation of manganese, iron, copper and zinc in the degenerating substantia nigra, disease-affected but non-degenerating fusiform gyrus, and unaffected occipital cortex in the post mortem Parkinson's disease brain compared with age-matched controls. An expected increase in iron and a decrease in copper concentration was isolated to the soluble cellular fraction, encompassing both interstitial and cytosolic metals and metal-binding proteins, rather than the membrane-associated or insoluble fractions. Manganese and zinc levels did not differ between experimental groups. Altered Fe and Cu levels were unrelated to Braak pathological staging in our cases of late-stage (Braak stage V and VI) disease. The data supports our hypothesis that regional alterations in Fe and Cu, and in proteins that utilise these metals, contribute to the regional selectively of neuronal vulnerability in this disorder.

  9. Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy.

    Science.gov (United States)

    von Jonquieres, Georg; Spencer, Ziggy H T; Rowlands, Benjamin D; Klugmann, Claudia B; Bongers, Andre; Harasta, Anne E; Parley, Kristina E; Cederholm, Jennie; Teahan, Orla; Pickford, Russell; Delerue, Fabien; Ittner, Lars M; Fröhlich, Dominik; McLean, Catriona A; Don, Anthony S; Schneider, Miriam; Housley, Gary D; Rae, Caroline D; Klugmann, Matthias

    2018-01-01

    N-Acetylaspartate (NAA) is the second most abundant organic metabolite in the brain, but its physiological significance remains enigmatic. Toxic NAA accumulation appears to be the key factor for neurological decline in Canavan disease-a fatal neurometabolic disorder caused by deficiency in the NAA-degrading enzyme aspartoacylase. To date clinical outcome of gene replacement therapy for this spongiform leukodystrophy has not met expectations. To identify the target tissue and cells for maximum anticipated treatment benefit, we employed comprehensive phenotyping of novel mouse models to assess cell type-specific consequences of NAA depletion or elevation. We show that NAA-deficiency causes neurological deficits affecting unconscious defensive reactions aimed at protecting the body from external threat. This finding suggests, while NAA reduction is pivotal to treat Canavan disease, abrogating NAA synthesis should be avoided. At the other end of the spectrum, while predicting pathological severity in Canavan disease mice, increased brain NAA levels are not neurotoxic per se. In fact, in transgenic mice overexpressing the NAA synthesising enzyme Nat8l in neurons, supra-physiological NAA levels were uncoupled from neurological deficits. In contrast, elimination of aspartoacylase expression exclusively in oligodendrocytes elicited Canavan disease like pathology. Although conditional aspartoacylase deletion in oligodendrocytes abolished expression in the entire CNS, the remaining aspartoacylase in peripheral organs was sufficient to lower NAA levels, delay disease onset and ameliorate histopathology. However, comparable endpoints of the conditional and complete aspartoacylase knockout indicate that optimal Canavan disease gene replacement therapies should restore aspartoacylase expression in oligodendrocytes. On the basis of these findings we executed an ASPA gene replacement therapy targeting oligodendrocytes in Canavan disease mice resulting in reversal of pre

  10. Physical Activity and Brain Function in Older Adults at Increased Risk for Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Stephen M. Rao

    2013-01-01

    Full Text Available Leisure-time physical activity (PA and exercise training are known to help maintain cognitive function in healthy older adults. However, relatively little is known about the effects of PA on cognitive function or brain function in those at increased risk for Alzheimer’s disease through the presence of the apolipoproteinE epsilon4 (APOE-ε4 allele, diagnosis of mild cognitive impairment (MCI, or the presence of metabolic disease. Here, we examine the question of whether PA and exercise interventions may differentially impact cognitive trajectory, clinical outcomes, and brain structure and function among individuals at the greatest risk for AD. The literature suggests that the protective effects of PA on risk for future dementia appear to be larger in those at increased genetic risk for AD. Exercise training is also effective at helping to promote stable cognitive function in MCI patients, and greater cardiorespiratory fitness is associated with greater brain volume in early-stage AD patients. In APOE-ε4 allele carriers compared to non-carriers, greater levels of PA may be more effective in reducing amyloid burden and are associated with greater activation of semantic memory-related neural circuits. A greater research emphasis should be placed on randomized clinical trials for exercise, with clinical, behavioral, and neuroimaging outcomes in people at increased risk for AD.

  11. Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s disease

    Science.gov (United States)

    Cabezas, Ricardo; Ávila, Marcos; Gonzalez, Janneth; El-Bachá, Ramon Santos; Báez, Eliana; García-Segura, Luis Miguel; Jurado Coronel, Juan Camilo; Capani, Francisco; Cardona-Gomez, Gloria Patricia; Barreto, George E.

    2014-01-01

    The blood–brain barrier (BBB) is a tightly regulated interface in the Central Nervous System (CNS) that regulates the exchange of molecules in and out from the brain thus maintaining the CNS homeostasis. It is mainly composed of endothelial cells (ECs), pericytes and astrocytes that create a neurovascular unit (NVU) with the adjacent neurons. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted factors that lead to the adequate association between the cells of the BBB and the formation of strong tight junctions. Under neurological disorders, such as chronic cerebral ischemia, brain trauma, Epilepsy, Alzheimer and Parkinson’s Diseases, a disruption of the BBB takes place, involving a lost in the permeability of the barrier and phenotypical changes in both the ECs and astrocytes. In this aspect, it has been established that the process of reactive gliosis is a common feature of astrocytes during BBB disruption, which has a detrimental effect on the barrier function and a subsequent damage in neuronal survival. In this review we discuss the implications of astrocyte functions in the protection of the BBB, and in the development of Parkinson’s disease (PD) and related disorders. Additionally, we highlight the current and future strategies in astrocyte protection aimed at the development of restorative therapies for the BBB in pathological conditions. PMID:25136294

  12. Altered modular organization of intrinsic brain functional networks in patients with Parkinson's disease.

    Science.gov (United States)

    Ma, Qing; Huang, Biao; Wang, Jinhui; Seger, Carol; Yang, Wanqun; Li, Changhong; Wang, Junjing; Feng, Jieying; Weng, Ling; Jiang, Wenjie; Huang, Ruiwang

    2017-04-01

    Although previous studies reported altered topology of brain functional networks in patients with Parkinson's disease (PD), the modular organization of brain functional networks in PD patients remains largely unknown. Using the resting-state functional MRI (R-fMRI) and graph theory, we examined the modular organization of brain functional networks in 32 unmedicated patients with early-to-mid motor stage PD and 31 healthy controls. Compared to the controls, the PD patients tended to show decreased integrity and segregation, both within and between modules. This was inferred by significantly increased intra-modular characteristic path length (L p) within four modules: mPFC, SN, SMN, and FPN, decreased inter-modular functional connectivity (FC) between mPFC and SN, SMN, and VN, and decreased intra-modular clustering in the PD patients. Intra-modular characteristic path length within the mPFC showed significantly positive correlation with general cognitive ability in the PD group. Receiver operating characteristic (ROC) analysis revealed that FC between mPFC and SN had the highest significant accuracy in differentiating the patients from the controls. Our findings may provide new insight in understanding the pathological changes that underlie impairment in cognition and movement in Parkinson's disease.

  13. PINK1 and its familial Parkinson's disease-associated mutation regulate brain vascular endothelial inflammation.

    Science.gov (United States)

    Yunfu, Wang; Guangjian, Liu; Ping, Zhong; Yanpeng, Sun; Xiaoxia, Fang; Wei, Hu; Jiang, Yuan; Jingquan, Hu; Songlin, Wang; Hongyan, Zhang; Yong, Liu; Shi, Chen

    2014-05-01

    Parkinson's disease (PD) is a debilitating disorder that affects movement. Inflammation-mediated endothelial dysfunction has been found to be involved in neurodegenerative diseases, including PD. More than 40 PTEN-induced putative kinase 1 (PINK1) mutations have been found in PD patients. The effects of PINK1 in vascular inflammation are as yet unknown. In this study, our findings revealed that PINK1 can be increased by the inflammatory cytokine tumor necrosis factor-α in primary human brain microvascular endothelial cells (HBMECs). We found that wild-type PINK1 prevents expression of the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1), thus inhibiting the attachment of monocytes to brain endothelial cells. However, PINK1G309D, the loss-of-function mutation associated with early-onset familial PD, promotes expression of VCAM-1 and exacerbates attachment of monocytes to brain endothelial cells. Mechanism studies revealed that overexpression of wild-type PINK1 inhibits the VCAM-1 promoter by inhibiting the transcriptional activity of interferon regulatory factor 1 (IRF-1). However, PINK1G309D promotes the VCAM-1 promoter by increasing the transcriptional activity of IRF-1.

  14. Maternal age affects brain metabolism in adult children of mothers affected by Alzheimer's disease.

    Science.gov (United States)

    Mosconi, Lisa; Tsui, Wai; Murray, John; McHugh, Pauline; Li, Yi; Williams, Schantel; Pirraglia, Elizabeth; Glodzik, Lidia; De Santi, Susan; Vallabhajosula, Shankar; de Leon, Mony J

    2012-03-01

    Cognitively normal (NL) individuals with a maternal history of late-onset Alzheimer's disease (MH) show reduced brain glucose metabolism on FDG-PET as compared to those with a paternal history (PH) and those with negative family history (NH) of Alzheimer's disease (AD). This FDG-PET study investigates whether metabolic deficits in NL MH are associated with advancing maternal age at birth. Ninety-six NL individuals with FDG-PET were examined, including 36 MH, 24 PH, and 36 NH. Regional-to-whole brain gray matter standardized FDG uptake value ratios were examined for associations with parental age across groups using automated regions-of-interest and statistical parametric mapping. Groups were comparable for clinical and neuropsychological measures. Brain metabolism in AD-vulnerable regions was lower in MH compared to NH and PH, and negatively correlated with maternal age at birth only in MH. There were no associations between paternal age and metabolism in any group. Evidence for a maternally inherited, maternal age-related mechanism provides further insight on risk factors and genetic transmission in late-onset AD. Published by Elsevier Inc.

  15. Astrocytic modulation of Blood Brain Barrier: Perspectives on Parkinson´s Disease

    Directory of Open Access Journals (Sweden)

    Ricardo eCabezas

    2014-08-01

    Full Text Available TThe blood–brain barrier (BBB is a tightly regulated interface in the Central Nervous System that regulates the exchange of molecules in and out from the brain thus maintaining the CNS homeostasis. It is mainly composed of endothelial cells, pericytes and astrocytes that create a neurovascular unit with the adjacent neurons. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted factors that lead to the adequate association between the cells of the BBB and the formation of strong tight junctions. Under neurological disorders, such as chronic cerebral ischemia, brain trauma, Epilepsy, Alzheimer and Parkinson´s Diseases, a disruption of the BBB takes place, involving a lost in the permeability of the barrier and phenotypical changes in both the endothelial cells and astrocytes. In this aspect, it has been established that the process of reactive gliosis is a common feature of astrocytes during BBB disruption, which has a detrimental effect on the barrier function and a subsequent damage in neuronal survival. In this review we discuss the implications of astrocyte functions in the protection of the BBB, and in the development of Parkinson´s disease and related disorders. Additionally, we highlight the current and future strategies in astrocyte protection aimed at the development of restorative therapies for the BBB in pathological conditions.

  16. Association Between Motor Symptoms and Brain Metabolism in Early Huntington Disease.

    Science.gov (United States)

    Gaura, Véronique; Lavisse, Sonia; Payoux, Pierre; Goldman, Serge; Verny, Christophe; Krystkowiak, Pierre; Damier, Philippe; Supiot, Frédéric; Bachoud-Levi, Anne-Catherine; Remy, Philippe

    2017-09-01

    Brain hypometabolism is associated with the clinical consequences of the degenerative process, but little is known about regional hypermetabolism, sometimes observed in the brain of patients with clinically manifest Huntington disease (HD). Studying the role of regional hypermetabolism is needed to better understand its interaction with the motor symptoms of the disease. To investigate the association between brain hypometabolism and hypermetabolism with motor scores of patients with early HD. This study started in 2001, and analysis was completed in 2016. Sixty symptomatic patients with HD and 15 healthy age-matched control individuals underwent positron emission tomography to measure cerebral metabolism in this cross-sectional study. They also underwent the Unified Huntington's Disease Rating Scale motor test, and 2 subscores were extracted: (1) a hyperkinetic score, combining dystonia and chorea, and (2) a hypokinetic score, combining bradykinesia and rigidity. Statistical parametric mapping software (SPM5) was used to identify all hypo- and hypermetabolic regions in patients with HD relative to control individuals. Correlation analyses (P < .001, uncorrected) between motor subscores and brain metabolic values were performed for regions with significant hypometabolism and hypermetabolism. Among 60 patients with HD, 22 were women (36.7%), and the mean (SD) age was 44.6 (7.6) years. Of the 15 control individuals, 7 were women (46.7%), and the mean (SD) age was 42.2 (7.3) years. In statistical parametric mapping, striatal hypometabolism was significantly correlated with the severity of all motor scores. Hypermetabolism was negatively correlated only with hypokinetic scores in the cuneus (z score = 3.95, P < .001), the lingual gyrus (z score = 4.31, P < .001), and the crus I/II of the cerebellum (z score = 3.77, P < .001), a region connected to associative cortical areas. More severe motor scores were associated with higher metabolic

  17. The brain in myotonic dystrophy 1 and 2: evidence for a predominant white matter disease.

    Science.gov (United States)

    Minnerop, Martina; Weber, Bernd; Schoene-Bake, Jan-Christoph; Roeske, Sandra; Mirbach, Sandra; Anspach, Christian; Schneider-Gold, Christiane; Betz, Regina C; Helmstaedter, Christoph; Tittgemeyer, Marc; Klockgether, Thomas; Kornblum, Cornelia

    2011-12-01

    Myotonic dystrophy types 1 and 2 are progressive multisystemic disorders with potential brain involvement. We compared 22 myotonic dystrophy type 1 and 22 myotonic dystrophy type 2 clinically and neuropsychologically well-characterized patients and a corresponding healthy control group using structural brain magnetic resonance imaging at 3 T (T(1)/T(2)/diffusion-weighted). Voxel-based morphometry and diffusion tensor imaging with tract-based spatial statistics were applied for voxel-wise analysis of cerebral grey and white matter affection (P(corrected) brain changes with clinical and neuropsychological data. White matter lesions rated visually were more prevalent and severe in myotonic dystrophy type 1 compared with controls, with frontal white matter most prominently affected in both disorders, and temporal lesions restricted to myotonic dystrophy type 1. Voxel-based morphometry analyses demonstrated extensive white matter involvement in all cerebral lobes, brainstem and corpus callosum in myotonic dystrophy types 1 and 2, while grey matter decrease (cortical areas, thalamus, putamen) was restricted to myotonic dystrophy type 1. Accordingly, we found more prominent white matter affection in myotonic dystrophy type 1 than myotonic dystrophy type 2 by diffusion tensor imaging. Association fibres throughout the whole brain, limbic system fibre tracts, the callosal body and projection fibres (e.g. internal/external capsules) were affected in myotonic dystrophy types 1 and 2. Central motor pathways were exclusively impaired in myotonic dystrophy type 1. We found mild executive and attentional deficits in our patients when neuropsychological tests were corrected for manual motor dysfunctioning. Regression analyses revealed associations of white matter affection with several clinical parameters in both disease entities, but not with neuropsychological performance. We showed that depressed mood and fatigue were more prominent in patients with myotonic dystrophy type 1

  18. Increased brain tissue sodium concentration in Huntington's Disease - a sodium imaging study at 4 T.

    Science.gov (United States)

    Reetz, Kathrin; Romanzetti, Sandro; Dogan, Imis; Saß, Christian; Werner, Cornelius J; Schiefer, Johannes; Schulz, Jörg B; Shah, N Jon

    2012-10-15

    The neuropathological hallmark of the autosomal dominantly inherited, neurodegenerative disorder Huntington's disease is progressive striatal loss starting several years prior to symptom manifestation. Magnetic resonance (MR) imaging has been widely used to detect altered structure in premanifest and early Huntington's disease. Given that neurodegeneration is likely preceded by substantial neuronal dysfunction, we used in vivo sodium MR imaging, which has been shown to be sensitive to cell death and viability, to investigate cellular and metabolic integrity of Huntington's disease brain tissue. We studied a total of thirteen healthy controls and thirteen Huntington's disease gene carriers (11 manifest and 2 premanifest). The manifest Huntington's disease group was subdivided into stages 1 and 2 according to their Total Functional Capacity scores. Clinical total motor and cognitive scores, as well as calibrated sodium and T1-weighted MR images were obtained with a 4 T Siemens MR scanner. Sodium images were acquired by means of a constant time imaging technique with an ultra-short "echo time". T1-weighted MR images were further analysed with voxel-based morphometry. The absolute total sodium concentration and grey matter values were measured in several Huntington's disease-specific and also non-specific areas. Statistical analysis of variance and Pearson correlation were applied. In Huntington's disease subjects, we found an increase of total sodium concentration of the entire brain compared to controls. Increased total sodium concentration values were found in structurally affected, but also in some non-affected, regions. The highest total sodium concentration values were found in the bilateral caudate, which was associated with caudate grey matter atrophy and CAG repeat length. In all Huntington's disease subjects we further found a profound increase of total sodium concentration in the putamen, pallidum, thalamus, hippocampus, insula, precuneus and occipital

  19. Changes in brain oxysterols at different stages of Alzheimer's disease: Their involvement in neuroinflammation

    Directory of Open Access Journals (Sweden)

    Gabriella Testa

    2016-12-01

    Full Text Available Alzheimer's disease (AD is a gradually debilitating disease that leads to dementia. The molecular mechanisms underlying AD are still not clear, and at present no reliable biomarkers are available for the early diagnosis. In the last several years, together with oxidative stress and neuroinflammation, altered cholesterol metabolism in the brain has become increasingly implicated in AD progression. A significant body of evidence indicates that oxidized cholesterol, in the form of oxysterols, is one of the main triggers of AD. The oxysterols potentially most closely involved in the pathogenesis of AD are 24-hydroxycholesterol and 27-hydroxycholesterol, respectively deriving from cholesterol oxidation by the enzymes CYP46A1 and CYP27A1. However, the possible involvement of oxysterols resulting from cholesterol autooxidation, including 7-ketocholesterol and 7β-hydroxycholesterol, is now emerging. In a systematic analysis of oxysterols in post-mortem human AD brains, classified by the Braak staging system of neurofibrillary pathology, alongside the two oxysterols of enzymatic origin, a variety of oxysterols deriving from cholesterol autoxidation were identified; these included 7-ketocholesterol, 7α-hydroxycholesterol, 4β-hydroxycholesterol, 5α,6α-epoxycholesterol, and 5β,6β-epoxycholesterol. Their levels were quantified and compared across the disease stages. Some inflammatory mediators, and the proteolytic enzyme matrix metalloprotease-9, were also found to be enhanced in the brains, depending on disease progression. This highlights the pathogenic association between the trends of inflammatory molecules and oxysterol levels during the evolution of AD. Conversely, sirtuin 1, an enzyme that regulates several pathways involved in the anti-inflammatory response, was reduced markedly with the progression of AD, supporting the hypothesis that the loss of sirtuin 1 might play a key role in AD. Taken together, these results strongly support the

  20. 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

  1. Regional brain stem atrophy in idiopathic Parkinson's disease detected by anatomical MRI.

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    Thomas Jubault

    Full Text Available Idiopathic Parkinson's disease (PD is a neurodegenerative disorder characterized by the dysfunction of dopaminergic dependent cortico-basal ganglia loops and diagnosed on the basis of motor symptoms (tremors and/or rigidity and bradykinesia. Post-mortem studies tend to show that the destruction of dopaminergic neurons in the substantia nigra constitutes an intermediate step in a broader neurodegenerative process rather than a unique feature of Parkinson's disease, as a consistent pattern of progression would exist, originating from the medulla oblongata/pontine tegmentum. To date, neuroimaging techniques have been unable to characterize the pre-symptomatic stages of PD. However, if such a regular neurodegenerative pattern were to exist, consistent damages would be found in the brain stem, even at early stages of the disease. We recruited 23 PD patients at Hoenn and Yahr stages I to II of the disease and 18 healthy controls (HC matched for age. T1-weighted anatomical scans were acquired (MPRAGE, 1 mm3 resolution and analyzed using an optimized VBM protocol to detect white and grey matter volume reduction without spatial a priori. When the HC group was compared to the PD group, a single cluster exhibited statistical difference (p<0.05 corrected for false detection rate, 4287 mm3 in the brain stem, between the pons and the medulla oblongata. The present study provides in-vivo evidence that brain stem damage may be the first identifiable stage of PD neuropathology, and that the identification of this consistent damage along with other factors could help with earlier diagnosis in the future. This damage could also explain some non-motor symptoms in PD that often precede diagnosis, such as autonomic dysfunction and sleep disorders.

  2. Effects of Parkinson's disease on brain-wave phase synchronisation and cross-modulation

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    Stumpf, K.; Schumann, A. Y.; Plotnik, M.; Gans, F.; Penzel, T.; Fietze, I.; Hausdorff, J. M.; Kantelhardt, J. W.

    2010-02-01

    We study the effects of Parkinson's disease (PD) on phase synchronisation and cross-modulation of instantaneous amplitudes and frequencies for brain waves during sleep. Analysing data from 40 full-night EEGs (electro-encephalograms) of ten patients with PD and ten age-matched healthy controls we find that phase synchronisation between the left and right hemisphere of the brain is characteristically reduced in patients with PD. Since there is no such difference in phase synchronisation for EEGs from the same hemisphere, our results suggest the possibility of a relation with problems in coordinated motion of left and right limbs in some patients with PD. Using the novel technique of amplitude and frequency cross-modulation analysis, relating oscillations in different EEG bands and distinguishing both positive and negative modulation, we observe an even more significant decrease in patients for several band combinations.

  3. Brain Functional Network in Alzheimer's Disease: Diagnostic Markers for Diagnosis and Monitoring

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    Guido Rodriguez

    2011-01-01

    Full Text Available Alzheimer's disease (AD is the most common type of dementia that is clinically characterized by the presence of memory impairment and later by impairment in other cognitive domains. The clinical diagnosis is based on interviews with the patient and his/her relatives and on neuropsychological assessment, which are also used to monitor cognitive decline over time. Several biomarkers have been proposed for detecting AD in its earliest stages, that is, in the predementia stage. In an attempt to find noninvasive biomarkers, researchers have investigated the feasibility of neuroimaging tools, such as MR, SPECT, and FDG-PET imaging, as well as neurophysiological measurements using EEG. In this paper, we investigate the brain functional networks in AD, focusing on main neurophysiological techniques, integrating with most relevant functional brain imaging findings.

  4. Deep brain stimulation for Parkinson's disease: current status and future outlook.

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    Smith, Kyle A; Pahwa, Rajesh; Lyons, Kelly E; Nazzaro, Jules M

    2016-08-01

    Parkinson's disease is a neurodegenerative condition secondary to loss of dopaminergic neurons in the substantia nigra pars compacta. Surgical therapy serves as an adjunct when unwanted medication side effects become apparent or additional therapy is needed. Deep brain stimulation emerged into the forefront in the 1990s. Studies have demonstrated improvement in all of the cardinal parkinsonian signs with stimulation. Frameless and 'mini-frame' stereotactic systems, improved MRI for anatomic visualization, and intraoperative MRI-guided placement are a few of the surgical advances in deep brain stimulation. Other advances include rechargeable pulse generators, voltage- or current-based stimulation, and enhanced abilities to 'steer' stimulation. Work is ongoing investigating closed-loop 'smart' stimulation in which stimulation is predicated on neuronal feedback.

  5. Role of Sex Hormones on Brain Mitochondrial Function, with Special Reference to Aging and Neurodegenerative Diseases

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    Pauline Gaignard

    2017-12-01

    Full Text Available The mitochondria have a fundamental role in both cellular energy supply and oxidative stress regulation and are target of the effects of sex steroids, particularly the neuroprotective ones. Aging is associated with a decline in the levels of different steroid hormones, and this decrease may underline some neural dysfunctions. Besides, modifications in mitochondrial functions associated with aging processes are also well documented. In this review, we will discuss studies that describe the modifications of brain mitochondrial function and of steroid levels associated with physiological aging and with neurodegenerative diseases. A special emphasis will be placed on describing and discussing our recent findings concerning the concomitant study of mitochondrial function (oxidative phosphorylation, oxidative stress and brain steroid levels in both young (3-month-old and aged (20-month-old male and female mice.

  6. Brain SPET abnormalities in Alzheimer's disease before and after atrophy correction

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    Matsuda, Hiroshi; Kanetaka, Hidekazu; Ohnishi, Takashi; Imabayashi, Etsuko; Katoh, Asako; Tanaka, Fumiko [Department of Radiology, National Center Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, 187-8551, Tokyo (Japan); Asada, Takashi [Department of Neuropsychiatry, Institute of Clinical Medicine, University of Tsukuba, Ibaraki (Japan); Nakano, Seigo [Department of Geriatric Medicine, National Center Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, Kodaira, Tokyo (Japan)

    2002-11-01

    The aim of this study was to determine which brain structures show the greatest influence of partial volume effects (PVE) in single-photon emission tomography (SPET) studies on Alzheimer's disease (AD). Brain perfusion SPET was performed in 30 patients with probable AD and 62 age-matched healthy volunteers. SPET images were corrected for PVE using grey matter volume segmented from magnetic resonance images. The most prominent changes after PVE correction were observed in the medial temporal structures. The PVE correction revealed a selective decrease in regional cerebral blood flow (rCBF) in the parahippocampal gyrus of AD without rCBF decreases in the hippocampus, which had been observed before correction. This correction seems to be essential in order to achieve accurate measurements of rCBF in SPET, which has limited spatial resolution. (orig.)

  7. Oscillations in Pedunculopontine Nucleus in Parkinson's disease and its relationship with deep brain stimulation

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    Min eLi

    2015-09-01

    Full Text Available The recent development of deep brain stimulation (DBS of the pedunculopontine nucleus (PPN for the treatment of parkinsonian patients, particularly those in advanced stages with axial symptoms, has ignited interest into the study of this brain nucleus. In contrast to the extensively studied alterations of neural activity that occur in the basal ganglia in Parkinson’s disease (PD, our understanding of the activity of the PPN remains insufficient. In recent years, however, a series of studies recording oscillatory activity in the PPN of parkinsonian patients have made important findings. Here, we briefly review recent studies that explore the different kinds of oscillations observed in the PPN of parkinsonian patients, and how they underlie the pathophysiology of PD and the efficacy of PPN DBS in these disorders.

  8. NEUROPSYCHOLOGICAL CHANGES ASSOCIATED WITH DEEP BRAIN STIMULATION OF PARKINSON DISEASE: THEORETICAL REVIEW

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    Oscar M. Aguilar

    2011-12-01

    Full Text Available Parkinson’s disease is a neurodegenerative disorder attributable to midbrain dopaminergiccell loss within the substantia nigra. This causes a dysfunction of thebasal ganglia manifested by motor symptoms such as tremor, rigidity, bradykinesiaamong others. With Deep Brain Stimulation (DBS, neurosurgery has emergedas a therapeutic option, being the subthalamic nucleus its main target area. Studiesshow significant improvement in motor deficits, but there is no knowledge on theneuropsychological changes in patients after DBS. A review of several studies thathave researched the cognitive, emotional and behavioral changes concluded thatmost cognitive skills are either maintained or improved after DBS, but there may beadverse emotional and behavioral changes that are related to the core brain wherethe electrode is implanted and with its premorbid personality characteristics.

  9. The reconstructive management of hardware-related scalp erosion in deep brain stimulation for Parkinson disease.

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    Gómez, Raúl; Hontanilla, Bernardo

    2014-09-01

    The presence of foreign material in deep brain stimulation is a risk factor for infection, and hardware-related pressure under the scalp may cause skin erosion. The aim of this article is to present our experience in the coverage of scalp in relation to underlying hardware. We analyzed 21 patients with Parkinson disease who had undergone deep brain stimulation surgery and developed scalp erosion with hardware exposition during follow-up. Nine patients were programmed for a scalp rotation flap, whereas free tisue transfer was performed in the rest of the patients. Minimum follow-up was 2 years. A hardware-related ulcer appeared in 5 of 9 rotation flap patients. No ulceration or major complications were observed in free flap patients. Free flaps are probably the best option for stable coverage in hardware-related scalp erosion with a high rate of success.

  10. Anaesthetic management of shoulder arthroscopic repair in Parkinson′s disease with deep brain stimulator

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    Ranju Gandhi

    2014-01-01

    Full Text Available We describe the anaesthetic management of arthroscopic repair for complete rotator cuff tear of shoulder in a 59-year-old female with Parkinson′s disease (PD with deep brain stimulator (DBS using a combination of general anaesthesia with interscalene approach to brachial plexus block. The DBS consists of implanted electrodes in the brain connected to the implantable pulse generator (IPG normally placed in the anterior chest wall subcutaneously. It can be programmed externally from a hand-held device placed directly over the battery stimulator unit. In our patient, IPG with its leads was located in close vicinity of the operative site with potential for DBS malfunction. Implications of DBS in a patient with PD for shoulder arthroscopy for anaesthesiologist are discussed along with a brief review of DBS.

  11. Infusion treatments and deep brain stimulation in Parkinson's Disease: The role of nursing.

    Science.gov (United States)

    De Rosa, Anna; Tessitore, Alessandro; Bilo, Leonilda; Peluso, Silvio; De Michele, Giuseppe

    Parkinson's Disease (PD) represents one of the most common neurodegenerative disorders in the elderly. PD is caused by a loss of dopaminergic cells in the substantia nigra pars compacta. The motor cardinal signs include a resting tremor, bradykinesia, rigidity and postural reflex impairment. Although levodopa represents the gold standard also in the advanced stage of the disease, over the years most patients develop disabling motor fluctuations, dyskinesias, and non-motor complications, which are difficult to manage. At this stage, more complex treatment approaches, such as infusion therapies (subcutaneous apomorphine and intraduodenal levodopa) and deep brain stimulation of the subthalamic nucleus or the globus pallidus internus should be considered. All three procedures require careful selection and good compliance of candidate patients. In particular, infusional therapies need adequate training both of caregivers and nursing staff in order to assist clinicians in the management of patients in the complicated stages of disease. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Deep brain stimulation for the treatment of Alzheimer disease and dementias.

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    Laxton, Adrian W; Lozano, Andres M

    2013-01-01

    To review the use of deep brain stimulation (DBS) for treatment of dementia. A PubMed literature search was conducted to identify all studies that have investigated the use of DBS for treatment of dementia. Three studies examined the use of DBS for dementia. One study involved fornix DBS for Alzheimer disease (AD), and two studies involved DBS of the nucleus basalis of Meynert, one to treat AD and one to treat Parkinson disease dementia. Evidence for the use of DBS to treat dementia is preliminary and limited. Fornix and nucleus basalis of Meynert DBS can influence activity in the pathologic neural circuits that underlie AD and Parkinson disease dementia. Further investigation into the potential clinical effects of DBS for dementia is warranted. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Amyloid-β Annular Protofibrils Evade Fibrillar Fate in Alzheimer Disease Brain*♦

    Science.gov (United States)

    Lasagna-Reeves, Cristian A.; Glabe, Charles G.; Kayed, Rakez

    2011-01-01

    Annular protofibrils (APFs) represent a new and distinct class of amyloid structures formed by disease-associated proteins. In vitro, these pore-like structures have been implicated in membrane permeabilization and ion homeostasis via pore formation. Still, evidence for their formation and relevance in vivo is lacking. Herein, we report that APFs are in a distinct pathway from fibril formation in vitro and in vivo. In human Alzheimer disease brain samples, amyloid-β APFs were associated with diffuse plaques, but not compact plaques; moreover, we show the formation of intracellular APFs. Our results together with previous studies suggest that the prevention of amyloid-β annular protofibril formation could be a relevant target for the prevention of amyloid-β toxicity in Alzheimer disease. PMID:21507938

  14. Amyloid-β annular protofibrils evade fibrillar fate in Alzheimer disease brain.

    Science.gov (United States)

    Lasagna-Reeves, Cristian A; Glabe, Charles G; Kayed, Rakez

    2011-06-24

    Annular protofibrils (APFs) represent a new and distinct class of amyloid structures formed by disease-associated proteins. In vitro, these pore-like structures have been implicated in membrane permeabilization and ion homeostasis via pore formation. Still, evidence for their formation and relevance in vivo is lacking. Herein, we report that APFs are in a distinct pathway from fibril formation in vitro and in vivo. In human Alzheimer disease brain samples, amyloid-β APFs were associated with diffuse plaques, but not compact plaques; moreover, we show the formation of intracellular APFs. Our results together with previous studies suggest that the prevention of amyloid-β annular protofibril formation could be a relevant target for the prevention of amyloid-β toxicity in Alzheimer disease.

  15. The role of vitamin D in the brain and related neurological diseases

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    Mustafa Yılmaz

    2013-09-01

    Full Text Available Vitamin D is a steroid hormone that is produced photochemicallyin epidermis. It is known that vitamin D involvedin the regulation of bone mineralization and calcium-phosphorus balance. However, in recent studies havesuggested that vitamin D may have a significant impactin the development of the cell proliferation, differentiation,neurotransmission, neuroplasticity, neurotropic andneuroprotective effects in central nervous system (CNS.For the reason of the effects, it can be considered as aneurosteroid was reported. It was discussed that the levelof vitamin D may be associated to neurodegenerativediseases such as Parkinson’s disease, Alzheimer’s disease,multiple sclerosis (MS, amyotrophic lateral sclerosis(ALS. The role of vitamin D and the mechanisms ofthese diseases will be discussed in the review. J Clin ExpInvest 2013; 4 (3: 411-415Key words: Vitamin D, neurosteroid, brain, neurologicdiseases

  16. Multifactorial causal model of brain (dis)organization and therapeutic intervention: Application to Alzheimer's disease.

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    Iturria-Medina, Yasser; Carbonell, Félix M; Sotero, Roberto C; Chouinard-Decorte, Francois; Evans, Alan C

    2017-05-15

    Generative models focused on multifactorial causal mechanisms in brain disorders are scarce and generally based on limited data. Despite the biological importance of the multiple interacting processes, their effects remain poorly characterized from an integrative analytic perspective. Here, we propose a spatiotemporal multifactorial causal model (MCM) of brain (dis)organization and therapeutic intervention that accounts for local causal interactions, effects propagation via physical brain networks, cognitive alterations, and identification of optimum therapeutic interventions. In this article, we focus on describing the model and applying it at the population-based level for studying late onset Alzheimer's disease (LOAD). By interrelating six different neuroimaging modalities and cognitive measurements, this model accurately predicts spatiotemporal alterations in brain amyloid-β (Aβ) burden, glucose metabolism, vascular flow, resting state functional activity, structural properties, and cognitive integrity. The results suggest that a vascular dysregulation may be the most-likely initial pathologic event leading to LOAD. Nevertheless, they also suggest that LOAD it is not caused by a unique dominant biological factor (e.g. vascular or Aβ) but by the complex interplay among multiple relevant direct interactions. Furthermore, using theoretical control analysis of the identified population-based multifactorial causal network, we show the crucial advantage of using combinatorial over single-target treatments, explain why one-target Aβ based therapies might fail to improve clinical outcomes, and propose an efficiency ranking of possible LOAD interventions. Although still requiring further validation at the individual level, this work presents the first analytic framework for dynamic multifactorial brain (dis)organization that may explain both the pathologic evolution of progressive neurological disorders and operationalize the influence of multiple interventional

  17. The Correlations Between Postmortem Brain Pathologies and Cognitive Dysfunction in Aging and Alzheimer's Disease.

    Science.gov (United States)

    Qiu, Wen-Ying; Yang, Qian; Zhang, Wanying; Wang, Naili; Zhang, Di; Huang, Yue; Ma, Chao

    2017-11-06

    Background The pathological diagnostic criteria for Alzheimer's disease (AD) updated by National Institute on Aging-Alzheimer's Association (NIA-AA) in 2012 has been widely adopted, but the clinicopathological relevance remained obscure in Chinese population. Objective This study aims to investigate the correlations between the antemortem clinical cognitive performances and the postmortem neuropathological changes in the aging and AD brains collected in a human brain bank in China. Method A total of 52 human brains with antemortem cognitive status information [Everyday Cognition (ECog)] were collected through the willed donation program by CAMS/PUMC Human Brain Bank. Pathological changes were evaluated with the "ABC" score following the guidelines of NIA-AA. The clinicopathological relationship was analyzed with correlation analysis and general linear multivariate model. Results The general ABC score has a significant correlation with global ECog score (r=0.37, p=0.014) and most of ECog domains. The CERAD score of neuritic plaques (C score) has a significant correlation with global ECog score (r=0.40, p=0.007) and the majority of ECog domains, such as memory (r=0.50, p=0.001), language (r=0.45, p=0.002), visuospatial functions (r=0.31, p=0.040), planning (r=0.35, p=0.021) and organization (r=0.39, p=0.010). The Braak stage of neurofibrillary tangles (NFTs) (B score) has a moderate correlation with memory (r=0.32, p=0.035). The Thal phases of amyloid-β (Aβ) deposits (A score) presents no significant correlation with any of ECog domains. Conclusion In this study, we verified the correlation of postmortem C and B scores, but not the A score with cognition performance in a collection of samples from the Chinese human brain bank. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Cortical brain volume abnormalities associated with few or multiple neuropsychiatric symptoms in Alzheimer's disease.

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    Lyssandra Dos Santos Tascone

    Full Text Available New research on assessing neuropsychiatric manifestations of Alzheimer´s Disease (AD involves grouping neuropsychiatric symptoms into syndromes. Yet this approach is limited by high inter-subject variability in neuropsychiatric symptoms and a relatively low degree of concordance across studies attempting to cluster neuropsychiatric symptoms into syndromes. An alternative strategy that involves dichotomizing AD subjects into those with few versus multiple neuropsychiatric symptoms is both consonant with real-world clinical practice and can contribute to understanding neurobiological underpinnings of neuropsychiatric symptoms in AD patients. The aim of this study was to address whether the number of neuropsychiatric symptoms (i.e., presence of few [≤2] versus multiple [≥3] symptoms in AD would be associated with degree of significant gray matter (GM volume loss. Of particular interest was volume loss in brain regions involved in memory, emotional processing and salience brain networks, including the prefrontal, lateral temporal and parietal cortices, anterior cingulate gyrus, temporo-limbic structures and insula. We recruited 19 AD patients and 13 healthy controls, which underwent an MRI and neuropsychiatric assessment. Regional brain volumes were determined using voxel-based morphometry and other advanced imaging processing methods. Our results indicated the presence of different patterns of GM atrophy in the two AD subgroups relative to healthy controls. AD patients with multiple neuropsychiatric manifestations showed more evident GM atrophy in the left superior temporal gyrus and insula as compared with healthy controls. In contrast, AD subjects with few neuropsychiatric symptoms displayed more GM atrophy in prefrontal regions, as well as in the dorsal anterior cingulate ad post-central gyri, as compared with healthy controls. Our findings suggest that the presence of multiple neuropsychiatric symptoms is more related to the degree of

  19. The immunology of traumatic brain injury: a prime target for Alzheimer’s disease prevention

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    Giunta Brian

    2012-08-01

    Full Text Available Abstract A global health problem, traumatic brain injury (TBI is especially prevalent in the current era of ongoing world military conflicts. Its pathological hallmark is one or more primary injury foci, followed by a spread to initially normal brain areas via cascades of inflammatory cytokines and chemokines resulting in an amplification of the original tissue injury by microglia and other central nervous system immune cells. In some cases this may predispose individuals to later development of Alzheimer’s disease (AD. The inflammatory-based progression of TBI has been shown to be active in humans for up to 17 years post TBI. Unfortunately, all neuroprotective drug trials have failed, and specific treatments remain less than efficacious. These poor results might be explained by too much of a scientific focus on neurons without addressing the functions of microglia in the brain, which are at the center of proinflammatory cytokine generation. To address this issue, we provide a survey of the TBI-related brain immunological mechanisms that may promote progression to AD. We discuss these immune and microglia-based inflammatory mechanisms involved in the progression of post-trauma brain damage to AD. Flavonoid-based strategies to oppose the antigen-presenting cell-like inflammatory phenotype of microglia will also be reviewed. The goal is to provide a rationale for investigations of inflammatory response following TBI which may represent a pathological link to AD. In the end, a better understanding of neuroinflammation could open therapeutic avenues for abrogation of secondary cell death and behavioral symptoms that may mediate the progression of TBI to later AD.

  20. Anatomical connectivity mapping: a new tool to assess brain disconnection in Alzheimer's disease.

    Science.gov (United States)

    Bozzali, Marco; Parker, Geoffrey J M; Serra, Laura; Embleton, Karl; Gili, Tommaso; Perri, Roberta; Caltagirone, Carlo; Cercignani, Mara

    2011-02-01

    Previous studies suggest that the clinical manifestations of Alzheimer's disease (AD) are not only associated with regional gray matter damage but also with abnormal functional integration of different brain regions by disconnection mechanisms. A measure of anatomical connectivity (anatomical connectivity mapping or ACM) can be obtained by initiating diffusion tractography streamlines from all parenchymal voxels and then counting the number of streamlines passing through each voxel of the brain. In order to assess the potential of this parameter for the study of disconnection in AD, we computed it in a group of patients with AD (N=9), in 16 patients with amnestic mild cognitive impairment (a-MCI, which is considered the prodromal stage of AD) and in 12 healthy volunteers. All subjects had an MRI scan at 3T, and diffusion MRI data were analyzed to obtain fractional anisotropy (FA) and ACM. Two types of ACM maps, absolute count (ac-ACM) and normalized by brain size count (nc-ACM), were obtained. No between group differences in FA surviving correction for multiple comparison were found, while areas of both decreased (in the supramarginal gyrus) and increased (in the putamen) ACM were found in patients with AD. Similar results were obtained with ac-ACM and nc-ACM. ACM of the supramarginal gyrus was strongly associated with measures of short-term memory in healthy subjects. This study shows that ACM provides information that is complementary to that offered by FA and appears to be more sensitive than FA to brain changes in patients with AD. The increased ACM in the putamen was unexpected. Given the nature of ACM, an increase of this parameter may reflect a change in any of the areas connected to it. One intriguing possibility is that this increase of ACM in AD patients might reflect processes of brain plasticity driven by cholinesterase inhibitors. Copyright © 2010 Elsevier Inc. All rights reserved.

  1. A neuroprotective brain-penetrating endopeptidase fusion protein ameliorates Alzheimer disease pathology and restores neurogenesis.

    Science.gov (United States)

    Spencer, Brian; Verma, Inder; Desplats, Paula; Morvinski, Dinorah; Rockenstein, Ed; Adame, Anthony; Masliah, Eliezer

    2014-06-20

    Alzheimer disease (AD) is characterized by widespread neurodegeneration throughout the association cortex and limbic system, deposition of amyloid-β peptide (Aβ) in the neuropil and around the blood vessels, and formation of neurofibrillary tangles. The endopeptidase neprilysin has been successfully used to reduce the accumulation of Aβ following intracranial viral vector delivery or ex vivo manipulated intracranial delivery. These therapies have relied on direct injections into the brain, whereas a clinically desirable therapy would involve i.v. infusion of a recombinant enzyme. We previously characterized a recombinant neprilysin that contained a 38-amino acid brain-targeting domain. Recombinant cell lines have been generated expressing this brain-targeted enzyme (ASN12). In this report, we characterize the ASN12 recombinant protein for pharmacology in a mouse as well as efficacy in two APPtg mouse models of AD. The recombinant ASN12 transited to the brain with a t½ of 24 h and accumulated to 1.7% of injected dose at 24 h following i.v. delivery. We examined pharmacodynamics in the tg2576 APPtg mouse with the prion promoter APP695 SWE mutation and in the Line41 mThy1 APP751 mutation mouse. Treatment of either APPtg mouse resulted in reduced Aβ, increased neuronal synapses, and improved learning and memory. In addition, the Line41 APPtg mice showed increased levels of C-terminal neuropeptide Y fragments and increased neurogenesis. These results suggest that the recombinant brain-targeted neprilysin, ASN12, may be an effective treatment for AD and warrant further investigation in clinical trials. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Listeria Monocytogenes Brain Abscess in Crohn’s Disease Treated with Adalimumab

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    Amporn Atsawarungruangkit

    2017-11-01

    Full Text Available Listeria monocytogenes is a gram-positive bacterium that causes listeriosis. Brain abscess is a very uncommon manifestation of listeriosis and has not been reported to be associated with adalimumab (humira, one of the approved medications for treating Crohn’s disease. A 45-year-old female with Crohn’s disease presented with sudden onset of fever, headache, nausea, vomiting, and altered mental status for 1 day. She was on prednisone and 6-mercaptopurine. She had started taking adalimumab 17 days prior to admission. She had signs of toxicity, confusion, and nuchal rigidity, but showed neither central nervous system deficits nor focal deficits. The laboratory results revealed Gram-positive coccobacillus, positive blood and cerebrospinal fluid culture for Listeria monocytogenes, and a 5 × 5 mm ring-enhancing lesion of brain abscess on MRI. After holding off 6-mercaptopurine and adalimumab, her mental status improved on the next day. Finally, she was discharged on day 7 of hospitalization with ampicillin 2 g intravenously every 4 h for a total of 2 weeks. Two weeks later, the follow-up MRI showed a 2-mm area of residual enhancement in the left temporal lobe at the site of the previous brain abscess. Adalimumab, as a tumor necrosis factor (TNF-alpha inhibitor, carries a risk of triggering opportunistic infection, such as listeriosis. With an altered mental status or neurological signs in patients receiving TNF-alpha antagonizing agent, physicians should suspect bacterial infection in the central nervous system and promptly initiate treatment for brain abscess if needed.

  3. Cloning the Antibody Response in Humans with Chronic Inflammatory Disease: Immunopanning of Subacute Sclerosing Panencephalitis (SSPE) Brain Sections with Antibody Phage Libraries Prepared from SSPE Brain Enriches for Antibody Recognizing Measles Virus Antigens In Situ

    Science.gov (United States)

    Owens, Gregory P.; Williamson, R. Anthony; Burgoon, Mark P.; Ghausi, Omar; Burton, Dennis R.; Gilden, Donald H.

    2000-01-01

    In central nervous system (CNS) infectious and inflammatory diseases of known cause, oligoclonal bands represent antibody directed against the causative agent. To determine whether disease-relevant antibodies can be cloned from diseased brain, we prepared an antibody phage display library from the brain of a human with subacute sclerosing panencephalitis (SSPE), a chronic encephalitis caused by measles virus, and selected the library against SSPE brain sections. Antibodies that were retrieved reacted strongly with measles virus cell extracts by enzyme-linked immunosorbent assay and were specific for the measles virus nucleocapsid protein. These antibodies immunostained cells in different SSPE brains but not in control brain. Our data provide the first demonstration that diseased brain can be used to select in situ for antibodies directed against the causative agent of disease and point to the potential usefulness of this approach in identifying relevant antibodies in chronic CNS or systemic inflammatory diseases of unknown cause. PMID:10627565

  4. Direct visualization of alpha-synuclein oligomers reveals previously undetected pathology in Parkinson's disease brain.

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    Roberts, Rosalind F; Wade-Martins, Richard; Alegre-Abarrategui, Javier

    2015-06-01

    Oligomeric forms of alpha-synuclein are emerging as key mediators of pathogenesis in Parkinson's disease. Our understanding of the exact contribution of alpha-synuclein oligomers to disease is limited by the lack of a technique for their specific detection. We describe a novel method, the alpha-synuclein proximity ligation assay, which specifically recognizes alpha-synuclein oligomers. In a blinded study with post-mortem brain tissue from patients with Parkinson's disease (n = 8, age range 73-92 years, four males and four females) and age- and sex-matched controls (n = 8), we show that the alpha-synuclein proximity ligation assay reveals previously unrecognized pathology in the form of extensive diffuse deposition of alpha-synuclein oligomers. These oligomers are often localized, in the absence of Lewy bodies, to neuroanatomical regions mildly affected in Parkinson's disease. Diffuse alpha-synuclein proximity ligation assay signal is significantly more abundant in patients compared to controls in regions including the cingulate cortex (1.6-fold increase) and the reticular formation of the medulla (6.5-fold increase). In addition, the alpha-synuclein proximity ligation assay labels very early perikaryal aggregates in morphologically intact neurons that may precede the development of classical Parkinson's disease lesions, such as pale bodies or Lewy bodies. Furthermore, the alpha-synuclein proximity ligation assay preferentially detects early-stage, loosely compacted lesions such as pale bodies in patient tissue, whereas Lewy bodies, considered heavily compacted late lesions are only very exceptionally stained. The alpha-synuclein proximity ligation assay preferentially labels alpha-synuclein oligomers produced in vitro compared to monomers and fibrils, while stained oligomers in human brain display a distinct intermediate proteinase K resistance, suggesting the detection of a conformer that is different from both physiological, presynaptic alpha

  5. Subthalamic nucleus deep brain stimulation is neuroprotective in the A53T ??synuclein Parkinson's disease rat model

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    Musacchio, Thomas; Rebenstorff, Maike; Fluri, Felix; Brotchie, Jonathan M.; Volkmann, Jens; Koprich, James B.; Ip, Chi Wang

    2017-01-01

    Objective Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective symptomatic therapy for motor deficits in Parkinson's disease (PD). An additional, disease?modifying effect has been suspected from studies in toxin?based PD animal models, but these models do not reflect the molecular pathology and progressive nature of PD that would be required to evaluate a disease?modifying action. Defining a disease?modifying effect could radically change the way in which DBS is...

  6. Programming Deep Brain Stimulation for Parkinson's Disease: The Toronto Western Hospital Algorithms.

    Science.gov (United States)

    Picillo, Marina; Lozano, Andres M; Kou, Nancy; Puppi Munhoz, Renato; Fasano, Alfonso

    2016-01-01

    Deep brain stimulation (DBS) is an established and effective treatment for Parkinson's disease (PD). After surgery, a number of extensive programming sessions are performed to define the most optimal stimulation parameters. Programming sessions mainly rely only on neurologist's experience. As a result, patients often undergo inconsistent and inefficient stimulation changes, as well as unnecessary visits. We reviewed the literature on initial and follow-up DBS programming procedures and integrated our current practice at Toronto Western Hospital (TWH) to develop standardized DBS programming protocols. We propose four algorithms including the initial programming and specific algorithms tailored to symptoms experienced by patients following DBS: speech disturbances, stimulation-induced dyskinesia and gait impairment. We conducted a literature search of PubMed from inception to July 2014 with the keywords "deep brain stimulation", "festination", "freezing", "initial programming", "Parkinson's disease", "postural instability", "speech disturbances", and "stimulation induced dyskinesia". Seventy papers were considered for this review. Based on the literature review and our experience at TWH, we refined four algorithms for: (1) the initial programming stage, and management of symptoms following DBS, particularly addressing (2) speech disturbances, (3) stimulation-induced dyskinesia, and (4) gait impairment. We propose four algorithms tailored to an individualized approach to managing symptoms associated with DBS and disease progression in patients with PD. We encourage established as well as new DBS centers to test the clinical usefulness of these algorithms in supplementing the current standards of care. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Weight change following GPi or STN deep brain stimulation in Parkinson’s disease and dystonia

    Science.gov (United States)

    Mills, Kelly A.; Scherzer, Rebecca; Starr, Philip A.; Ostrem, Jill L.

    2013-01-01

    Background Weight gain has been described in Parkinson’s disease (PD) patients after subthalamic nucleus (STN) deep brain stimulation (DBS). Objectives We examined change in weight following DBS in both PD and dystonia patients to further investigate the role of disease and brain target (STN or GPi) specificity. Methods Data was retrospectively collected on 61 PD DBS patients (STN (n=31) or GPi (n=30)) and on 36 dystonia DBS patients (STN (n=9) and GPi (n=27)) before and after surgery. Annual change in body mass index (BMI) was evaluated with non-parametric tests between groups and multiple quantile regression. Results PD patients treated with STN DBS had a small increase in median BMI while those with GPi had a small decrease in BMI. Dystonia patients treated with STN DBS had a greater increase in BMI per year compared to those treated with GPi. Multivariable regression analyses for each disease showed little difference between targets in weight gain in those with PD, but STN target was strongly associated with weight gain in dystonia patients (STN vs. GPi, +7.99 kg, p=0.012). Conclusions Our results support previous reports of weight gain after DBS in PD. This is the first report to suggest a target-specific increase in weight following STN DBS in dystonia patients. PMID:22922491

  8. Hierarchical brain tissue segmentation and its application in multiple sclerosis and Alzheimer's disease

    Science.gov (United States)

    Lei, Tianhu; Udupa, Jayaram K.; Moonis, Gul; Schwartz, Eric; Balcer, Laura

    2005-04-01

    Based on Fuzzy Connectedness (FC) object delineation principles and algorithms, a hierarchical brain tissue segmentation technique has been developed for MR images. After MR image background intensity inhomogeneity correction and intensity standardization, three FC objects for cerebrospinal fluid (CSF), gray matter (GM), and white matter (WM) are generated via FC object delineation, and an intracranial (IC) mask is created via morphological operations. Then, the IC mask is decomposed into parenchymal (BP) and CSF masks, while the BP mask is separated into WM and GM masks. WM mask is further divided into pure and dirty white matter masks (PWM and DWM). In Multiple Sclerosis studies, a severe white matter lesion (LS) mask is defined from DWM mask. Based on the segmented brain tissue images, a histogram-based method has been developed to find disease-specific, image-based quantitative markers for characterizing the macromolecular manifestation of the two diseases. These same procedures have been applied to 65 MS (46 patients and 19 normal subjects) and 25 AD (15 patients and 10 normal subjects) data sets, each of which consists of FSE PD- and T2-weighted MR images. Histograms representing standardized PD and T2 intensity distributions and their numerical parameters provide an effective means for characterizing the two diseases. The procedures are systematic, nearly automated, robust, and the results are reproducible.

  9. Expression of interferon gamma in the brain of cats with natural Borna disease virus infection.

    Science.gov (United States)

    Wensman, Jonas Johansson; Ilbäck, Carolina; Hjertström, Elina; Blomström, Anne-Lie; Gustavsson, Malin Hagberg; Jäderlund, Karin Hultin; Ström-Holst, Bodil; Belák, Sándor; Berg, Anna-Lena; Berg, Mikael

    2011-05-15

    Borna disease virus (BDV) is a neurotropic, negative-stranded RNA virus, which causes a non-suppurative meningoencephalomyelitis in a wide range of animals. In cats, BDV infection leads to staggering disease. In spite of a vigorous immune response the virus persists in the central nervous system (CNS) in both experimentally and naturally infected animals. Since the CNS is vulnerable to cytotoxic effects mediated via NK-cells and cytotoxic T-cells, other non-cytolytic mechanisms such as the interferon (IFN) system is favourable for viral clearance. In this study, IFN-γ expression in the brain of cats with clinical signs of staggering disease (N=12) was compared to the expression in cats with no signs of this disease (N=7) by quantitative RT-PCR. The IFN-γ expression was normalised against the expression of three reference genes (HPRT, RPS7, YWHAZ). Cats with staggering disease had significantly higher expression of IFN-γ compared to the control cats (p-value ≤ 0.001). There was no significant difference of the IFN-γ expression in BDV-positive (N=7) and -negative (N=5) cats having clinical signs of staggering disease. However, as BDV-RNA still could be detected, despite an intense IFN-γ expression, BDV needs to have mechanisms to evade this antiviral immune response of the host, to be able to persist. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. Physical inactivity is a disease synonymous for a non-permissive brain disorder.

    Science.gov (United States)

    Pruimboom, Leo

    2011-11-01

    The evolution of human kind has taken millions of years in which environmental factors gradually shaped the actual genome adapted to those circumstances. One of the most vital behavioural adaptations of mammals in general and especially humans is their capability of self-sufficiency through physical activity. Physical activity abilities, including long distance running, jumping, climbing and carrying things have probably been necessary to outrun wild animals, search for food and hide for danger. In contrast, individuals physically or psychologically unable to "take care of themselves" were more susceptible for early death and therefore for genetic extinction. The actual society is characterized by sedentary instead of "moving" individuals. Physical inactivity is not just a possible factor related with chronic disease, but should be considered the actual cause of the majority of human illness. Individuals know that exercise is necessary and beneficial. Nevertheless almost 75% of the actual population does not reach the estimated minimum of necessary activity. Physical inactivity belongs to the characteristics of sickness behaviour; the latter which probably is protective for the organism. Sickness behaviour, including depressive mood, seems to protect against infection, injury, social conflict and facilitates energy conservation. Sickness behaviour is based on immune-brain mechanisms and can be defined as non-permissive behaviour. Long-term non-permissive behaviour can lead to chronic disease because of reduction of physical activity and self-defeating coping styles, converting non-permissive behaviour in a non-permissive brain disorder. We propose that physical inactivity disease is synonymous for a non-permissive brain disorder and that NPBD produces a so called "reptile phenotype", characterized by hypothermia, poor hair growth, decreased fertility and low basal metabolic rate. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. The brain renin-angiotensin system: a diversity of functions and implications for CNS diseases.

    Science.gov (United States)

    Wright, John W; Harding, Joseph W

    2013-01-01

    The classic renin-angiotensin system (RAS) was initially described as a hormone system designed to mediate cardiovascular and body water regulation, with angiotensin II as its major effector. The discovery of an independent local brain RAS composed of the necessary functional components (angiotensinogen, peptidases, angiotensins, and specific receptor proteins) significantly expanded the possible physiological and pharmacological functions of this system. This review first describes the enzymatic pathways resulting in active angiotensin ligands and their interaction with AT(1), AT(2), and AT(4) receptor subtypes. Next, we discuss the classic physiologies and behaviors controlled by the RAS including cardiovascular, thirst, and sodium appetite. A final section summarizes non-classic functions and clinical conditions mediated by the brain RAS with focus on memory and Alzheimer's disease. There is no doubt that the brain RAS is an important component in the development of dementia. It also appears to play a role in normal memory consolidation and retrieval. The presently available anti-dementia drugs are proving to be reasonably ineffective, thus alternative treatment approaches must be developed. At the same time, presently available drugs must be tested for their efficacy to treat newly identified syndromes and diseases connected with the RAS. The list of non-classic physiologies and behaviors is ever increasing in both number and scope, attesting to the multidimensional influences of the RAS. Such diversity in function presents a dilemma for both researchers and clinicians. Namely, the blunting of RAS subsystems in the hopes of combating one constellation of underlying causes and disease symptoms may be counter-balanced by unanticipated and unwanted consequences to another RAS subsystem. For example, the use of angiotensin-converting enzyme inhibitors and AT(1) and/or AT(2) receptor blockers have shown great promise in the treatment of cardiovascular related

  12. Weight and body mass index in Parkinson's disease patients after deep brain stimulation surgery.

    Science.gov (United States)

    Tuite, Paul J; Maxwell, Robert E; Ikramuddin, Sayeed; Kotz, Catherine M; Kotzd, Catherine M; Billington, Charles J; Billingtond, Charles J; Laseski, Maggie A; Thielen, Scott D

    2005-06-01

    A retrospective chart review characterizing changes in 17 male and 10 female Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) surgery indicated that 6 mo before surgery, patients lost a mean of 5.1 lbs, whereas in the 6 mo after surgery, subjects gained a mean of 10.1 lbs; 22% gained more than 14 lbs. In 10 patients followed an additional 6 mo, weight gain continued. This weight gain may be associated with decreased energy expenditure due to subsidence of chronic tremor. The magnitude of gain underscores the need for proactive management of body weight in PD patients undergoing DBS.

  13. Systematic review of the risk of Parkinson's disease after mild traumatic brain injury

    DEFF Research Database (Denmark)

    Marras, Connie; Hincapié, Cesar A; Kristman, Vicki L

    2014-01-01

    OBJECTIVE: To synthesize the best available evidence on the risk of Parkinson's disease (PD) after mild traumatic brain injury (MTBI). DATA SOURCES: MEDLINE and other databases were searched (1990-2012) with terms including "craniocerebral trauma" and "parkinsonian disorders." Reference lists......: The best available evidence argues against an important causal association between MTBI and PD. There are few high-quality studies on this topic. Prospective studies of long duration would address the limitations of recall of head injury and the possibility of reverse causation....

  14. Combined thalamic and subthalamic deep brain stimulation for tremor-dominant Parkinson's disease.

    Science.gov (United States)

    Oertel, Markus F; Schüpbach, W Michael M; Ghika, Joseph-André; Stieglitz, Lennart H; Fiechter, Michael; Kaelin-Lang, Alain; Raabe, Andreas; Pollo, Claudio

    2017-02-01

    Deep brain stimulation (DBS) in the thalamic ventral intermediate (Vim) or the subthalamic nucleus (STN) reportedly improves medication-refractory Parkinson's disease (PD) tremor. However, little is known about the potential synergic effects of combined Vim and STN DBS. We describe a 79-year-old man with medication-refractory tremor-dominant PD. Bilateral Vim DBS electrode implantation produced insufficient improvement. Therefore, the patient underwent additional unilateral left-sided STN DBS. Whereas Vim or STN stimulation alone led to partial improvement, persisting tremor resolution occurred after simultaneous stimulation. The combination of both targets may have a synergic effect and is an alternative option in suitable cases.

  15. Genetic impact on cognition and brain function in newly diagnosed Parkinson's disease: ICICLE-PD study.

    Science.gov (United States)

    Nombela, Cristina; Rowe, James B; Winder-Rhodes, Sophie E; Hampshire, Adam; Owen, Adrian M; Breen, David P; Duncan, Gordon W; Khoo, Tien K; Yarnall, Alison J; Firbank, Michael J; Chinnery, Patrick F; Robbins, Trevor W; O'Brien, John T; Brooks, David J; Burn, David J; Barker, Roger A

    2014-10-01

    associated with memory encoding. This study demonstrates that neurocognitive deficits are common even in recently diagnosed patients with Parkinson's disease, and that the associated regional brain activations are influenced by genotype. These data further support the dual syndrome hypothesis of cognitive change in Parkinson's disease. Longitudinal data will confirm the extent to which these early neurocognitive changes, and their genetic factors, influence the long-term risk of dementia in Parkinson's disease. The combination of genetics and functional neuroimaging provides a potentially useful method for stratification and identification of candidate markers, in future clinical trials against cognitive decline in Parkinson's disease. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.

  16. Functional brain networks in Alzheimer's disease: EEG analysis based on limited penetrable visibility graph and phase space method

    Science.gov (United States)

    Wang, Jiang; Yang, Chen; Wang, Ruofan; Yu, Haitao; Cao, Yibin; Liu, Jing

    2016-10-01

    In this paper, EEG series are applied to construct functional connections with the correlation between different regions in order to investigate the nonlinear characteristic and the cognitive function of the brain with Alzheimer's disease (AD). First, limited penetrable visibility graph (LPVG) and phase space method map single EEG series into networks, and investigate the underlying chaotic system dynamics of AD brain. Topological properties of the networks are extracted, such as average path length and clustering coefficient. It is found that the network topology of AD in several local brain regions are different from that of the control group with no statistically significant difference existing all over the brain. Furthermore, in order to detect the abnormality of AD brain as a whole, functional connections among different brain regions are reconstructed based on similarity of clustering coefficient sequence (CCSS) of EEG series in the four frequency bands (delta, theta, alpha, and beta), which exhibit obvious small-world properties. Graph analysis demonstrates that for both methodologies, the functional connections between regions of AD brain decrease, particularly in the alpha frequency band. AD causes the graph index complexity of the functional network decreased, the small-world properties weakened, and the vulnerability increased. The obtained results show that the brain functional network constructed by LPVG and phase space method might be more effective to distinguish AD from the normal control than the analysis of single series, which is helpful for revealing the underlying pathological mechanism of the disease.

  17. Passage of amyloid beta protein antibody across the blood-brain barrier in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Banks, William A; Terrell, Brie; Farr, Susan A; Robinson, Sandra M; Nonaka, Naoko; Morley, John E

    2002-12-01

    Vaccinations against amyloid beta protein (A beta P) reduce amyloid deposition and reverse learning and memory deficits in mouse models of Alzheimer's disease. This has raised the question of whether circulating antibodies, normally restricted by the blood-brain barrier (BBB), can enter the brain [Nat. Med. 7 (2001) 369-372]. Here, we show that antibody directed against A beta P does cross the BBB at a very low rate. Entry is by way of the extracellular pathways with about 0.11% of an intravenous (i.v.) dose entering the brain by 1h. Clearance of antibody from brain increasingly dominates over time, but antibody is still detectable in brain 72 h after i.v. injection. Uptake and clearance is not altered in mice overexpressing A beta P. This ability to enter and exit the brain even in the presence of increased brain ligand supports the use of antibody in the treatment of Alzheimer's and other diseases of the brain.

  18. BRAIM: A computer-aided diagnosis system for neurodegenerative diseases and brain lesion monitoring from volumetric analyses.

    Science.gov (United States)

    Morales, Sandra; Bernabeu-Sanz, Angela; López-Mir, Fernando; González, Pablo; Luna, Luis; Naranjo, Valery

    2017-07-01

    This paper presents BRAIM, a computer-aided diagnosis (CAD) system to help clinicians in diagnosing and treatment monitoring of brain diseases from magnetic resonance image processing. BRAIM can be used for early diagnosis of neurodegenerative diseases such as Parkinson, Alzheimer or Multiple Sclerosis and also for brain lesion diagnosis and monitoring. The developed CAD system includes different user-friendly tools for segmenting and determining whole brain and brain structure volumes in an easy and accurate way. Specifically, three types of measurements can be performed: (1) total volume of white, gray matter and cerebrospinal fluid; (2) brain structure volumes (volume of putamen, thalamus, hippocampus and caudate nucleus); and (3) brain lesion volumes. As a proof of concept, some study cases were analyzed with the presented system achieving promising results. In addition to be used to quantify treatment effectiveness in patients with brain lesions, it was demonstrated that BRAIM is able to classify a subject according to the brain volume measurements using as reference a healthy control database created for this purpose. The CAD system presented in this paper simplifies the daily work of clinicians and provides them with objective and quantitative volume data for prospective and retrospective analyses. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent.

    Science.gov (United States)

    Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

    2013-01-01

    Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in v

  20. Brain network alterations in Alzheimer's disease measured by Eigenvector centrality in fMRI are related to cognition and CSF biomarkers

    NARCIS (Netherlands)

    Binnewijzend, M.A.A.; Adriaanse, S.M.; van der Flier, W.M.; Teunissen, C.E.; de Munck, J.C.; Stam, C.J.; Scheltens, P.; van Berckel, B.N.M.; Barkhof, F.; Wink, A.M.

    2014-01-01

    Recent imaging studies have demonstrated functional brain network changes in patients with Alzheimer's disease (AD). Eigenvector centrality (EC) is a graph analytical measure that identifies prominent regions in the brain network hierarchy and detects localized differences between patient

  1. Quantitative Evaluation of Brain Stem Atrophy Using Magnetic Resonance Imaging in Adult Patients with Alexander Disease.

    Science.gov (United States)

    Yoshida, Tomokatsu; Yasuda, Rei; Mizuta, Ikuko; Nakagawa, Masanori; Mizuno, Toshiki

    2017-01-01

    Brain MRI in adult patients with Alexander disease (AxD) mainly shows atrophy in the medulla oblongata. However, currently there is no quantitative standard for assessing this atrophy. In this study, we quantitatively evaluated the brain stem of AxD patients with glial fibrillary acidic protein (GFAP) mutation using conventional MRI to evaluate its usefulness as an aid to diagnosing AxD in daily clinical practice. Nineteen AxD patients with GFAP mutation were compared with 14 patients negative for GFAP mutation in whom AxD was suspected due to "atrophy of the medulla oblongata." In the GFAP mutation-positive group, the sagittal diameter of the medulla oblongata, the ratio of the diameter of the medulla oblongata to that of the midbrain (MO/MB), and the ratio of the sagittal diameter of the medulla oblongata to that of the pons (MO/Po) were significantly smaller compared to those of the GFAP mutation-negative group (p < 0.01). The sensitivity and specificity of each parameter were 87.5 and 92.3%, 91.7 and 81.3%, and 88.2 and 100% with a sagittal diameter of the medulla oblongata <9.0 mm, MO/MB <0.60, and sagittal MO/Po <0.46, respectively. These parameters can provide very useful information to differentially diagnose AxD from other disorders associated with brain stem atrophy in adult patients. © 2017 S. Karger AG, Basel.

  2. Apomorphine pump in advanced Parkinson's disease: Effects on motor and nonmotor symptoms with brain metabolism correlations.

    Science.gov (United States)

    Auffret, Manon; Le Jeune, Florence; Maurus, Anne; Drapier, Sophie; Houvenaghel, Jean-François; Robert, Gabriel Hadrien; Sauleau, Paul; Vérin, Marc

    2017-01-15

    Patients with advanced Parkinson's disease (PD) and contraindications for subthalamic nucleus deep brain stimulation (DBS) could particularly benefit from subcutaneous infusion therapy with apomorphine. This original study was designed to evaluate the general efficacy of add-on apomorphine in motor and nonmotor symptoms in advanced PD, while characterizing the changes induced in brain glucose metabolism. The aim was to look at the underlying anatomical-functional pathways. 12 patients with advanced PD were assessed before and after 6months of add-on apomorphine, using resting-state (18)F-fluorodeoxyglucose positron emission tomography and exhaustive clinical assessments. After 6months of therapy, oral treatment was significantly reduced. Both motor and nonmotor scores improved, with a beneficial effect on executive functions, quality of life and apathy. Significant metabolic changes were observed, with overall increases in the right fusiform gyrus and hippocampus, alongside a decrease in the left middle frontal gyrus. Consistent correlations between significant changes in clinical scores and metabolism were established. Well tolerated, add-on apomorphine appears to be an interesting option for patients with fluctuations and contra-indications for DBS. Changes in brain metabolism, with beneficial effects on motor and nonmotor symptoms were observed after 6months. These preliminary results have to be confirmed by further studies. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. MR of brain involvement in progressive facial hemiatrophy (Romberg disease): Reconsideration of a syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Terstegge, K.; Hosten, N. (Universitaetsklinikum Rudolf Virchow, Berlin (Germany)); Kunath, B. (Klinik und Poliklinik fuer Neurologie, Dresden (Germany)); Felber, S.; Henkes, H. (Universitaetskliniken der Universitaet Homburg (Germany)); Speciali, J.G. (Universidade de Sao Paolo (Brazil))

    1994-01-01

    To gain further insight into the pathogenesis of progressive facial hemiatrophy, a sporadic disease of unclear etiology characterized by shrinking and deformation of one side of the face. We investigated possible brain involvement. MR of the head and face was performed in three female patients with progressive facial hemiatrophy. The central-nervous-system findings were correlated to a clinical protocol and a review of the literature. One patient with epilepsy had abnormal brain findings confined to the cerebral hemisphere homolateral to the facial hemiatrophy. These consisted of monoventricular enlargement, meningocortical dysmorphia, and white-matter changes. These MR findings, and corresponding neuroradiologic data disclosed by the review, indicate that homolateral hemiatrophy occasionally occurs in a subgroup of patients with progressive facial hemiatrophy. The MR features do not seem consistent with an underlying simple or nutritive atrophic process. We propose chronic localized meningoencephalitis with vascular involvement as a possible underlying cause of the occasional brain involvement in progressive facial hemiatrophy. 29 refs., 2 figs.

  4. Relating Education, Brain Structure, and Cognition: The Role of Cardiovascular Disease Risk Factors

    Directory of Open Access Journals (Sweden)

    Moyra E. Mortby

    2014-01-01

    Full Text Available The protective effect of education on cognitive and brain health is well established. While the direct effects of individual cardiovascular disease (CVD risk factors (i.e., hypertension, smoking, diabetes, and obesity on cerebral structure have been investigated, little is understood about the possible interaction between the protective effect of education and the deleterious effects of CVD risk factors in predicting brain ageing and cognition. Using data from the PATH Through Life study (N=266, we investigated the protective effect of education on cerebral structure and function and tested a possible mediating role of CVD risk factors. Higher education was associated with larger regional grey/white matter volumes in the prefrontal cortex in men only. The association between education and cognition was mediated by brain volumes but only for grey matter and only in relation to information processing speed. CVD risk factors did not mediate the association between regional volumes and cognition. This study provides additional evidence in support for a protective effect of education on cerebral structures and cognition. However, it does not provide support for a mediating role of CVD risk factors in these associations.

  5. Effects of alternating current stimulation on the healthy and diseased brain

    Directory of Open Access Journals (Sweden)

    Aini Ismafairus eAbd Hamid

    2015-10-01

    Full Text Available Cognitive and neurological dysfunctions can severely impact a patient’s daily activities. In addition to medical treatment, non-invasive transcranial alternating current stimulation (tACS has been proposed as a therapeutic technique to improve the functional state of the brain. Although during the last years tACS was applied in numerous studies to improve motor, somatosensory, visual and higher order cognitive functions, our knowledge is still limited regarding the mechanisms as to which type of ACS can affect cortical functions and altered neuronal oscillations seem to be the key mechanism. Because alternating current send pulses to the brain at predetermined frequencies, the online- and after-effects of ACS strongly depend on the stimulation parameters so that ‘optimal’ ACS paradigms could be achieved. This is of interest not only for neuroscience research but also for clinical practice. In this study, we summarize recent findings on ACS-effects under both normal conditions and in brain diseases.

  6. Group-Level Progressive Alterations in Brain Connectivity Patterns Revealed by Diffusion-Tensor Brain Networks across Severity Stages in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Javier Rasero

    2017-07-01

    Full Text Available Alzheimer’s disease (AD is a chronically progressive neurodegenerative disease highly correlated to aging. Whether AD originates by targeting a localized brain area and propagates to the rest of the brain across disease-severity progression is a question with an unknown answer. Here, we aim to provide an answer to this question at the group-level by looking at differences in diffusion-tensor brain networks. In particular, making use of data from Alzheimer’s Disease Neuroimaging Initiative (ADNI, four different groups were defined (all of them matched by age, sex and education level: G1 (N1 = 36, healthy control subjects, Control, G2 (N2 = 36, early mild cognitive impairment, EMCI, G3 (N3 = 36, late mild cognitive impairment, LMCI and G4 (N4 = 36, AD. Diffusion-tensor brain networks were compared across three disease stages: stage I (Control vs. EMCI, stage II (Control vs. LMCI and stage III (Control vs. AD. The group comparison was performed using the multivariate distance matrix regression analysis, a technique that was born in genomics and was recently proposed to handle brain functional networks, but here applied to diffusion-tensor data. The results were threefold: First, no significant differences were found in stage I. Second, significant differences were found in stage II in the connectivity pattern of a subnetwork strongly associated to memory function (including part of the hippocampus, amygdala, entorhinal cortex, fusiform gyrus, inferior and middle temporal gyrus, parahippocampal gyrus and temporal pole. Third, a widespread disconnection across the entire AD brain was found in stage III, affecting more strongly the same memory subnetwork appearing in stage II, plus the other new subnetworks, including the default mode network, medial visual network, frontoparietal regions and striatum. Our results are consistent with a scenario where progressive alterations of connectivity arise as the disease severity increases and provide the

  7. Excessive early-life dietary exposure: a potential source of elevated brain iron and a risk factor for Parkinson's disease.

    Science.gov (United States)

    Hare, Dominic J; Cardoso, Bárbara Rita; Raven, Erika P; Double, Kay L; Finkelstein, David I; Szymlek-Gay, Ewa A; Biggs, Beverley-Ann

    2017-01-01

    Iron accumulates gradually in the ageing brain. In Parkinson's disease, iron deposition within the substantia nigra is further increased, contributing to a heightened pro-oxidant environment in dopaminergic neurons. We hypothesise that individuals in high-income countries, where cereals and infant formulae have historically been fortified with iron, experience increased early-life iron exposure that predisposes them to age-related iron accumulation in the brain. Combined with genetic factors that limit iron regulatory capacity and/or dopamine metabolism, this may increase the risk of Parkinson's diseases. We propose to (a) validate a retrospective biomarker of iron exposure in children; (b) translate this biomarker to adults; (c) integrate it with in vivo brain iron in Parkinson's disease; and (d) longitudinally examine the relationships between early-life iron exposure and metabolism, brain iron deposition and Parkinson's disease risk. This approach will provide empirical evidence to support therapeutically addressing brain iron deposition in Parkinson's diseases and produce a potential biomarker of Parkinson's disease risk in preclinical individuals.

  8. The role of the cell surface LRP and soluble LRP in blood-brain barrier Abeta clearance in Alzheimer's disease.

    Science.gov (United States)

    Deane, R; Sagare, A; Zlokovic, B V

    2008-01-01

    Low-density lipoprotein receptor related protein-1 (LRP) is a member of the low-density lipoprotein (LDL) receptor family which has been linked to Alzheimer's disease (AD) by biochemical and genetic evidence. Levels of neurotoxic amyloid beta-peptide (Abeta) in the brain are elevated in AD contributing to the disease process and neuropathology. Faulty Abeta clearance from the brain appears to mediate focal Abeta accumulations in AD. Central and peripheral production of Abeta from Abeta-precursor protein (APP), transport of peripheral Abeta into the brain across the blood-brain barrier (BBB) via receptor for advanced glycation end products (RAGE), enzymatic Abeta degradation, Abeta oligomerization and aggregation, neuroinflammatory changes and microglia activation, and Abeta elimination from brain across the BBB by cell surface LRP; all may control brain Abeta levels. Recently, we have shown that a soluble form of LRP (sLRP) binds 70 to 90 % of plasma Abeta, preventing its access to the brain. In AD individuals, the levels of LRP at the BBB are reduced, as are levels of Abeta binding to sLRP in plasma. This, in turn, may increase Abeta brain levels through a decreased efflux of brain Abeta at the BBB and/or reduced sequestration of plasma Abeta associated with re-entry of free Abeta into the brain via RAGE. Thus, therapies which increase LRP expression at the BBB and/or enhance the peripheral Abeta "sink" activity of sLRP, hold potential to control brain Abeta accumulations, neuroinflammation and cerebral blood flow reductions in AD.

  9. Decreased Complexity in Alzheimer's Disease: Resting-State fMRI Evidence of Brain Entropy Mapping

    Directory of Open Access Journals (Sweden)

    Bin Wang

    2017-11-01

    Full Text Available Alzheimer's disease (AD is a frequently observed, irreversible brain function disorder among elderly individuals. Resting-state functional magnetic resonance imaging (rs-fMRI has been introduced as an alternative approach to assessing brain functional abnormalities in AD patients. However, alterations in the brain rs-fMRI signal complexities in mild cognitive impairment (MCI and AD patients remain unclear. Here, we described the novel application of permutation entropy (PE to investigate the abnormal complexity of rs-fMRI signals in MCI and AD patients. The rs-fMRI signals of 30 normal controls (NCs, 33 early MCI (EMCI, 32 late MCI (LMCI, and 29 AD patients were obtained from the Alzheimer's disease Neuroimaging Initiative (ADNI database. After preprocessing, whole-brain entropy maps of the four groups were extracted and subjected to Gaussian smoothing. We performed a one-way analysis of variance (ANOVA on the brain entropy maps of the four groups. The results after adjusting for age and sex differences together revealed that the patients with AD exhibited lower complexity than did the MCI and NC controls. We found five clusters that exhibited significant differences and were distributed primarily in the occipital, frontal, and temporal lobes. The average PE of the five clusters exhibited a decreasing trend from MCI to AD. The AD group exhibited the least complexity. Additionally, the average PE of the five clusters was significantly positively correlated with the Mini-Mental State Examination (MMSE scores and significantly negatively correlated with Functional Assessment Questionnaire (FAQ scores and global Clinical Dementia Rating (CDR scores in the patient groups. Significant correlations were also found between the PE and regional homogeneity (ReHo in the patient groups. These results indicated that declines in PE might be related to changes in regional functional homogeneity in AD. These findings suggested that complexity analyses using PE

  10. Brain-specific fatty acid-binding protein is elevated in serum of patients with dementia-related diseases

    NARCIS (Netherlands)

    Teunissen, C.E.; Veerhuis, R.; de Vente, J.; Verhey, F.R.J.; Vreeling, F.; van Boxtel, M.P.J.; Glatz, J.F.C.; Pelsers, M.A.L.

    2011-01-01

    Background: There is a need for biomarkers in accessible matrices, such as blood, for the diagnosis of neurodegenerative diseases. The aim of this study was to measure the serum levels of brain-type fatty acid-binding protein (FABP) and heart-type FABP in patients with dementia-involving diseases.

  11. Age-associated changes of brain copper, iron, and zinc in Alzheimer's disease and dementia with Lewy bodies.

    Science.gov (United States)

    Graham, Stewart F; Nasaruddin, Muhammad Bin; Carey, Manus; Holscher, Christian; McGuinness, Bernadette; Kehoe, Patrick G; Love, Seth; Passmore, Peter; Elliott, Christopher T; Meharg, Andrew A; Green, Brian D

    2014-01-01

    Disease-, age-, and gender-associated changes in brain copper, iron, and zinc were assessed in postmortem neocortical tissue (Brodmann area 7) from patients with moderate Alzheimer's disease (AD) (n = 14), severe AD (n = 28), dementia with Lewy bodies (n = 15), and normal age-matched control subjects (n = 26). Copper was lower (20%; p copper and iron, suggesting gradual age-associated decline of these metals in healthy non-cognitively impaired individuals. Zinc was unaffected in any disease pathologies and no age-associated changes were apparent. Age-associated changes in brain elements warrant further investigation.

  12. Subthalamic nucleus deep brain stimulation for Parkinson's disease: evidence for effectiveness and limitations from 12 years' experience.

    Science.gov (United States)

    Chan, Anne Y Y; Yeung, Jonas H M; Mok, Vincent C T; Ip, Vincent H L; Wong, Adrian; Kuo, S H; Chan, Danny T M; Zhu, X L; Wong, Edith; Lau, Claire K Y; Wong, Rosanna K M; Tang, Venus; Lau, Christine; Poon, W S

    2014-12-01

    To present the result and experience of subthalamic nucleus deep brain stimulation for Parkinson's disease. Case series. Prince of Wales Hospital, Hong Kong. A cohort of patients with Parkinson's disease received subthalamic nucleus deep brain stimulation from September 1998 to January 2010. Patient assessment data before and after the operation were collected prospectively. Forty-one patients (21 male and 20 female) with Parkinson's disease underwent bilateral subthalamic nucleus deep brain stimulation and were followed up for a median interval of 12 months. For the whole group, the mean improvements of Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III were 32.5% and 31.5%, respectively (Pdeep brain stimulation protocol evolved and was substantiated by updated patient selection criteria and outcome assessment, integrated imaging and neurophysiological targeting, refinement of surgical technique as well as the accumulation of experience in deep brain stimulation programming. Most of the structural improvement occurred before mid-2005. Patients receiving the operation before June 2005 (19 cases) and after (22 cases) were compared; the improvements in UPDRS part III were 13.2% and 55.2%, respectively (Pdeep brain stimulation. A dedicated multidisciplinary team building, refined protocol for patient selection and assessment, improvement of targeting methods, meticulous surgical technique, and experience in programming are the key factors contributing to the improved outcome.

  13. Differences in brain activation between tremor- and nontremor-dominant Parkinson disease.

    Science.gov (United States)

    Prodoehl, Janey; Planetta, Peggy J; Kurani, Ajay S; Comella, Cynthia L; Corcos, Daniel M; Vaillancourt, David E

    2013-01-01

    OBJECTIVE To compare differences in functional brain activity between tremor- and nontremor-dominant subtypes of Parkinson disease (PD) using functional magnetic resonance imaging. DESIGN In our study, patients with tremor-dominant PD and those with nontremor-dominant PD performed a grip task, and the results obtained were compared using voxelwise analysis. Areas of the brain that were significantly different were then examined using a region-of-interest analysis to compare these patients with healthy controls. Voxel-based morphometry was used to determine macroscopic differences in gray and white matter volume between patient groups. SETTING University-affiliated research institution. PARTICIPANTS A total of 20 drug-naive patients with PD (10 with tremor-dominant PD and 10 with nontremor-dominant PD) and a total of 20 healthy controls. MAIN OUTCOME MEASURES Blood oxygenation level-dependent activation and percent signal change. RESULTS Robust findings across both voxelwise and region-of-interest analyses showed that, compared with patients with tremor-dominant PD, patients with nontremor-dominant PD had reduced activation in the ipsilateral dorsolateral prefrontal cortex, the globus pallidus interna, and the globus pallidus externa. Region-of-interest analyses confirmed that patients with nontremor-dominant PD had reduced activity in the ipsilateral dorsolateral prefrontal cortex, the globus pallidus interna, and the globus pallidus externa compared with patients with tremor-dominant PD and healthy controls. Patients with tremor-dominant PD had increased activity in the contralateral dorsolateral prefrontal cortex compared with patients with nontremor-dominant PD and healthy controls. These results could not be explained by differences in gray or white matter volume. CONCLUSIONS Reduced brain activity occurs in the prefrontal cortex and globus pallidus of patients with nontremor-dominant PD compared with both patients with tremor-dominant PD and healthy controls

  14. Increased Pittsburgh Compound-B Accumulation in the Subcortical White Matter of Alzheimer's Disease Brain.

    Science.gov (United States)

    Wakabayashi, Yuichi; Ishii, Kazunari; Hosokawa, Chisa; Hyodo, Tomoko; Kaida, Hayato; Yamada, Minoru; Yagyu, Yukinobu; Tsurusaki, Masakatsu; Kozuka, Takenori; Sugimura, Kazuro; Murakami, Takamichi

    2017-03-13

    Using 11C-Pittsburgh compound B (PiB)-PET and MRI volume data, we investigated whether white matter (WM) PiB uptake in Alzheimer's disease (AD) brain is larger than that of cortical PiB uptake-negative (PiB-negative) brain. Forty-five subjects who underwent both PiB-PET and MRI were included in the study (32 AD patients with cortical PiB-positive and 13 cortical amyloid -negative patients). Individual areas of gray matter (GM) and WM were segmented, then regional GM and WM standard uptake value ratio (SUVR) normalized to cerebellar GM with partial volume effects correction was calculated. Three regional SUVRs except WM in the centrum semiovale in the AD group were significantly larger than those in the PiB-negative groups. Frontal WM SUVR in the AD group vs frontal WM SUVR in the PiB-negative group was 2.57 ± 0.55 vs 1.64 ± 0.22; parietal, 2.50 ± 0.52 vs 1.74 ± 0.22; posterior cingulate, 2.84 ± 0.59 vs 1.73 ± 0.22; and WM in the centrum semiovale, 2.21 ± 0.53 vs 2.42 ± 0.36, respectively. We found that PiB uptake in AD brain is significantly larger than that in PiB-negative brain in the frontal, parietal and posterior cingulate subcortical WM, except in the centrum semiovale.

  15. Neuronal and glial purinergic receptors functions in neuron development and brain disease.

    Science.gov (United States)

    Del Puerto, Ana; Wandosell, Francisco; Garrido, Juan José

    2013-10-28

    Brain development requires the interaction of complex signaling pathways, involving different cell types and molecules. For a long time, most attention has focused on neurons in a neuronocentric conceptualization of central nervous system development, these cells fulfilling an intrinsic program that establishes the brain's morphology and function. By contrast, glia have mainly been studied as support cells, offering guidance or as the cells that react to brain injury. However, new evidence is appearing that demonstrates a more fundamental role of glial cells in the control of different aspects of neuronal development and function, events in which the influence of neurons is at best weak. Moreover, it is becoming clear that the function and organization of the nervous system depends heavily on reciprocal neuron-glia interactions. During development, neurons are often generated far from their final destination and while intrinsic mechanisms are responsible for neuronal migration and growth, they need support and regulatory influences from glial cells in order to migrate correctly. Similarly, the axons emitted by neurons often have to reach faraway targets and in this sense, glia help define the way that axons grow. Moreover, oligodendrocytes and Schwann cells ultimately envelop axons, contributing to the generation of nodes of Ranvier. Finally, recent publications show that astrocytes contribute to the modulation of synaptic transmission. In this sense, purinergic receptors are expressed widely by glial cells and neurons, and recent evidence points to multiple roles of purines and purinergic receptors in neuronal development and function, from neurogenesis to axon growth and functional axonal maturation, as well as in pathological conditions in the brain. This review will focus on the role of glial and neuronal secreted purines, and on the purinergic receptors, fundamentally in the control of neuronal development and function, as well as in diseases of the nervous

  16. Non-invasive brain stimulation for the treatment of brain diseases in childhood and adolescence: state of the art, current limits and future challenges

    Directory of Open Access Journals (Sweden)

    Carmelo Mario Vicario

    2013-11-01

    Full Text Available In the last decades interest in application of non-invasive brain stimulation for enhancing neural functions is growing continuously. However, the use of such techniques in pediatric populations remains rather limited and mainly confined to the treatment of severe neurological and psychiatric diseases. In this article we provide a complete review of non-invasive brain stimulation studies conducted in pediatric populations. We also provide a brief discussion about the current limitations and future directions in a field of research still very young and full of issues to be explored.

  17. Apathy in patients with Parkinson's disease following deep brain stimulation of the subthalamic nucleus.

    Science.gov (United States)

    Hindle Fisher, Isabel; Pall, Hardev S; Mitchell, Rosalind D; Kausar, Jamilla; Cavanna, Andrea E

    2016-06-01

    Apathy has been reported as a possible adverse effect of deep brain stimulation of the subthalamic nucleus (STN-DBS). We investigated the prevalence and severity of apathy in 22 patients with Parkinson's disease (PD) who underwent STN-DBS, as well as the effects of apathy on quality of life (QOL). All patients were assessed with the Lille Apathy Rating Scale (LARS), the Apathy Scale (AS), and the Parkinson's Disease Questionnaire and were compared to a control group of 38 patients on pharmacotherapy alone. There were no significant differences in the prevalence or severity of apathy between patients who had undergone STN-DBS and those on pharmacotherapy alone. Significant correlations were observed between poorer QOL and degree of apathy, as measured by the LARS (papathy ratings (papathy in the PD population; however, more severe apathy appears to be associated with a higher level of disability due to PD and worse QOL, but no other clinico-demographic characteristics.

  18. Clinical NMR imaging of the brain in children: normal and neurologic disease

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, M.A, (Hammersmith Hospital, London, England); Pennock, J.M.; Bydder, G.M.; Steiner, R.E.; Thomas, D.J.; Hayward, R.; Bryant, D.R.T.; Payne, J.A.; Levene, M.I.; Whitelaw, A.; Dubowitz, L.M.S.; Dubowitz, V.

    1983-11-01

    The results of initial clinical nuclear magnetic resonance imaging of the brain in eight normal and 52 children with a wide variety of neurologic diseases were reviewed. The high level of gray-white matter contrast available with inversion-recovery sequences provided a basis for visualizing normal myelination as well as delays or deficits in this process. The appearances seen in cases of parenchymal hemorrhage, cerebral infarction, and proencephalic cysts are described. Ventricular enlargement was readily identified and marginal edema was demonstrated with spin-echo sequences. Abnormalities were seen in cerebral palsy, congenital malformations, Hallervorden-Spatz disease, aminoaciduria, and meningitis. Space-occupying lesions were identified by virtue of their increased relaxation times and mass effects. Nuclear magnetic resonance imaging has considerable potential in pediatric neuroradiologic practice, in some conditions supplying information not available by computed tomography or sonography.

  19. Brain transplants. A new approach to the therapy of neurodegenerative disease.

    Science.gov (United States)

    Tulipan, N

    1988-05-01

    There is now a wealth of experimental evidence to suggest that transplantation to the brain may ameliorate a variety of neurologic and endocrine disorders. Many unanswered questions remain. Chief among these questions are the duration of any salutary effects and the potential long-term risks to the host CNS. Answers to these questions will only come with carefully controlled long-term clinical studies. Given the high incidence and devastating nature of many of these diseases, such studies will have enormous scientific and social impact. Regardless of the outcome, there is the potential for a greater understanding of the pathologic mechanisms underlying neurodegenerative diseases and, thus, the possibility that definitive therapies will be found as a result.

  20. Current research into brain barriers and the delivery of therapeutics for neurological diseases

    DEFF Research Database (Denmark)

    Greenwood, John; Hammarlund-Udenaes, Margareta; Jones, Hazel C

    2017-01-01

    This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consi...... consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers.......This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers...

  1. Association of Parkinson disease-related protein PINK1 with Alzheimer disease and multiple sclerosis brain lesions.

    Science.gov (United States)

    Wilhelmus, Micha M M; van der Pol, Susanne M A; Jansen, Quentin; Witte, Maarten E; van der Valk, Paul; Rozemuller, Annemieke J M; Drukarch, Benjamin; de Vries, Helga E; Van Horssen, Jack

    2011-02-01

    Mitochondrial dysfunction and oxidative stress are hallmarks of various neurological disorders, including multiple sclerosis (MS), Alzheimer disease (AD), and Parkinson disease (PD). Mutations in PINK1, a mitochondrial kinase, have been linked to the occurrence of early onset parkinsonism. Currently, various studies support the notion of a neuroprotective role for PINK1, as it protects cells from stress-mediated mitochondrial dysfunction, oxidative stress, and apoptosis. Because information about the distribution pattern of PINK1 in neurological diseases other than PD is scarce, we here investigated PINK1 expression in well-characterized brain samples derived from MS and AD individuals using immunohistochemistry. In control gray matter PINK1 immunoreactivity was observed in neurons, particularly neurons in layers IV-VI. Astrocytes were the most prominent cell type decorated by anti-PINK1 antibody in the white matter. In addition, PINK1 staining was observed in the cerebrovasculature. In AD, PINK1 was found to colocalize with classic senile plaques and vascular amyloid depositions, as well as reactive astrocytes associated with the characteristic AD lesions. Interestingly, PINK1 was absent from neurofibrillary tangles. In active demyelinating MS lesions we observed a marked astrocytic PINK1 immunostaining, whereas astrocytes in chronic lesions were weakly stained. Taken together, we observed PINK1 immunostaining in both AD and MS lesions, predominantly in reactive astrocytes associated with these lesions, suggesting that the increase in astrocytic PINK1 protein might be an intrinsic protective mechanism to limit cellular injury. Copyright © 2010 Elsevier Inc. All rights reserved.

  2. CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease.

    Science.gov (United States)

    Zhang, Deng-Feng; Li, Jin; Wu, Huan; Cui, Yue; Bi, Rui; Zhou, He-Jiang; Wang, Hui-Zhen; Zhang, Chen; Wang, Dong; Kong, Qing-Peng; Li, Tao; Fang, Yiru; Jiang, Tianzi; Yao, Yong-Gang

    2016-03-01

    The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (P(meta)=5.0 × 10(-4)) and rs800292 (P(meta)=1.3 × 10(-5)) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16 795 controls). Rs1061170 (P=2.5 × 10(-3)) and rs800292 (P=4.7 × 10(-4)) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and Aβ levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress.

  3. Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging and neurodegenerative diseases.

    Science.gov (United States)

    Mendelsohn, Andrew R; Larrick, James W

    2013-12-01

    Decline of cognition and increasing risk of neurodegenerative diseases are major problems associated with aging in humans. Of particular importance is how the brain removes potentially toxic biomolecules that accumulate with normal neuronal function. Recently, a biomolecule clearance system using convective flow between the cerebrospinal fluid (CSF) and interstitial fluid (ISF) to remove toxic metabolites in the brain was described. Xie and colleagues now report that in mice the clearance activity of this so-called "glymphatic system" is strongly stimulated by sleep and is associated with an increase in interstitial volume, possibly by shrinkage of astroglial cells. Moreover, anesthesia and attenuation of adrenergic signaling can activate the glymphatic system to clear potentially toxic proteins known to contribute to the pathology of Alzheimer disease (AD) such as beta-amyloid (Abeta). Clearance during sleep is as much as two-fold faster than during waking hours. These results support a new hypothesis to answer the age-old question of why sleep is necessary. Glymphatic dysfunction may pay a hitherto unsuspected role in the pathogenesis of neurodegenerative diseases as well as maintenance of cognition. Furthermore, clinical studies suggest that quality and duration of sleep may be predictive of the onset of AD, and that quality sleep may significantly reduce the risk of AD for apolipoprotein E (ApoE) ɛ4 carriers, who have significantly greater chances of developing AD. Further characterization of the glymphatic system in humans may lead to new therapies and methods of prevention of neurodegenerative diseases. A public health initiative to ensure adequate sleep among middle-aged and older people may prove useful in preventing AD, especially in apolipoprotein E (ApoE) ɛ4 carriers.

  4. Hippocampal sclerosis of aging, a prevalent and high-morbidity brain disease.

    Science.gov (United States)

    Nelson, Peter T; Smith, Charles D; Abner, Erin L; Wilfred, Bernard J; Wang, Wang-Xia; Neltner, Janna H; Baker, Michael; Fardo, David W; Kryscio, Richard J; Scheff, Stephen W; Jicha, Gregory A; Jellinger, Kurt A; Van Eldik, Linda J; Schmitt, Frederick A

    2013-08-01

    Hippocampal sclerosis of aging (HS-Aging) is a causative factor in a large proportion of elderly dementia cases. The current definition of HS-Aging rests on pathologic criteria: neuronal loss and gliosis in the hippocampal formation that is out of proportion to AD-type pathology. HS-Aging is also strongly associated with TDP-43 pathology. HS-Aging pathology appears to be most prevalent in the oldest-old: autopsy series indicate that 5-30 % of nonagenarians have HS-Aging pathology. Among prior studies, differences in study design have contributed to the study-to-study variability in reported disease prevalence. The presence of HS-Aging pathology correlates with significant cognitive impairment which is often misdiagnosed as AD clinically. The antemortem diagnosis is further confounded by other diseases linked to hippocampal atrophy including frontotemporal lobar degeneration and cerebrovascular pathologies. Recent advances characterizing the neurocognitive profile of HS-Aging patients have begun to provide clues that may help identify living individuals with HS-Aging pathology. Structural brain imaging studies of research subjects followed to autopsy reveal hippocampal atrophy that is substantially greater in people with eventual HS-Aging pathology, compared to those with AD pathology alone. Data are presented from individuals who were followed with neurocognitive and neuroradiologic measurements, followed by neuropathologic evaluation at the University of Kentucky. Finally, we discuss factors that are hypothesized to cause or modify the disease. We conclude that the published literature on HS-Aging provides strong evidence of an important and under-appreciated brain disease of aging. Unfortunately, there is no therapy or preventive strategy currently available.

  5. Brain plasticity in the motor network is correlated with disease progression in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Poujois, Aurélia; Schneider, Fabien C; Faillenot, Isabelle; Camdessanché, Jean-Philippe; Vandenberghe, Nadia; Thomas-Antérion, Catherine; Antoine, Jean-Christophe

    2013-10-01

    To test the influence of functional cerebral reorganization in amyotrophic lateral sclerosis (ALS) on disease progression. Nineteen predominantly right-handed ALS patients and 21 controls underwent clinical evaluation, functional Magnetic Resonance Imaging (fMRI), and diffusion tensor imaging. Patients were clinically re-evaluated 1 year later and followed until death. For fMRI, subjects executed and imagined a simple hand-motor task. Between-group comparisons were performed, and correlations were searched with motor deficit arm Medical Research Council (MRC) score, disease progression ALS Functional Rating Scale (ALSFRS), and survival time. By the MRC score, the hand strength was lowered by 12% in the ALS group predominating on the right side in accordance with an abnormal fractional anisotropy (FA) limited to the left corticospinal tract (37.3% reduction vs. controls P < 0.01). Compared to controls, patients displayed overactivations in the controlateral parietal (P < 0.004) and somatosensory (P < 0.004) cortex and in the ipsilateral parietal (P < 0.01) and somatosensory (P < 0.01) cortex to right-hand movement. Movement imagination gave similar results while no difference occurred with left-hand tasks. Stepwise regression analysis corrected for multiple comparisons showed that controlateral parietal activity was inversely correlated with disease progression (R(2) = 0.43, P = 0.001) and ipsilateral somatosensory activations with the severity of the right-arm deficit (R(2) = 0.48, P = 0.001). Cortical Blood Oxygen Level Dependent (BOLD) signal changes occur in the brain of ALS patients during a simple hand-motor task when the motor deficit is still moderate. It is correlated with the rate of disease progression suggesting that brain functional rearrangement in ALS may have prognostic implications. Copyright © 2012 Wiley Periodicals, Inc.

  6. Disrupted nodal and hub organization account for brain network abnormalities in Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Yuko Koshimori

    2016-11-01

    Full Text Available The recent application of graph theory to brain networks promises to shed light on complex diseases such as Parkinson’s disease. This study aimed to investigate functional changes in sensorimotor and cognitive networks in parkinsonian patients, with a focus on inter- and intra-connectivity organization in the disease-associated nodal and hub regions using the graph theoretical analyses. Resting-state functional MRI data of a total of 65 participants, including 23 healthy controls and 42 patients, were investigated in 120 nodes for local efficiency, betweenness centrality, and degree. Hub regions were identified in the healthy control and patient groups. We found nodal and hub changes in patients compared with healthy controls, including the right pre-supplementary motor area, left anterior insula, bilateral mid-insula, bilateral dorsolateral prefrontal cortex, and right caudate nucleus. In general, nodal regions within the sensorimotor network (i.e. right pre-supplementary motor area and right mid-insula displayed weakened connectivity, with the former node associated with more severe bradykinesia, and impaired integration with default mode network regions. The left mid-insula also lost its hub properties in patients. Within the executive networks, the left anterior insular cortex lost its hub properties in patients, while a new hub region was identified in the right caudate nucleus, paralleled by an increased level of inter- and intra-connectivity in the bilateral dorsolateral prefrontal cortex possibly representing compensatory mechanisms. These findings highlight the diffuse changes in nodal organization and regional hub disruption accounting for the distributed abnormalities across brain networks and the clinical manifestations of Parkinson’s disease.

  7. Speech disorders in Parkinson's disease: early diagnostics and effects of medication and brain stimulation.

    Science.gov (United States)

    Brabenec, L; Mekyska, J; Galaz, Z; Rektorova, Irena

    2017-03-01

    Hypokinetic dysarthria (HD) occurs in 90% of Parkinson's disease (PD) patients. It manifests specifically in the areas of articulation, phonation, prosody, speech fluency, and faciokinesis. We aimed to systematically review papers on HD in PD with a special focus on (1) early PD diagnosis and monitoring of the disease progression using acoustic voice and speech analysis, and (2) functional imaging studies exploring neural correlates of HD in PD, and (3) clinical studies using acoustic analysis to evaluate effects of dopaminergic medication and brain stimulation. A systematic literature search of articles written in English before March 2016 was conducted in the Web of Science, PubMed, SpringerLink, and IEEE Xplore databases using and combining specific relevant keywords. Articles were categorized into three groups: (1) articles focused on neural correlates of HD in PD using functional imaging (n = 13); (2) articles dealing with the acoustic analysis of HD in PD (n = 52); and (3) articles concerning specifically dopaminergic and brain stimulation-related effects as assessed by acoustic analysis (n = 31); the groups were then reviewed. We identified 14 combinations of speech tasks and acoustic features that can be recommended for use in describing the main features of HD in PD. While only a few acoustic parameters correlate with limb motor symptoms and can be partially relieved by dopaminergic medication, HD in PD seems to be mainly related to non-dopaminergic deficits and associated particularly with non-motor symptoms. Future studies should combine non-invasive brain stimulation with voice behavior approaches to achieve the best treatment effects by enhancing auditory-motor integration.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Glycosphingolipid studies of visceral tissues and brain from type 1 Gaucher disease variants.

    Science.gov (United States)

    Nilsson, O; Grabowski, G A; Ludman, M D; Desnick, R J; Svennerholm, L

    1985-05-01

    Glucosylceramide and glucosylsphingosine isolated from spleen, liver and brain were quantitated and characterized in two unrelated patients with Gaucher disease, neither of whom had clinical or neuropathologic evidence of neuronal involvement. Visceral glucosylceramide accumulation did not differ in the two patients. Hepatic glucosylsphingosine content was 2-fold greater in a young severely affected 3-year-old American Black patient compared to that in a 56-year-old Ashkenazi Jewish patient. In contrast, significant differences in glycosphingolipid content and composition were observed in the brains of these two cases. Cerebral and cerebellar cortical glucosylceramide accumulated to a greater extent (3-fold) in the severely affected 3-year-old patient compared to that in the older case. The compositions of the acyl and sphingosyl base residues of glucosylceramide in the cerebral and cerebellar cortices from the Ashkenazi Jewish patient were similar to those in normal individuals. In comparison, the gray matter glucosylceramide in the severely affected patient had increased percentages of stearic acid (18:0) and eicosasphingenine (d20:1), suggesting that the accumulated substrate was derived from the brain ganglioside pool. Glucosylsphingosine was found in large amounts only in cerebral and cerebellar cortices from the severely affected patient. The glycolipid content and composition in this patient was similar to that found in the Norrbottnian (Type 3) form of Gaucher disease. The differences in glucosylceramide acyl and sphingosyl base composition in gray matter from the severely affected patient and that in the Ashkenazi Jewish patient suggested that the accumulated substrates were metabolized differently by the residual enzymes in each case.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Posterolateral Trajectories Favor a Longer Motor Domain in Subthalamic Nucleus Deep Brain Stimulation for Parkinson Disease.

    Science.gov (United States)

    Tamir, Idit; Marmor-Levin, Odeya; Eitan, Renana; Bergman, Hagai; Israel, Zvi

    2017-10-01

    The clinical outcome of patients with Parkinson disease (PD) who undergo subthalamic nucleus (STN) deep brain stimulation (DBS) is, in part, determined by the length of the electrode trajectory through the motor STN domain, the dorsolateral oscillatory region (DLOR). Trajectory length has been found to correlate with the stimulation-related improvement in patients' motor function (estimated by part III of the United Parkinson's Disease Rating Scale [UPDRS]). Therefore, it seems that ideally trajectories should have maximal DLOR length. We retrospectively studied the influence of various anatomic aspects of the brains of patients with PD and the geometry of trajectories planned on the length of the DLOR and STN recorded during DBS surgery. We examined 212 trajectories and 424 microelectrode recording tracks in 115 patients operated on in our center between 2010 and 2015. We found a strong correlation between the length of the recorded DLOR and STN. Trajectories that were more lateral and/or posterior in orientation had a longer STN and DLOR pass, although the DLOR/STN fraction length remained constant. The STN target was more lateral when the third ventricle was wider, and the latter correlated with older age and male gender. Trajectory angles correlate with the recorded STN and DLOR lengths, and should be altered toward a more posterolateral angle in older patients and atrophied brains to compensate for the changes in STN location and geometry. These fine adjustments should yield a longer motor domain pass, thereby improving the patient's predicted outcome. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Frameless stereotactic deep brain stimulation for Parkinson′s disease: A case report and technical note

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    Chun-Chieh Lin

    2014-01-01

    Full Text Available Because deep brain stimulation (DBS implantations and other stereotactic and functional surgical procedures require accurate, precise, and safe targeting of the brain structure, the technical aids for preoperative planning, intervention, and postoperative follow-up have become increasingly important. In this paper, we introduce a case of advanced Parkinson′s disease with 10 years of medical control in which the patient received subthalamic nuclei (STN DBS therapy through frameless surgery. A preliminary outcomes analysis is also provided. The STN DBS was implanted using a frameless stereotaxy protocol. After identifying the STN by microelectrode recording (MER, the DBS electrodes were implanted and connected to an implanted programmable generator. Programming started 1 month after the operation, and the patient was followed up on regularly and 12 months of post-STN DBS unified Parkinson′s disease rating scale were recorded. After 12 months of follow-up, the patient who received the frameless surgery showed a significant improvement in clinical motor functions compared with his preoperative scores. The frameless system has the advantage of providing accuracy in postoperative lead position survey and target deviation measurements with comparison to the preoperative planning image. The outcomes of frameless DBS surgery are similar to those of frame-based surgery, with the advantages being that frameless surgery can reduce the patient′s discomfort, shorten the operation and MER time, and decrease the MER trajectory number.

  12. Dopamine transporter changes after unilateral deep brain stimulation in progressive Parkinson's disease: a case report

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    Zhang HW

    2014-04-01

    Full Text Available Huiwei Zhang,1,* Yuanyuan Wang,1,* Jinchuan Liang,2 Stefan Förster,3 Ping Wu,1 Jun Zhao,1 Yihui Guan,1 Chuantao Zuo1 1PET Center, Huashan Hospital, Fudan University, 2Department of Neurosurgery, Changhai Hospital, Shanghai, People's Republic of China; 3Department of Nuclear Medicine and TUM-Neuroimaging Center, Technical University Munich, Munich, Germany *These authors contributed equally to this work Abstract: Deep brain stimulation (DBS at the subthalamic nucleus has been approved as an effective treatment for refractory symptoms of Parkinson's disease (PD. Studies have shown that bilateral DBS surgery in PD patients results in clinical improvement without reducing dopamine transporter function. Here, we report our longitudinal findings in one PD patient, ie, decreases in striatal dopamine transporter binding during one year of follow-up after unilateral DBS at the subthalamic nucleus. Based on this case, we hypothesize that clinical benefit after unilateral DBS may be not directly associated with changes in function at the subthalamic nucleus. Keywords: deep brain stimulation, Parkinson's disease, dopamine transporter, positron emission tomography

  13. Characterizing brain patterns in conversion from mild cognitive impairment (MCI) to Alzheimer's disease

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    Silva R., Santiago S.; Giraldo, Diana L.; Romero, Eduardo

    2017-11-01

    Structural Magnetic Resonance (MR) brain images should provide quantitative information about the stage and progression of Alzheimer's disease. However, the use of MRI is limited and practically reduced to corroborate a diagnosis already performed with neuropsychological tools. This paper presents an automated strategy for extraction of relevant anatomic patterns related with the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) using T1-weighted MR images. The process starts by representing each of the possible classes with models generated from a linear combination of volumes. The difference between models allows us to establish which are the regions where relevant patterns might be located. The approach searches patterns in a space of brain sulci, herein approximated by the most representative gradients found in regions of interest defined by the difference between the linear models. This hypothesis is assessed by training a conventional SVM model with the found relevant patterns under a leave-one-out scheme. The resultant AUC was 0.86 for the group of women and 0.61 for the group of men.

  14. Modular reorganization of brain resting state networks and its independent validation in Alzheimer's disease patients.

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    Chen, Guangyu; Zhang, Hong-Ying; Xie, Chunming; Chen, Gang; Zhang, Zhi-Jun; Teng, Gao-Jun; Li, Shi-Jiang

    2013-01-01

    Previous studies have demonstrated disruption in structural and functional connectivity occurring in the Alzheimer's Disease (AD). However, it is not known how these disruptions alter brain network reorganization. With the modular analysis method of graph theory, and datasets acquired by the resting-state functional connectivity MRI (R-fMRI) method, we investigated and compared the brain organization patterns between the AD group and the cognitively normal control (CN) group. Our main finding is that the largest homotopic module (defined as the insula module) in the CN group was broken down to the pieces in the AD group. Specifically, it was discovered that the eight pairs of the bilateral regions (the opercular part of inferior frontal gyrus, area triangularis, insula, putamen, globus pallidus, transverse temporal gyri, superior temporal gyrus, and superior temporal pole) of the insula module had lost symmetric functional connection properties, and the corresponding gray matter concentration (GMC) was significant lower in AD group. We further quantified the functional connectivity changes with an index (index A) and structural changes with the GMC index in the insula module to demonstrate their great potential as AD biomarkers. We further validated these results with six additional independent datasets (271 subjects in six groups). Our results demonstrated specific underlying structural and functional reorganization from young to old, and for diseased subjects. Further, it is suggested that by combining the structural GMC analysis and functional modular analysis in the insula module, a new biomarker can be developed at the single-subject level.

  15. High Frequency Deep Brain Stimulation and Neural Rhythms in Parkinson's Disease.

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    Blumenfeld, Zack; Brontë-Stewart, Helen

    2015-12-01

    High frequency (HF) deep brain stimulation (DBS) is an established therapy for the treatment of Parkinson's disease (PD). It effectively treats the cardinal motor signs of PD, including tremor, bradykinesia, and rigidity. The most common neural target is the subthalamic nucleus, located within the basal ganglia, the region most acutely affected by PD pathology. Using chronically-implanted DBS electrodes, researchers have been able to record underlying neural rhythms from several nodes in the PD network as well as perturb it using DBS to measure the ensuing neural and behavioral effects, both acutely and over time. In this review, we provide an overview of the PD neural network, focusing on the pathophysiological signals that have been recorded from PD patients as well as the mechanisms underlying the therapeutic benefits of HF DBS. We then discuss evidence for the relationship between specific neural oscillations and symptoms of PD, including the aberrant relationships potentially underlying functional connectivity in PD as well as the use of different frequencies of stimulation to more specifically target certain symptoms. Finally, we briefly describe several current areas of investigation and how the ability to record neural data in ecologically-valid settings may allow researchers to explore the relationship between brain and behavior in an unprecedented manner, culminating in the future automation of neurostimulation therapy for the treatment of a variety of neuropsychiatric diseases.

  16. Mood stability in Parkinson disease following deep brain stimulation: a 6-month prospective follow-up study.

    Science.gov (United States)

    Chopra, Amit; Abulseoud, Osama A; Sampson, Shirlene; Lee, Kendall H; Klassen, Bryan T; Fields, Julie A; Matsumoto, Joseph Y; Adams, Andrea C; Stoppel, Cynthia J; Geske, Jennifer R; Frye, Mark A

    2014-01-01

    Deep brain stimulation for Parkinson disease has been associated with psychiatric adverse effects including anxiety, depression, mania, psychosis, and suicide. The purpose of this study was to evaluate the safety of deep brain stimulation in a large Parkinson disease clinical practice. Patients approved for surgery by the Mayo Clinic deep brain stimulation clinical committee participated in a 6-month prospective naturalistic follow-up study. In addition to the Unified Parkinson's Disease Rating Scale, stability and psychiatric safety were measured using the Beck Depression Inventory, Hamilton Depression Rating Scale, and Young Mania Rating scale. Outcomes were compared in patients with Parkinson disease who had a psychiatric history to those with no co-morbid psychiatric history. The study was completed by 49 of 54 patients. Statistically significant 6-month baseline to end-point improvement was found in motor and mood scales. No significant differences were found in psychiatric outcomes based on the presence or absence of psychiatric comorbidity. Our study suggests that patients with Parkinson disease who have a history of psychiatric co-morbidity can safely respond to deep brain stimulation with no greater risk of psychiatric adverse effect occurrence. A multidisciplinary team approach, including careful psychiatric screening ensuring mood stabilization and psychiatric follow-up, should be viewed as standard of care to optimize the psychiatric outcome in the course of deep brain stimulation treatment. © 2013 Published by The Academy of Psychosomatic Medicine on behalf of The Academy of Psychosomatic Medicine.

  17. Brain Changes in Responders versus Non-Responders in Chronic Migraine: Markers of Disease Reversal

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    Catherine S Hubbard

    2016-10-01

    Full Text Available The aim of this study was to identify structural and functional brain changes that accompanied the transition from chronic (CM; ≥ 15 headache days/month to episodic (EM; < 15 headache days/month migraine following prophylactic treatment with onabotulinumtoxinA. Specifically, we examined whether CM patients responsive to prophylaxis (responders; n = 11, as evidenced by a reversal in disease status (defined by at least a 50% reduction in migraine frequency and < 15 headache days/month, compared to CM patients whose migraine frequency remained unchanged (non-responders; n = 12, showed differences in cortical thickness using surface-based morphometry. We also investigated whether areas showing group differences in cortical thickness displayed altered resting-state functional connectivity (RS-FC using seed-to-voxel analyses. Migraine characteristics measured across groups included disease duration, pain intensity and headache frequency. Patient reports’ of headache frequency over the four weeks prior to (pre-treatment and following (post-treatment prophylaxis were compared (post minus pre and this measure served as the clinical endpoint that determined group assignment. All patients were scanned within two weeks of the post-treatment visit. Results revealed that responders showed significant cortical thickening in the right primary somatosensory cortex (SI and anterior insula, and left superior temporal gyrus and pars opercularis compared to non-responders. In addition, disease duration was negatively correlated with cortical thickness in fronto-parietal and temporo-occipital regions in responders but not non-responders, with the exception of the primary motor cortex (MI that showed the opposite pattern; disease duration was positively associated with MI cortical thickness in responders versus non-responders. Our seed-based RS-FC analyses revealed anti-correlations between the SI seed and lateral occipital (LOC and dorsomedial prefrontal cortices

  18. Gut-brain axis: Role of lipids in the regulation of inflammation, pain and CNS diseases.

    Science.gov (United States)

    Russo, Roberto; Cristiano, Claudia; Avagliano, Carmen; De Caro, Carmen; La Rana, Giovanna; Raso, Giuseppina Mattace; Canani, Roberto Berni; Meli, Rosaria; Calignano, Antonio

    2017-02-16

    The human gut is a composite anaerobic environment with a large, diverse and dynamic enteric microbiota, represented by more than 100 trillion microorganisms, including at least 1000 distinct species. The discovery that a different microbial composition can influence behavior and cognition, and in turn the nervous system can indirectly influence enteric microbiota composition, has significantly contributed to establish the well-accepted concept of gut-brain axis. This hypothesis is supported by several evidence showing mutual mechanisms, which involve the vague nerve, the immune system, the hypothalamic-pituitary-adrenal (HPA) axis modulation and the bacteria-derived metabolites. Many studies have focused on delineating a role for this axis in health and disease, ranging from stress-related disorders such as depression, anxiety and irritable bowel syndrome (IBS) to neurodevelopmental disorders, such as autism, and to neurodegenerative diseases, such as Parkinson Disease, Alzheimer Disease etc. Based on this background, and considering the relevance of alteration of the symbiotic state between host and microbiota, this review focuses on the role and the involvement of bioactive lipids, such as the N-acylethanolamine (NAE) family whose main members are N-arachidonoylethanolamine (AEA), palmitoylethanolamide (PEA) and oleoilethanolamide (OEA), and short chain fatty acids (SCFAs), such as butyrate, belonging to a large group of bioactive lipids able to modulate peripheral and central pathologic processes. It is well established their effective role in inflammation, acute and chronic pain, obesity and central nervous system diseases. It has been shown a possible correlation between these lipids and gut microbiota through different mechanisms. Indeed, systemic administration of specific bacteria can reduce abdominal pain through the involvement of cannabinoid receptor 1 in rat; on the other hand, PEA reduces inflammation markers in a murine model of inflammatory bowel

  19. Recursive cluster elimination based support vector machine for disease state prediction using resting state functional and effective brain connectivity.

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    Gopikrishna Deshpande

    2010-12-01

    Full Text Available Brain state classification has been accomplished using features such as voxel intensities, derived from functional magnetic resonance imaging (fMRI data, as inputs to efficient classifiers such as support vector machines (SVM and is based on the spatial localization model of brain function. With the advent of the connectionist model of brain function, features from brain networks may provide increased discriminatory power for brain state classification.In this study, we introduce a novel framework where in both functional connectivity (FC based on instantaneous temporal correlation and effective connectivity (EC based on causal influence in brain networks are used as features in an SVM classifier. In order to derive those features, we adopt a novel approach recently introduced by us called correlation-purged Granger causality (CPGC in order to obtain both FC and EC from fMRI data simultaneously without the instantaneous correlation contaminating Granger causality. In addition, statistical learning is accelerated and performance accuracy is enhanced by combining recursive cluster elimination (RCE algorithm with the SVM classifier. We demonstrate the efficacy of the CPGC-based RCE-SVM approach using a specific instance of brain state classification exemplified by disease state prediction. Accordingly, we show that this approach is capable of predicting with 90.3% accuracy whether any given human subject was prenatally exposed to cocaine or not, even when no significant behavioral differences were found between exposed and healthy subjects.The framework adopted in this work is quite general in nature with prenatal cocaine exposure being only an illustrative example of the power of this approach. In any brain state classification approach using neuroimaging data, including the directional connectivity information may prove to be a performance enhancer. When brain state classification is used for disease state prediction, our approach may aid the

  20. Multifunctional liposomes reduce brain β-amyloid burden and ameliorate memory impairment in Alzheimer's disease mouse models.

    Science.gov (United States)

    Balducci, Claudia; Mancini, Simona; Minniti, Stefania; La Vitola, Pietro; Zotti, Margherita; Sancini, Giulio; Mauri, Mario; Cagnotto, Alfredo; Colombo, Laura; Fiordaliso, Fabio; Grigoli, Emanuele; Salmona, Mario; Snellman, Anniina; Haaparanta-Solin, Merja; Forloni, Gianluigi; Masserini, Massimo; Re, Francesca

    2014-10-15

    Alzheimer's disease is characterized by the accumulation and deposition of plaques of β-amyloid (Aβ) peptide in the brain. Given its pivotal role, new therapies targeting Aβ are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of Aβ assemblies and evaluated their efficiency in reducing the Aβ burden in Alzheimer's disease mouse models. Liposomes were bifunctionalized with a peptide derived from the apolipoprotein-E receptor-binding domain for blood-brain barrier targeting and with phosphatidic acid for Aβ binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, Aβ assemblies in vitro (EM experiments). Administration of bifunctionalized liposomes to APP/presenilin 1 transgenic mice (aged 10 months) for 3 weeks (three injections per week) decreased total brain-insoluble Aβ1-42 (-33%), assessed by ELISA, and the number and total area of plaques (-34%) detected histologically. Also, brain Aβ oligomers were reduced (-70.5%), as assessed by SDS-PAGE. Plaque reduction was confirmed in APP23 transgenic mice (aged 15 months) either histologically or by PET imaging with [(11)C]Pittsburgh compound B (PIB). The reduction of brain Aβ was associated with its increase in liver (+18%) and spleen (+20%). Notably, the novel-object recognition test showed that the treatment ameliorated mouse impaired memory. Finally, liposomes reached the brain in an intact form, as determined by confocal microscopy experiments with fluorescently labeled liposomes. These data suggest that bifunctionalized liposomes destabilize brain Aβ aggregates and promote peptide removal across the blood-brain barrier and its peripheral clearance. This all-in-one multitask therapeutic device can be considered as a candidate for the treatment of Alzheimer's disease. Copyright © 2014 the authors 0270-6474/14/3414013-09$15.00/0.

  1. Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease.

    Science.gov (United States)

    Appu, Abhilash P; Moffett, John R; Arun, Peethambaran; Moran, Sean; Nambiar, Vikram; Krishnan, Jishnu K S; Puthillathu, Narayanan; Namboodiri, Aryan M A

    2017-01-01

    Canavan disease is caused by mutations in the gene encoding aspartoacylase (ASPA), a deacetylase that catabolizes N-acetylaspartate (NAA). The precise involvement of elevated NAA in the pathogenesis of Canavan disease is an ongoing debate. In the present study, we tested the effects of elevated NAA in the brain during postnatal development. Mice were administered high doses of the hydrophobic methyl ester of NAA (M-NAA) twice daily starting on day 7 after birth. This treatment increased NAA levels in the brain to those observed in the brains of Nur7 mice, an established model of Canavan disease. We evaluated various serological parameters, oxidative stress, inflammatory and neurodegeneration markers and the results showed that there were no pathological alterations in any measure with increased brain NAA levels. We examined oxidative stress markers, malondialdehyde content (indicator of lipid peroxidation), expression of NADPH oxidase and nuclear translocation of the stress-responsive transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF-2) in brain. We also examined additional pathological markers by immunohistochemistry and the expression of activated caspase-3 and interleukin-6 by Western blot. None of the markers were increased in the brains of M-NAA treated mice, and no vacuoles were observed in any brain region. These results show that ASPA expression prevents the pathologies associated with excessive NAA concentrations in the brain during postnatal myelination. We hypothesize that the pathogenesis of Canavan disease involves not only disrupted NAA metabolism, but also excessive NAA related signaling processes in oligodendrocytes that have not been fully determined and we discuss some of the potential mechanisms.

  2. Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease

    Directory of Open Access Journals (Sweden)

    Abhilash P. Appu

    2017-06-01

    Full Text Available Canavan disease is caused by mutations in the gene encoding aspartoacylase (ASPA, a deacetylase that catabolizes N-acetylaspartate (NAA. The precise involvement of elevated NAA in the pathogenesis of Canavan disease is an ongoing debate. In the present study, we tested the effects of elevated NAA in the brain during postnatal development. Mice were administered high doses of the hydrophobic methyl ester of NAA (M-NAA twice daily starting on day 7 after birth. This treatment increased NAA levels in the brain to those observed in the brains of Nur7 mice, an established model of Canavan disease. We evaluated various serological parameters, oxidative stress, inflammatory and neurodegeneration markers and the results showed that there were no pathological alterations in any measure with increased brain NAA levels. We examined oxidative stress markers, malondialdehyde content (indicator of lipid peroxidation, expression of NADPH oxidase and nuclear translocation of the stress-responsive transcription factor nuclear factor (erythroid-derived 2-like 2 (NRF-2 in brain. We also examined additional pathological markers by immunohistochemistry and the expression of activated caspase-3 and interleukin-6 by Western blot. None of the markers were increased in the brains of M-NAA treated mice, and no vacuoles were observed in any brain region. These results show that ASPA expression prevents the pathologies associated with excessive NAA concentrations in the brain during postnatal myelination. We hypothesize that the pathogenesis of Canavan disease involves not only disrupted NAA metabolism, but also excessive NAA related signaling processes in oligodendrocytes that have not been fully determined and we discuss some of the potential mechanisms.

  3. Ivy Sign on Fluid-Attenuated Inversion Recovery Images in Moyamoya Disease: Correlation with Clinical Severity and Old Brain Lesions

    OpenAIRE

    Seo, Kwon-Duk; Suh, Sang Hyun; Kim, Yong Bae; Kim, Ji Hwa; Ahn, Sung Jun; Kim, Dong-Seok; Lee, Kyung-Yul

    2015-01-01

    Purpose Leptomeningeal collateral, in moyamoya disease (MMD), appears as an ivy sign on fluid-attenuated inversion-recovery (FLAIR) images. There has been little investigation into the relationship between presentation of ivy signs and old brain lesions. We aimed to evaluate clinical significance of ivy signs and whether they correlate with old brain lesions and the severity of clinical symptoms in patients with MMD. Materials and Methods FLAIR images of 83 patients were reviewed. Each cerebr...

  4. Selective vulnerability of Rich Club brain regions is an organizational principle of structural connectivity loss in Huntington's disease.

    Science.gov (United States)

    McColgan, Peter; Seunarine, Kiran K; Razi, Adeel; Cole, James H; Gregory, Sarah; Durr, Alexandra; Roos, Raymund A C; Stout, Julie C; Landwehrmeyer, Bernhard; Scahill, Rachael I; Clark, Chris A; Rees, Geraint; Tabrizi, Sarah J

    2015-11-01

    Huntington's disease can be predicted many years before symptom onset, and thus makes an ideal model for studying the earliest mechanisms of neurodegeneration. Diffuse patterns of structural connectivity loss occur in the basal ganglia and cortex early in the disease. However, the organizational principles that underlie these changes are unclear. By understanding such principles we can gain insight into the link between the cellular pathology caused by mutant huntingtin and its downstream effect at the macroscopic level. The 'rich club' is a pattern of organization established in healthy human brains, where specific hub 'rich club' brain regions are more highly connected to each other than other brain regions. We hypothesized that selective loss of rich club connectivity might represent an organizing principle underlying the distributed pattern of structural connectivity loss seen in Huntington's disease. To test this hypothesis we performed diffusion tractography and graph theoretical analysis in a pseudo-longitudinal study of 50 premanifest and 38 manifest Huntington's disease participants compared with 47 healthy controls. Consistent with our hypothesis we found that structural connectivity loss selectively affected rich club brain regions in premanifest and manifest Huntington's disease participants compared with controls. We found progressive network changes across controls, premanifest Huntington's disease and manifest Huntington's disease characterized by increased network segregation in the premanifest stage and loss of network integration in manifest disease. These regional and whole brain network differences were highly correlated with cognitive and motor deficits suggesting they have pathophysiological relevance. We also observed greater reductions in the connectivity of brain regions that have higher network traffic and lower clustering of neighbouring regions. This provides a potential mechanism that results in a characteristic pattern of structural

  5. Subthalamic deep brain stimulation versus best medical therapy for L-dopa responsive pain in Parkinson's disease.

    Science.gov (United States)

    Sürücü, Oguzkan; Baumann-Vogel, Heide; Uhl, Mechtild; Imbach, Lukas L; Baumann, Christian R

    2013-08-01

    Pain is a frequently observed non-motor symptom of patients with Parkinson's disease. In some patients, Parkinson's-related pain responds to dopaminergic treatment. In the present study, we aimed to elucidate whether subthalamic deep brain stimulation has a similar beneficial effect on pain in Parkinson's disease, and whether this effect can be predicted by a pre-operative l-dopa challenge test assessing pain severity. We prospectively analyzed 14 consecutive Parkinson's patients with severe pain who underwent subthalamic deep brain stimulation. In 8 of these patients, pain severity decreased markedly with high doses of l-dopa, irrespective of the type and localization of the pain symptoms. In these patients, subthalamic deep brain stimulation provided an even higher reduction of pain severity than did dopaminergic treatment, and the majority of this group was pain-free after surgery. This effect lasted for up to 41 months. In the remaining 6 patients, pain was not improved by dopaminergic treatment nor by deep brain stimulation. Thus, we conclude that pain relief following subthalamic deep brain stimulation is superior to that following dopaminergic treatment, and that the response of pain symptoms to deep brain stimulation can be predicted by l-dopa challenge tests assessing pain severity. This diagnostic procedure could contribute to the decision on whether or not a Parkinson's patient with severe pain should undergo deep brain stimulation for potential pain relief. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  6. The study on a real-time remote monitoring system for Parkinson's disease patients with deep brain stimulators.

    Science.gov (United States)

    Chen, Yue; Hao, Hongwei; Chen, Hao; Tian, Ye; Li, Luming

    2014-01-01

    The Deep Brain Stimulation (DBS) has become a well-accepted treatment for Parkinson's disease patients around the world. However, postoperative care of the stimulators usually puts a heavy burden on the patients' families, especially in China. To solve the problem, this study developed a real-time remote monitoring system for deep brain stimulators. Based on Internet technologies, the system offers remote adjustment service so that in vivo stimulators could be programmed at patients' home by clinic caregivers. We tested the system on an experimental condition and the results have proved that this early exploration of remote monitoring deep brain stimulators was successful.

  7. Comparison of Metal Levels between Postmortem Brain and Ventricular Fluid in Alzheimer?s Disease and Nondemented Elderly Controls

    OpenAIRE

    Szabo, Steven T.; Harry, G. Jean; Hayden, Kathleen M.; Szabo, David T.; Birnbaum, Linda

    2015-01-01

    An essential metal hypothesis for neurodegenerative disease suggests an alteration in metal homeostasis contributing to the onset and progression of disease. Similar associations have been proposed for nonessential metals. To examine the relationship between metal levels in brain tissue and ventricular fluid (VF), postmortem samples of frontal cortex (FC) and VF from Alzheimer?s disease (AD) cases and nondemented elderly subjects were analyzed for arsenic (As), cadmium (Cd), chromium (Cr), co...

  8. Q: Is Addiction a Brain Disease or a Moral Failing? A: Neither.

    Science.gov (United States)

    Heather, Nick

    2017-01-01

    This article uses Marc Lewis' work as a springboard to discuss the socio-political context of the brain disease model of addiction (BDMA). The claim that promotion of the BDMA is the only way the general public can be persuaded to withhold blame and punishment from addicts is critically examined. After a discussion of public understandings of the disease concept of addiction, it is pointed out that it is possible to develop a scientific account of addiction which is neither a disease nor a moral model but which the public could understand. Evidence is reviewed to suggest that public acceptance of the disease concept is largely lip-service and that the claim the BDMA removes stigma among the public and professionals is unsupported by evidence. Further, there is good evidence that biogenetic explanations of mental/behavioural disorders in general have been counterproductive in the attempt to ally stigma. A model of addiction as a disorder of choice may attract special problems in public-facing communications and risks being misunderstood. However, ways of presenting this model to the public are suggested that may avoid such risks. Lastly, the claim that the BDMA is the only way of ensuring access to treatment and of maintaining research funding for addiction is disputed and a way in which these benefits can be retained under a disorder-of-choice model proposed. The article concludes by enthusiastically endorsing Lewis' call for a third stage in the governing image of addiction.

  9. Edible and Medicinal Mushrooms: Emerging Brain Food for the Mitigation of Neurodegenerative Diseases.

    Science.gov (United States)

    Phan, Chia-Wei; David, Pamela; Sabaratnam, Vikineswary

    2017-01-01

    There is an exponential increase in dementia in old age at a global level because of increasing life expectancy. The prevalence of neurodegenerative diseases such as dementia and Alzheimer's disease (AD) will continue to rise steadily, and is expected to reach 42 million cases worldwide in 2020. Despite the advancement of medication, the management of these diseases remains largely ineffective. Therefore, it is vital to explore novel nature-based nutraceuticals to mitigate AD and other age-related neurodegenerative disorders. Mushrooms and their extracts appear to hold many health benefits, including immune-modulating effects. A number of edible mushrooms have been shown to contain rare and exotic compounds that exhibit positive effects on brain cells both in vitro and in vivo. In this review, we summarize the scientific information on edible and culinary mushrooms with regard to their antidementia/AD active compounds and/or pharmacological test results. The bioactive components in these mushrooms and the underlying mechanism of their activities are discussed. In short, these mushrooms may be regarded as functional foods for the mitigation of neurodegenerative diseases.

  10. Preserving cortico-striatal function: Deep brain stimulation in Huntington's disease

    Directory of Open Access Journals (Sweden)

    Sean J Nagel

    2015-03-01

    Full Text Available Huntington’s disease (HD is an incurable neurodegenerative disease characterized by the triad of chorea, cognitive dysfunction and psychiatric disturbances. Since the discovery of the HD gene, the pathogenesis has been outlined, but to date a cure has not been found. Disease modifying therapies are needed desperately to improve function, alleviate suffering, and provide hope for symptomatic patients. Deep brain stimulation (DBS, a proven therapy for managing the symptoms of some neurodegenerative movement disorders, including Parkinson’s disease, has been reported as a palliative treatment in select cases of HD with debilitating chorea with variable success. New insights into the mechanism of action of DBS suggest it may have the potential to circumvent other manifestations of HD including cognitive deterioration. Furthermore, because DBS is already widely used, reversible, and has a risk profile that is relatively low, new studies can be initiated. In this article we contend that new clinical trials be considered to test the effects of DBS for HD

  11. Increased oxidation, glycoxidation, and lipoxidation of brain proteins in prion disease.

    Science.gov (United States)

    Pamplona, Reinald; Naudí, Alba; Gavín, Rosalina; Pastrana, Miguel A; Sajnani, Gustavo; Ilieva, Ekaterina V; Del Río, José Antonio; Portero-Otín, Manuel; Ferrer, Isidre; Requena, Jesús R

    2008-10-15

    The basic molecular underpinnings of the pathological changes that unfold in prion disease remain elusive. A key role of increased oxidative stress has been hypothesized. Given the transient nature of most intermediate molecules implicated, increased oxidative stress is better assessed by quantitating the damage it causes to macromolecules. We used mass spectrometry-based methods to measure specific products of protein oxidation, glycoxidation, and lipoxidation in brains from patients suffering from Creutzfeldt-Jakob disease and Syrian hamsters affected by scrapie. In both cases, increased amounts of glutamic and aminoadipic semialdehydes, products of metal-catalyzed oxidation, malondialdehydelysine (a product of lipoxidation), N-epsilon-carboxyethyllysine (a product of glycoxidation), and N-epsilon-carboxymethyllysine (generated by lipoxidation and glycoxidation) were measured. PrP(Sc), the infectious isoform of the prion protein that accumulates in prion disease, was itself shown to be a target of increased oxidative modification. These changes were accompanied by alterations in fatty acid composition and increased phosphorylation of ERK(1/2) and p38, protein kinases known to respond to increased flows of ROS. These data support an important role of oxidative damage in the pathology of prion disease.

  12. Metabolomics of human brain aging and age-related neurodegenerative diseases.

    Science.gov (United States)

    Jové, Mariona; Portero-Otín, Manuel; Naudí, Alba; Ferrer, Isidre; Pamplona, Reinald

    2014-07-01

    Neurons in the mature human central nervous system (CNS) perform a wide range of motor, sensory, regulatory, behavioral, and cognitive functions. Such diverse functional output requires a great diversity of CNS neuronal and non-neuronal populations. Metabolomics encompasses the study of the complete set of metabolites/low-molecular-weight intermediates (metabolome), which are context-dependent and vary according to the physiology, developmental state, or pathologic state of the cell, tissue, organ, or organism. Therefore, the use of metabolomics can help to unravel the diversity-and to disclose the specificity-of metabolic traits and their alterations in the brain and in fluids such as cerebrospinal fluid and plasma, thus helping to uncover potential biomarkers of aging and neurodegenerative diseases. Here, we review the current applications of metabolomics in studies of CNS aging and certain age-related neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis. Neurometabolomics will increase knowledge of the physiologic and pathologic functions of neural cells and will place the concept of selective neuronal vulnerability in a metabolic context.

  13. Neuropsychological profile of Parkinson's disease patients selected for deep brain stimulation surgery

    Directory of Open Access Journals (Sweden)

    Flavia Amaral Machado

    Full Text Available ABSTRACT Background: Parkinson's disease (PD shows symptoms involving motor and non-motor complications, including cognitive and behavioral changes, such changes might to contraindicate deep brain stimulation surgery (DBS. Objective: The aim of study was to investigate the neuropsychological profile of patients with PD in a waiting list for DBS. Methods: The neuropsychological evaluation was held in 30 patients of the ISCMPA Movement Disorders Clinic, with surgical indication based on the criteria of the responsible neurologists, in the period of 12 months. Instruments used: MMSE, FAB, MoCA, BDI, Semantic Verbal Fluency, PDQ-39, PDSS; and the UPDRS and Hoehn-Yahr scale. Results: The patients were mostly male (66.7% with a mean age of 59.37 (SD 10.60 and disease duration 9.33 (SD 4.08. There was cognitive impairment in 56.7% of patients by FAB and 76.7% by MoCA. Conclusion: Even in the earliest stages of the disease, there is the incidence of non-motor symptoms, especially in those subjects who had an early onset of the disease.

  14. DNA methylation map of mouse and human brain identifies target genes in Alzheimer’s disease

    Science.gov (United States)

    Sanchez-Mut, Jose V.; Aso, Ester; Panayotis, Nicolas; Lott, Ira; Dierssen, Mara; Rabano, Alberto; Urdinguio, Rocio G.; Fernandez, Agustin F.; Astudillo, Aurora; Martin-Subero, Jose I.; Balint, Balazs; Fraga, Mario F.; Gomez, Antonio; Gurnot, Cecile; Roux, Jean-Christophe; Avila, Jesus; Hensch, Takao K.; Ferrer, Isidre

    2013-01-01

    The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer’s disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5’-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer’s disease. We were able to translate these findings to patients with Alzheimer’s disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease. PMID:24030951

  15. Importance of the Brain Angiotensin System in Parkinson’s Disease

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    John W. Wright

    2012-01-01

    Full Text Available Parkinson’s disease (PD has become a major health problem affecting 1.5% of the world’s population over 65 years of age. As life expectancy has increased so has the occurrence of PD. The primary direct consequence of this disease is the loss of dopaminergic (DA neurons in the substantia nigra and striatum. As the intensity of motor dysfunction increases, the symptomatic triad of bradykinesia, tremors-at-rest, and rigidity occur. Progressive neurodegeneration may also impact non-DA neurotransmitter systems including cholinergic, noradrenergic, and serotonergic, often leading to the development of depression, sleep disturbances, dementia, and autonomic nervous system failure. L-DOPA is the most efficacious oral delivery treatment for controlling motor symptoms; however, this approach is ineffective regarding nonmotor symptoms. New treatment strategies are needed designed to provide neuroprotection and encourage neurogenesis and synaptogenesis to slow or reverse this disease process. The hepatocyte growth factor (HGF/c-Met receptor system is a member of the growth factor family and has been shown to protect against degeneration of DA neurons in animal models. Recently, small angiotensin-based blood-brain barrier penetrant mimetics have been developed that activate this HGF/c-Met system. These compounds may offer a new and novel approach to the treatment of Parkinson’s disease.

  16. Brain Basics

    Medline Plus

    Full Text Available ... depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are the basic working unit of ... but sometimes give rise to disabilities or diseases. neural circuit —A network of neurons and their interconnections. ...

  17. Alteration of brain insulin and leptin signaling promotes energy homeostasis impairment and neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Taouis Mohammed

    2011-09-01

    Full Text Available The central nervous system (CNS controls vital functions, by efficiently coordinating peripheral and central cascades of signals and networks in a coordinated manner. Historically, the brain was considered to be an insulin-insensitive tissue. But, new findings demonstrating that insulin is present in different regions of themammalian brain, in particular the hypothalamus and the hippocampus. Insulin acts through specific receptors and dialogues with numerous peptides, neurotransmitters and adipokines such as leptin. The cross-talk between leptin and insulin signaling pathways at the hypothalamic level is clearly involved in the control of energy homeostasis. Both hormones are anorexigenic through their action on hypothalamic arcuate nucleus by inducing the expression of anorexigenic neuropetides such as POMC (pro-opiomelanocortin, the precursor of aMSH and reducing the expression of orexigenic neuropeptide such as NPY (Neuropeptide Y. Central defect of insulin and leptin signaling predispose to obesity (leptin-resistant state and type-2 diabetes (insulin resistant state. Obesity and type-2 diabetes are associated to deep alterations in energy homeostasis control but also to other alterations of CNS functions as the predisposition to neurodegenerative diseases such as Alzheimer’s disease (AD. AD is a neurodegenerative disorder characterized by distinct hallmarks within the brain. Postmortem observation of AD brains showed the presence of parenchymal plaques due to the accumulation of the amyloid beta (AB peptide and neurofibrillary tangles. These accumulations result from the hyperphosphorylation of tau (a mictrotubule-interacting protein. Both insulin and leptin have been described to modulate tau phosphorylation and therefore in leptin and insulin resistant states may contribute to AD. The concentrations of leptin and insulin cerebrospinal fluid are decreased type2 diabetes and obese patients. In addition, the concentration of insulin in the

  18. The hunt for brain Aβ oligomers by peripherally circulating multi-functional nanoparticles: Potential therapeutic approach for Alzheimer disease.

    Science.gov (United States)

    Mancini, Simona; Minniti, Stefania; Gregori, Maria; Sancini, Giulio; Cagnotto, Alfredo; Couraud, Pierre-Olivier; Ordóñez-Gutiérrez, Lara; Wandosell, Francisco; Salmona, Mario; Re, Francesca

    2016-01-01

    We previously showed the ability of liposomes bi-functionalized with phosphatidic acid and an ApoE-derived peptide (mApoE-PA-LIP) to reduce brain Aβ in transgenic Alzheimer mice. Herein we investigated the efficacy of mApoE-PA-LIP to withdraw Aβ peptide in different aggregation forms from the brain, using a transwell cellular model of the blood-brain barrier and APP/PS1 mice. The spontaneous efflux of Aβ oligomers (Aβo), but not of Aβ fibrils, from the 'brain' side of the transwell was strongly enhanced (5-fold) in presence of mApoE-PA-LIP in the 'blood' compartment. This effect is due to a withdrawal of Aβo exerted by peripheral mApoE-PA-LIP by sink effect, because, when present in the brain side, they did not act as Aβo carrier and limit the oligomer efflux. In vivo peripheral administration of mApoE-PA-LIP significantly increased the plasma Aβ level, suggesting that Aβ-binding particles exploiting the sink effect can be used as a therapeutic strategy for Alzheimer disease. From the Clinical Editor: Alzheimer disease (AD) at present is an incurable disease, which is thought to be caused by an accumulation of amyloid-β (Aβ) peptides in the brain. Many strategies in combating this disease have been focused on either the prevention or dissolving these peptides. In this article, the authors showed the ability of liposomes bi-functionalized with phosphatidic acid and with an ApoE- derived peptide to withdraw amyloid peptides from the brain. The data would help the future design of more novel treatment for Alzheimer disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. A role for the brain RAS in Alzheimer's and Parkinson's diseases

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    John William Wright

    2013-10-01

    Full Text Available The brain renin-angiotensin system (RAS has available the necessary functional components to produce the active ligands angiotensins II, III, IV, angiotensin (1-7, and angiotensin (3-7. These ligands interact with several receptor proteins including AT1, AT2, AT4 and Mas distributed within the central and peripheral nervous systems as well as local RASs in several organs. This review first describes the enzymatic pathways in place to synthesize these ligands and the binding characteristics of these angiotensin receptor subtypes. We next discuss current hypotheses to explain the disorders of Alzheimer’s disease (AD and Parkinson’s disease (PD, as well as research efforts focused on the use of angiotensin converting enzyme (ACE inhibitors and angiotensin receptor blockers (ARBs, in their treatment. ACE inhibitors and ARBs are showing promise in the treatment of several neurodegenerative pathologies; however, there is a need for the development of analogues capable of penetrating the blood-brain barrier and acting as agonists or antagonists at these receptor sites. Angiotensins II (AngII and IV (Ang(IV have been shown to play opposing roles regarding memory acquisition and consolidation in animal models. We discuss the development of efficacious AngIV analogues in the treatment of animal models of AD and PD. These AngIV analogues act via the AT4 receptor subtype which may coincide with the hepatocyte growth factor (HGF/c-Met receptor system. Finally, future research directions are described concerning new approaches to the treatment of these two neurological diseases.

  20. Microvascular pathology and morphometrics of sporadic and hereditary small vessel diseases of the brain.

    Science.gov (United States)

    Craggs, Lucinda J L; Yamamoto, Yumi; Deramecourt, Vincent; Kalaria, Raj N

    2014-09-01

    Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology. © 2014 International Society of Neuropathology.

  1. A Prospective Pilot Trial for Pallidal Deep Brain Stimulation in Huntington's Disease.

    Science.gov (United States)

    Wojtecki, Lars; Groiss, Stefan J; Ferrea, Stefano; Elben, Saskia; Hartmann, Christian J; Dunnett, Stephen B; Rosser, Anne; Saft, Carsten; Südmeyer, Martin; Ohmann, Christian; Schnitzler, Alfons; Vesper, Jan

    2015-01-01

    Movement disorders in Huntington's disease are often medically refractive. The aim of the trial was assessment of procedure safety of deep brain stimulation, equality of internal- and external-pallidal stimulation and efficacy followed-up for 6 months in a prospective pilot trial. In a controlled double-blind phase six patients (four chorea-dominant, two Westphal-variant) with predominant movement disorder were randomly assigned to either the sequence of 6-week internal- or 6-week external-pallidal stimulation, or vice versa, followed by further 3 months chronic pallidal stimulation at the target with best effect-side-effect ratio. Primary endpoints were changes in the Unified Huntington's Disease Rating Scale motor-score, chorea subscore, and total motor-score 4 (blinded-video ratings), comparing internal- versus external-pallidal stimulation, and 6 months versus baseline. Secondary endpoints assessed scores on dystonia, hypokinesia, cognition, mood, functionality/disability, and quality-of-life. Intention-to-treat analysis of all patients (n = 3 in each treatment sequence): Both targets were equal in terms of efficacy. Chorea subscores decreased significantly over 6 months (-5.3 (60.2%), p = 0.037). Effects on dystonia were not significant over the group due to it consisting of three responders (>50% improvement) and three non-responders. Westphal patients did not improve. Cognition was stable. Mood and some functionality/disability and quality-of-life scores improved significantly. Eight adverse events and two additional serious adverse events - mostly internal-pallidal stimulation-related - resolved without sequalae. No procedure-related complications occurred. Pallidal deep brain stimulation was demonstrated to be a safe treatment option for the reduction of chorea in Huntington's disease. Their effects on chorea and dystonia and on quality-of-life should be examined in larger controlled trials.

  2. Metastatic brain cancer: prediction of response to whole-brain helical tomotherapy with simultaneous intralesional boost for metastatic disease using quantitative MR imaging features

    Science.gov (United States)

    Sharma, Harish; Bauman, Glenn; Rodrigues, George; Bartha, Robert; Ward, Aaron

    2014-03-01

    The sequential application of whole brain radiotherapy (WBRT) and more targeted stereotactic radiosurgery (SRS) is frequently used to treat metastatic brain tumors. However, SRS has side effects related to necrosis and edema, and requires separate and relatively invasive localization procedures. Helical tomotherapy (HT) allows for a SRS-type simultaneous infield boost (SIB) of multiple brain metastases, synchronously with WBRT and without separate stereotactic procedures. However, some patients' tumors may not respond to HT+SIB, and would be more appropriately treated with radiosurgery or conventional surgery despite the additional risks and side effects. As a first step toward a broader objective of developing a means for response prediction to HT+SIB, the goal of this study was to investigate whether quantitative measurements of tumor size and appearance (including first- and second-order texture features) on a magnetic resonance imaging (MRI) scan acquired prior to treatment could be used to differentiate responder and nonresponder patient groups after HT+SIB treatment of metastatic disease of the brain. Our results demonstrated that smaller lesions may respond better to this form of therapy; measures of appearance provided limited added value over measures of size for response prediction. With further validation on a larger data set, this approach may lead to a means for prediction of individual patient response based on pre-treatment MRI, supporting appropriate therapy selection for patients with metastatic brain cancer.

  3. Towards a Pathway Inventory of the Human Brain for Modeling Disease Mechanisms Underlying Neurodegeneration.

    Science.gov (United States)

    Iyappan, Anandhi; Gündel, Michaela; Shahid, Mohammad; Wang, Jiali; Li, Hui; Mevissen, Heinz-Theodor; Müller, Bernd; Fluck, Juliane; Jirsa, Viktor; Domide, Lia; Younesi, Erfan; Hofmann-Apitius, Martin

    2016-04-12

    Molecular signaling pathways have been long used to demonstrate interactions among upstream causal molecules and downstream biological effects. They show the signal flow between cell compartments, the majority of which are represented as cartoons. These are often drawn manually by scanning through the literature, which is time-consuming, static, and non-interoperable. Moreover, these pathways are often devoid of context (condition and tissue) and biased toward certain disease conditions. Mining the scientific literature creates new possibilities to retrieve pathway information at higher contextual resolution and specificity. To address this challenge, we have created a pathway terminology system by combining signaling pathways and biological events to ensure a broad coverage of the entire pathway knowledge domain. This terminology was applied to mining biomedical papers and patents about neurodegenerative diseases with focus on Alzheimer's disease. We demonstrate the power of our approach by mapping literature-derived signaling pathways onto their corresponding anatomical regions in the human brain under healthy and Alzheimer's disease states. We demonstrate how this knowledge resource can be used to identify a putative mechanism explaining the mode-of-action of the approved drug Rasagiline, and show how this resource can be used for fingerprinting patents to support the discovery of pathway knowledge for Alzheimer's disease. Finally, we propose that based on next-generation cause-and-effect pathway models, a dedicated inventory of computer-processable pathway models specific to neurodegenerative diseases can be established, which hopefully accelerates context-specific enrichment analysis of experimental data with higher resolution and richer annotations.

  4. Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous L-DOPA in a unilateral rat model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Ravenstijn Paulien GM

    2012-02-01

    Full Text Available Abstract Background Changes in blood-brain barrier (BBB functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both control and diseased cerebral hemispheres in the unilateral rat rotenone model of Parkinson's disease. Methods In Lewis rats,