Science.gov

Sample records for alzheimer disease brains

  1. Brain Imaging in Alzheimer Disease

    PubMed Central

    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

  2. Brain imaging in Alzheimer disease.

    PubMed

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

    2012-04-01

    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.

  3. Brain Stimulation in Alzheimer's Disease.

    PubMed

    Fried, Itzhak

    2016-09-06

    Deep brain stimulation has been successfully used in treatment of motor symptoms of Parkinson's disease and other movement disorders. In a recent multi-center prospectively randomized study, deep brain stimulation of the fornix was administered in order to ameliorate the cognitive symptoms and clinical course of Alzheimer's disease (AD). The study points to the possibility of modest slowing of the cognitive decline in AD in a subset of patients older than 65, while at the same time highlights the risk of stimulation in exacerbation of this decline in younger patients. The logic of conducting large clinical trials in the face of limited scientific understanding of the pathophysiology of AD and response of affected brain regions to electrical stimulation, is discussed with emphasis on the need to conduct: (i) animal studies in AD models, using precise focused stimulation; (ii) studies in patients who are implanted with depth electrodes for established clinical reasons (i.e., patients with epilepsy or movement disorders); and (iii) smaller adaptive studies in AD patients with systematic alterations of therapeutic parameters such as stimulation protocol.

  4. Physical activity, brain plasticity, and Alzheimer's disease.

    PubMed

    Erickson, Kirk I; Weinstein, Andrea M; Lopez, Oscar L

    2012-11-01

    In this review we summarize the epidemiological, cross-sectional, and interventional studies examining the association between physical activity and brain volume, function, and risk for Alzheimer's disease. The epidemiological literature provides compelling evidence that greater amounts of physical activity are associated with a reduced risk of dementia in late life. In addition, randomized interventions using neuroimaging tools have reported that participation in physical activity increases the size of prefrontal and hippocampal brain areas, which may lead to a reduction in memory impairments. Consistent with these findings, longitudinal studies using neuroimaging tools also find that the volume of prefrontal and hippocampal brain areas are larger in individuals who engaged in more physical activity earlier in life. We conclude from this review that there is convincing evidence that physical activity has a consistent and robust association with brain regions implicated in age-related cognitive decline and Alzheimer's disease. In addition to summarizing this literature we provide recommendations for future research on physical activity and brain health. Copyright © 2012 IMSS. Published by Elsevier Inc. All rights reserved.

  5. Metabolic profiling of Alzheimer's disease brains

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed

    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).

  7. Alzheimer disease

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000760.htm Alzheimer disease To use the sharing features on this page, ... of brain function that occurs with certain diseases. Alzheimer disease is one form of dementia. It affects memory, ...

  8. Brain PET in the diagnosis of Alzheimer's disease.

    PubMed

    Marcus, Charles; Mena, Esther; Subramaniam, Rathan M

    2014-10-01

    The aim of this article was to review the current role of brain PET in the diagnosis of Alzheimer dementia. The characteristic patterns of glucose metabolism on brain FDG-PET can help in differentiating Alzheimer's disease from other causes of dementia such as frontotemporal dementia and dementia of Lewy body. Amyloid brain PET may exclude significant amyloid deposition and thus Alzheimer's disease in appropriate clinical setting. FDG-PET and amyloid PET imaging are valuable in the assessment of patients with Alzheimer's disease.

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

    PubMed

    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.

  10. The blood brain barrier in Alzheimer's disease.

    PubMed

    Chakraborty, A; de Wit, N M; van der Flier, W M; de Vries, H E

    2017-02-01

    Alzheimer's disease (AD) is the most common form of dementia, affecting millions of people worldwide. One of the prominent causative factors of AD pathogenesis is cerebral vascular dysfunction, which results in diminished cerebral perfusion. Moreover, due to the loss of the protective function of the blood-brain barrier (BBB), impaired clearance of excess neurotoxic amyloid beta (Aβ) occurs, causing vascular perturbation and diminished cognitive functioning. The relationship between the prevalence of AD and vascular risk factors is complex and not fully understood. In this review we illustrate the vascular risk factors, their effects on BBB function and their contributions to the onset of AD. Additionally, we discuss the underlying factors that may lead to altered neurovascular function and/or cerebral hypoperfusion in AD. Copyright © 2016 Elsevier Inc. All rights reserved.

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

    PubMed

    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.

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

    PubMed

    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

  13. Evidence for a membrane defect in Alzheimer disease brain.

    PubMed Central

    Nitsch, R M; Blusztajn, J K; Pittas, A G; Slack, B E; Growdon, J H; Wurtman, R J

    1992-01-01

    To determine whether neurodegeneration in Alzheimer disease brain is associated with degradation of structural cell membrane molecules, we measured tissue levels of the major membrane phospholipids and their metabolites in three cortical areas from postmortem brains of Alzheimer disease patients and matched controls. Among phospholipids, there was a significant (P less than 0.05) decrease in phosphatidylcholine and phosphatidylethanolamine. There were significant (P less than 0.05) decreases in the initial phospholipid precursors choline and ethanolamine and increases in the phospholipid deacylation product glycerophosphocholine. The ratios of glycerophosphocholine to choline and glycerophosphoethanolamine to ethanolamine were significantly increased in all examined Alzheimer disease brain regions. The activity of the glycerophosphocholine-degrading enzyme glycerophosphocholine choline-phosphodiesterase was normal in Alzheimer disease brain. There was a near stoichiometric relationship between the decrease in phospholipids and the increase of phospholipid catabolites. These data are consistent with increased membrane phospholipid degradation in Alzheimer disease brain. Similar phospholipid abnormalities were not detected in brains of patients with Huntington disease, Parkinson disease, or Down syndrome. We conclude that the phospholipid abnormalities described here are not an epiphenomenon of neurodegeneration and that they may be specific for the pathomechanism of Alzheimer disease. PMID:1311847

  14. Evidence for a membrane defect in Alzheimer disease brain

    NASA Technical Reports Server (NTRS)

    Nitsch, R. M.; Blusztajn, J. K.; Pittas, A. G.; Slack, B. E.; Growdon, J. H.; Wurtman, R. J.

    1992-01-01

    To determine whether neurodegeneration in Alzheimer disease brain is associated with degradation of structural cell membrane molecules, we measured tissue levels of the major membrane phospholipids and their metabolites in three cortical areas from postmortem brains of Alzheimer disease patients and matched controls. Among phospholipids, there was a significant (P less than 0.05) decrease in phosphatidylcholine and phosphatidylethanolamine. There were significant (P less than 0.05) decreases in the initial phospholipid precursors choline and ethanolamine and increases in the phospholipid deacylation product glycerophosphocholine. The ratios of glycerophosphocholine to choline and glycerophosphoethanolamine to ethanolamine were significantly increased in all examined Alzheimer disease brain regions. The activity of the glycerophosphocholine-degrading enzyme glycerophosphocholine choline-phosphodiesterase was normal in Alzheimer disease brain. There was a near stoichiometric relationship between the decrease in phospholipids and the increase of phospholipid catabolites. These data are consistent with increased membrane phospholipid degradation in Alzheimer disease brain. Similar phospholipid abnormalities were not detected in brains of patients with Huntington disease, Parkinson disease, or Down syndrome. We conclude that the phospholipid abnormalities described here are not an epiphenomenon of neurodegeneration and that they may be specific for the pathomechanism of Alzheimer disease.

  15. Evidence for a membrane defect in Alzheimer disease brain

    NASA Technical Reports Server (NTRS)

    Nitsch, R. M.; Blusztajn, J. K.; Pittas, A. G.; Slack, B. E.; Growdon, J. H.; Wurtman, R. J.

    1992-01-01

    To determine whether neurodegeneration in Alzheimer disease brain is associated with degradation of structural cell membrane molecules, we measured tissue levels of the major membrane phospholipids and their metabolites in three cortical areas from postmortem brains of Alzheimer disease patients and matched controls. Among phospholipids, there was a significant (P less than 0.05) decrease in phosphatidylcholine and phosphatidylethanolamine. There were significant (P less than 0.05) decreases in the initial phospholipid precursors choline and ethanolamine and increases in the phospholipid deacylation product glycerophosphocholine. The ratios of glycerophosphocholine to choline and glycerophosphoethanolamine to ethanolamine were significantly increased in all examined Alzheimer disease brain regions. The activity of the glycerophosphocholine-degrading enzyme glycerophosphocholine choline-phosphodiesterase was normal in Alzheimer disease brain. There was a near stoichiometric relationship between the decrease in phospholipids and the increase of phospholipid catabolites. These data are consistent with increased membrane phospholipid degradation in Alzheimer disease brain. Similar phospholipid abnormalities were not detected in brains of patients with Huntington disease, Parkinson disease, or Down syndrome. We conclude that the phospholipid abnormalities described here are not an epiphenomenon of neurodegeneration and that they may be specific for the pathomechanism of Alzheimer disease.

  16. Brain injury, neuroinflammation and Alzheimer's disease

    PubMed Central

    Breunig, Joshua J.; Guillot-Sestier, Marie-Victoire; Town, Terrence

    2013-01-01

    With as many as 300,000 United States troops in Iraq and Afghanistan having suffered head injuries (Miller, 2012), traumatic brain injury (TBI) has garnered much recent attention. While the cause and severity of these injuries is variable, severe cases can lead to lifelong disability or even death. While aging is the greatest risk factor for Alzheimer's disease (AD), it is now becoming clear that a history of TBI predisposes the individual to AD later in life (Sivanandam and Thakur, 2012). In this review article, we begin by defining hallmark pathological features of AD and the various forms of TBI. Putative mechanisms underlying the risk relationship between these two neurological disorders are then critically considered. Such mechanisms include precipitation and ‘spreading’ of cerebral amyloid pathology and the role of neuroinflammation. The combined problems of TBI and AD represent significant burdens to public health. A thorough, mechanistic understanding of the precise relationship between TBI and AD is of utmost importance in order to illuminate new therapeutic targets. Mechanistic investigations and the development of preclinical therapeutics are reliant upon a clearer understanding of these human diseases and accurate modeling of pathological hallmarks in animal systems. PMID:23874297

  17. Brain injury, neuroinflammation and Alzheimer's disease.

    PubMed

    Breunig, Joshua J; Guillot-Sestier, Marie-Victoire; Town, Terrence

    2013-01-01

    With as many as 300,000 United States troops in Iraq and Afghanistan having suffered head injuries (Miller, 2012), traumatic brain injury (TBI) has garnered much recent attention. While the cause and severity of these injuries is variable, severe cases can lead to lifelong disability or even death. While aging is the greatest risk factor for Alzheimer's disease (AD), it is now becoming clear that a history of TBI predisposes the individual to AD later in life (Sivanandam and Thakur, 2012). In this review article, we begin by defining hallmark pathological features of AD and the various forms of TBI. Putative mechanisms underlying the risk relationship between these two neurological disorders are then critically considered. Such mechanisms include precipitation and 'spreading' of cerebral amyloid pathology and the role of neuroinflammation. The combined problems of TBI and AD represent significant burdens to public health. A thorough, mechanistic understanding of the precise relationship between TBI and AD is of utmost importance in order to illuminate new therapeutic targets. Mechanistic investigations and the development of preclinical therapeutics are reliant upon a clearer understanding of these human diseases and accurate modeling of pathological hallmarks in animal systems.

  18. Therapeutic Noninvasive Brain Stimulation in Alzheimer's Disease.

    PubMed

    Gonsalvez, Irene; Baror, Roey; Fried, Peter; Santarnecchi, Emiliano; Pascual-Leone, Alvaro

    2017-01-01

    Alzheimer's disease (AD) is a looming public health crisis that currently lacks an effective treatment. Noninvasive Brain Stimulation (NBS), particularly transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), offers a promising alternative approach to pharmacological interventions for an increasing number of neurological and psychiatric conditions. The aim of this review is summarize data from therapeutic trials of NBS in AD and other dementing illnesses. Despite the potential of NBS, there is limited theoretical framework and a lack of guidelines for its applications to AD. Several published clinical trials failed to report key parameters of the interventions thus limiting the utility of the study to assess efficacy and safety. Our review concludes with some suggestions for future studies aimed to advance research into NBS as a potential treatment for the symptoms and disabilities caused by AD and to enable comparison of results across trials. Ultimately, appropriately powered, and controlled, multi-site randomized clinical trials will be needed to evaluate the therapeutic potential of NBS in AD.

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

    PubMed

    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.

  20. The rationale for deep brain stimulation in Alzheimer's disease.

    PubMed

    Mirzadeh, Zaman; Bari, Ausaf; Lozano, Andres M

    2016-07-01

    Alzheimer's disease is a major worldwide health problem with no effective therapy. Deep brain stimulation (DBS) has emerged as a useful therapy for certain movement disorders and is increasingly being investigated for treatment of other neural circuit disorders. Here we review the rationale for investigating DBS as a therapy for Alzheimer's disease. Phase I clinical trials of DBS targeting memory circuits in Alzheimer's disease patients have shown promising results in clinical assessments of cognitive function, neurophysiological tests of cortical glucose metabolism, and neuroanatomical volumetric measurements showing reduced rates of atrophy. These findings have been supported by animal studies, where electrical stimulation of multiple nodes within the memory circuit have shown neuroplasticity through stimulation-enhanced hippocampal neurogenesis and improved performance in memory tasks. The precise mechanisms by which DBS may enhance memory and cognitive functions in Alzheimer's disease patients and the degree of its clinical efficacy continue to be examined in ongoing clinical trials.

  1. Antibodies to human brain spectrin in Alzheimer's disease.

    PubMed

    Vázquez, J; Fernández-Shaw, C; Marina, A; Haas, C; Cacabelos, R; Valdivieso, F

    1996-08-01

    We investigated the existence of antibodies in sera of Alzheimer's disease patients which immunoreact with specific antigens from crude human brain extracts. We found that 49% of patients, per only 5% of control subjects, had increased levels of antibodies to a 240 kDa protein. On the basis of immunological criteria and internal amino acid sequencing, this antigen was identified as brain spectrin, a cytoskeletal protein which appears to be implicated in synaptic plasticity. Our data raises the possibility that anti-spectrin antibodies could be implicated in Alzheimer's disease pathogenesis.

  2. CARS microscopy of Alzheimer's diseased brain tissue

    NASA Astrophysics Data System (ADS)

    Enejder, Annika; Kiskis, Juris; Fink, Helen; Nyberg, Lena; Thyr, Jakob; Li, Jia-Yi

    2014-02-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder currently without cure, characterized by the presence of extracellular plaques surrounded by dystrophic neurites. In an effort to understand the underlying mechanisms, biochemical analysis (protein immunoblot) of plaque extracts reveals that they consist of amyloid-beta (Aβ) peptides assembled as oligomers, protofibrils and aggregates. Their spatial distribution has been confirmed by Thioflavin-S or immuno-staining with fluorescence microscopy. However, it is increasingly understood that the protein aggregation is only one of several mechanism that causes neuronal dysfunction and death. This raises the need for a more complete biochemical analysis. In this study, we have complemented 2-photon fluorescence microscopy of Thioflavin-S and Aβ immuno-stained human AD plaques with CARS microscopy. We show that the chemical build-up of AD plaques is more complex and that Aβ staining does not provide the complete picture of the spatial distribution or the molecular composition of AD plaques. CARS images provide important complementary information to that obtained by fluorescence microscopy, motivating a broader introduction of CARS microscopy in the AD research field.

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

    PubMed

    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.

  4. Alzheimer's disease.

    PubMed

    Scheltens, Philip; Blennow, Kaj; Breteler, Monique M B; de Strooper, Bart; Frisoni, Giovanni B; Salloway, Stephen; Van der Flier, Wiesje Maria

    2016-07-30

    Although the prevalence of dementia continues to increase worldwide, incidence in the western world might have decreased as a result of better vascular care and improved brain health. Alzheimer's disease, the most prevalent cause of dementia, is still defined by the combined presence of amyloid and tau, but researchers are gradually moving away from the simple assumption of linear causality as proposed in the original amyloid hypothesis. Age-related, protective, and disease-promoting factors probably interact with the core mechanisms of the disease. Amyloid β42, and tau proteins are established core cerebrospinal biomarkers; novel candidate biomarkers include amyloid β oligomers and synaptic markers. MRI and fluorodeoxyglucose PET are established imaging techniques for diagnosis of Alzheimer's disease. Amyloid PET is gaining traction in the clinical arena, but validity and cost-effectiveness remain to be established. Tau PET might offer new insights and be of great help in differential diagnosis and selection of patients for trials. In the search for understanding the disease mechanism and keys to treatment, research is moving increasingly into the earliest phase of disease. Preclinical Alzheimer's disease is defined as biomarker evidence of Alzheimer's pathological changes in cognitively healthy individuals. Patients with subjective cognitive decline have been identified as a useful population in whom to look for preclinical Alzheimer's disease. Moderately positive results for interventions targeting several lifestyle factors in non-demented elderly patients and moderately positive interim results for lowering amyloid in pre-dementia Alzheimer's disease suggest that, ultimately, there will be a future in which specific anti-Alzheimer's therapy will be combined with lifestyle interventions targeting general brain health to jointly combat the disease. In this Seminar, we discuss the main developments in Alzheimer's research.

  5. Alzheimer S Disease and Brain Development: Common Molecular Pathways

    PubMed Central

    Jordan-Sciutto, Kelly; Bowser, Robert

    2013-01-01

    Research on the causes and treatments of Alzheimer's disease (AD) has led investigators down numerous avenues. Although many models have been proposed, no single model of AD satisfactorily accounts for all neuropathologic findings as well as the requirement of aging for disease onset. The mechanisms of disease progression are equally unclear. We hypothesize that alternative gene expression during AD plays a critical role in disease progression. Numerous developmentally regulated genes and cell cycle proteins have been shown to be re-expressed or activated during AD. These proteins include transcription factors, members of the cell cycle regulatory machinery, and programmed cell death genes. Such proteins play an important role during brain development and would likely exert powerful effects if re-expressed in the adult brain. We propose that the re-expression or activation of developmentally regulated genes define molecular mechanisms active both during brain development and in AD PMID:9422711

  6. Brain hydrogen sulfide is severely decreased in Alzheimer's disease.

    PubMed

    Eto, Ko; Asada, Takashi; Arima, Kunimasa; Makifuchi, Takao; Kimura, Hideo

    2002-05-24

    Although hydrogen sulfide (H2S) is generally thought of in terms of a poisonous gas, it is endogenously produced in the brain from cysteine by cystathionine beta-synthase (CBS). H2S functions as a neuromodulator as well as a smooth muscle relaxant. Here we show that the levels of H2S are severely decreased in the brains of Alzheimer's disease (AD) patients compared with the brains of the age matched normal individuals. In addition to H2S production CBS also catalyzes another metabolic pathway in which cystathionine is produced from the substrate homocysteine. Previous findings, which showed that S-adenosyl-l-methionine (SAM), a CBS activator, is much reduced in AD brain and that homocysteine accumulates in the serum of AD patients, were confirmed. These observations suggest that CBS activity is reduced in AD brains and the decrease in H2S may be involved in some aspects of the cognitive decline in AD.

  7. Brain sex matters: estrogen in cognition and Alzheimer's disease.

    PubMed

    Li, Rena; Cui, Jie; Shen, Yong

    2014-05-25

    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.

  8. Benefits from dietary polyphenols for brain aging and Alzheimer's disease.

    PubMed

    Rossi, L; Mazzitelli, S; Arciello, M; Capo, C R; Rotilio, G

    2008-12-01

    Brain aging and the most diffused neurodegenerative diseases of the elderly are characterized by oxidative damage, redox metals homeostasis impairment and inflammation. Food polyphenols can counteract these alterations in vitro and are therefore suggested to have potential anti-aging and brain-protective activities, as also indicated by the results of some epidemiological studies. Despite the huge and increasing amount of the in vitro studies trying to unravel the mechanisms of action of dietary polyphenols, the research in this field is still incomplete, and questions about bioavailability, biotransformation, synergism with other dietary factors, mechanisms of the antioxidant activity, risks inherent to their possible pro-oxidant activities are still unanswered. Most of all, the capacity of the majority of these compounds to cross the blood-brain barrier and reach brain is still unknown. This commentary discusses recent data on these aspects, particularly focusing on effects of curcumin, resveratrol and catechins on Alzheimer's disease.

  9. Structural changes in Alzheimer's disease brain microvessels.

    PubMed

    Christov, Alexander; Ottman, J; Hamdheydari, L; Grammas, Paula

    2008-08-01

    Brain microvascular alterations are thought to contribute to the development of stroke and dementia. Structural changes in capillaries of elderly patients correlate positively with advanced age and dementia. The objective of this study is to use laser-induced fluorescence spectroscopy to compare structural (collagen content) and functional (apoptosis) parameters in brain tissues and isolated vessels of AD patients to age-matched controls. Our results show significantly higher fluorescent labeling for apoptosis in AD vessels compared to controls. Also, there is significantly higher autofluorescence (reflecting levels of collagen and other proteins that autofluoresce) in AD brain and vessels compared to controls. Western blot analysis of collagen subtypes shows elevated type I and type III and reduced type IV levels in AD vessels. These data demonstrate that changes in the amount and type of collagen occur in AD brain and suggest that cerebral vessel injury is part of AD pathology.

  10. Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia.

    PubMed

    Thompson, Paul M; Hayashi, Kiralee M; Sowell, Elizabeth R; Gogtay, Nitin; Giedd, Jay N; Rapoport, Judith L; de Zubicaray, Greig I; Janke, Andrew L; Rose, Stephen E; Semple, James; Doddrell, David M; Wang, Yalin; van Erp, Theo G M; Cannon, Tyrone D; Toga, Arthur W

    2004-01-01

    This paper describes algorithms that can identify patterns of brain structure and function associated with Alzheimer's disease, schizophrenia, normal aging, and abnormal brain development based on imaging data collected in large human populations. Extraordinary information can be discovered with these techniques: dynamic brain maps reveal how the brain grows in childhood, how it changes in disease, and how it responds to medication. Genetic brain maps can reveal genetic influences on brain structure, shedding light on the nature-nurture debate, and the mechanisms underlying inherited neurobehavioral disorders. Recently, we created time-lapse movies of brain structure for a variety of diseases. These identify complex, shifting patterns of brain structural deficits, revealing where, and at what rate, the path of brain deterioration in illness deviates from normal. Statistical criteria can then identify situations in which these changes are abnormally accelerated, or when medication or other interventions slow them. In this paper, we focus on describing our approaches to map structural changes in the cortex. These methods have already been used to reveal the profile of brain anomalies in studies of dementia, epilepsy, depression, childhood- and adult-onset schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, fetal alcohol syndrome, Tourette syndrome, Williams syndrome, and in methamphetamine abusers. Specifically, we describe an image analysis pipeline known as cortical pattern matching that helps compare and pool cortical data over time and across subjects. Statistics are then defined to identify brain structural differences between groups, including localized alterations in cortical thickness, gray matter density (GMD), and asymmetries in cortical organization. Subtle features, not seen in individual brain scans, often emerge when population-based brain data are averaged in this way. Illustrative examples are presented to show the profound

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

    PubMed

    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.

  12. Alzheimer Disease

    MedlinePlus

    ... CPR: A Real Lifesaver Kids Talk About: Coaches Alzheimer Disease KidsHealth > For Kids > Alzheimer Disease Print A ... slow it down. When Someone You Love Has Alzheimer Disease You might feel sad or angry — or ...

  13. Brain Biomarkers in Familial Alzheimer's Disease Mouse Models.

    PubMed

    Kuttner-Hirshler, Yafit; Venkatasubramanian, Palamadai N; Apolinario, Joan; Bonds, Jacqueline; Wyrwicz, Alice M; Lazarov, Orly

    2017-09-08

    Alzheimer's disease (AD) is characterized by progressive loss of memory and cognitive deterioration. It is thought that the onset of the disease takes place several decades before memory deficits are apparent. Reliable biomarkers for the diagnosis or prognostication of the disease are highly desirable. Neural stem cells (NSC) exist in the adult brain throughout life and give rise to neural progenitor cells (NPC), which differentiate into neurons or glia. The level of NPC proliferation and new neuron formation is significantly compromised in mouse models of familial Alzheimer's disease (FAD). These deficits are readily detected in young adults, at 2-3 months of age, preceding amyloid deposition and cognitive impairments, which may indicate that impaired neurogenesis can be an early biomarker for cognitive deficits in AD. Recent studies suggest that NSC can be detected in live rodents, noninvasively, using proton magnetic resonance spectroscopy (1H-MRS) at 1.28 ppm signal. Here we examined the use of 1H-MRS for determining the extent of neurogenesis in the brains of FAD mice. We observed that the reduction in neurogenesis in the FAD mice as observed by immunohistochemistry, was not manifested by a reduction in the 1.28 ppm signal, suggesting that this marker is either not specific for neurogenesis or not sensitive enough for the detection of alterations in hippocampal neurogenesis in the brains of FAD mice.

  14. Genetic variants in Alzheimer disease - molecular and brain network approaches.

    PubMed

    Gaiteri, Chris; Mostafavi, Sara; Honey, Christopher J; De Jager, Philip L; Bennett, David A

    2016-07-01

    Genetic studies in late-onset Alzheimer disease (LOAD) are aimed at identifying core disease mechanisms and providing potential biomarkers and drug candidates to improve clinical care of AD. However, owing to the complexity of LOAD, including pathological heterogeneity and disease polygenicity, extraction of actionable guidance from LOAD genetics has been challenging. Past attempts to summarize the effects of LOAD-associated genetic variants have used pathway analysis and collections of small-scale experiments to hypothesize functional convergence across several variants. In this Review, we discuss how the study of molecular, cellular and brain networks provides additional information on the effects of LOAD-associated genetic variants. We then discuss emerging combinations of these omic data sets into multiscale models, which provide a more comprehensive representation of the effects of LOAD-associated genetic variants at multiple biophysical scales. Furthermore, we highlight the clinical potential of mechanistically coupling genetic variants and disease phenotypes with multiscale brain models.

  15. Molecular mechanisms of regeneration in Alzheimer's disease brain.

    PubMed

    Uchida, Yoko

    2010-07-01

    Regenerative responses, including re-expression of developmentally regulated proteins, occur in Alzheimer's disease (AD) brain and in beta-amyloid (Abeta)-treated neuronal cultures. Brain microenvironment might also be altered by Abeta or by unknown materials in AD brain to make neurons or progenitor cells regenerative. However, these responses and alterations might not be sufficient to replace neuronal loss, but rather might act as an effecter of cell death. For instance, downregulation of growth inhibitory factor/metallothionein-III and upregulation of MAP1B result in both neurite sprouting and neuronal death. The deteriorative regulation of Mash1 and Olig2 by Abeta also leads to differentiation and death of progenitor cells. Clarifying the cell death mechanism accompanied with regenerative responses might be necessary for repairing the nervous system or slowing disease progression in AD.

  16. Different Brain Regions are Infected with Fungi in Alzheimer's Disease.

    PubMed

    Pisa, Diana; Alonso, Ruth; Rábano, Alberto; Rodal, Izaskun; Carrasco, Luis

    2015-10-15

    The possibility that Alzheimer's disease (AD) has a microbial aetiology has been proposed by several researchers. Here, we provide evidence that tissue from the central nervous system (CNS) of AD patients contain fungal cells and hyphae. Fungal material can be detected both intra- and extracellularly using specific antibodies against several fungi. Different brain regions including external frontal cortex, cerebellar hemisphere, entorhinal cortex/hippocampus and choroid plexus contain fungal material, which is absent in brain tissue from control individuals. Analysis of brain sections from ten additional AD patients reveals that all are infected with fungi. Fungal infection is also observed in blood vessels, which may explain the vascular pathology frequently detected in AD patients. Sequencing of fungal DNA extracted from frozen CNS samples identifies several fungal species. Collectively, our findings provide compelling evidence for the existence of fungal infection in the CNS from AD patients, but not in control individuals.

  17. Genetics Home Reference: Alzheimer disease

    MedlinePlus

    ... Email Facebook Twitter Home Health Conditions Alzheimer disease Alzheimer disease Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Alzheimer disease is a degenerative disease of the brain ...

  18. Brain amyloid-β oligomers in ageing and Alzheimer's disease.

    PubMed

    Lesné, Sylvain E; Sherman, Mathew A; Grant, Marianne; Kuskowski, Michael; Schneider, Julie A; Bennett, David A; Ashe, Karen H

    2013-05-01

    Alzheimer's disease begins about two decades before the onset of symptoms or neuron death, and is believed to be caused by pathogenic amyloid-β aggregates that initiate a cascade of molecular events culminating in widespread neurodegeneration. The microtubule binding protein tau may mediate the effects of amyloid-β in this cascade. Amyloid plaques comprised of insoluble, fibrillar amyloid-β aggregates are the most characteristic feature of Alzheimer's disease. However, the correspondence between the distribution of plaques and the pattern of neurodegeneration is tenuous. This discrepancy has stimulated the investigation of other amyloid-β aggregates, including soluble amyloid-β oligomers. Different soluble amyloid-β oligomers have been studied in several mouse models, but not systematically in humans. Here, we measured three amyloid-β oligomers previously described in mouse models-amyloid-β trimers, Aβ*56 and amyloid-β dimers-in brain tissue from 75 cognitively intact individuals, ranging from young children to the elderly, and 58 impaired subjects with mild cognitive impairment or probable Alzheimer's disease. As in mouse models, where amyloid-β trimers appear to be the fundamental amyloid-β assembly unit of Aβ*56 and are present in young mice prior to memory decline, amyloid-β trimers in humans were present in children and adolescents; their levels rose gradually with age and were significantly above baseline in subjects in their 70s. Aβ*56 levels were negligible in children and young adults, rose significantly above baseline in subjects in their 40s and increased steadily thereafter. Amyloid-β dimers were undetectable until subjects were in their 60s; their levels then increased sharply and correlated with plaque load. Remarkably, in cognitively intact individuals we found strong positive correlations between Aβ*56 and two pathological forms of soluble tau (tau-CP13 and tau-Alz50), and negative correlations between Aβ*56 and two postsynaptic

  19. Converging perturbed microvasculature and microglial clusters characterize Alzheimer disease brain.

    PubMed

    Jantaratnotai, N; Schwab, C; Ryu, J K; McGeer, P L; McLarnon, J G

    2010-11-01

    We have investigated physical properties of microvasculature and vessel association with microglial clusters in cortical tissue from Alzheimer disease individuals, classified as severe (ADsev) or mild (ADmild), and nondemented controls (ND). Immunostaining with laminin or von Willerbrand factor demonstrated numbers of microvessels and microvascular density were significantly higher in ADsev cases compared with levels in ADmild or ND cases suggesting proangiogenic activity in ADsev brain. Evidence for extravascular laminin immunoreactivity was found in ADsev tissue and was largely absent in ADmild and ND cases suggesting vascular remodeling in ADsev brain included abnormalities in blood vessels. Microgliosis was progressively increased from ND to ADmild to ADsev with the latter demonstrating areas of clustered microglia (groupings of three or more cells) rarely observed in ADmild or ND cases. Microglial clusters in ADsev brain were in close proximity with extravascular laminin and also plasma protein, fibrinogen, implicating vascular perturbation as a component of inflammatory reactivity. ADsev brain also exhibited elevated levels of the pro-inflammatory/angiogenic factors tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) in association, relative to non-association, with microglial clusters. The presence of extravascular laminin and fibrinogen and the vascular modifying factors, TNF-α and VEGF in localization with clusters of activated microglia, is consistent with microglial-induced vascular remodeling in ADsev brain. Microglial-vascular reciprocal interactions could serve a critical role in the amplification and perpetuation of inflammatory reactivity in AD brain.

  20. Brain-targeted proanthocyanidin metabolites for Alzheimer's disease treatment.

    PubMed

    Wang, Jun; Ferruzzi, Mario G; Ho, Lap; Blount, Jack; Janle, Elsa M; Gong, Bing; Pan, Yong; Gowda, G A Nagana; Raftery, Daniel; Arrieta-Cruz, Isabel; Sharma, Vaishali; Cooper, Bruce; Lobo, Jessica; Simon, James E; Zhang, Chungfen; Cheng, Alice; Qian, Xianjuan; Ono, Kenjiro; Teplow, David B; Pavlides, Constantine; Dixon, Richard A; Pasinetti, Giulio M

    2012-04-11

    While polyphenolic compounds have many health benefits, the potential development of polyphenols for the prevention/treatment of neurological disorders is largely hindered by their complexity as well as by limited knowledge regarding their bioavailability, metabolism, and bioactivity, especially in the brain. We recently demonstrated that dietary supplementation with a specific grape-derived polyphenolic preparation (GP) significantly improves cognitive function in a mouse model of Alzheimer's disease (AD). GP is comprised of the proanthocyanidin (PAC) catechin and epicatechin in monomeric (Mo), oligomeric, and polymeric forms. In this study, we report that following oral administration of the independent GP forms, only Mo is able to improve cognitive function and only Mo metabolites can selectively reach and accumulate in the brain at a concentration of ∼400 nM. Most importantly, we report for the first time that a biosynthetic epicatechin metabolite, 3'-O-methyl-epicatechin-5-O-β-glucuronide (3'-O-Me-EC-Gluc), one of the PAC metabolites identified in the brain following Mo treatment, promotes basal synaptic transmission and long-term potentiation at physiologically relevant concentrations in hippocampus slices through mechanisms associated with cAMP response element binding protein (CREB) signaling. Our studies suggest that select brain-targeted PAC metabolites benefit cognition by improving synaptic plasticity in the brain, and provide impetus to develop 3'-O-Me-EC-Gluc and other brain-targeted PAC metabolites to promote learning and memory in AD and other forms of dementia.

  1. Oligomeric Neuronal Protein Aggregates as Biomarkers for Traumatic Brain Injury (TBI) and Alzheimer Disease (AD)

    DTIC Science & Technology

    2013-10-01

    as Biomarkers for Traumatic Brain Injury (TBI) and Alzheimer Disease (AD) PRINCIPAL INVESTIGATOR: Michael Sierks CONTRACTING...Oligomeric Neuronal Protein Aggregates as Biomarkers for Traumatic Brain Injury (TBI) and Alzheimer Disease (AD) 5b. GRANT NUMBER 12109023 5c...AD so treatment can begin early and the effectiveness of the treatments can be monitored. Major Findings: We have essentially finished development

  2. Mouse brain magnetic resonance microscopy: Applications in Alzheimer disease.

    PubMed

    Lin, Lan; Fu, Zhenrong; Xu, Xiaoting; Wu, Shuicai

    2015-05-01

    Over the past two decades, various Alzheimer's disease (AD) trangenetic mice models harboring genes with mutation known to cause familial AD have been created. Today, high-resolution magnetic resonance microscopy (MRM) technology is being widely used in the study of AD mouse models. It has greatly facilitated and advanced our knowledge of AD. In this review, most of the attention is paid to fundamental of MRM, the construction of standard mouse MRM brain template and atlas, the detection of amyloid plaques, following up on brain atrophy and the future applications of MRM in transgenic AD mice. It is believed that future testing of potential drugs in mouse models with MRM will greatly improve the predictability of drug effect in preclinical trials. © 2015 Wiley Periodicals, Inc.

  3. Free radical damage to cerebral cortex in Alzheimer's disease, microvascular brain injury, and smoking.

    PubMed

    Sonnen, Joshua A; Larson, Eric B; Gray, Shelly L; Wilson, Angela; Kohama, Steven G; Crane, Paul K; Breitner, John C S; Montine, Thomas J

    2009-02-01

    Evidence supports a pathogenic role for free radical injury to brain in Alzheimer's disease; however, clinical trial results are only mildly encouraging. Examining brains from The Adult Changes in Thought study offers a unique perspective. Selectively increased free radical damage to cerebral cortex was associated with Alzheimer's disease, microvascular brain injury, and current smoking, but not with antioxidant supplement usage. Our results support suppression of free radical injury to brain as a therapeutic target for Alzheimer's disease and microvascular brain injury; however, future clinical trials should consider other antioxidants or doses than those identified in our study.

  4. Loss of functional GABAA receptors in the Alzheimer diseased brain

    PubMed Central

    Limon, Agenor; Reyes-Ruiz, Jorge Mauricio; Miledi, Ricardo

    2012-01-01

    The cholinergic and glutamatergic neurotransmission systems are known to be severely disrupted in Alzheimer's disease (AD). GABAergic neurotransmission, in contrast, is generally thought to be well preserved. Evidence from animal models and human postmortem tissue suggest GABAergic remodeling in the AD brain. Nevertheless, there is no information on changes, if any, in the electrophysiological properties of human native GABA receptors as a consequence of AD. To gain such information, we have microtransplanted cell membranes, isolated from temporal cortices of control and AD brains, into Xenopus oocytes, and recorded the electrophysiological activity of the transplanted GABA receptors. We found an age-dependent reduction of GABA currents in the AD brain. This reduction was larger when the AD membranes were obtained from younger subjects. We also found that GABA currents from AD brains have a faster rate of desensitization than those from non-AD brains. Furthermore, GABA receptors from AD brains were slightly, but significantly, less sensitive to GABA than receptors from non-AD brains. The reduction of GABA currents in AD was associated with reductions of mRNA and protein of the principal GABA receptor subunits normally present in the temporal cortex. Pairwise analysis of the transcripts within control and AD groups and analyses of the proportion of GABA receptor subunits revealed down-regulation of α1 and γ2 subunits in AD. In contrast, the proportions of α2, β1, and γ1 transcripts were up-regulated in the AD brains. Our data support a functional remodeling of GABAergic neurotransmission in the human AD brain. PMID:22691495

  5. Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease.

    PubMed

    Zhang, Liang; Trushin, Sergey; Christensen, Trace A; Bachmeier, Benjamin V; Gateno, Benjamin; Schroeder, Andreas; Yao, Jia; Itoh, Kie; Sesaki, Hiromi; Poon, Wayne W; Gylys, Karen H; Patterson, Emily R; Parisi, Joseph E; Diaz Brinton, Roberta; Salisbury, Jeffrey L; Trushina, Eugenia

    2016-01-05

    Altered brain metabolism is associated with progression of Alzheimer's Disease (AD). Mitochondria respond to bioenergetic changes by continuous fission and fusion. To account for three dimensional architecture of the brain tissue and organelles, we applied 3-dimensional electron microscopy (3D EM) reconstruction to visualize mitochondrial structure in the brain tissue from patients and mouse models of AD. We identified a previously unknown mitochondrial fission arrest phenotype that results in elongated interconnected organelles, "mitochondria-on-a-string" (MOAS). Our data suggest that MOAS formation may occur at the final stages of fission process and was not associated with altered translocation of activated dynamin related protein 1 (Drp1) to mitochondria but with reduced GTPase activity. Since MOAS formation was also observed in the brain tissue of wild-type mice in response to hypoxia or during chronological aging, fission arrest may represent fundamental compensatory adaptation to bioenergetic stress providing protection against mitophagy that may preserve residual mitochondrial function. The discovery of novel mitochondrial phenotype that occurs in the brain tissue in response to energetic stress accurately detected only using 3D EM reconstruction argues for a major role of mitochondrial dynamics in regulating neuronal survival.

  6. Brain imaging of neurovascular dysfunction in Alzheimer's disease.

    PubMed

    Montagne, Axel; Nation, Daniel A; Pa, Judy; Sweeney, Melanie D; Toga, Arthur W; Zlokovic, Berislav V

    2016-05-01

    Neurovascular dysfunction, including blood-brain barrier (BBB) breakdown and cerebral blood flow (CBF) dysregulation and reduction, are increasingly recognized to contribute to Alzheimer's disease (AD). The spatial and temporal relationships between different pathophysiological events during preclinical stages of AD, including cerebrovascular dysfunction and pathology, amyloid and tau pathology, and brain structural and functional changes remain, however, still unclear. Recent advances in neuroimaging techniques, i.e., magnetic resonance imaging (MRI) and positron emission tomography (PET), offer new possibilities to understand how the human brain works in health and disease. This includes methods to detect subtle regional changes in the cerebrovascular system integrity. Here, we focus on the neurovascular imaging techniques to evaluate regional BBB permeability (dynamic contrast-enhanced MRI), regional CBF changes (arterial spin labeling- and functional-MRI), vascular pathology (structural MRI), and cerebral metabolism (PET) in the living human brain, and examine how they can inform about neurovascular dysfunction and vascular pathophysiology in dementia and AD. Altogether, these neuroimaging approaches will continue to elucidate the spatio-temporal progression of vascular and neurodegenerative processes in dementia and AD and how they relate to each other.

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

    PubMed

    Weintraub, Daniel; 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 in

  8. Network Analysis of Intrinsic Functional Brain Connectivity in Alzheimer's Disease

    PubMed Central

    Supekar, Kaustubh; Menon, Vinod; Rubin, Daniel; Musen, Mark; Greicius, Michael D.

    2008-01-01

    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. PMID:18584043

  9. Amino Acid Catabolism in Alzheimer's Disease Brain: Friend or Foe?

    PubMed Central

    2017-01-01

    There is a dire need to discover new targets for Alzheimer's disease (AD) drug development. Decreased neuronal glucose metabolism that occurs in AD brain could play a central role in disease progression. Little is known about the compensatory neuronal changes that occur to attempt to maintain energy homeostasis. In this review using the PubMed literature database, we summarize evidence that amino acid oxidation can temporarily compensate for the decreased glucose metabolism, but eventually altered amino acid and amino acid catabolite levels likely lead to toxicities contributing to AD progression. Because amino acids are involved in so many cellular metabolic and signaling pathways, the effects of altered amino acid metabolism in AD brain are far-reaching. Possible pathological results from changes in the levels of several important amino acids are discussed. Urea cycle function may be induced in endothelial cells of AD patient brains, possibly to remove excess ammonia produced from increased amino acid catabolism. Studying AD from a metabolic perspective provides new insights into AD pathogenesis and may lead to the discovery of dietary metabolite supplements that can partially compensate for alterations of enzymatic function to delay AD or alleviate some of the suffering caused by the disease. PMID:28261376

  10. Brain-derived neurotrophic factor levels in Alzheimer's disease.

    PubMed

    O'Bryant, Sid E; Hobson, Valerie; Hall, James R; Waring, Stephen C; Chan, Wenyan; Massman, Paul; Lacritz, Laura; Cullum, C Munro; Diaz-Arrastia, Ramon

    2009-01-01

    The current search for biomarkers that are diagnostic and/or prognostic of Alzheimer's disease (AD) is of vital importance given the rapidly aging population. It was recently reported that brain-derived neurotrophic factor (BDNF) fluctuated according to AD severity, suggesting that BDNF might have utility for diagnostics and monitoring of therapeutic efficacy. The current study sought to examine whether BDNF levels varied according to AD severity, as previously reported. There were 196 participants (Probable AD, n = 98; Controls, n = 98) in the Texas Alzheimer's Research Consortium (TARC) Longitudinal Research Cohort available for analysis. BDNF levels were assayed via multiplex immunoassay. Regression analyses were utilized to examine the relation between BDNF levels, Mini-Mental Status Examination, and Clinical Dementia Rating scores adjusting for age and gender. In adjusted models, BDNF levels did not distinguish between AD patients and normal controls and did not significantly predict AD severity or global cognitive functioning. In conclusion, these findings do not support the notion that BDNF serves as a diagnostic marker for AD or disease severity. It is likely that the most accurate approach to identifying biomarkers of AD will be through an algorithmic approach that combines multiple markers reflective of various pathways.

  11. Increased caveolin-1 expression in Alzheimer's disease brain.

    PubMed

    Gaudreault, Sophie B; Dea, Doris; Poirier, Judes

    2004-07-01

    Increasing evidence suggests that cholesterol plays a central role in the pathophysiology of Alzheimer's disease (AD). Caveolin is a cholesterol-binding membrane protein involved in cellular cholesterol transport. We investigated the changes in the protein amount of hippocampal caveolin of autopsy-confirmed AD and aged-matched control subjects. Our results demonstrate that caveolin protein levels in the hippocampus and caveolin mRNA in the frontal cortex are up-regulated in AD by approximately two-fold, compared to control brains. These results suggest a relationship between caveolin-1 expression levels and a dysregulation of cholesterol homeostasis at the plasma membrane of brain cells. In support of this hypothesis, a significant increase in caveolin protein levels has also been observed in hippocampal tissue from ApoE-deficient (knockout) and aged wild-type mice; two situations associated with modifications of transbilayer distribution of cholesterol in brain synaptic plasma membranes. These results indicate that caveolin over-expression is linked to alterations of cholesterol distribution in the plasma membrane of brain cells and are consistent with the notion of a deterioration of cholesterol homeostasis in AD.

  12. Brain Imaging of Nicotinic Receptors in Alzheimer's Disease

    PubMed Central

    Wu, Jin; Ishikawa, Masatomo; Zhang, Jichun; Hashimoto, Kenji

    2010-01-01

    Neuronal nicotinic acetylcholine receptors (nAChRs) are a family of ligand-gated ion channels which are widely distributed in the human brain. Several lines of evidence suggest that two major subtypes (α4β2 and α7) of nAChRs play an important role in the pathophysiology of Alzheimer's disease (AD). Postmortem studies demonstrated alterations in the density of these subtypes of nAChRs in the brain of patients with AD. Currently, nAChRs are one of the most attractive therapeutic targets for AD. Therefore, several researchers have made an effort to develop novel radioligands that can be used to study quantitatively the distribution of these two subtypes in the human brain with positron emission tomography (PET) and single-photon emission computed tomography (SPECT). In this paper, we discuss the current topics on in vivo imaging of two subtypes of nAChRs in the brain of patients with AD. PMID:21253523

  13. Plasma Biomarkers of Brain Atrophy in Alzheimer's Disease

    PubMed Central

    Thambisetty, Madhav; Simmons, Andrew; Hye, Abdul; Campbell, James; Westman, Eric; Zhang, Yi; Wahlund, Lars-Olof; Kinsey, Anna; Causevic, Mirsada; Killick, Richard; Kloszewska, Iwona; Mecocci, Patrizia; Soininen, Hilkka; Tsolaki, Magda; Vellas, Bruno; Spenger, Christian; Lovestone, Simon

    2011-01-01

    Peripheral biomarkers of Alzheimer's disease (AD) reflecting early neuropathological change are critical to the development of treatments for this condition. The most widely used indicator of AD pathology in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with brain atrophy in AD. Using gel based proteomics we previously identified seven plasma proteins that were significantly associated with hippocampal volume in a combined cohort of subjects with AD (N = 27) and MCI (N = 17). In the current report, we validated this finding in a large independent cohort of AD (N = 79), MCI (N = 88) and control (N = 95) subjects using alternative complementary methods—quantitative immunoassays for protein concentrations and estimation of pathology by whole brain volume. We confirmed that plasma concentrations of five proteins, together with age and sex, explained more than 35% of variance in whole brain volume in AD patients. These proteins are complement components C3 and C3a, complement factor-I, γ-fibrinogen and alpha-1-microglobulin. Our findings suggest that these plasma proteins are strong predictors of in vivo AD pathology. Moreover, these proteins are involved in complement activation and coagulation, providing further evidence for an intrinsic role of these pathways in AD pathogenesis. PMID:22205954

  14. Directed Progression Brain Networks in Alzheimer's Disease: Properties and Classification

    PubMed Central

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

    2014-01-01

    Abstract 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. PMID:24901258

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

    PubMed

    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 [(11)C]-(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.

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

    SciTech Connect

    Nilsson, Tatjana . E-mail: Tatjana.Nilsson@ki.se; Bogdanovic, Nenad; Volkman, Inga; Winblad, Bengt; Folkesson, Ronnie; Benedikz, Eirikur

    2006-06-02

    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) brains. In frontal cortex and hippocampus of control cases, the most pronounced ODC immunoreactivity was found in the nucleus. In possible and definite AD the immunoreactivity had shifted to the cytoplasm. In cerebellum of control cases, ODC staining was found in a small portion of Purkinje cells, mostly in the nucleus. In AD, both possible and definite, the number of stained Purkinje cells increased significantly and immunoreactivity was shifted to the cytoplasm, even though it was still prominent in the nucleus. In conclusion, our study reveals an early shift of the ODC immunoreactivity in AD from the nuclear compartment towards the cytoplasm.

  17. Brain tocopherols related to Alzheimer's disease neuropathology in humans.

    PubMed

    Morris, Martha Clare; Schneider, Julie A; Li, Hong; Tangney, Christy C; Nag, Sukriti; Bennett, David A; Honer, William G; Barnes, Lisa L

    2015-01-01

    Randomized trials of α-tocopherol supplements on cognitive decline are negative, whereas studies of dietary tocopherols have shown benefit. We investigated these inconsistencies by analyzing the relations of α- and γ-tocopherol brain concentrations to Alzheimer's disease (AD) neuropathology among 115 deceased participants of the prospective Rush Memory and Aging Project. Associations of amyloid load and neurofibrillary tangle severity with brain tocopherol concentrations were examined in separate adjusted linear regression models. γ-Tocopherol concentrations were associated with lower amyloid load (β = -2.10, P = .002) and lower neurofibrillary tangle severity (β = -1.16, P = .02). Concentrations of α-tocopherol were not associated with AD neuropathology, except as modified by γ-tocopherol: high α-tocopherol was associated with higher amyloid load when γ-tocopherol levels were low and with lower amyloid levels when γ-tocopherol levels were high (P for interaction = 0.03). Brain concentrations of γ- and α-tocopherols may be associated with AD neuropathology in interrelated, complex ways. Randomized trials should consider the contribution of γ-tocopherol.

  18. Polymicrobial Infections In Brain Tissue From Alzheimer's Disease Patients.

    PubMed

    Pisa, Diana; Alonso, Ruth; Fernández-Fernández, Ana M; Rábano, Alberto; Carrasco, Luis

    2017-07-17

    Several studies have advanced the idea that the etiology of Alzheimer's disease (AD) could be microbial in origin. In the present study, we tested the possibility that polymicrobial infections exist in tissue from the entorhinal cortex/hippocampus region of patients with AD using immunohistochemistry (confocal laser scanning microscopy) and highly sensitive (nested) PCR. We found no evidence for expression of early (ICP0) or late (ICP5) proteins of herpes simplex virus type 1 (HSV-1) in brain sections. A polyclonal antibody against Borrelia detected structures that appeared not related to spirochetes, but rather to fungi. These structures were not found with a monoclonal antibody. Also, Borrelia DNA was undetectable by nested PCR in the ten patients analyzed. By contrast, two independent Chlamydophila antibodies revealed several structures that resembled fungal cells and hyphae, and prokaryotic cells, but most probably were unrelated to Chlamydophila spp. Finally, several structures that could belong to fungi or prokaryotes were detected using peptidoglycan and Clostridium antibodies, and PCR analysis revealed the presence of several bacteria in frozen brain tissue from AD patients. Thus, our results show that polymicrobial infections consisting of fungi and bacteria can be revealed in brain tissue from AD patients.

  19. Altered brain response for semantic knowledge in Alzheimer's disease.

    PubMed

    Wierenga, Christina E; Stricker, Nikki H; McCauley, Ashley; Simmons, Alan; Jak, Amy J; Chang, Yu-Ling; Nation, Daniel A; Bangen, Katherine J; Salmon, David P; Bondi, Mark W

    2011-02-01

    Word retrieval deficits are common in Alzheimer's disease (AD) and are thought to reflect a degradation of semantic memory. Yet, the nature of semantic deterioration in AD and the underlying neural correlates of these semantic memory changes remain largely unknown. We examined the semantic memory impairment in AD by investigating the neural correlates of category knowledge (e.g., living vs. nonliving) and featural processing (global vs. local visual information). During event-related fMRI, 10 adults diagnosed with mild AD and 22 cognitively normal (CN) older adults named aloud items from three categories for which processing of specific visual features has previously been dissociated from categorical features. Results showed widespread group differences in the categorical representation of semantic knowledge in several language-related brain areas. For example, the right inferior frontal gyrus showed selective brain response for nonliving items in the CN group but living items in the AD group. Additionally, the AD group showed increased brain response for word retrieval irrespective of category in Broca's homologue in the right hemisphere and rostral cingulate cortex bilaterally, which suggests greater recruitment of frontally mediated neural compensatory mechanisms in the face of semantic alteration. Copyright © 2010 Elsevier Ltd. All rights reserved.

  20. Brain Tocopherols Related to Alzheimer Disease Neuropathology in Humans

    PubMed Central

    Morris, Martha Clare; Schneider, Julie A; Li, Hong; Tangney, Christy C; Nag, Sukrit; Bennett, David A; Honer, William G.; Barnes, Lisa

    2014-01-01

    Randomized trials of α-tocopherol supplements on cognitive decline are negative whereas studies of dietary tocopherols show benefit. We investigated these inconsistencies by analyzing the relations of α- and γ-tocopherol brain concentrations to Alzheimer disease (AD) neuropathology among 115 deceased participants of the prospective Rush Memory and Aging Project. Associations of amyloid load and neurofibrillary tangle severity with brain tocopherol concentrations were examined in separate adjusted linear regression models. γ-tocopherol concentrations were associated with lower amyloid load (β= −2.10; p=.002) and lower neurofibrillary tangle severity (β= −1.16; p=0.02). Concentrations of α-tocopherol were not associated with AD neuropathology except as modified by γ-tocopherol: high α-tocopherol was associated with higher amyloid load when γ-tocopherol levels were low and with lower amyloid levels when γ-tocopherol levels were high (P for interaction=0.03). Brain concentrations of γ- and α-tocopherols may be associated with AD neuropathology in interrelated, complex ways. Randomized trials should consider the contribution of γ-tocopherol. PMID:24589434

  1. Measuring Glial Metabolism in Repetitive Brain Trauma and Alzheimer’s Disease

    DTIC Science & Technology

    2016-09-01

    AWARD NUMBER: W81XWH-15-1-0412 TITLE: Measuring Glial Metabolism in Repetitive Brain Trauma and Alzheimer’s Disease PRINCIPAL INVESTIGATOR...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Measuring Glial Metabolism in Repetitive Brain Trauma and Alzheimer’s Disease 5b. GRANT NUMBER WX81XWH-15...15. SUBJECT TERMS Repetitive brain trauma, glial metabolism, glutamate, multinuclear spectroscopy, chronic traumatic encephalopathy, Alzheimer’s

  2. Brain biometals and Alzheimer's disease - boon or bane?

    PubMed

    Prakash, Atish; Dhaliwal, Gagandeep Kaur; Kumar, Puneet; Majeed, Abu Bakar Abdul

    2017-02-01

    Alzheimer's disease (AD) is the most common form of dementia. Several hypotheses have been put forward to explain the basis of disease onset and progression. A complicated array of molecular events has been implicated in the pathogenesis of AD. It is attributed to a variety of pathological conditions that share similar critical processes, such as oxidative stress, proteinaceous aggregations, mitochondrial dysfunctions and energy failure. There is increasing evidence suggesting that metal homeostasis is dysregulated in the pathology of AD. Biometals play an important role in the normal body functioning but AD may be mediated or triggered by disproportion of metal ions leading to changes in critical biological systems and initiating a cascade of events finally leading to neurodegeneration and cell death. The link is multifactorial, and although the source of the shift in oxidative homeostasis is still unclear, current evidence points to changes in the balance of redox transition metals, especially iron, copper (Cu) and other trace metals. Their levels in the brain are found to be elevated in AD. In other neurodegenerative disorders, Cu, zinc, aluminum and manganese are involved. This paper is a review of recent advances of the role of metals in the pathogenesis and pathophysiology of AD and related neurodegenerative diseases.

  3. Brain SPECT findings of anosognosia in Alzheimer's disease.

    PubMed

    Sedaghat, Fereshteh; Dedousi, Eleni; Baloyannis, Ioannis; Tegos, Thomas; Costa, Vasiliki; Dimitriadis, Athanasios S; Baloyannis, Stavros J

    2010-01-01

    Anosognosia is a common symptom of dementia. The aim of this study was to evaluate the contribution of different regions of the brain to anosognosia in Alzheimer's disease (AD) brains using single photon emission computed tomography (SPECT). Forty-two patients with AD were included in this study. After clinical interviews with the patients and their relatives, the patients were divided into two groups: Anosognosia and No-anosognosia. The patients were studied regarding the severity of dementia. They underwent SPECT with HMPAO and regional cerebral blood flow (rCBF) was measured. Regional CBF significantly differed between Anosognosia and No-anosognosia groups in right prefrontal (P < or = 0.02), right inferior parietal (P < or = 0.00), and right (P < or = 0.01) and left (P < or = 0.01) medial temporal cortex. There was a significant correlation between the severity of dementia and rCBF in medial temporal regions. When comparisons were made between mild and moderate stages separately, the 'right inferior parietal region' was the common region which showed hypoperfusion in both anosognosia subgroups. We conclude that anosognosia may be a reflection of functional impairment in right prefrontal, right frontal and especially right inferior parietal regions in AD.

  4. Alzheimer's disease, brain immune privilege and memory: a hypothesis.

    PubMed

    Arshavsky, Y I

    2006-11-01

    The most distinctive feature of Alzheimer's disease (AD) is the specific degeneration of the neurons involved in memory consolidation, storage, and retrieval. Patients suffering from AD forget basic information about their past, loose linguistic and calculative abilities and communication skills. Thus, understanding the etiology of AD may provide insights into the mechanisms of memory and vice versa. The brain is an immunologically privileged site protected from the organism's immune reactions by the blood-brain barrier (BBB). All risk factors for AD (both cardiovascular and genetic) lead to destruction of the BBB. Evidence emerging from recent literature indicates that AD may have an autoimmune nature associated with BBB impairments. This hypothesis suggests that the process of memory consolidation involves the synthesis of novel macromolecules recognized by the immune system as "non-self" antigens. The objective of this paper is to stimulate new approaches to studies of neural mechanisms underpinning memory consolidation and its breakdown during AD. If the hypothesis on the autoimmune nature of AD is correct, the identification of the putative antigenic macromolecules might be critical to understanding the etiology and prevention of AD, as well as for elucidating cellular mechanisms of learning and memory.

  5. Phospholipase C isozymes in the human brain and their changes in Alzheimer's disease.

    PubMed

    Shimohama, S; Sasaki, Y; Fujimoto, S; Kamiya, S; Taniguchi, T; Takenawa, T; Kimura, J

    1998-02-01

    Phosphoinositide-specific phospholipase C is a key enzyme in signal transduction. We have previously demonstrated that an isozyme of phospholipase C, phospholipase C-delta1, accumulates aberrantly in the brains of patients with Alzheimer's disease. In the present study, we examined the property of phospholipase C isozymes in human brains using the methods of chromatofocusing and gel filtration chromatography, and investigated their changes in Alzheimer's disease brains. The chromatofocusing profile of human brain phospholipase C activity on a Mono P HR column demonstrated that phospholipase C-gamma1, exhibiting an isoelectric point value of 5.2, and phospholipase C-delta1, exhibiting isoelectric point values of 5.2 and 4.6, are partly overlapped in their elution. In contrast, the elution profiles of control and Alzheimer's disease brain phospholipase C on Superdex 200 pg column gel filtration chromatography indicated that phospholipase C-gamma1 and phospholipase C-delta1 can be separated with the elution position having a molecular weight of about 240,000 and 140,000, respectively, in the human brain. Using this gel filtration chromatography it was revealed that the phospholipase C-gamma1 activity was significantly decreased and the phospholipase C-delta1 activity was significantly increased in Alzheimer's disease brains compared with controls. These results suggest that the phospholipase C isozymes are differentially involved in Alzheimer's disease.

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

    PubMed Central

    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. Objectives: To use fMRI to study brain activation with rivastigmine treatment. Methods: The effect on brain activation of a single dose of rivastigmine was tested in seven patients with mild Alzheimer's disease using fMRI during face encoding, and in five patients during a parametric working memory task. Results: During face encoding, rivastigmine increased bilateral activation in the fusiform gyrus. Brain activation was also enhanced in the prefrontal cortex in a simple working memory task. When working memory load was further increased, not only was increased activation seen, but in certain areas there was also decreased activation. Conclusions: These findings link the previously observed increase in cognitive performance in Alzheimer's disease after treatment with a cholinesterase inhibitor to altered brain activation. Although the results cannot be generalised to the Alzheimer's disease population at large, they provide evidence that in mild Alzheimer's disease, rivastigmine enhances brain activation in the fusiform and frontal cortices. This is compatible with the concept of cholinergic circuitry. PMID:12438467

  7. A derangement of the brain wound healing process may cause some cases of Alzheimer's disease.

    PubMed

    Lehrer, Steven; Rheinstein, Peter H

    2016-08-01

    A derangement of brain wound healing may cause some cases of Alzheimer's disease. Wound healing, a highly complex process, has four stages: hemostasis, inflammation, repair, and remodeling. Hemostasis and the initial phases of inflammation in brain tissue are typical of all vascularized tissue, such as skin. However, distinct differences arise in brain tissue during the later stages of inflammation, repair, and remodeling, and closely parallel the changes of Alzheimer's disease. Our hypothesis -- Alzheimer's disease is brain wound healing gone awry at least in some cases -- could be tested by measuring progression with biomarkers for the four stages of wound healing in humans or appropriate animal models. Autopsy studies might be done. Chronic traumatic encephalopathy might also result from the brain wound healing process.

  8. Imaging the Alzheimer Brain

    PubMed Central

    Ashford, J. Wesson; Salehi, Ahmad; Furst, Ansgar; Bayley, Peter; Frisoni, Giovanni B.; Jack, Clifford R.; Sabri, Osama; Adamson, Maheen M.; Coburn, Kerry L.; Olichney, John; Schuff, Norbert; Spielman, Daniel; Edland, Steven D.; Black, Sandra; Rosen, Allyson; Kennedy, David; Weiner, Michael; Perry, George

    2013-01-01

    This supplement to the Journal of Alzheimer's Disease contains more than half of the chapters from The Handbook of Imaging the Alzheimer Brain, which was first presented at the International Conference on Alzheimer's Disease in Paris, in July, 2011. While the Handbook contains 27 chapters that are modified articles from 2009, 2010, and 2011 issues of the Journal of Alzheimer's Disease, this supplement contains the 31 new chapters of that book and an introductory article drawn from the introductions to each section of the book. The Handbook was designed to provide a multilevel overview of the full field of brain imaging related to Alzheimer's disease (AD). The Handbook, as well as this supplement, contains both reviews of the basic concepts of imaging, the latest developments in imaging, and various discussions and perspectives of the problems of the field and promising directions. The Handbook was designed to be useful for students and clinicians interested in AD as well as scientists studying the brain and pathology related to AD. PMID:21971448

  9. Alzheimer Disease

    PubMed Central

    Apostolova, Liana G.

    2016-01-01

    ABSTRACT Purpose of Review: This article discusses the recent advances in the diagnosis and treatment of Alzheimer disease (AD). Recent Findings: In recent years, significant advances have been made in the fields of genetics, neuroimaging, clinical diagnosis, and staging of AD. One of the most important recent advances in AD is our ability to visualize amyloid pathology in the living human brain. The newly revised criteria for diagnosis of AD dementia embrace the use for biomarkers as supportive evidence for the underlying pathology. Guidelines for the responsible use of amyloid positron emission tomography (PET) have been developed, and the clinical and economic implications of amyloid PET imaging are actively being explored. Summary: Our improved understanding of the clinical onset, progression, neuroimaging, pathologic features, genetics, and other risk factors for AD impacts the approaches to clinical diagnosis and future therapeutic interventions. PMID:27042902

  10. Alzheimer Disease.

    PubMed

    Apostolova, Liana G

    2016-04-01

    This article discusses the recent advances in the diagnosis and treatment of Alzheimer disease (AD). In recent years, significant advances have been made in the fields of genetics, neuroimaging, clinical diagnosis, and staging of AD. One of the most important recent advances in AD is our ability to visualize amyloid pathology in the living human brain. The newly revised criteria for diagnosis of AD dementia embrace the use for biomarkers as supportive evidence for the underlying pathology. Guidelines for the responsible use of amyloid positron emission tomography (PET) have been developed, and the clinical and economic implications of amyloid PET imaging are actively being explored. Our improved understanding of the clinical onset, progression, neuroimaging, pathologic features, genetics, and other risk factors for AD impacts the approaches to clinical diagnosis and future therapeutic interventions.

  11. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease.

    PubMed

    Griffin, W S; Stanley, L C; Ling, C; White, L; MacLeod, V; Perrot, L J; White, C L; Araoz, C

    1989-10-01

    Interleukin 1, an immune response-generated cytokine that stimulates astrocyte proliferation and reactivity (astrogliosis), was present in up to 30 times as many glial cells in tissue sections of brain from patients with Down syndrome and Alzheimer disease compared with age-matched control subjects. Most interleukin 1-immunoreactive glia in Down syndrome and Alzheimer disease were classified as microglia. The number of interleukin 1 immunoreactive neurons did not appear to differ in Down syndrome and Alzheimer disease compared with control brain. Numerous temporal lobe astrocytes in Alzheimer disease and postnatal Down syndrome were intensely interleukin 1-, S-100-, and glial fibrillary acidic protein-immunoreactive and had reactive structure. Interleukin 1 levels in Alzheimer disease temporal lobe homogenates were elevated, as were the levels of S-100 and glial fibrillary acidic protein, two proteins reportedly elevated in reactive astrocytes. These data suggest that increased expression of S-100 in Down syndrome, resulting from duplication of the gene on chromosome 21 that encodes the beta subunit of S-100, may be augmented by elevation of interleukin 1. As a corollary, the astrogliosis in Alzheimer disease may be promoted by elevation of interleukin 1.

  12. Sticky Brain 'Plaques' Implicated in Alzheimer's Again

    MedlinePlus

    ... fullstory_166550.html Sticky Brain 'Plaques' Implicated in Alzheimer's Again Researchers believe these substances form in early ... in the brain signals an early stage of Alzheimer's disease. It's been known for years that in ...

  13. Blood-brain barrier P-glycoprotein function in Alzheimer's disease.

    PubMed

    van Assema, Daniëlle M E; Lubberink, Mark; Bauer, Martin; van der Flier, Wiesje M; Schuit, Robert C; Windhorst, Albert D; Comans, Emile F I; Hoetjes, Nikie J; Tolboom, Nelleke; Langer, Oliver; Müller, Markus; Scheltens, Philip; Lammertsma, Adriaan A; van Berckel, Bart N M

    2012-01-01

    A major pathological hallmark of Alzheimer's disease is accumulation of amyloid-β in senile plaques in the brain. Evidence is accumulating that decreased clearance of amyloid-β from the brain may lead to these elevated amyloid-β levels. One of the clearance pathways of amyloid-β is transport across the blood-brain barrier via efflux transporters. P-glycoprotein, an efflux pump highly expressed at the endothelial cells of the blood-brain barrier, has been shown to transport amyloid-β. P-glycoprotein function can be assessed in vivo using (R)-[(11)C]verapamil and positron emission tomography. The aim of this study was to assess blood-brain barrier P-glycoprotein function in patients with Alzheimer's disease compared with age-matched healthy controls using (R)-[(11)C]verapamil and positron emission tomography. In 13 patients with Alzheimer's disease (age 65 ± 7 years, Mini-Mental State Examination 23 ± 3), global (R)-[(11)C]verapamil binding potential values were increased significantly (P = 0.001) compared with 14 healthy controls (aged 62 ± 4 years, Mini-Mental State Examination 30 ± 1). Global (R)-[(11)C]verapamil binding potential values were 2.18 ± 0.25 for patients with Alzheimer's disease and 1.77 ± 0.41 for healthy controls. In patients with Alzheimer's disease, higher (R)-[(11)C]verapamil binding potential values were found for frontal, parietal, temporal and occipital cortices, and posterior and anterior cingulate. No significant differences between groups were found for medial temporal lobe and cerebellum. These data show altered kinetics of (R)-[(11)C]verapamil in Alzheimer's disease, similar to alterations seen in studies where P-glycoprotein is blocked by a pharmacological agent. As such, these data indicate that P-glycoprotein function is decreased in patients with Alzheimer's disease. This is the first direct evidence that the P-glycoprotein transporter at the blood-brain barrier is compromised in sporadic

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

    PubMed

    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.

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

    PubMed Central

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

    2015-01-01

    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. PMID:26844268

  16. Platelets in the Alzheimer's disease brain: do they play a role in cerebral amyloid angiopathy?

    PubMed

    Kniewallner, Kathrin M; Ehrlich, Daniela; Kiefer, Andreas; Marksteiner, Josef; Humpel, Christian

    2015-01-01

    Alzheimer's disease (AD) is characterized by extracellular beta-amyloid plaques and intracellular tau tangles. AD-related pathology is often accompanied by vascular changes. The predominant vascular lesions in AD are cerebral amyloid angiopathy (CAA) and arteriosclerosis. Platelets circulate along the vessel wall responding immediately to vascular injury. The aim of the present study was to explore the presence and migration of platelets (thrombocytes) to sites of small vascular bleedings and/or to beta-amyloid plaques in the brain. We infused fluorescently labeled red PKH26 mouse platelets into transgenic Alzheimer mice overexpressing APP with Swedish/Dutch/Iowa mutations (APP_SDI) and explored if platelets migrate into the brain. Further we studied whether platelets accumulate in the vicinity of β-amyloid plaques. Our animal data shows that infused platelets are found in the liver and partly in the lung, while in the brain platelets were visible to a minor degree. In mice, we did not observe a significant association of platelets with beta-amyloid plaques or vessels. In the brain of Alzheimer postmortem patients platelets could be detected by immunohistochemistry for CD41 and CD62P, but the majority was found in vessels with or without beta-amyloid load, and only a few single platelets migrated deeper into the brain. Our findings suggest that platelets do not migrate into the brains of Alzheimer disease but are concentrated in brain vessels.

  17. Immunotherapy for Alzheimer disease.

    PubMed

    Gouras, Gunnar K

    2009-01-01

    Immunotherapy approaches for Alzheimer disease currently are among the leading therapeutic directions for the disease. Active and passive immunotherapy against the beta-amyloid peptides that aggregate and accumulate in the brain of those afflicted by the disease have been shown by numerous groups to reduce plaque pathology and improve behavior in transgenic mouse models of the disease. Several ongoing immunotherapy clinical trials for Alzheimer disease are in progress. The background and ongoing challenges for these immunological approaches for the treatment of Alzheimer disease are discussed.

  18. Alzheimer's disease.

    PubMed

    De-Paula, Vanessa J; Radanovic, Marcia; Diniz, Breno S; Forlenza, Orestes V

    2012-01-01

    Alzheimer's disease (AD) is a chronic neurodegenerative disease with well-defined pathophysiological mechanisms, mostly affecting medial temporal lobe and associative neocortical structures. Neuritic plaques and neurofibrillary tangles represent the pathological hallmarks of AD, and are respectively related to the accumulation of the amyloid-beta peptide (Aβ) in brain tissues, and to cytoskeletal changes that arise from the hyperphosphorylation of microtubule-associated Tau protein in neurons. According to the amyloid hypothesis of AD, the overproduction of Aβ is a consequence of the disruption of homeostatic processes that regulate the proteolytic cleavage of the amyloid precursor protein (APP). Genetic, age-related and environmental factors contribute to a metabolic shift favoring the amyloidogenic processing of APP in detriment of the physiological, secretory pathway. Aβ peptides are generated by the successive cleavage of APP by beta-secretase (BACE-1) and gamma-secretase, which has been recently characterized as part of the presenilin complex. Among several beta-amyloid isoforms that bear subtle differences depending on the number of C-terminal amino acids, Aβ (1-42) plays a pivotal role in the pathogenesis of AD. The neurotoxic potential of the Aβ peptide results from its biochemical properties that favor aggregation into insoluble oligomers and protofibrils. These further originate fibrillary Aβ species that accumulate into senile and neuritic plaques. These processes, along with a reduction of Aβ clearance from the brain, leads to the extracellular accumulation of Aβ, and the subsequent activation of neurotoxic cascades that ultimately lead to cytoskeletal changes, neuronal dysfunction and cellular death. Intracerebral amyloidosis develops in AD patients in an age-dependent manner, but recent evidence indicate that it may be observed in some subjects as early as in the third or fourth decades of life, with increasing magnitude in late middle age

  19. Neuroimaging and genetic risk for Alzheimer's disease and addiction-related degenerative brain disorders.

    PubMed

    Roussotte, Florence F; Daianu, Madelaine; Jahanshad, Neda; Leonardo, Cassandra D; Thompson, Paul M

    2014-06-01

    Neuroimaging offers a powerful means to assess the trajectory of brain degeneration in a variety of disorders, including Alzheimer's disease (AD). Here we describe how multi-modal imaging can be used to study the changing brain during the different stages of AD. We integrate findings from a range of studies using magnetic resonance imaging (MRI), positron emission tomography (PET), functional MRI (fMRI) and diffusion weighted imaging (DWI). Neuroimaging reveals how risk genes for degenerative disorders affect the brain, including several recently discovered genetic variants that may disrupt brain connectivity. We review some recent neuroimaging studies of genetic polymorphisms associated with increased risk for late-onset Alzheimer's disease (LOAD). Some genetic variants that increase risk for drug addiction may overlap with those associated with degenerative brain disorders. These common associations offer new insight into mechanisms underlying neurodegeneration and addictive behaviors, and may offer new leads for treating them before severe and irreversible neurological symptoms appear.

  20. Disease-Induced Alterations in Brain Drug Transporters in Animal Models of Alzheimer's Disease.

    PubMed

    Vellonen, Kati-Sisko; Ihalainen, Jouni; Boucau, Marie-Christine; Gosselet, Fabien; Picardat, Théo; Gynther, Mikko; Kanninen, Katja M; White, Anthony R; Malm, Tarja; Koistinaho, Jari; Forsberg, Markus M; Ruponen, Marika

    2017-09-26

    Alzheimer's disease (AD) may disturb functions of the blood-brain barrier and change the disposition of drugs to the brain. This study assessed the disease-induced changes in drug transporters in the brain capillaries of transgenic AD mice. Eighteen drug transporters and four tight junction-associated proteins were analyzed by RT-qPCR in cortex, hippocampus and cerebellum tissue samples of 12-16-month-old APdE9, Tg2576 and APP/PS1 transgenic mice and their healthy age-matched controls. In addition, microvessel fractions enriched from 1-3-month-old APdE9 mice were analyzed using RT-qPCR and Western blotting. Brain transport of methotrexate in APdE9 mice was assessed by in vivo microdialysis. The expression profiles of studied genes were similar in brain tissues of AD and control mice. Instead, in the microvessel fraction in APdE9 mice, >2-fold alterations were detected in the expressions of 11 genes but none at the protein level. In control mice strains, >5-fold changes between different brain regions were identified for Slc15a2, Slc22a3 and occludin. Methotrexate distribution into hippocampus of APdE9 mice was faster than in controls. The expression profile of mice carrying presenilin and amyloid precursor protein mutations is comparable to controls, but clear regional differences exist in the expression of drug transporters in brain.

  1. Focally Elevated Creatine Detected in Amyloid Precursor Protein (APP) Transgenic Mice and Alzheimer Disease Brain Tissue

    SciTech Connect

    Gallant,M.; Rak, M.; Szeghalmi, A.; Del Bigio, M.; Westaway, D.; Yang, J.; Julian, R.; Gough, K.

    2006-01-01

    The creatine/phosphocreatine system, regulated by creatine kinase, plays an important role in maintaining energy balance in the brain. Energy metabolism and the function of creatine kinase are known to be affected in Alzheimer diseased brain and in cells exposed to the {beta}-amyloid peptide. We used infrared microspectroscopy to examine hippocampal, cortical, and caudal tissue from 21-89-week-old transgenic mice expressing doubly mutant (K670N/M671L and V717F) amyloid precursor protein and displaying robust pathology from an early age. Microcrystalline deposits of creatine, suggestive of perturbed energetic status, were detected by infrared microspectroscopy in all animals with advanced plaque pathology. Relatively large creatine deposits were also found in hippocampal sections from post-mortem Alzheimer diseased human brain, compared with hippocampus from non-demented brain. We therefore speculate that this molecule is a marker of the disease process.

  2. Preclinical Alzheimer Disease: Brain Oxidative Stress, Aβ Peptide & Proteomics

    PubMed Central

    Aluise, Christopher D.; Robinson, Renã A. Sowell; Beckett, Tina L.; Murphy, M. Paul; Cai, Jian; Pierce, William M.; Markesbery, William R.; Butterfield, D. Allan

    2010-01-01

    Alzheimer disease (AD) is a neurodegenerative disorder characterized clinically by progressive memory loss and subsequent dementia and neuropathologically by senile plaques, neurofibrillary tangles, and synapse loss. Interestingly, a small percentage of individuals with normal antemortem psychometric scores meet the neuropathological criteria for AD (termed `preclinical' AD (PCAD)). In this study, inferior parietal lobule (IPL) from PCAD and control subjects were compared for oxidative stress markers by immunochemistry, amyloid beta-peptide by ELISA, and identification of protein expression differences by proteomics. We observed a significant increase in highly insoluble monomeric Aβ42, but no significant differences in oligomeric Aβ nor in oxidative stress measurements between controls and PCAD subjects. Expression proteomics identified proteins whose trends in PCAD are indicative of cellular protection, possibly correlating with previous studies showing no cell loss in PCAD. Our analyses may reveal processes involved in a period of protection from neurodegeneration that mimic the clinical phenotype of PCAD. PMID:20399861

  3. Identification of Alzheimer disease risk genotype that predicts efficiency of SORL1 expression in the brain.

    PubMed

    Caglayan, Safak; Bauerfeind, Anja; Schmidt, Vanessa; Carlo, Anne-Sophie; Prabakaran, Thaneas; Hübner, Norbert; Willnow, Thomas E

    2012-03-01

    To identify SORL1 risk genotypes that determine receptor protein expression in the human brain. DNA, RNA, and proteins were extracted from brain autopsies of Alzheimer disease cases and used for SORL1 genotyping, RNA profiling, and SORLA protein quantification, respectively. Specimens were provided by the MRC London Brain Bank for Neurodegenerative Diseases and the Netherlands Brain Bank. Brain autopsy material (frontal cortex) from 88 confirmed cases of sporadic Alzheimer disease. Our studies identified a SORL1 haplotype in the 3' gene region consisting of single-nucleotide polymorphisms rs1699102 and rs2070045 that is associated with poor receptor expression in the brain of patients with Alzheimer disease. These gene variations alter the SORL1 transcript sequence, resulting in a change from frequent to rare codon usage in the minor risk genotype. Studies in cultured cells confirm less efficient translation of the minor receptor transcripts into protein. Our findings suggest a functional mechanism that correlates SORL1 genotype with efficiency of receptor expression in the human brain.

  4. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease.

    PubMed

    Murer, M G; Yan, Q; Raisman-Vozari, R

    2001-01-01

    Brain-derived neurotrophic factor (BDNF) is a small dimeric protein, structurally related to nerve growth factor, which is abundantly and widely expressed in the adult mammalian brain. BDNF has been found to promote survival of all major neuronal types affected in Alzheimer's disease and Parkinson's disease, like hippocampal and neocortical neurons, cholinergic septal and basal forebrain neurons, and nigral dopaminergic neurons. In this article, we summarize recent work on the molecular and cellular biology of BDNF, including current ideas about its intracellular trafficking, regulated synthesis and release, and actions at the synaptic level, which have considerably expanded our conception of BDNF actions in the central nervous system. But our primary aim is to review the literature regarding BDNF distribution in the human brain, and the modifications of BDNF expression which occur in the brain of individuals with Alzheimer's disease and Parkinson's disease. Our knowledge concerning BDNF actions on the neuronal populations affected in these pathological states is also reviewed, with an aim at understanding its pathogenic and pathophysiological relevance.

  5. Microprobe PIXE analysis of aluminium in the brains of patients with Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Yumoto, S.; Horino, Y.; Mokuno, Y.; Kakimi, S.; Fujii, K.

    1996-04-01

    To investigate the cause of Alzheimer's disease (senile dementia), we examined aluminium (Al) in the rat liver, and in the brains (hippocampus) of Alzheimer's disease patients using heavy ion (5 MeV Si 3+) microprobe and proton (2 MeV) microprobe PIXE analysis. Heavy ion microprobes (3 MeV Si 2+) have several time's higher sensitivity for Al detection than 2 MeV proton microprobes. (1) In the rat liver, Al was detected in the cell nuclei, where phosphorus (P) was most densely distributed. (2) We also demonstrated Al in the cell nuclei isolated from Alzheimer's disease brains using heavy ion (5 MeV Si 3+) microprobes. Al spectra were detected using 2 MeV proton microprobes in the isolated brain cell nuclei. Al could not be observed in areas where P was present in relatively small amounts, or was absent. Our results indicate that Alzheimer's disease is caused by irreversible accumulation of Al in the nuclei of brain cells.

  6. Exosomal biomarkers of brain insulin resistance associated with regional atrophy in Alzheimer's disease.

    PubMed

    Mullins, Roger J; Mustapic, Maja; Goetzl, Edward J; Kapogiannis, Dimitrios

    2017-04-01

    Brain insulin resistance (IR), which depends on insulin-receptor-substrate-1 (IRS-1) phosphorylation, is characteristic of Alzheimer's disease (AD). Previously, we demonstrated higher pSer312-IRS-1 (ineffective insulin signaling) and lower p-panTyr-IRS-1 (effective insulin signaling) in neural origin-enriched plasma exosomes of AD patients vs.

  7. Clock Drawing Performance and Brain Morphology in Mild Cognitive Impairment and Alzheimer's Disease

    ERIC Educational Resources Information Center

    Thomann, Philipp A.; Toro, Pablo; Santos, Vasco Dos; Essig, Marco; Schroder, Johannes

    2008-01-01

    The Clock Drawing Test (CDT) is a widely used instrument in the neuropsychological assessment of Alzheimer's disease (AD). As CDT performance necessitates several cognitive functions (e.g., visuospatial and constructional abilities, executive functioning), an interaction of multiple brain regions is likely. Fifty-one subjects with mild cognitive…

  8. Clock Drawing Performance and Brain Morphology in Mild Cognitive Impairment and Alzheimer's Disease

    ERIC Educational Resources Information Center

    Thomann, Philipp A.; Toro, Pablo; Santos, Vasco Dos; Essig, Marco; Schroder, Johannes

    2008-01-01

    The Clock Drawing Test (CDT) is a widely used instrument in the neuropsychological assessment of Alzheimer's disease (AD). As CDT performance necessitates several cognitive functions (e.g., visuospatial and constructional abilities, executive functioning), an interaction of multiple brain regions is likely. Fifty-one subjects with mild cognitive…

  9. Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease.

    PubMed

    Yarchoan, Mark; Arnold, Steven E

    2014-07-01

    A growing body of clinical and epidemiological research suggests that two of the most common diseases of aging, type 2 diabetes (T2DM) and Alzheimer disease (AD), are linked. The nature of the association is not known, but this observation has led to the notion that drugs developed for the treatment of T2DM may be beneficial in modifying the pathophysiology of AD and maintaining cognitive function. Recent advances in the understanding of the biology of T2DM have resulted in a growing number of therapies that are approved or in clinical development for this disease. This review summarizes the evidence that T2DM and AD are linked, with a focus on the cellular and molecular mechanisms in common, and then assesses the various clinical-stage diabetes drugs for their potential activity in AD. At a time when existing therapies for AD offer only limited symptomatic benefit for some patients, additional clinical trials of diabetes drugs are needed to at least advance the care of T2DM patients at risk for or with comorbid AD and also to determine their value for AD in general. © 2014 by the American Diabetes Association.

  10. Synchrotron FTIR microspectroscopy of Alzheimer's diseased brain tissue at the SRC beamline

    NASA Astrophysics Data System (ADS)

    Bromberg, Pam S.; Gough, Kathleen M.; Ogg, Mandy; Del Bigio, M. R.; Julian, Robert

    1999-10-01

    Alzheimer's Disease is a neurodegenerative disorder marked by progressive cognitive decline. AD presents with many of the same clinical symptoms as senile dementia, but the diagnosis of AD must be confirmed by post-mortem examination of the morphological and histopathological features of the brain. The two classical lesions found in the cortical and hippocampal regions of the brain are the (beta) -amyloid- bearing neuritic plaques and the intraneuronal neurofibrillary tangles.

  11. Increased acetyl and total histone levels in post-mortem Alzheimer's disease brain.

    PubMed

    Narayan, Pritika J; Lill, Claire; Faull, Richard; Curtis, Maurice A; Dragunow, Mike

    2015-02-01

    Histone acetylation is an epigenetic modification that plays a critical role in chromatin remodelling and transcriptional regulation. There is increasing evidence that epigenetic modifications may become compromised in aging and increase susceptibility to the development of neurodegenerative disorders such as Alzheimer's disease. Immunohistochemical labelling of free-floating sections from the inferior temporal gyrus (Alzheimer's disease, n=14; control, n=17) and paraffin-embedded tissue microarrays containing tissue from the middle temporal gyrus (Alzheimer's disease, n=29; control, n=28) demonstrated that acetyl histone H3 and acetyl histone H4 levels, as well as total histone H3 and total histone H4 protein levels, were significantly increased in post-mortem Alzheimer's disease brain tissue compared to age- and sex-matched neurologically normal control brain tissue. Changes in acetyl histone levels were proportional to changes in total histone levels. The increase in acetyl histone H3 and H4 was observed in Neuronal N immunopositive pyramidal neurons in Alzheimer's disease brain. Using immunolabelling, histone markers correlated significantly with the level of glial fibrillary acidic protein and HLA-DP, -DQ and -DR immunopositive cells and with the pathological hallmarks of Alzheimer's disease (hyperphosphorylated tau load and β-amyloid plaques). Given that histone acetylation changes were correlated with changes in total histone protein, it was important to evaluate if protein degradation pathways may be compromised in Alzheimer's disease. Consequently, significant positive correlations were also found between ubiquitin load and histone modifications. The relationship between histone acetylation and ubiquitin levels was further investigated in an in vitro model of SK-N-SH cells treated with the proteasome inhibitor Mg132 and the histone deacetylase inhibitor valproic acid. In this model, compromised protein degradation caused by Mg132 lead to elevated histone

  12. [The role of chronic brain hypoperfusion in the pathogenesis of Alzheimer's disease--facts and hypotheses].

    PubMed

    Zádori, Dénes; Datki, Zsolt; Penke, Botond

    2007-11-30

    In Alzheimer's disease, which belongs to the neurodegenerative disorders, the ethiopathogenetic role of several risk factors has been proved. A considerable number of them are mainly known as cardiovascular risk factors and can precipitate chronic brain hypoperfusion. Using functional imaging techniques, this hypoperfusion and the resulting hypometabolism become detectable in the watershed areas of the brain as early as in the stage of mild cognitive impairment. Hypoperfusion leads to the degeneration of capillaries in this area causing the deterioration of diffusion. The further reduction of nutrient and oxygen support of neurons is capable to initiate a neurodegenerative process which spreads along the glutaminergic system arising from the neurons of the association cortices. The neuropathological lesions of this neuronal system, such as the neurofibrillary tangles and the beta-amyloid plaques, are known to be the characteristic markers of Alzheimer's disease. In our review we present the development of hypoperfusion and its consequences in the watershed areas of the brain and describe the neurodegenerative process of the neuronal system arising from the neurons of the association cortices in the early stage of Alzheimer's disease. Considering the previous hypotheses and the neuropathological lesions of Alzheimer's disease we give a new consensus model to characterize the pathomechanism of the disorder.

  13. The balance between cognitive reserve and brain imaging biomarkers of cerebrovascular and Alzheimer's diseases.

    PubMed

    Murray, Alison D; Staff, Roger T; McNeil, Christopher J; Salarirad, Sima; Ahearn, Trevor S; Mustafa, Nazahah; Whalley, Lawrence J

    2011-12-01

    The cognitive reserve hypothesis explains the disparity between clinical and pathological phenotypes and why, in two individuals with the same extent of neuropathology, one may be demented while the other remains cognitively intact. We examined the balance between brain magnetic resonance imaging measures of the two most common pathologies associated with brain ageing, cerebrovascular disease and Alzheimer's disease, and parameters of cerebral reserve in well-characterized participants born in 1936, for whom childhood intelligence is known. Brain magnetic resonance imaging was carried out at 1.5T using fluid attenuation inversion recovery and T(1)-weighted volumetric sequences in 249 participants. Cerebrovascular disease was quantified by measuring brain white matter hyperintensities on fluid attenuation inversion recovery images using Scheltens' scale and Alzheimer's disease was measured from volumetric data using FreeSurfer to extract whole brain volume and hippocampal volumes in turn. The effect of these measures of brain burden on life-long cognitive ageing from the age of 11 to 68 years was compared with the effect of educational attainment and occupational grade using structural equation modelling. Complete brain burden and reserve data were available in 224 participants. We found that educational attainment, but not occupation, has a measurable and positive effect, with a standardized regression weight of +0.23, on late life cognitive ability in people without cognitive impairment aged 68 years, allowing for the influence of childhood intelligence and the two most common subclinical brain pathological burdens in the ageing brain. In addition, we demonstrate that the magnitude of the contribution of education is greater than the negative impact of either neuropathological burden alone, with standardized regression weights of -0.14 for white matter hyperintensities and -0.20 for hippocampal atrophy. This study illustrates how education counteracts the

  14. Treatments for Alzheimer's Disease

    MedlinePlus

    ... 3900 Find your chapter: search by state Home > Alzheimer's Disease > Treatments Overview What Is Dementia? What Is Alzheimer's? ... and move closer to a cure. Treatments for Alzheimer's disease Currently, there is no cure for Alzheimer's. But ...

  15. Improved language performance in Alzheimer disease following brain stimulation.

    PubMed

    Cotelli, Maria; Calabria, Marco; Manenti, Rosa; Rosini, Sandra; Zanetti, Orazio; Cappa, Stefano F; Miniussi, Carlo

    2011-07-01

    Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a possible treatment for the cognitive deficits associated with Alzheimer disease (AD). The aim of this study was to assess the long-term effects, on cognitive performance, of rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) in AD patients. Ten AD patients were randomly assigned to one of two study groups. Multiple-baseline design was used.The first group underwent a 4-week real rTMS stimulation protocol, while the second underwent a 2-week placebo treatment, followed by 2 weeks of real rTMS stimulation. Each session consisted of the application of rhythmic high-frequency rTMS over the DLPFC for 25 min. Sessions occurred once daily, 5 days/week. The main analysed outcome was the change in cognitive test performance at 2 and 4 weeks after rTMS treatment initiation, with a follow-up performed 8 weeks after the end of rTMS, in comparison with baseline performance. A significant difference was found between groups over sessions in terms of the percentage of correct responses of auditory sentence comprehension. Only real treatment induced an improvement in performance with respect to baseline or placebo. Moreover, both groups showed a lasting effect on the improved performance 8 weeks after the end of treatment. The findings provide initial evidence for the persistent beneficial effects of rTMS on sentence comprehension in AD patients. Rhythmic rTMS, in conjunction with other therapeutic interventions, may represent a novel approach to the treatment of language dysfunction in AD patients.

  16. Pathogenesis and Therapeutic Strategies in Alzheimer's Disease: From Brain to Periphery.

    PubMed

    Yu, Jin-Tai; Zhang, Can

    2016-02-01

    Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder. At present, there are no effective disease-modifying therapies, and the cause of the disease remains unclear. Previously, almost all researchers focus on the brain for exploring the pathogenesis and therapeutic strategies in AD. A recent study by Xiang et al. (Acta Neuropathol 130:487-499, 2015) reported the significance of the physiological capacity of peripheral tissues and organs in clearing brain-derived amyloid-beta (Aβ), which opens a novel avenue to understand the AD pathogenesis and develop therapies for AD.

  17. [Alzheimer and the discovery of Alzheimer's disease].

    PubMed

    Zhagn, Lili; Li, Zhiping

    2014-09-01

    Alzheimer was born in Germany in 1864. In 1887, Alzheimer graduated with a medical doctor degree at the University of Würzburg. In 1888, Alzheimer began to work in the Community Hospital for Mental and Epileptic Patients in Frankfurt am Main for 14 years. During this time, Alzheimer published the six-volume Histologic and Histopathologic Studies of the Cerebral Cortex, with co-author Franz Nissl. In 1903, Alzheimer came to work in the Royal Psychiatric Clinic of the University of Munich. One year later, he published his postdoctoral paper of Histological Studies about the Differential Diagnosis of Progressive Paralysis in 1904. In 1912, Alzheimer was provided the chair of psychiatry at the University of Breslau. On the way to Breslau, Alzheimer got sick, and eventually died in 1915. In 1906, Alzheimer found numerous amyloid plaques and neurofibrillary tangles in the brain of a patient called Auguste under the microscope. In November of the same year, Alzheimer gave a lecture about Auguste's case at the 37(th) Conference of South-West German Psychiatrists in Tübingen, which received little attention. In 1910, Kraepelin mentioned "Alzheimer's disease" for the first time to name the disease of what Auguste got in the 8th edition of Handbook of Psychiatry. Therefore, Alzheimer achieved worldwide recognition.

  18. Differential phosphorylation of tau proteins during kitten brain development and Alzheimer's disease.

    PubMed

    Riederer, B M; Mourton-Gilles, C; Frey, P; Delacourte, A; Probst, A

    2001-02-01

    Differential distribution and phosphorylation of tau proteins were studied in developing kitten brain by using several antibodies, and was compared to phosphorylation in Alzheimer's disease. Several antibodies demonstrated the presence of phosphorylated tau proteins during kitten brain development and identified pathological structures in human brain tissue. Antibody AD2, recognized tau in kittens and adult cats, but reacted in Alzheimer's tissue only with a pathological tau form. Antibody AT8 was prominent in developing kitten neurons and was found in axons and dendrites. After the first postnatal month this phosphorylation type disappeared from axons. Furthermore, dephosphorylation of kitten tau with alkaline phosphatase abolished immunoreactivity of AT8, but not that of AD2, pointing to a protection of the AD2 epitope in cats. Tau proteins during early cat brain development are phosphorylated at several sites that are also phosphorylated in paired helical filaments during Alzheimer's disease. In either event, phosphorylation of tau may play a crucial role to modulate microtubule dynamics, contributing to increased microtubule instability and promoting growth of processes during neuronal development or changing dynamic properties of the cytoskeleton and contributing to the formation of pathological structures in neurodegenerative diseases.

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

    SciTech Connect

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

    1999-06-10

    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 degree sign 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.

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

    NASA Astrophysics Data System (ADS)

    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.

  1. The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update.

    PubMed

    Hoyer, S

    2002-03-01

    Nosologically, Alzheimer disease may not be considered to be a single disorder in spite of a common clinical phenotype. Only a small proportion of about 5% to 10% of all Alzheimer cases is due to genetic mutations (type I) whereas the great majority of patients was found to be sporadic in origin. It may be assumed that susceptibility genes along with lifestyle risk factors contribute to the causation of the age-related sporadic Alzheimer disease (type II). In this context, the desensitization of the neuronal insulin receptor similar to not-insulin dependent diabetes mellitus may be of pivotal significance. This abnormality along with a reduction in brain insulin concentration is assumed to induce a cascade-like process of disturbances including cellular glucose, acetylcholine, cholesterol, and ATP associated with abnormalities in membrane pathology and the formation of both amyloidogenic derivatives and hyperphosphorylated tau protein. Sporadic Alzheimer disease may, thus, be considered to be the brain type of diabetes mellitus II. Experimental evidence is provided and discussed.

  2. Energy and the Alzheimer brain.

    PubMed

    Mamelak, Mortimer

    2017-04-01

    The high energy demands of the poorly myelinated long axon hippocampal and cortical neurons render these neurons selectively vulnerable to degeneration in Alzheimer's disease. However, pathology engages all of the major elements of the neurovascular unit of the mature Alzheimer brain, the neurons, glia and blood vessels. Neurons present with retrograde degeneration of the axodendritic tree, capillaries with string vessels and markedly reduced densities and glia with signs of inflammatory activation. The neurons, capillaries and astrocytes of the mature Alzheimer brain harbor structurally defective mitochondria. Clinically, reduced glucose utilization, decades before cognitive deterioration, betrays ongoing energy insufficiency. β-hydroxybutyrate and γ-hydroxybutyrate can both provide energy to the brain when glucose utilization is blocked. Early work in mouse models of Alzheimer's disease demonstrate their ability to reverse the pathological changes in the Alzheimer brain and initial clinical trials reveal their ability to improve cognition and every day function. Supplying the brain with energy holds great promise for delaying the onset of Alzheimer's disease and slowing its progress.

  3. Neuroinflammation in Alzheimer's disease.

    PubMed

    Heneka, Michael T; Carson, Monica J; El Khoury, Joseph; Landreth, Gary E; Brosseron, Frederic; Feinstein, Douglas L; Jacobs, Andreas H; Wyss-Coray, Tony; Vitorica, Javier; Ransohoff, Richard M; Herrup, Karl; Frautschy, Sally A; Finsen, Bente; Brown, Guy C; Verkhratsky, Alexei; Yamanaka, Koji; Koistinaho, Jari; Latz, Eicke; Halle, Annett; Petzold, Gabor C; Town, Terrence; Morgan, Dave; Shinohara, Mari L; Perry, V Hugh; Holmes, Clive; Bazan, Nicolas G; Brooks, David J; Hunot, Stéphane; Joseph, Bertrand; Deigendesch, Nikolaus; Garaschuk, Olga; Boddeke, Erik; Dinarello, Charles A; Breitner, John C; Cole, Greg M; Golenbock, Douglas T; Kummer, Markus P

    2015-04-01

    Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

  4. Drug delivery to the brain in Alzheimer's disease: consideration of the blood-brain barrier.

    PubMed

    Banks, William A

    2012-05-15

    The successful treatment of Alzheimer's disease (AD) will require drugs that can negotiate the blood-brain barrier (BBB). However, the BBB is not simply a physical barrier, but a complex interface that is in intimate communication with the rest of the central nervous system (CNS) and influenced by peripheral tissues. This review examines three aspects of the BBB in AD. First, it considers how the BBB may be contributing to the onset and progression of AD. In this regard, the BBB itself is a therapeutic target in the treatment of AD. Second, it examines how the BBB restricts drugs that might otherwise be useful in the treatment of AD and examines strategies being developed to deliver drugs to the CNS for the treatment of AD. Third, it considers how drug penetration across the AD BBB may differ from the BBB of normal aging. In this case, those differences can complicate the treatment of CNS diseases such as depression, delirium, psychoses, and pain control in the AD population.

  5. A culture-brain link: Negative age stereotypes predict Alzheimer's disease biomarkers.

    PubMed

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

    2016-02-01

    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 dementia-free participants, in the Baltimore Longitudinal Study of Aging, whose age stereotypes were assessed decades before yearly magnetic resonance images and brain autopsies were performed. Those holding more-negative age stereotypes earlier in life had significantly steeper hippocampal-volume loss and significantly greater accumulation of neurofibrillary tangles and amyloid plaques, adjusting for relevant covariates. These findings suggest a new pathway to identifying mechanisms and potential interventions related to the pathology of Alzheimer's disease.

  6. Low brain ascorbic acid increases susceptibility to seizures in mouse models of decreased brain ascorbic acid transport and Alzheimer's disease.

    PubMed

    Warner, Timothy A; Kang, Jing-Qiong; Kennard, John A; Harrison, Fiona E

    2015-02-01

    Seizures are a known co-occurring symptom of Alzheimer's disease, and they can accelerate cognitive and neuropathological dysfunction. Sub-optimal vitamin C (ascorbic acid) deficiency, that is low levels that do not lead the sufferer to present with clinical signs of scurvy (e.g. lethargy, hemorrhage, hyperkeratosis), are easily obtainable with insufficient dietary intake, and may contribute to the oxidative stress environment of both Alzheimer's disease and epilepsy. The purpose of this study was to test whether mice that have diminished brain ascorbic acid in addition to carrying human Alzheimer's disease mutations in the amyloid precursor protein (APP) and presenilin 1 (PSEN1) genes, had altered electrical activity in the brain (electroencephalography; EEG), and were more susceptible to pharmacologically induced seizures. Brain ascorbic acid was decreased in APP/PSEN1 mice by crossing them with sodium vitamin C transporter 2 (SVCT2) heterozygous knockout mice. These mice have an approximately 30% decrease in brain ascorbic acid due to lower levels of SVCT2 that supplies the brain with ASC. SVCT2+/-APP/PSEN1 mice had decreased ascorbic acid and increased oxidative stress in brain, increased mortality, faster seizure onset latency following treatment with kainic acid (10 mg/kg i.p.), and more ictal events following pentylenetetrazol (50 mg/kg i.p.) treatment. Furthermore, we report the entirely novel phenomenon that ascorbic acid deficiency alone increased the severity of kainic acid- and pentylenetetrazol-induced seizures. These data suggest that avoiding ascorbic acid deficiency may be particularly important in populations at increased risk for epilepsy and seizures, such as Alzheimer's disease. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Conversion from mild cognitive impairment to probable Alzheimer's disease predicted by brain magnetic resonance spectroscopy.

    PubMed

    Modrego, Pedro J; Fayed, Nicolás; Pina, Miguel A

    2005-04-01

    Mild cognitive impairment has been regarded as a pre-Alzheimer condition, but some patients do not develop dementia. Given the available therapies for Alzheimer's disease, early diagnosis is of paramount importance. The authors' objective was to determine whether findings from magnetic resonance spectroscopy (MRS) of the hippocampus and other cortical areas would predict conversion from amnestic mild cognitive impairment to probable Alzheimer's disease. A longitudinal inception cohort of 53 consecutive and incident subjects fulfilling the criteria of amnestic mild cognitive impairment was followed for a mean period of 3 years. At baseline, a neuropsychological examination (Mini-Mental State Examination, Blessed Dementia Rating Scale, Clinical Dementia Rating, verbal fluency test, and memory tests) and standard blood tests were performed, and three cortical areas were examined by proton MRS: left hippocampus, right parietal cortex, and left occipital cortex. The patients were evaluated periodically to detect conversion to probable Alzheimer's disease. The statistical analysis of predictions was based on receiver operating characteristic curves. By the follow-up assessment that occurred on average after 3 years, 29 patients (55%) had developed probable Alzheimer's disease. An occipital cortex N-acetylaspartate/creatine ratio < or =1.61 predicted dementia at 100% sensitivity and 75% specificity (area under the curve=0.91, 95% CI=0.80-0.97). The positive predictive value was 83%, and the negative predictive value was 100%, with an overall cross-validated classification accuracy of 88.7%. None of the values in the hippocampus and parietal cortex had significant predictive value. MRS of the brain performed on patients with mild cognitive impairment is a valuable tool in predicting conversion to probable Alzheimer's disease. Occipital values were more reliable than hippocampal values in this prediction.

  8. Forecasting Alzheimer's Disease.

    ERIC Educational Resources Information Center

    Fackelmann, Kathleen

    1996-01-01

    Suggests that doctors may one day be able to identify healthy people who will develop Alzheimer's disease. Discusses recent studies in which characteristics of a person's writing early in life appear to predict the disease, and brain scans can highlight changes that may precede dementia. (CCM)

  9. Useful Information on...Alzheimer's Disease.

    ERIC Educational Resources Information Center

    Cohen, Gene D.

    This brochure provides information on Alzheimer's disease by examining who gets Alzheimer's disease and what to expect when someone has Alzheimer's disease. Abnormal brain tissue findings are discussed and three clinical features of Alzheimer's disease are listed: dementia; insidious onset of symptoms; and exclusion of all other specific causes of…

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

    PubMed

    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

    2017-01-11

    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

  11. Effects of traumatic brain injury and posttraumatic stress disorder on Alzheimer's disease in veterans, using the Alzheimer's Disease Neuroimaging Initiative.

    PubMed

    Weiner, Michael W; Veitch, Dallas P; Hayes, Jacqueline; Neylan, Thomas; Grafman, Jordan; Aisen, Paul S; Petersen, Ronald C; Jack, Clifford; Jagust, William; Trojanowski, John Q; Shaw, Leslie M; Saykin, Andrew J; Green, Robert C; Harvey, Danielle; Toga, Arthur W; Friedl, Karl E; Pacifico, Anthony; Sheline, Yvette; Yaffe, Kristine; Mohlenoff, Brian

    2014-06-01

    Both traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are common problems resulting from military service, and both have been associated with increased risk of cognitive decline and dementia resulting from Alzheimer's disease (AD) or other causes. This study aims to use imaging techniques and biomarker analysis to determine whether traumatic brain injury (TBI) and/or PTSD resulting from combat or other traumas increase the risk for AD and decrease cognitive reserve in Veteran subjects, after accounting for age. Using military and Department of Veterans Affairs records, 65 Vietnam War veterans with a history of moderate or severe TBI with or without PTSD, 65 with ongoing PTSD without TBI, and 65 control subjects are being enrolled in this study at 19 sites. The study aims to select subject groups that are comparable in age, gender, ethnicity, and education. Subjects with mild cognitive impairment (MCI) or dementia are being excluded. However, a new study just beginning, and similar in size, will study subjects with TBI, subjects with PTSD, and control subjects with MCI. Baseline measurements of cognition, function, blood, and cerebrospinal fluid biomarkers; magnetic resonance images (structural, diffusion tensor, and resting state blood-level oxygen dependent (BOLD) functional magnetic resonance imaging); and amyloid positron emission tomographic (PET) images with florbetapir are being obtained. One-year follow-up measurements will be collected for most of the baseline procedures, with the exception of the lumbar puncture, the PET imaging, and apolipoprotein E genotyping. To date, 19 subjects with TBI only, 46 with PTSD only, and 15 with TBI and PTSD have been recruited and referred to 13 clinics to undergo the study protocol. It is expected that cohorts will be fully recruited by October 2014. This study is a first step toward the design and statistical powering of an AD prevention trial using at-risk veterans as subjects, and provides the

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

    NASA Astrophysics Data System (ADS)

    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.

  13. Amyloid tracers detect multiple binding sites in Alzheimer's disease brain tissue.

    PubMed

    Ni, Ruiqing; Gillberg, Per-Göran; Bergfors, Assar; Marutle, Amelia; Nordberg, Agneta

    2013-07-01

    Imaging fibrillar amyloid-β deposition in the human brain in vivo by positron emission tomography has improved our understanding of the time course of amyloid-β pathology in Alzheimer's disease. The most widely used amyloid-β imaging tracer so far is (11)C-Pittsburgh compound B, a thioflavin derivative but other (11)C- and (18)F-labelled amyloid-β tracers have been studied in patients with Alzheimer's disease and cognitively normal control subjects. However, it has not yet been established whether different amyloid tracers bind to identical sites on amyloid-β fibrils, offering the same ability to detect the regional amyloid-β burden in the brains. In this study, we characterized (3)H-Pittsburgh compound B binding in autopsied brain regions from 23 patients with Alzheimer's disease and 20 control subjects (aged 50 to 88 years). The binding properties of the amyloid tracers FDDNP, AV-45, AV-1 and BF-227 were also compared with those of (3)H-Pittsburgh compound B in the frontal cortices of patients with Alzheimer's disease. Saturation binding studies revealed the presence of high- and low-affinity (3)H-Pittsburgh compound B binding sites in the frontal cortex (K(d1): 3.5 ± 1.6 nM; K(d2): 133 ± 30 nM) and hippocampus (K(d1):5.6 ± 2.2 nM; K(d2): 181 ± 132 nM) of Alzheimer's disease brains. The relative proportion of high-affinity to low-affinity sites was 6:1 in the frontal cortex and 3:1 in the hippocampus. One control showed both high- and low-affinity (3)H-Pittsburgh compound B binding sites (K(d1): 1.6 nM; K(d2): 330 nM) in the cortex while the others only had a low-affinity site (K(d2): 191 ± 70 nM). (3)H-Pittsburgh compound B binding in Alzheimer's disease brains was higher in the frontal and parietal cortices than in the caudate nucleus and hippocampus, and negligible in the cerebellum. Competitive binding studies with (3)H-Pittsburgh compound B in the frontal cortices of Alzheimer's disease brains revealed high- and low-affinity binding sites for BTA

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

    PubMed

    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.

  15. Dynamics of brain structure and cognitive function in the Alzheimer's disease neuroimaging initiative.

    PubMed

    Song, Xiaowei; Mitnitski, Arnold; Zhang, Ningnannan; Chen, Wei; Rockwood, Kenneth

    2013-01-01

    On average, cognition declines as people age, but improvement can also occur. To evaluate the dynamics of age-related changes in brain structure and cognitive function in patients with mild Alzheimer's disease (AD) and mild cognitive impairment (MCI) and in healthy control (HC) older adults. High-resolution 3-Tesla MRI and clinical data were obtained from the Alzheimer's Disease Neuroimaging Initiative in 187 subjects (a cohort aged 55-91 years; AD=43, MCI=84, HC=60). At 24 months, 151 people had clinical and 128 had MRI follow-up. Brain structure was assessed using the Medial Temporal Atrophy Scale (MTAS) and the Brain Atrophy and Lesion Index (BALI). Cognition was assessed using the Mini-Mental State Examination (MMSE) and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). Responsiveness was tested. Changes were analysed using a multistate dynamic model, adjusted for age, gender, ApoE4 genotype and vascular risk factors. Over 2 years, decline in brain structure and cognition predominated, each showing detectable effect sizes (Cohen's d=0.33 for MTAS, 0.32 for BALI, 0.41 for MMSE, 0.38 for ADAS-cog; standard response mean=0.71, 0.69, 0.50 and 0.47, respectively). Structural improvement was observed (10.2% in BALI and 0.8% in MTAS), as was cognitive improvement (23.2% MMSE, 27.2% ADAS-cog). Most people (66.7%) whose BALI score improved also improved in either the MMSE or ADAS-cog. No patient with MCI whose MTAS or BALI improved converted to AD. Despite average decline in brain structure, improvement was observed and related to cognition and MCI-AD conversion. Ageing-related brain changes reflect a dynamic process.

  16. Ethical Considerations for Deep Brain Stimulation Trials in Patients with Early-Onset Alzheimer's Disease.

    PubMed

    Viaña, John Noel M; Bittlinger, Merlin; Gilbert, Frederic

    2017-01-01

    Several studies of deep brain stimulation (DBS) of the fornix or the nucleus basalis of Meynert have been recently conducted in people with Alzheimer's disease, with several recruiting participants <65 and thus have early-onset Alzheimer's disease (EOAD). Although EOAD accounts for less than 5.5% of AD cases, ethical considerations must still be made when performing DBS trials including these participants since a portion of people with EOAD, especially those possessing autosomal-dominant mutations, have an atypical and more aggressive disease progression. These considerations include appropriate patient selection and signing of an informed consent for genetic testing; appropriate study design; potential outcomes that people with EOAD could expect; and accurate interpretation and balanced discussion of trial results. Finally, recommendations for future DBS for AD trials will be made to ensure that EOAD patients will not experience avoidable harms should they be enrolled in these experimental studies.

  17. Alzheimer's Disease Detection in Brain Magnetic Resonance Images Using Multiscale Fractal Analysis

    PubMed Central

    Lahmiri, Salim; Boukadoum, Mounir

    2013-01-01

    We present a new automated system for the detection of brain magnetic resonance images (MRI) affected by Alzheimer's disease (AD). The MRI is analyzed by means of multiscale analysis (MSA) to obtain its fractals at six different scales. The extracted fractals are used as features to differentiate healthy brain MRI from those of AD by a support vector machine (SVM) classifier. The result of classifying 93 brain MRIs consisting of 51 images of healthy brains and 42 of brains affected by AD, using leave-one-out cross-validation method, yielded 99.18% ± 0.01 classification accuracy, 100% sensitivity, and 98.20% ± 0.02 specificity. These results and a processing time of 5.64 seconds indicate that the proposed approach may be an efficient diagnostic aid for radiologists in the screening for AD. PMID:24967286

  18. Changes in brain gene expression shared by scrapie and Alzheimer disease.

    PubMed Central

    Duguid, J R; Bohmont, C W; Liu, N G; Tourtellotte, W W

    1989-01-01

    We have isolated two recombinant cDNAs whose corresponding RNAs have an increased abundance in scrapie-infected hamster brain. DNA sequence analysis has shown that these two recombinants represent the genes for sulfated glycoprotein 2 and transferrin. The abundance of sulfated glycoprotein 2 RNA is increased in hippocampus from patients with Alzheimer disease and Pick disease, whereas transferrin RNA is not strongly modulated in these conditions. Expression of two previously identified scrapie-modulated genes, encoding glial fibrillary acidic protein and metallothionein, is also increased in both of these neurodegenerative diseases. Images PMID:2780570

  19. DNA methylation of Alzheimer disease and tauopathy-related genes in postmortem brain.

    PubMed

    Barrachina, Marta; Ferrer, Isidre

    2009-08-01

    DNA methylation occurs predominantly at cytosines that precede guanines in dinucleotide CpG sites; it is one of the most important mechanisms for epigenetic DNA regulation during normal development and for aberrant DNA in cancer. To determine the feasibility of DNA methylation studies in the postmortem human brain, we evaluated brain samples with variable postmortem artificially increased delays up to 48 hours. DNA methylation was analyzed in selected regions of MAPT, APP, and PSEN1 in the frontal cortex and hippocampus of controls (n=26) and those with Alzheimer disease at Stages I to II (n=17); Alzheimer disease at Stages III to IV (n=15); Alzheimer disease at Stages V to VI (n=12); argyrophilic grain disease (n=10); frontotemporal lobar degeneration linked to tau mutations (n=6); frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions (n=4); frontotemporal lobar degeneration with motor neuron disease (n=3); Pick disease (n=3); Parkinson disease (n=8); dementia with Lewy bodies, pure form (n=5); and dementia with Lewy bodies, common form (n=15). UCHL1 (ubiquitin carboxyl-terminal hydrolase 1 gene) was analyzed in the frontal cortex of controls and those with Parkinson disease and related synucleinopathies. DNA methylation sites were very reproducible in every case. No differences in the percentage of CpG methylation were found between control and disease samples or among the different pathological entities in any region analyzed. Because small changes in methylation of DNA promoters in vulnerable cells might have not been detected in total homogenates, however, these results should be interpreted with caution, particularly as they relate to chronic degenerative diseases in which small modifications may be sufficient to modulate disease progression.

  20. CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer's disease.

    PubMed

    Djelti, Fathia; Braudeau, Jerome; Hudry, Eloise; Dhenain, Marc; Varin, Jennifer; Bièche, Ivan; Marquer, Catherine; Chali, Farah; Ayciriex, Sophie; Auzeil, Nicolas; Alves, Sandro; Langui, Dominique; Potier, Marie-Claude; Laprevote, Olivier; Vidaud, Michel; Duyckaerts, Charles; Miles, Richard; Aubourg, Patrick; Cartier, Nathalie

    2015-08-01

    Abnormalities in neuronal cholesterol homeostasis have been suspected or observed in several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and Huntington's disease. However, it has not been demonstrated whether an increased abundance of cholesterol in neurons in vivo contributes to neurodegeneration. To address this issue, we used RNA interference methodology to inhibit the expression of cholesterol 24-hydroxylase, encoded by the Cyp46a1 gene, in the hippocampus of normal mice. Cholesterol 24-hydroxylase controls cholesterol efflux from the brain and thereby plays a major role in regulating brain cholesterol homeostasis. We used an adeno-associated virus vector encoding short hairpin RNA directed against the mouse Cyp46a1 mRNA to decrease the expression of the Cyp46a1 gene in hippocampal neurons of normal mice. This increased the cholesterol concentration in neurons, followed by cognitive deficits and hippocampal atrophy due to apoptotic neuronal death. Prior to neuronal death, the recruitment of the amyloid protein precursor to lipid rafts was enhanced leading to the production of β-C-terminal fragment and amyloid-β peptides. Abnormal phosphorylation of tau and endoplasmic reticulum stress were also observed. In the APP23 mouse model of Alzheimer's disease, the abundance of amyloid-β peptides increased following inhibition of Cyp46a1 expression, and neuronal death was more widespread than in normal mice. Altogether, these results suggest that increased amounts of neuronal cholesterol within the brain may contribute to inducing and/or aggravating Alzheimer's disease. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  1. Increased brain iron coincides with early plaque formation in a mouse model of Alzheimer's disease

    SciTech Connect

    Leskovjan, A.C.; Miller, L.; Kretlow, A.; Lanzirotti, A.; Barrea,R.; Vogt, S.

    2010-11-23

    Elevated brain iron content, which has been observed in late-stage human Alzheimer's disease, is a potential target for early diagnosis. However, the time course for iron accumulation is currently unclear. Using the PSAPP mouse model of amyloid plaque formation, we conducted a time course study of metal ion content and distribution [iron (Fe), copper (Cu), and zinc (Zn)] in the cortex and hippocampus using X-ray fluorescence microscopy (XFM). We found that iron in the cortex was 34% higher than age-matched controls at an early stage, corresponding to the commencement of plaque formation. The elevated iron was not associated with the amyloid plaques. Interestingly, none of the metal ions were elevated in the amyloid plaques until the latest time point (56 weeks), where only the Zn content was significantly elevated by 38%. Since neuropathological changes in human Alzheimer's disease are presumed to occur years before the first cognitive symptoms appear, quantification of brain iron content could be a powerful marker for early diagnosis of Alzheimer's disease.

  2. Alzheimer's Disease Brain Areas: The Machine Learning Support for Blind Localization.

    PubMed

    Vigneron, V; Kodewitz, A; Tome, A M; Lelandais, S; Lang, E

    2016-01-01

    The analysis of positron emission tomography (PET) scan image is challenging due to a high level of noise and a low resolution and also because differences between healthy and demented are very subtle. High dimensional classification methods based on PET have been proposed to automatically discriminate between normal control group (NC) patients and patients with Alzheimer's disease (AD), with mild cognitive impairment (MCI), and mild cognitive impairment converting to Alzheimer's disease (MCIAD ) (a group of patients that clearly degrades to AD). We developed a voxelbased method for volumetric image analysis. We performed 3 classification experiments AD vs CG, AD vs MCI, MCIAD vs MCI. We will also give a small demonstration of the presented method on a set of face images. This method is capable to extract information about the location of metabolic changes induced by Alzheimer's disease that directly relies statistical features and brain regions of interest (ROIs). We produce "maps" to visualize the most informative regions of the brain and compare them with voxel-wise statistics. Using the mean intensity of about 2000 6 × 6 × 6mm patches, selected by the extracted map, as input for a classifier we obtain a classification rate of 95.5%.

  3. Transcranial magnetic stimulation of degenerating brain: a comparison of normal aging, Alzheimer's, Parkinson's and Huntington's disease.

    PubMed

    Ljubisavljevic, M R; Ismail, F Y; Filipovic, S

    2013-07-01

    Although the brain's ability to change constantly in response to external and internal inputs is now well recognized the mechanisms behind it in normal aging and neurodegeneration are less well understood. To gain a better understanding, transcranial magnetic stimulation (TMS) has been used extensively to characterize non-invasively the cortical neurophysiology of the aging and degenerating brain. Furthermore, there has been a surge of studies examining whether repetitive TMS (rTMS) can be used to improve functional deficits in various conditions including normal aging, Alzheimer's and Parkinson's disease. The results of these studies in normal aging and neurodegeneration have emerged reasonably coherent in delineating the main pathology in spite of considerable technical limitations, omnipresent methodological variability, and extraordinary patient heterogeneity. Nevertheless, comparing and integrating what is known about TMS measurements of cortical excitability and plasticity in disorders that predominantly affect cortical brain structures with disorders that predominantly affect subcortical brain structures may provide better understanding of normal and abnormal brain aging fostering new. The present review provides a TMS perspective of changes in cortical neurophysiology and neurochemistry in normal aging and neurodegeneration by integrating what is revealed in individual TMS measurements of cortical excitability and plasticity in physiological aging, Alzheimer's, Parkinson's, and Huntington's, disease. The paper also reflects on current developments in utilizing TMS as a physiologic biomarker to discriminate physiologic aging from neurodegeneration and its potential as a method of therapeutic intervention.

  4. Brain collection, standardized neuropathologic assessment, and comorbidity in Alzheimer's Disease Neuroimaging Initiative 2 participants.

    PubMed

    Franklin, Erin E; Perrin, Richard J; Vincent, Benjamin; Baxter, Michael; Morris, John C; Cairns, Nigel J

    2015-07-01

    The Alzheimer's Disease Neuroimaging Initiative Neuropathology Core (ADNI-NPC) facilitates brain donation, ensures standardized neuropathologic assessments, and maintains a tissue resource for research. The ADNI-NPC coordinates with performance sites to promote autopsy consent, facilitate tissue collection and autopsy administration, and arrange sample delivery to the NPC, for assessment using National Institute on Aging-Alzheimer's Association neuropathologic diagnostic criteria. The ADNI-NPC has obtained 45 participant specimens, and neuropathologic assessments have been completed in 36 to date. Challenges in obtaining consent at some sites have limited the voluntary autopsy rate to 58%. Among assessed cases, clinical diagnostic accuracy for Alzheimer disease (AD) is 97%; however, 58% of cases show neuropathologic comorbidities. Challenges facing autopsy consent and coordination are largely resource related. The neuropathologic assessments indicate that ADNI's clinical diagnostic accuracy for AD is high; however, many AD cases have comorbidities that may impact the clinical presentation, course, and imaging and biomarker results. These neuropathologic data permit multimodal and genetic studies of these comorbidities to improve diagnosis and provide etiologic insights. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  5. Predicting brain network changes in Alzheimer's disease with link prediction algorithms.

    PubMed

    Sulaimany, Sadegh; Khansari, Mohammad; Zarrineh, Peyman; Daianu, Madelaine; Jahanshad, Neda; Thompson, Paul M; Masoudi-Nejad, Ali

    2017-03-28

    Link prediction is a promising research area for modeling various types of networks and has mainly focused on predicting missing links. Link prediction methods may be valuable for describing brain connectivity, as it changes in Alzheimer's disease (AD) and its precursor, mild cognitive impairment (MCI). Here, we analyzed 3-tesla whole-brain diffusion-weighted images from 202 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) - 50 healthy controls, 72 with earlyMCI (eMCI) and 38 with lateMCI (lMCI) and 42 AD patients. We introduce a novel approach for Mixed Link Prediction (MLP) to test and define the percent of predictability of each heightened stage of dementia from its previous, less impaired stage, in the simplest case. Using well-known link prediction algorithms as the core of MLP, we propose a new approach that predicts stages of cognitive impairment by simultaneously adding and removing links in the brain networks of elderly individuals. We found that the optimal algorithm, called "Adamic and Adar", had the best fit and most accurately predicted the stages of AD from their previous stage. When compared to the other link prediction algorithms, that mainly only predict the added links, our proposed approach can more inclusively simulate the brain changes during disease by both adding and removing links of the network. Our results are also in line with computational neuroimaging and clinical findings and can be improved for better results.

  6. Parvalbumin-immunoreactive neurons in the hippocampal formation of Alzheimer's diseased brain.

    PubMed

    Brady, D R; Mufson, E J

    1997-10-01

    The number and topographic distribution of immunocytochemically stained parvalbumin interneurons was determined in the hippocampal formation of control and Alzheimer's diseased brain. In control hippocampus, parvalbumin interneurons were aspiny and pleomorphic, with extensive dendritic arbors. In dentate gyrus, parvalbumin cells, as well as a dense plexus of fibers and puncta, were associated with the granule cell layer. A few cells also occupied the molecular layer. In strata oriens and pyramidale of CA1-CA3 subfields, parvalbumin neurons gave rise to dendrites that extended into adjacent strata. Densely stained puncta and beaded fibers occupied stratum pyramidale, with less dense staining in adjacent strata oriens and radiatum. Virtually no parvalbumin profiles were observed in stratum lacunosum-moleculare or the alveus. Numerous polymorphic parvalbumin neurons and a dense plexus of fibers and puncta characterized the deep layer of the subiculum and the lamina principalis externa of the presubiculum. In Alzheimer's diseased hippocampus, there was an approximate 60% decrease in the number of parvalbumin interneurons in the dentate gyrus/CA4 subfield (P<0.01) and subfields CA1-CA2 (P<0.01). In contrast, parvalbumin neurons did not statistically decline in subfields CA3, subiculum or presubiculum in Alzheimer's diseased brains relative to controls. Concurrent staining with Thioflavin-S histochemistry did not reveal degenerative changes within parvalbumin-stained profiles. These findings reveal that parvalbumin interneurons within specific hippocampal subfields are selectively vulnerable in Alzheimer's disease. This vulnerability may be related to their differential connectivity, e.g., those regions connectionally related to the cerebral cortex (dentate gyrus and CA1) are more vulnerable than those regions connectionally related to subcortical loci (subiculum and presubiculum).

  7. Terahertz spectroscopy of brain tissue from a mouse model of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Shi, Lingyan; Shumyatsky, Pavel; Rodríguez-Contreras, Adrián; Alfano, Robert

    2016-01-01

    The terahertz (THz) absorption and index of refraction of brain tissues from a mouse model of Alzheimer's disease (AD) and a control wild-type (normal) mouse were compared using THz time-domain spectroscopy (THz-TDS). Three dominating absorption peaks associated to torsional-vibrational modes were observed in AD tissue, at about 1.44, 1.8, and 2.114 THz, closer to the peaks of free tryptophan molecules than in normal tissue. A possible reason is that there is more free tryptophan in AD brain tissue, while in normal brain tissue more tryptophan is attached to other molecules. Our study suggests that THz-absorption modes may be used as an AD biomarker fingerprint in brain, and that THz-TDS is a promising technique for early diagnosis of AD.

  8. Increased selenoprotein P in choroid plexus and cerebrospinal fluid in Alzheimer's disease brain.

    PubMed

    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.

  9. A Structural Parametrization of the Brain Using Hidden Markov Models-Based Paths in Alzheimer's Disease.

    PubMed

    Martinez-Murcia, Francisco J; Górriz, Juan M; Ramírez, Javier; Ortiz, Andres

    2016-11-01

    The usage of biomedical imaging in the diagnosis of dementia is increasingly widespread. A number of works explore the possibilities of computational techniques and algorithms in what is called computed aided diagnosis. Our work presents an automatic parametrization of the brain structure by means of a path generation algorithm based on hidden Markov models (HMMs). The path is traced using information of intensity and spatial orientation in each node, adapting to the structure of the brain. Each path is itself a useful way to characterize the distribution of the tissue inside the magnetic resonance imaging (MRI) image by, for example, extracting the intensity levels at each node or generating statistical information of the tissue distribution. Additionally, a further processing consisting of a modification of the grey level co-occurrence matrix (GLCM) can be used to characterize the textural changes that occur throughout the path, yielding more meaningful values that could be associated to Alzheimer's disease (AD), as well as providing a significant feature reduction. This methodology achieves moderate performance, up to 80.3% of accuracy using a single path in differential diagnosis involving Alzheimer-affected subjects versus controls belonging to the Alzheimer's disease neuroimaging initiative (ADNI).

  10. Genetic variants in Alzheimer disease – molecular and brain network approaches

    PubMed Central

    Gaiteri, Chris; Mostafavi, Sara; Honey, Christopher; De Jager, Philip L.; Bennett, David A.

    2016-01-01

    Genetic studies in late-onset Alzheimer disease (LOAD) are aimed at identifying core disease mechanisms and providing potential biomarkers and drug candidates to improve clinical care for AD. However, due to the complexity of LOAD, including pathological heterogeneity and disease polygenicity, extracting actionable guidance from LOAD genetics has been challenging. Past attempts to summarize the effects of LOAD-associated genetic variants have used pathway analysis and collections of small-scale experiments to hypothesize functional convergence across several variants. In this review, we discuss how the study of molecular, cellular and brain networks provides additional information on the effect of LOAD-associated genetic variants. We then discuss emerging combinations of omic data types in multiscale models, which provide a more comprehensive representation of the effect of LOAD-associated genetic variants at multiple biophysical scales. Further, we highlight the clinical potential of mechanistically coupling genetic variants and disease phenotypes with multiscale brain models. PMID:27282653

  11. Epidemiology of Alzheimer disease.

    PubMed

    Mayeux, Richard; Stern, Yaakov

    2012-08-01

    The global prevalence of dementia has been estimated to be as high as 24 million, and is predicted to double every 20 years until at least 2040. As the population worldwide continues to age, the number of individuals at risk will also increase, particularly among the very old. Alzheimer disease is the leading cause of dementia beginning with impaired memory. The neuropathological hallmarks of Alzheimer disease include diffuse and neuritic extracellular amyloid plaques in brain that are frequently surrounded by dystrophic neurites and intraneuronal neurofibrillary tangles. The etiology of Alzheimer disease remains unclear, but it is likely to be the result of both genetic and environmental factors. In this review we discuss the prevalence and incidence rates, the established environmental risk factors, and the protective factors, and briefly review genetic variants predisposing to disease.

  12. Epidemiology of Alzheimer Disease

    PubMed Central

    Mayeux, Richard; Stern, Yaakov

    2012-01-01

    The global prevalence of dementia has been estimated to be as high as 24 million, and is predicted to double every 20 years until at least 2040. As the population worldwide continues to age, the number of individuals at risk will also increase, particularly among the very old. Alzheimer disease is the leading cause of dementia beginning with impaired memory. The neuropathological hallmarks of Alzheimer disease include diffuse and neuritic extracellular amyloid plaques in brain that are frequently surrounded by dystrophic neurites and intraneuronal neurofibrillary tangles. The etiology of Alzheimer disease remains unclear, but it is likely to be the result of both genetic and environmental factors. In this review we discuss the prevalence and incidence rates, the established environmental risk factors, and the protective factors, and briefly review genetic variants predisposing to disease. PMID:22908189

  13. Cross-region reduction in 5-hydroxymethylcytosine in Alzheimer's disease brain.

    PubMed

    Condliffe, Daniel; Wong, Andrew; Troakes, Claire; Proitsi, Petroula; Patel, Yogen; Chouliaras, Leonidas; Fernandes, Cathy; Cooper, Jonathan; Lovestone, Simon; Schalkwyk, Leonard; Mill, Jonathan; Lunnon, Katie

    2014-08-01

    Epigenetic processes play a key role in the central nervous system and altered levels of 5-methylcytosine have been associated with a number of neurologic phenotypes, including Alzheimer's disease (AD). Recently, 3 additional cytosine modifications have been identified (5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine), which are thought to be intermediate steps in the demethylation of 5-methylcytosine to unmodified cytosine. Little is known about the frequency of these modifications in the human brain during health or disease. In this study, we used immunofluorescence to confirm the presence of each modification in human brain and investigate their cross-tissue abundance in AD patients and elderly control samples. We identify a significant AD-associated decrease in global 5-hydroxymethylcytosine in entorhinal cortex and cerebellum, and differences in 5-formylcytosine levels between brain regions. Our study further implicates a role for epigenetic alterations in AD.

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

    PubMed

    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.

  15. Head or brain injuries and Alzheimer's disease: A nested case-control register study.

    PubMed

    Tolppanen, Anna-Maija; Taipale, Heidi; Hartikainen, Sirpa

    2017-06-07

    Many previous studies have been limited by self- or proxy-reported injury or short follow-up. We investigated whether head or brain injuries are associated with Alzheimer's disease (AD), possible modifying factors and dose-response relationship. Nested register-based case-control study of all community dwellers who received clinically verified AD diagnosis in Finland in 2005 to 2011 (n = 70,719) and one to four matched controls for each case (n of controls = 282,862). The magnitude of association between hospital-treated head and/or brain injuries was strongly dependent on the lag time between exposure and outcome. With a 5-year lag time, head injury (adjusted odds ratio; 95% confidence interval 1.19; 1.15-1.23) or brain injury (1.23; 1.18-1.29) was associated with higher risk of AD. Dose-response relationship with number and severity of injuries was observed. Associations were stronger in those with earlier onset of AD. Stronger associations with shorter lag times indicate that head and/or brain injuries may also reflect the ongoing AD disease process. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  16. Brain glucose metabolism: Role of Wnt signaling in the metabolic impairment in Alzheimer's disease.

    PubMed

    Cisternas, Pedro; Inestrosa, Nibaldo C

    2017-06-15

    The brain is an organ that has a high demand for glucose. In the brain, glucose is predominantly used in energy production, with almost 70% of the energy used by neurons. The importance of the energy requirement in neurons is clearly demonstrated by the fact that all neurodegenerative disorders exhibit a critical metabolic impairment that includes decreased glucose uptake/utilization and decreased mitochondrial activity, with a consequent diminution in ATP production. In fact, in Alzheimer's disease, the measurement of the general metabolic rate of the brain has been reported to be an accurate tool for diagnosis. Additionally, the administration of metabolic activators such as insulin/glucagon-like peptide 1 can improve memory/learning performance. Despite the importance of energy metabolism in the brain, little is known about the cellular pathways involved in the regulation of this process. Several reports postulate a role for Wnt signaling as a general metabolic regulator. Thus, in the present review, we discuss the antecedents that support the relationship between Wnt signaling and energy metabolism in the Alzheimer's disease. Copyright © 2017. Published by Elsevier Ltd.

  17. DNA methylation map of mouse and human brain identifies target genes in Alzheimer's disease.

    PubMed

    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; Esteller, Manel

    2013-10-01

    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.

  18. Impact of Angiotensin receptor blockers on Alzheimer disease neuropathology in a large brain autopsy series.

    PubMed

    Hajjar, Ihab; Brown, Lauren; Mack, Wendy J; Chui, Helena

    2012-12-01

    BACKGROUND Angiotensin II may be involved in amyloid metabolism in the brain. Angiotensin receptor blockers (ARBs) may also prevent cognitive decline. OBJECTIVE To evaluate the impact of treatment with ARBs on the neuropathology of Alzheimer disease (AD) in the National Alzheimer Coordinating Center database, which includes aggregated data and brain autopsies from 29 AD centers throughout the United States. DESIGN Multiple logistic regression was used to compare the pathologic findings in hypertensive subjects taking ARBs with those taking other antihypertensive treatments as well as with hypertensive subjects who did not receive antihypertensive medications. SETTING Neuropathologic data included neuritic plaque and neurofibrillary tangle measures and vascular injury markers. PATIENTS Data were collected from participants who were self-referred or provider-referred and included those with and without cognitive disorders. Our sample included only hypertensive participants and excluded cognitively and neuropathologically normal participants (N = 890; mean age at death, 81 years [range, 39-107 years]; 43% women; 94% white). RESULTS Participants with or without AD who were treated with ARBs showed less amyloid deposition markers compared with those treated with other antihypertensive medications (lower Consortium to Establish a Registry of Alzheimer Disease score: odds ratio, 0.47, 95% CI, 0.27-0.81; Alzheimer Disease and Related Disorders Association score: odds ratio, 0.43, 95% CI, 0.21-0.91; Braak and Braak stage: odds ratio, 0.52, 95% CI, 0.31-0.85; neuritic plaques: odds ratio, 0.59, 95% CI, 0.37-0.96). They also had less AD-related pathology compared with untreated hypertensive subjects. Participants who received ARBs were more likely to have had a stroke; hence, they had more frequent pathologic evidence of large vessel infarct and hemorrhage. CONCLUSION Treatment with ARBs is associated with less AD-related pathology on autopsy evaluations. The effect of ARBs

  19. Aluminium exposure induces Alzheimer's disease-like histopathological alterations in mouse brain.

    PubMed

    Rodella, L F; Ricci, F; Borsani, E; Stacchiotti, A; Foglio, E; Favero, G; Rezzani, R; Mariani, C; Bianchi, R

    2008-04-01

    Aluminium (Al) is a neurotoxic metal and Al exposure may be a factor in the aetiology of various neurodegenerative diseases such as Alzheimer's disease (AD). The major pathohistological findings in the AD brain are the presence of neuritic plaques containing beta-amyloid (Abeta) which may interfere with neuronal communication. Moreover, it has been observed that GRP78, a stress-response protein induced by conditions that adversely affect endoplasmic reticulum (ER) function, is reduced in the brain of AD patients. In this study, we investigated the correlation between the expression of Abeta and GRP78 in the brain cortex of mice chronically treated with aluminium sulphate. Chronic exposure over 12 months to aluminium sulphate in drinking water resulted in deposition of Abeta similar to that seen in congophilic amyloid angiopathy (CAA) in humans and a reduction in neuronal expression of GRP78 similar to what has previously been observed in Alzheimer's disease. So, we hypothesise that chronic Al administration is responsible for oxidative cell damage that interferes with ER functions inducing Abeta accumulation and neurodegenerative damage.

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

    PubMed

    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).

  1. Traumatic Brain Injury as a Risk Factor for Alzheimer's Disease: Is Inflammatory Signaling a Key Player?

    PubMed

    Djordjevic, Jelena; Sabbir, Mohammad Golam; Albensi, Benedict C

    2016-01-01

    Traumatic brain injury (TBI) has become a significant medical and social concern within the last 30 years. TBI has acute devastating effects, and in many cases, seems to initiate long-term neurodegeneration. With advances in medical technology, many people are now surviving severe brain injuries and their long term consequences. Post trauma effects include communication problems, sensory deficits, emotional and behavioral problems, physical complications and pain, increased suicide risk, dementia, and an increased risk for chronic CNS diseases, such as Alzheimer's disease (AD). In this review, we provide an introduction to TBI and hypothesize how it may lead to neurodegenerative disease in general and AD in particular. In addition, we discuss the evidence that supports the hypothesis that TBI may lead to AD. In particular, we focus on inflammatory responses as key processes in TBI-induced secondary injury, with emphasis on nuclear factor kappa B (NF-κB) signaling.

  2. Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease

    PubMed Central

    Chen, Xuesong; Gawryluk, Jeremy W; Wagener, John F; Ghribi, Othman; Geiger, Jonathan D

    2008-01-01

    High levels of serum cholesterol and disruptions of the blood brain barrier (BBB) have all been implicated as underlying mechanisms in the pathogenesis of Alzheimer's disease. Results from studies conducted in animals and humans suggest that caffeine might be protective against Alzheimer's disease but by poorly understood mechanisms. Using rabbits fed a cholesterol-enriched diet, we tested our hypothesis that chronic ingestion of caffeine protects against high cholesterol diet-induced disruptions of the BBB. New Zealand rabbits were fed a 2% cholesterol-enriched diet, and 3 mg caffeine was administered daily in drinking water for 12 weeks. Total cholesterol and caffeine concentrations from blood were measured. Olfactory bulbs (and for some studies hippocampus and cerebral cortex as well) were evaluated for BBB leakage, BBB tight junction protein expression levels, activation of astrocytes, and microglia density using histological, immunostaining and immunoblotting techniques. We found that caffeine blocked high cholesterol diet-induced increases in extravasation of IgG and fibrinogen, increases in leakage of Evan's blue dye, decreases in levels of the tight junction proteins occludin and ZO-1, increases in astrocytes activation and microglia density where IgG extravasation was present. Chronic ingestion of caffeine protects against high cholesterol diet-induced increases in disruptions of the BBB, and caffeine and drugs similar to caffeine might be useful in the treatment of Alzheimer's disease. PMID:18387175

  3. Distribution of PSA-NCAM in normal, Alzheimer's and Parkinson's disease human brain.

    PubMed

    Murray, Helen C; Low, Victoria F; Swanson, Molly E V; Dieriks, Birger V; Turner, Clinton; Faull, Richard L M; Curtis, Maurice A

    2016-08-25

    Polysialated neural cell adhesion molecule (PSA-NCAM) is a membrane bound glycoprotein widely expressed during nervous system development. While commonly described in the neurogenic niches of the adult human brain, there is limited evidence of its distribution in other brain regions. PSA-NCAM is an important regulator of cell-cell interactions and facilitates cell migration and plasticity. Recent evidence suggests these functions may be altered in neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD). This study provides a detailed description of the PSA-NCAM distribution throughout the human brain and quantitatively compares the staining load in cortical regions and sub-cortical structures between the control, AD and PD brain. Our results provide evidence of widespread, yet specific, PSA-NCAM expression throughout the human brain including regions devoid of PSA-NCAM in the rodent brain such as the caudate nucleus (CN) and cerebellum (CB). We also detected a significant reduction in PSA-NCAM load in the entorhinal cortex (EC) of cases that was inversely correlated with hyperphosphorylated tau load. These results demonstrate that PSA-NCAM-mediated structural plasticity may not be limited to neurogenic niches and is conserved in the aged brain. We also provide evidence that PSA-NCAM is reduced in the EC, a region severely affected by AD pathology. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Regional analysis of the magnetization transfer ratio of the brain in mild Alzheimer disease and amnestic mild cognitive impairment.

    PubMed

    Mascalchi, M; Ginestroni, A; Bessi, V; Toschi, N; Padiglioni, S; Ciulli, S; Tessa, C; Giannelli, M; Bracco, L; Diciotti, S

    2013-01-01

    Manually drawn VOI-based analysis shows a decrease in magnetization transfer ratio in the hippocampus of patients with Alzheimer disease. We investigated with whole-brain voxelwise analysis the regional changes of the magnetization transfer ratio in patients with mild Alzheimer disease and patients with amnestic mild cognitive impairment. Twenty patients with mild Alzheimer disease, 27 patients with amnestic mild cognitive impairment, and 30 healthy elderly control subjects were examined with high-resolution T1WI and 3-mm-thick magnetization transfer images. Whole-brain voxelwise analysis of magnetization transfer ratio maps was performed by use of Statistical Parametric Mapping 8 software and was supplemented by the analysis of the magnetization transfer ratio in FreeSurfer parcellation-derived VOIs. Voxelwise analysis showed 2 clusters of significantly decreased magnetization transfer ratio in the left hippocampus and amygdala and in the left posterior mesial temporal cortex (fusiform gyrus) of patients with Alzheimer disease as compared with control subjects but no difference between patients with amnestic mild cognitive impairment and either patients with Alzheimer disease or control subjects. VOI analysis showed that the magnetization transfer ratio in the hippocampus and amygdala was significantly lower (bilaterally) in patients with Alzheimer disease when compared with control subjects (ANOVA with Bonferroni correction, at P < .05). Mean magnetization transfer ratio values in the hippocampus and amygdala in patients with amnestic mild cognitive impairment were between those of healthy control subjects and those of patients with mild Alzheimer disease. Support vector machine-based classification demonstrated improved classification performance after inclusion of magnetization transfer ratio-related features, especially between patients with Alzheimer disease versus healthy subjects. Bilateral but asymmetric decrease of magnetization transfer ratio reflecting

  5. Rubidium and potassium levels are altered in Alzheimer's disease brain and blood but not in cerebrospinal fluid.

    PubMed

    Roberts, Blaine R; Doecke, James D; Rembach, Alan; Yévenes, L Fernanda; Fowler, Christopher J; McLean, Catriona A; Lind, Monica; Volitakis, Irene; Masters, Colin L; Bush, Ashley I; Hare, Dominic J

    2016-11-14

    Loss of intracellular compartmentalization of potassium is a biochemical feature of Alzheimer's disease indicating a loss of membrane integrity and mitochondrial dysfunction. We examined potassium and rubidium (a biological proxy for potassium) in brain tissue, blood fractions and cerebrospinal fluid from Alzheimer's disease and healthy control subjects to investigate the diagnostic potential of these two metal ions. We found that both potassium and rubidium levels were significantly decreased across all intracellular compartments in the Alzheimer's disease brain. Serum from over 1000 participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL), showed minor changes according to disease state. Potassium and rubidium levels in erythrocytes and cerebrospinal fluid were not significantly different according to disease state, and rubidium was slightly decreased in Alzheimer's disease patients compared to healthy controls. Our data provides evidence that contrasts the hypothesized disruption of the blood-brain barrier in Alzheimer's disease, with the systemic decrease in cortical potassium and rubidium levels suggesting influx of ions from the blood is minimal and that the observed changes are more likely indicative of an internal energy crisis within the brain. These findings may be the basis for potential diagnostic imaging studies using radioactive potassium and rubidium tracers.

  6. [Biomarkers of Alzheimer disease].

    PubMed

    Rachel, Wojciech; Grela, Agatha; Zyss, Tomasz; Zieba, Andrzej; Piekoszewski, Wojciech

    2014-01-01

    Cognitive impairment is one of the most abundant age-related psychiatric disorders. The outcome of cognitive impairment in Alzheimer's disease has both individual (the patients and their families) and socio-economic effects. The prevalence of Alzheimer's disease doubles after the age of 65 years, every 4.5 years. An etiologically heterogenic group of disorders related to aging as well as genetic and environmental interactions probably underlie the impairment in Alzheimer's disease. Those factors cause the degeneration of brain tissue which leads to significant cognitive dysfunction. There are two main hypotheses that are linked to the process of neurodegeneration: (i) amyloid cascade and (ii) the role of secretases and dysfunction of mitochondria. From the therapeutic standpoint it is crucial to get an early diagnosis and start with an adequate treatment. The undeniable progress in the field of biomarker research should lead to a better understanding of the early stages of the disorder. So far, the best recognised and described biomarkers of Alzheimer's disease, which can be detected in both cerebrospinal fluid and blood, are: beta-amyloid, tau-protein and phosphorylated tau-protein (phospho-tau). The article discusses the usefulness of the known biomarkers of Alzheimer's disease in early diagnosis.

  7. Predicting Alzheimer's disease by classifying 3D-Brain MRI images using SVM and other well-defined classifiers

    NASA Astrophysics Data System (ADS)

    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.

  8. Altered brain uptake of therapeutics in a triple transgenic mouse model of Alzheimer's disease.

    PubMed

    Mehta, Dharmini C; Short, Jennifer L; Nicolazzo, Joseph A

    2013-11-01

    The purpose of this study was to systematically assess the impact of Alzheimer's disease (AD)-associated blood-brain barrier (BBB) alterations on the uptake of therapeutics into the brain. The brain uptake of probe compounds was measured in 18-20 month old wild type (WT) and triple transgenic (3×TG) AD mice using an in situ transcardiac perfusion technique. These results were mechanistically correlated with immunohistochemical and molecular studies. The brain uptake of the paracellular marker, [(14)C] sucrose, did not differ between WT and 3×TG mice. The brain uptake of passively diffusing markers, [(3)H] diazepam and [(3)H] propranolol, decreased 54-60% in 3×TG mice, consistent with a 33.5% increase in the thickness of the cerebrovascular basement membrane in 3×TG mice. Despite a 42.4% reduction in P-gp expression in isolated brain microvessels from a sub-population of 3×TG mice (relative to WT mice), the brain uptake of P-gp substrates ([(3)H] digoxin, [(3)H] loperamide and [(3)H] verapamil) was not different between genotypes, likely due to a compensatory thickening in the cerebrovascular basement membrane counteracting any reduced efflux of these lipophilic substrates. These studies systematically assessed the impact of AD on BBB drug transport in a relevant animal model, and have demonstrated a reduction in the brain uptake of passively-absorbed molecules in this mouse model of AD.

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

    PubMed

    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.

  10. Reactive microglia specifically associated with amyloid plaques in Alzheimer's disease brain tissue express melanotransferrin.

    PubMed

    Jefferies, W A; Food, M R; Gabathuler, R; Rothenberger, S; Yamada, T; Yasuhara, O; McGeer, P L

    1996-03-11

    Several investigations have implicated the involvement of metals in neuropathologies. In particular, the disruption of iron metabolism and iron transport molecules have been demonstrated in Alzheimer's disease (AD). We have identified a novel pathway of iron uptake into mammalian cells involving melanotransferrin, or p97, which is independent of the transferrin receptor. Here we investigated whether there is a possible link between this molecule and the pathology of AD. The distributions of melanotransferrin, transferrin and the transferrin receptor were studied immunohistochemically in brain tissues from AD cases. In brain tissues from AD, melanotransferrin and the transferrin receptor were highly localized to capillary endothelium, while transferrin itself was mainly localized to glial cells. In brain tissue derived from AD patients, melanotransferrin was additionally detected in a subset of reactive microglia associated with senile plaques. Our demonstration that melanotransferrin mediates iron uptake through a pathway independent of the transferrin receptor indicates that this mechanism may have a role in AD.

  11. African American participation in Alzheimer's disease research that includes brain donation.

    PubMed

    Darnell, Kathryn R; McGuire, Caitlin; Danner, Deborah D

    2011-09-01

    Historically, minority groups have been underrepresented in research and clinical trials. The lack of participation by minorities has been attributed to a variety of factors including a mistrust of the predominately white research establishments and a lack of education about the purpose of research. The current study was designed to determine African American interest in Alzheimer's disease (AD) research and to recruit African Americans as normal controls in current AD studies with the goal of eventually gaining consent for brain donation upon death. Participants were 46 African Americans aged 65 or older, who were interviewed about the knowledge of medical procedures and experience with research. After initial recruitment interviews, 31.7% of participants agreed to yearly testing with eventual brain donation. Study findings suggest a moderate relationship between participants' knowledge of medical procedures used to prolong life and willingness to donate one's brain.

  12. Instrumental neutron activation analysis of brain aluminum in Alzheimer disease and aging.

    PubMed

    Markesbery, W R; Ehmann, W D; Hossain, T I; Alauddin, M; Goodin, D T

    1981-12-01

    Instrumental neutron activation analysis procedures were used to determine the aluminum content of various brain regions in histologically verified Alzheimer disease (AD) and in controls. The grand mean aluminum level for 74 AD specimens was 0.372 +/- 0.058 microgram/gm and for 137 adult controls, 0.467 +/- 0.033 microgram/gm, both on a wet weight basis. No difference was found at the bulk sample level between AD and adult controls, corrected for age and sex, or when frontal, temporal, and hippocampal specimens were compared. Control specimens (infancy to 85 years) showed an increase in brain aluminum concentration with age. Comparison of freeze-dried to wet weight ratios of AD and controls revealed a small increase in water content in AD brains.

  13. Oxidative modification of proteins in the frontal cortex of Alzheimer's disease brain.

    PubMed

    Korolainen, Minna A; Goldsteins, Gundars; Nyman, Tuula A; Alafuzoff, Irina; Koistinaho, Jari; Pirttilä, Tuula

    2006-01-01

    There is a large body of evidence highlighting the importance of oxidative stress in the pathogenesis of Alzheimer's disease (AD). We have previously standardised a method that can be applied to study oxidative changes in individual brain proteins by using two-dimensional oxyblots (Korolainen MA, Goldsteins G, Alafuzoff I, Koistinaho J, Pirttilä T. Proteomic analysis of protein oxidation in Alzheimer's disease brain. Electrophoresis 2002;23(19):3428-33). Here we have identified proteins that exhibited oxidative changes in AD when compared to age-matched controls and these protein changes have been further examined in relation to the neuropathological data. Indeed, several Tris-HCl soluble proteins tended to be less oxidised in AD when compared to controls. Two enzymes, mitochondrial glutamate dehydrogenase and cytosolic malate dehydrogenase, were increased in amount but showed significantly decreased degree of oxidation in AD brains when compared to controls. Furthermore, some changes related to the amounts or oxidation statuses of proteins were associated with the duration of the clinical impairment and also with the neuropathology. These results do not contradict the hypothesis of increased oxidative stress in AD but may represent co-existing compensatory changes in response to oxidative stress.

  14. Properties of glutamate receptors of Alzheimer's disease brain transplanted to frog oocytes

    PubMed Central

    Bernareggi, Annalisa; Dueñas, Zulma; Reyes-Ruiz, Jorge Mauricio; Ruzzier, Fabio; Miledi, Ricardo

    2007-01-01

    It is known that Alzheimer's disease (AD) is a synaptic disease that involves various neurotransmitter systems, particularly those where synaptic transmission is mediated by acetylcholine or glutamate (Glu). Nevertheless, very little is known about the properties of neurotransmitter receptors of the AD human brain. We have shown previously that cell membranes, carrying neurotransmitter receptors from the human postmortem brain, can be transplanted to frog oocytes, and their receptors will still be functional. Taking advantage of this fact, we have now studied the properties of Glu receptors (GluRs) from the cerebral cortices of AD and non-AD brains and found that oocytes injected with AD membranes acquired GluRs that have essentially the same functional properties as those of oocytes injected with membranes from non-AD brains. However, the amplitudes of the currents elicited by Glu were always smaller in the oocytes injected with membranes from AD brains. Western blot analyses of the same membrane preparations used for the electrophysiological studies showed that AD membranes contained significantly fewer GluR2/3 subunit proteins. Furthermore, the corresponding mRNAs were also diminished in the AD brain. Therefore, the smaller amplitude of membrane currents elicited by Glu in oocytes injected with membranes from an AD brain is a consequence of a reduced number of GluRs in cell membranes transplanted from the AD brain. Thus, using the comparatively simple method of microtransplantation of receptors, it is now possible to determine the properties of neurotransmitter receptors of normal and diseased human brains. That knowledge may help to decipher the etiology of the diseases and also to develop new treatments. PMID:17301224

  15. Tool use in left brain damage and Alzheimer's disease: What about function and manipulation knowledge?

    PubMed

    Jarry, Christophe; Osiurak, François; Besnard, Jérémy; Baumard, Josselin; Lesourd, Mathieu; Croisile, Bernard; Etcharry-Bouyx, Frédérique; Chauviré, Valérie; Le Gall, Didier

    2016-03-01

    Tool use disorders are usually associated with difficulties in retrieving function and manipulation knowledge. Here, we investigate tool use (Real Tool Use, RTU), function (Functional Association, FA) and manipulation knowledge (Gesture Recognition, GR) in 17 left-brain-damaged (LBD) patients and 14 AD patients (Alzheimer disease). LBD group exhibited predicted deficit on RTU but not on FA and GR while AD patients showed deficits on GR and FA with preserved tool use skills. These findings question the role played by function and manipulation knowledge in actual tool use. © 2016 The British Psychological Society.

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

    PubMed

    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

  17. Brain expression of presenilins in sporadic and early-onset, familial Alzheimer's disease.

    PubMed Central

    Mathews, P. M.; Cataldo, A. M.; Kao, B. H.; Rudnicki, A. G.; Qin, X.; Yang, J. L.; Jiang, Y.; Picciano, M.; Hulette, C.; Lippa, C. F.; Bird, T. D.; Nochlin, D.; Walter, J.; Haass, C.; Lévesque, L.; Fraser, P. E.; Andreadis, A.; Nixon, R. A.

    2000-01-01

    BACKGROUND: Mutations in the presenilin proteins cause early-onset, familial Alzheimer's disease (FAD). MATERIALS AND METHODS: We characterized the cellular localization and endoproteolysis of presenilin 2 (PS2) and presenilin 1 (PS1) in brains from 25 individuals with presenilin-mutations causing FAD, as well as neurologically normal individuals and individuals with sporadic Alzheimer's disease (AD). RESULTS: Amino-terminal antibodies to both presenilins predominantly decorated large neurons. Regional differences between the broad distributions of the two presenilins were greatest in the cerebellum, where most Purkinje cells showed high levels of only PS2 immunoreactivity. PS2 endoproteolysis in brain yielded multiple amino-terminal fragments similar in size to the PS1 amino-terminal fragments detected in brain. In addition, two different PS2 amino-terminal antibodies also detected a prominent 42 kDa band that may represent a novel PS2 form in human brain. Similar to PS1 findings, neither amino-terminal nor antiloop PS2 antibodies revealed substantial full-length PS2 in brain. Immunocytochemical examination of brains from individuals with the N141I PS2 mutation or eight different PS1 mutations, spanning the molecule from the second transmembrane domain to the large cytoplasmic loop domain, revealed immunodecoration of no senile plaques and only neurofibrillary tangles in the M139I PS1 mutation stained with PS1 antibodies. CONCLUSIONS: Overall presenilin expression and the relative abundance of full-length and amino-terminal fragments in presenilin FAD cases were similar to control cases and sporadic AD cases. Thus, accumulation of full-length protein or other gross mismetabolism of neither PS2 nor PS1 is a consequence of the FAD mutations examined. PMID:11126202

  18. Cerebrolysin in Alzheimer's disease.

    PubMed

    Antón Álvarez, X; Fuentes, Patricio

    2011-07-01

    Cerebrolysin is a neuropeptide preparation mimicking the action of endogenous neurotrophic factors. Positive effects of Cerebrolysin on β-amyloid- and tau-related pathologies, neuroinflammation, neurotrophic factors, oxidative stress, excitotoxicity, neurotransmission, brain metabolism, neuroplasticity, neuronal apoptosis and degeneration, neurogenesis and cognition were demonstrated in experimental conditions. These pleiotropic effects of Cerebrolysin on Alzheimer's disease-related pathogenic events are consistent with a neurotrophic-like mode of action, and seems to involve the activation of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 β intracellular signaling pathway. The clinical efficacy of Cerebrolysin in Alzheimer's disease was evaluated in several randomized, double-blind, clinical trials, showing consistent benefits on global clinical function and cognition, improvements in behavior at high doses, and minor effects on daily living activities in patients with mild to moderate Alzheimer's disease, as well as in subgroups of moderate to moderately severe patients. In addition, the clinical benefits of Cerebrolysin were largely maintained for several months after ending treatment, a finding that supports its discontinuous administration. Cerebrolysin was generally well tolerated and did not induce significant adverse events in Alzheimer's patients. Although long-term studies are needed, the data available suggest that Cerebrolysin is effective as monotherapy and constitutes a promising option for combined therapy in Alzheimer's disease.

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

    PubMed

    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.

  20. BrainAGE in Mild Cognitive Impaired Patients: Predicting the Conversion to Alzheimer's Disease.

    PubMed

    Gaser, Christian; Franke, Katja; Klöppel, Stefan; Koutsouleris, Nikolaos; Sauer, Heinrich

    2013-01-01

    Alzheimer's disease (AD), the most common form of dementia, shares many aspects of abnormal brain aging. We present a novel magnetic resonance imaging (MRI)-based biomarker that predicts the individual progression of mild cognitive impairment (MCI) to AD on the basis of pathological brain aging patterns. By employing kernel regression methods, the expression of normal brain-aging patterns forms the basis to estimate the brain age of a given new subject. If the estimated age is higher than the chronological age, a positive brain age gap estimation (BrainAGE) score indicates accelerated atrophy and is considered a risk factor for conversion to AD. Here, the BrainAGE framework was applied to predict the individual brain ages of 195 subjects with MCI at baseline, of which a total of 133 developed AD during 36 months of follow-up (corresponding to a pre-test probability of 68%). The ability of the BrainAGE framework to correctly identify MCI-converters was compared with the performance of commonly used cognitive scales, hippocampus volume, and state-of-the-art biomarkers derived from cerebrospinal fluid (CSF). With accuracy rates of up to 81%, BrainAGE outperformed all cognitive scales and CSF biomarkers in predicting conversion of MCI to AD within 3 years of follow-up. Each additional year in the BrainAGE score was associated with a 10% greater risk of developing AD (hazard rate: 1.10 [CI: 1.07-1.13]). Furthermore, the post-test probability was increased to 90% when using baseline BrainAGE scores to predict conversion to AD. The presented framework allows an accurate prediction even with multicenter data. Its fast and fully automated nature facilitates the integration into the clinical workflow. It can be exploited as a tool for screening as well as for monitoring treatment options.

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

    NASA Astrophysics Data System (ADS)

    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.

  2. Role of nanomedicines in delivery of anti-acetylcholinesterase compounds to the brain in Alzheimer's disease.

    PubMed

    Ahmad, Mohammad Z; Ahmad, Javed; Amin, Saima; Rahman, Mahfoozur; Anwar, Mohammad; Mallick, Neha; Ahmad, Farhan J; Rahman, Ziyaur; Kamal, Mohammad A; Akhter, Sohail

    2014-01-01

    Alzheimer's disease (AD) is a multifarious progressive neuro-degenerative state among elders. Potentiation of central cholinergic activity by using acetylcholinesterase inhibitors (AChEI) is considered as one of the major pharmacological means for the management of AD. Investigation in the past and the rest decades revealed that many drugs with anti-AD activity, including the AChEI have been discovered from natural and synthetic origin but getting success in their brain delivery is still limited. However, barriers like blood-brain barrier, blood-cerebrospinal fluid barrier and p-glycoproteins restrict the effective and safe drug delivery to the brain in patients with AD. Advancement in nanotechnology-based drug delivery systems over the last decade exemplifies the effective drug delivery and targeting to the brain with controlled rate in various diseases including AD. Till recently, diverse kinds of nanomedicines for targeting of the anti-AD drugs in brain are being studied. In this review, we have highlighted the recent progress in AChEI, challenges in their effective brain delivery (physicochemical properties and biological barriers) and possible nanotechnology-based strategies that can deliver drugs across the CNS barriers during AD.

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

    NASA Astrophysics Data System (ADS)

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

    1999-05-01

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

  4. Effects of polyphenols on brain ageing and Alzheimer's disease: focus on mitochondria.

    PubMed

    Schaffer, Sebastian; Asseburg, Heike; Kuntz, Sabine; Muller, Walter E; Eckert, Gunter P

    2012-08-01

    The global trend of the phenomenon of population ageing has dramatic consequences on public health and the incidence of neurodegenerative diseases. Physiological changes that occur during normal ageing of the brain may exacerbate and initiate pathological processes that may lead to neurodegenerative disorders, especially Alzheimer's disease (AD). Hence, the risk of AD rises exponentially with age. While there is no cure currently available, sufficient intake of certain micronutrients and secondary plant metabolites may prevent disease onset. Polyphenols are highly abundant in the human diet, and several experimental and epidemiological evidences indicate that these secondary plant products have beneficial effects on AD risks. This study reviews current knowledge on the potential of polyphenols and selected polyphenol-rich diets on memory and cognition in human subjects, focusing on recent data showing in vivo efficacy of polyphenols in preventing neurodegenerative events during brain ageing and in dementia. Concentrations of polyphenols in animal brains following oral administration have been consistently reported to be very low, thus eliciting controversial discussion on their neuroprotective effects and potential mechanisms. Whether polyphenols exert any direct antioxidant effects in the brain or rather act by evoking alterations in regulatory systems of the brain or even the body periphery is still unclear. To understand the mechanisms behind the protective abilities of polyphenol-rich foods, an overall understanding of the biotransformation of polyphenols and identification of the various metabolites arising in the human body is also urgently needed.

  5. Brain changes in Alzheimer's disease patients with implanted encapsulated cells releasing nerve growth factor.

    PubMed

    Ferreira, Daniel; Westman, Eric; Eyjolfsdottir, Helga; Almqvist, Per; Lind, Göran; Linderoth, Bengt; Seiger, Ake; Blennow, Kaj; Karami, Azadeh; Darreh-Shori, Taher; Wiberg, Maria; Simmons, Andrew; Wahlund, Lars-Olof; Wahlberg, Lars; Eriksdotter, Maria

    2015-01-01

    New therapies with disease-modifying effects are urgently needed for treating Alzheimer's disease (AD). Nerve growth factor (NGF) protein has demonstrated regenerative and neuroprotective effects on basal forebrain cholinergic neurons in animal studies. In addition, AD patients treated with NGF have previously shown improved cognition, EEG activity, nicotinic binding, and glucose metabolism. However, no study to date has analyzed brain atrophy in patients treated with NGF producing cells. In this study we present MRI results of the first clinical trial in patients with AD using encapsulated NGF biodelivery to the basal forebrain. Six AD patients received the treatment during twelve months. Patients were grouped as responders and non-responders according to their twelve-months change in MMSE. Normative values were created from 131 AD patients from ADNI, selecting 36 age- and MMSE-matched patients for interpreting the longitudinal changes in MMSE and brain atrophy. Results at baseline indicated that responders showed better clinical status and less pathological levels of cerebrospinal fluid (CSF) Aβ1-42. However, they showed more brain atrophy, and neuronal degeneration as evidenced by higher CSF levels of T-tau and neurofilaments. At follow-up, responders showed less brain shrinkage and better progression in the clinical variables and CSF biomarkers. Noteworthy, two responders showed less brain shrinkage than the normative ADNI group. These results together with previous evidence supports the idea that encapsulated biodelivery of NGF might have the potential to become a new treatment strategy for AD with both symptomatic and disease-modifying effects.

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

    PubMed Central

    Momčilović, Berislav; Lykken, Glenn I; Cooley, Marvin

    2006-01-01

    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). PMID:16965619

  7. Intranasal telmisartan ameliorates brain pathology in five familial Alzheimer's disease mice.

    PubMed

    Torika, Nofar; Asraf, Keren; Cohen, Hagit; Fleisher-Berkovich, Sigal

    2017-08-01

    The renin-angiotensin system (RAS) is a major circulative system engaged in homeostasis modulation. Angiotensin II (Ang II) serves as its main effector hormone upon binding to its primary receptor, Ang II receptor type 1 (AT1R). It is well established that an intrinsic independent brain RAS exists. Abnormal AT1R activation both in the periphery and in the brain probably contributes to the development of Alzheimer's disease (AD) pathology that is characterized, among others, by brain inflammation. Moreover, treatment with drugs that block AT1R (AT1R blockers, ARBs) ameliorates most of the clinical risk factors leading to AD. Previously we showed that short period of intranasal treatment with telmisartan (a brain penetrating ARB) reduced brain inflammation and ameliorated amyloid burden (a component of Alzheimer's plaques) in AD transgenic mouse model. In the present study, we aimed to examine the long-term effect of intranasally administrated telmisartan on brain inflammation features including microglial activation, astrogliosis, neuronal loss and hippocampus-dependent cognition in five-familial AD mouse model (5XFAD). Five month of intranasal treatment with telmisartan significantly reduced amyloid burden in the cortex and hippocampus of 5XFAD mice as compared with the vehicle-treated 5XFAD group. Similar effects were also observed for CD11b staining, which is a marker for microglial accumulation. Telmisartan also significantly reduced astrogliosis and neuronal loss in the cortex of 5XFAD mice compared with the vehicle-treated group. Improved spatial acquisition of the 5XFAD mice following long-term intranasal administration of telmisartan was also observed. Taken together, our data suggest a significant role for AT1R blockage in mediating neuronal loss and cognitive behavior, possibly through regulation of amyloid burden and glial inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Multistimulation group therapy in Alzheimer's disease promotes changes in brain functioning.

    PubMed

    Baglio, Francesca; Griffanti, Ludovica; Saibene, Francesca Lea; Ricci, Cristian; Alberoni, Margherita; Critelli, Raffaella; Villanelli, Fabiana; Fioravanti, Raffaella; Mantovani, Federica; D'amico, Alessandra; Cabinio, Monia; Preti, Maria Giulia; Nemni, Raffaello; Farina, Elisabetta

    2015-01-01

    Background. The growing social emergency represented by Alzheimer's disease (AD) and the lack of medical treatments able to modify the disease course have kindled the interest in nonpharmacological therapies. Objective. We introduced a novel nonpharmacological approach for people with AD (PWA) named Multidimensional Stimulation group Therapy (MST) to improve PWA condition in different disease domains: cognition, behavior, and motor functioning. Methods. Enrolling 60 PWA in a mild to moderate stage of the disease, we evaluated the efficacy of MST with a randomized-controlled study. Neuropsychological and neurobehavioral measures and functional magnetic resonance imaging (fMRI) data were considered as outcome measures. Results. The following significant intervention-related changes were observed: reduction in Neuropsychiatric Inventory scale score, improvement in language and memory subscales of Alzheimer's Disease Assessment Scale-Cognitive subscale, and increased fMRI activations in temporal brain areas, right insular cortex, and thalamus. Conclusions. Cognitive-behavioral and fMRI results support the notion that MST has significant effects in improving PWA cognitive-behavioral status by restoring neural functioning. © The Author(s) 2014.

  9. Redox proteomics analysis to decipher the neurobiology of Alzheimer-like neurodegeneration: overlaps in Down's syndrome and Alzheimer's disease brain.

    PubMed

    Butterfield, D Allan; Di Domenico, Fabio; Swomley, Aaron M; Head, Elizabeth; Perluigi, Marzia

    2014-10-15

    Accumulation of oxidative damage is a common feature of neurodegeneration that, together with mitochondrial dysfunction, point to the fact that reactive oxygen species are major contributors to loss of neuronal homoeostasis and cell death. Among several targets of oxidative stress, free-radical-mediated damage to proteins is particularly important in aging and age-related neurodegenerative diseases. In the majority of cases, oxidative-stress-mediated post-translational modifications cause non-reversible modifications of protein structure that consistently lead to impaired function. Redox proteomics methods are powerful tools to unravel the complexity of neurodegeneration, by identifying brain proteins with oxidative post-translational modifications that are detrimental for protein function. The present review discusses the current literature showing evidence of impaired pathways linked to oxidative stress possibly involved in the neurodegenerative process leading to the development of Alzheimer-like dementia. In particular, we focus attention on dysregulated pathways that underlie neurodegeneration in both aging adults with DS (Down's syndrome) and AD (Alzheimer's disease). Since AD pathology is age-dependent in DS and shows similarities with AD, identification of common oxidized proteins by redox proteomics in both DS and AD can improve our understanding of the overlapping mechanisms that lead from normal aging to development of AD. The most relevant proteomics findings highlight that disturbance of protein homoeostasis and energy production are central mechanisms of neurodegeneration and overlap in aging DS and AD. Protein oxidation affects crucial intracellular functions and may be considered a 'leitmotif' of degenerating neurons. Therapeutic strategies aimed at preventing/reducing multiple components of processes leading to accumulation of oxidative damage will be critical in future studies.

  10. Alzheimer's disease and the "Valley Of Death": not enough guidance from human brain tissue?

    PubMed

    Beach, Thomas G

    2013-01-01

    Medical science is currently perceived as underperforming. This is because of the relatively slow recent rate of development of new disease treatments. This has been blamed on cultural, regulatory, and economic factors that generate a so-called "Valley of Death", hindering new drug candidates from being moved into clinical trials and eventually approved for use. We propose, however, that for neurodegenerative diseases, a relative decline of human brain tissue research is also a contributor. The present pharmacological agents for treating Alzheimer's disease (AD) were identified through direct examination of postmortem human brain tissue more than 30 years ago. Since that time the percentage of research grants awarded to human brain tissue-using projects has dropped precipitously and publication rates have stagnated. As human brain tissue research has played a central and often initiating role in identifying most of the targets that have gone to AD clinical trials, it is proposed that the rate of discovery of new targets has been curtailed. Additionally, the continued rejection of cortical biopsy as a diagnostic method for AD has most probably depressed the perceived effect sizes of new medications and contributed to the high Phase II clinical trial failure rates. Despite the relative lack of funding, human brain discovery research has continued to make important contributions to our understanding of neurodegenerative disease, and brain banks have played an essential role. It is likely that the pace of discovery will dramatically accelerate over the coming decades as increasingly powerful tools including genomics, epigenetics, transcriptomics, regulatory RNA, gene expression profiling, proteomics, and metabolomics are applied. To optimize the promise of these new technologies, however, it is critical that brain banks are rejuvenated by enhanced governmental and/or private support.

  11. Is Alzheimer's Disease Autoimmune Inflammation of the Brain That Can be Treated With Nasal Nonsteroidal Anti-Inflammatory Drugs?

    PubMed

    Lehrer, Steven; Rheinstein, Peter H

    2015-05-01

    The Alzheimer's Association recently reported that a woman's estimated lifetime risk of developing Alzheimer's at age 65 is 1 in 6, compared to nearly 1 in 11 for a man (ie, female to male ratio 1.8). Based on female to male ratio, Alzheimer's disease could well be an autoimmune disorder. Like Alzheimer's, multiple sclerosis, an autoimmune inflammation of the central nervous system, has a female to male ratio of 2.3. Also based on female to male ratio, Alzheimer's resembles the autoimmune inflammatory disease rheumatoid arthritis, which has a female to male ratio of 2.7. The reasons for the female preponderance in autoimmune disease are unclear, but nonsteroidal anti-inflammatory drugs (NSAIDs) are widely and successfully employed to treat autoimmune anti-inflammatory disease and dramatically relieve symptoms. Moreover, oral NSAIDs consistently reduce the risk of Alzheimer's disease, although they have been totally ineffective as a treatment in multiple failed clinical trials. A basis for this failure might well be that the brain dose after oral administration is too small and not sufficiently early in the pathogenesis of the disorder. But NSAID brain dose could be significantly increased by delivering the NSAIDs intranasally.

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

    PubMed

    Car, Halina; Zendzian-Piotrowska, Małgorzata; Fiedorowicz, Anna; Prokopiuk, Sławomir; Sadowska, Anna; Kurek, Krzysztof

    2012-05-30

     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.

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

    NASA Astrophysics Data System (ADS)

    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%.

  14. The construction of common and specific significance subnetworks of Alzheimer's disease from multiple brain regions.

    PubMed

    Kong, Wei; Mou, Xiaoyang; Zhang, Na; Zeng, Weiming; Li, Shasha; Yang, Yang

    2015-01-01

    Alzheimer's disease (AD) is a progressively and fatally neurodegenerative disorder and leads to irreversibly cognitive and memorial damage in different brain regions. The identification and analysis of the dysregulated pathways and subnetworks among affected brain regions will provide deep insights for the pathogenetic mechanism of AD. In this paper, commonly and specifically significant subnetworks were identified from six AD brain regions. Protein-protein interaction (PPI) data were integrated to add molecular biological information to construct the functional modules of six AD brain regions by Heinz algorithm. Then, the simulated annealing algorithm based on edge weight is applied to predicting and optimizing the maximal scoring networks for common and specific genes, respectively, which can remove the weak interactions and add the prediction of strong interactions to increase the accuracy of the networks. The identified common subnetworks showed that inflammation of the brain nerves is one of the critical factors of AD and calcium imbalance may be a link among several causative factors in AD pathogenesis. In addition, the extracted specific subnetworks for each brain region revealed many biologically functional mechanisms to understand AD pathogenesis.

  15. Disrupted global metastability and static and dynamic brain connectivity across individuals in the Alzheimer's disease continuum.

    PubMed

    Córdova-Palomera, Aldo; Kaufmann, Tobias; Persson, Karin; Alnæs, Dag; Doan, Nhat Trung; Moberget, Torgeir; Lund, Martina Jonette; Barca, Maria Lage; Engvig, Andreas; Brækhus, Anne; Engedal, Knut; Andreassen, Ole A; Selbæk, Geir; Westlye, Lars T

    2017-01-11

    As findings on the neuropathological and behavioral components of Alzheimer's disease (AD) continue to accrue, converging evidence suggests that macroscale brain functional disruptions may mediate their association. Recent developments on theoretical neuroscience indicate that instantaneous patterns of brain connectivity and metastability may be a key mechanism in neural communication underlying cognitive performance. However, the potential significance of these patterns across the AD spectrum remains virtually unexplored. We assessed the clinical sensitivity of static and dynamic functional brain disruptions across the AD spectrum using resting-state fMRI in a sample consisting of AD patients (n = 80) and subjects with either mild (n = 44) or subjective (n = 26) cognitive impairment (MCI, SCI). Spatial maps constituting the nodes in the functional brain network and their associated time-series were estimated using spatial group independent component analysis and dual regression, and whole-brain oscillatory activity was analyzed both globally (metastability) and locally (static and dynamic connectivity). Instantaneous phase metrics showed functional coupling alterations in AD compared to MCI and SCI, both static (putamen, dorsal and default-mode) and dynamic (temporal, frontal-superior and default-mode), along with decreased global metastability. The results suggest that brains of AD patients display altered oscillatory patterns, in agreement with theoretical premises on cognitive dynamics.

  16. Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer's disease.

    PubMed

    Cunnane, Stephen C; Schneider, Julie A; Tangney, Christine; Tremblay-Mercier, Jennifer; Fortier, Mélanie; Bennett, David A; Morris, Martha Clare

    2012-01-01

    Alzheimer's disease (AD) is generally associated with lower omega-3 fatty acid intake from fish but despite numerous studies, it is still unclear whether there are differences in omega-3 fatty acids in plasma or brain. In matched plasma and brain samples provided by the Memory and Aging Project, fatty acid profiles were quantified in several plasma lipid classes and in three brain cortical regions. Fatty acid data were expressed as % composition and as concentrations (mg/dL for plasma or mg/g for brain). Differences in plasma fatty acid profiles between AD, mild cognitive impairment (MCI), and those with no cognitive impairment (NCI) were most apparent in the plasma free fatty acids (lower oleic acid isomers and omega-6 fatty acids in AD) and phospholipids (lower omega-3 fatty acids in AD). In brain, % DHA was lower only in phosphatidylserine of mid-frontal cortex and superior temporal cortex in AD compared to NCI (-14% and -12%, respectively; both p < 0.05). The only significant correlation between plasma and brain fatty acids was between % DHA in plasma total lipids and % DHA in phosphatidylethanolamine of the angular gyrus, but only in the NCI group (+0.77, p < 0.05). We conclude that AD is associated with altered plasma status of both DHA and other fatty acids unrelated to DHA, and that the lipid class-dependent nature of these differences reflects a combination of differences in intake and metabolism.

  17. Lipid alterations in lipid rafts from Alzheimer's disease human brain cortex.

    PubMed

    Martín, Virginia; Fabelo, Noemí; Santpere, Gabriel; Puig, Berta; Marín, Raquel; Ferrer, Isidre; Díaz, Mario

    2010-01-01

    Lipid rafts are membrane microdomains intimately associated with cell signaling. These biochemical microstructures are characterized by their high contents of sphingolipids, cholesterol and saturated fatty acids and a reduced content of polyunsaturated fatty acids (PUFA). Here, we have purified lipid rafts of human frontal brain cortex from normal and Alzheimer's disease (AD) and characterized their biochemical lipid composition. The results revealed that lipid rafts from AD brains exhibit aberrant lipid profiles compared to healthy brains. In particular, lipid rafts from AD brains displayed abnormally low levels of n-3 long chain polyunsaturated fatty acids (LCPUFA, mainly 22:6n-3, docosahexaenoic acid) and monoenes (mainly 18:1n-9, oleic acid), as well as reduced unsaturation and peroxidability indexes. Also, multiple relationships between phospholipids and fatty acids were altered in AD lipid rafts. Importantly, no changes were observed in the mole percentage of lipid classes and fatty acids in rafts from normal brains throughout the lifespan (24-85 years). These indications point to the existence of homeostatic mechanisms preserving lipid raft status in normal frontal cortex. The disruption of such mechanisms in AD brains leads to a considerable increase in lipid raft order and viscosity, which may explain the alterations in lipid raft signaling observed in AD.

  18. Antioxidant therapies for Alzheimer's disease.

    PubMed

    Feng, Ye; Wang, Xiaochuan

    2012-01-01

    Alzheimer's disease (AD) is the most common neurodegenerative disease featuring progressive impairments in memory, cognition, and behavior and ultimately leads to death. The histopathological changes of Alzheimer's disease include neuronal and synaptic loss, formation of extracellular senile plaques and intracellular neurofibrillary tangles in brain. Multiple lines of evidence indicate that oxidative stress not only strongly participates in an early stage of Alzheimer's disease prior to cytopathology, but plays an important role in inducing and activating multiple cell signaling pathways that contribute to the lesion formations of toxic substances and then promotes the development of Alzheimer's disease. Many years of studies show that antioxidant therapies have enjoyed general success in preclinical studies. Therefore, this paper mainly focuses on the recent developments of common used antioxidant therapies for Alzheimer's disease and thus provides indications for future potential antioxidant therapeutic strategies of neurodegenerative diseases.

  19. Deep brain stimulation for the treatment of Alzheimer disease and dementias.

    PubMed

    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.

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

    PubMed

    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.

  1. Identifying dysfunctional crosstalk of pathways in various regions of Alzheimer's disease brains

    PubMed Central

    2010-01-01

    Background Alzheimer's disease (AD) is a major neurodegenerative disorder leading to amnesia, cognitive impairment and dementia in the elderly. Usually this type of lesions results from dysfunctional protein cooperations in the biological pathways. In addition, AD progression is known to occur in different brain regions with particular features. Thus identification and analysis of crosstalk among dysregulated pathways as well as identification of their clusters in various diseased brain regions are expected to provide deep insights into the pathogenetic mechanism. Results Here we propose a network-based systems biology approach to detect the crosstalks among AD related pathways, as well as their dysfunctions in the six brain regions of AD patients. Through constructing a network of pathways, the relationships among AD pathway and its neighbor pathways are systematically investigated and visually presented by their intersections. We found that the significance degree of pathways related to the fatal disorders and the pathway overlapping strength can indicate the impacts of these neighbored pathways to AD development. Furthermore, the crosstalks among pathways reveal some evidence that the neighbor pathways of AD pathway closely cooperate and play important tasks in the AD progression. Conclusions Our study identifies the common and distinct features of the dysfunctional crosstalk of pathways in various AD brain regions. The global pathway crosstalk network and the clusters of relevant pathways of AD provide evidence of cooperativity among pathways for potential pathogenesis of the neuron complex disease. PMID:20840725

  2. Effects of cholinesterase inhibition on brain white matter volume in Alzheimer's disease.

    PubMed

    Venneri, Annalena; Lane, Roger

    2009-02-18

    Brain white matter volume changes were quantified by using voxel-based morphometry in 26 minimal-to-mild Alzheimer's disease patients receiving cholinesterase inhibitors over 20 weeks. Patients treated with rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, did not show those reductions in white matter volume that were observed in patients treated with acetylcholinesterase-selective agents, donepezil and galantamine. This is the first time that dual cholinesterase inhibition has been shown to influence white matter volume specifically. The findings are consistent with a thesis that dual cholinesterase inhibition may have neuroprotective potential. Attenuated loss of brain volumes and delayed/slower long-term clinical decline in patients treated with agents such as rivastigmine may be due to less extensive white matter damage and loss of corticosubcortical connectivity.

  3. Contribution of brain imaging to the understanding of gait disorders in Alzheimer's disease: a systematic review.

    PubMed

    Annweiler, Cédric; Beauchet, Olivier; Celle, Sébastien; Roche, Frédéric; Annweiler, Thierry; Allali, Gilles; Bartha, Robert; Montero-Odasso, Manuel

    2012-09-01

    Although gait disorders are common in Alzheimer's disease (AD), determining which brain structures and related lesions are specifically involved is a goal yet to be reached. Our objective was to systematically review all published data that examined associations between gait disorders and brain imaging in AD. Of 486 selected studies, 4 observational studies met the selection criteria. The number of participants ranged from 2 to 61 community dwellers (29%-100% female) with prodromal or dementia-stage AD. Quantitative gait disorders (ie, slower gait velocity explained by shorter stride length) were associated with white matter lesions, mainly in the medial frontal lobes and basal ganglia. The nigrostriatal dopamine system was unaffected. Qualitative gait disorders (ie, higher stride length variability) correlated with lower hippocampal volume and function. Gait disorders in AD could be explained by a high burden of age-related subcortical hyperintensities on the frontal-subcortical circuits (nonspecific) together with hippocampal atrophy and hypometabolism (specific).

  4. Alzheimer's disease drug development and the problem of the blood-brain barrier

    PubMed Central

    Pardridge, William M.

    2009-01-01

    Alzheimer's disease (AD) drug development is limited by the presence of the blood-brain barrier (BBB). More than 98% of all small molecule drugs, and ∼100% of all large molecule drugs, do not cross the BBB. Despite the fact that the vast majority of AD drug candidates do not cross the BBB, the present-day AD drug development effort is characterized by an imbalance, whereby >99% of the drug development effort is devoted to CNS drug discovery, and <1% of drug development is devoted to CNS drug delivery. Future AD drug development needs a concerted effort to incorporate the BBB sciences early in the CNS drug discovery process. This can be accomplished by a reallocation of resources, and an expansion of the effort in the pure science of BBB biology and the applied science of brain drug targeting technology. PMID:19751922

  5. Microglia in Alzheimer Brain: A Neuropathological Perspective

    PubMed Central

    Mrak, Robert E.

    2012-01-01

    Microglia have long been noted to be present and activated in Alzheimer brain. Demonstrations that these microglia are associated with the specific lesions of Alzheimer disease—Aβ plaques and neurofibrillary tangles—and that these microglia overexpress the potent proinflammatory cytokine interleukin-1 led to the recognition of a potential pathogenic role for these cells in initiation and progression of disease. Activated, cytokine-overexpressing microglia are near-universal components of Aβ plaques at early (diffuse) and mid (neuritic) stages of progression in Alzheimer brain, and only decline in end-stage, dense core plaques. They correlate with plaque distribution across cerebral cortical cytoarchitectonic layers and across brain regions. They also show close associations with tangle-bearing neurons in Alzheimer brain. Microglial activation is a consistent feature in conditions that confer increased risk for Alzheimer disease or that are associated with accelerated appearance of Alzheimer-type neuropathological changes. These include normal ageing, head injury, diabetes, heart disease, and chronic intractable epilepsy. The neuropathological demonstration of microglial activation in Alzheimer brain and in Alzheimer-related conditions opened the field of basic and applied investigations centered on the idea of a pathogenically important neuroinflammatory process in Alzheimer disease. PMID:22655212

  6. Brain imaging evidence of early involvement of subcortical regions in familial and sporadic Alzheimer's disease.

    PubMed

    Tentolouris-Piperas, Vasileios; Ryan, Natalie S; Thomas, David L; Kinnunen, Kirsi M

    2017-01-15

    Recent brain imaging studies have found changes in subcortical regions in presymptomatic autosomal dominant Alzheimer's disease (ADAD). These regions are also affected in sporadic Alzheimer's disease (sAD), but whether such changes are seen in early-stage disease is still uncertain. In this review, we discuss imaging studies published in the past 12 years that have found evidence of subcortical involvement in early-stage ADAD and/or sAD. Several papers have reported amyloid deposition in the striatum of presymptomatic ADAD mutation carriers, prior to amyloid deposition elsewhere. Altered caudate volume has also been implicated in early-stage ADAD, but findings have been variable. Less is known about subcortical involvement in sAD: the thalamus and striatum have been found to be atrophied in symptomatic patients, but their involvement in the preclinical phase remains unclear, in part due to the difficulties of studying this stage in sporadic disease. Longitudinal imaging studies comparing ADAD mutation carriers with individuals at high-risk for sAD may be needed to elucidate the significance of subcortical involvement in different AD clinical stages. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Glucose Metabolic Brain Networks in Early-Onset vs. Late-Onset Alzheimer's Disease

    PubMed Central

    Chung, Jinyong; Yoo, Kwangsun; Kim, Eunjoo; Na, Duk L.; Jeong, Yong

    2016-01-01

    Objective: Early-onset Alzheimer's disease (EAD) shows distinct features from late-onset Alzheimer's disease (LAD). To explore the characteristics of EAD, clinical, neuropsychological, and functional imaging studies have been conducted. However, differences between EAD and LAD are not clear, especially in terms of brain connectivity and networks. In this study, we investigated the differences in metabolic connectivity between EAD and LAD by adopting graph theory measures. Methods: We analyzed 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) images to investigate the distinct features of metabolic connectivity between EAD and LAD. Using metabolic connectivity and graph theory analysis, metabolic network differences between LAD and EAD were explored. Results: Results showed the decreased connectivity centered in the cingulate gyri and occipital regions in EAD, whereas decreased connectivity in the occipital and temporal regions as well as increased connectivity in the supplementary motor area were observed in LAD when compared with age-matched control groups. Global efficiency and clustering coefficients were decreased in EAD but not in LAD. EAD showed progressive network deterioration as a function of disease severity and clinical dementia rating (CDR) scores, mainly in terms of connectivity between the cingulate gyri and occipital regions. Global efficiency and clustering coefficients were also decreased along with disease severity. Conclusion: These results indicate that EAD and LAD have distinguished features in terms of metabolic connectivity, with EAD demonstrating more extensive and progressive deterioration. PMID:27445800

  8. Loss of functional GABA(A) receptors in the Alzheimer diseased brain.

    PubMed

    Limon, Agenor; Reyes-Ruiz, Jorge Mauricio; Miledi, Ricardo

    2012-06-19

    The cholinergic and glutamatergic neurotransmission systems are known to be severely disrupted in Alzheimer's disease (AD). GABAergic neurotransmission, in contrast, is generally thought to be well preserved. Evidence from animal models and human postmortem tissue suggest GABAergic remodeling in the AD brain. Nevertheless, there is no information on changes, if any, in the electrophysiological properties of human native GABA receptors as a consequence of AD. To gain such information, we have microtransplanted cell membranes, isolated from temporal cortices of control and AD brains, into Xenopus oocytes, and recorded the electrophysiological activity of the transplanted GABA receptors. We found an age-dependent reduction of GABA currents in the AD brain. This reduction was larger when the AD membranes were obtained from younger subjects. We also found that GABA currents from AD brains have a faster rate of desensitization than those from non-AD brains. Furthermore, GABA receptors from AD brains were slightly, but significantly, less sensitive to GABA than receptors from non-AD brains. The reduction of GABA currents in AD was associated with reductions of mRNA and protein of the principal GABA receptor subunits normally present in the temporal cortex. Pairwise analysis of the transcripts within control and AD groups and analyses of the proportion of GABA receptor subunits revealed down-regulation of α1 and γ2 subunits in AD. In contrast, the proportions of α2, β1, and γ1 transcripts were up-regulated in the AD brains. Our data support a functional remodeling of GABAergic neurotransmission in the human AD brain.

  9. Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain.

    PubMed

    Busser, J; Geldmacher, D S; Herrup, K

    1998-04-15

    Alzheimer's disease (AD) is a major dementing illness characterized by regional concentrations of senile plaques, neurofibrillary tangles, and extensive neuronal cell death. Although cell and synaptic loss is most directly linked to the severity of symptoms, the mechanisms leading to the neuronal death remain unclear. Based on evidence linking neuronal death during development to unexpected reappearance of cell cycle events, we investigated the brains of 12 neuropathologically verified cases of Alzheimer's disease and eight age-matched, disease-free controls for the presence of cell cycle proteins. Aberrant expression of cyclin D, cdk4, proliferating cell nuclear antigen, and cyclin B1 were identified in the hippocampus, subiculum, locus coeruleus, and dorsal raphe nuclei, but not inferotemporal cortex or cerebellum of AD cases. With only one exception, control subjects showed no significant expression of cell cycle markers in any of the six regions. We propose that disregulation of various components of the cell cycle is a significant contributor to regionally specific neuronal death in AD.

  10. Amyloid precursor protein mRNA levels in Alzheimer's disease brain.

    PubMed

    Preece, Paul; Virley, David J; Costandi, Moheb; Coombes, Robert; Moss, Stephen J; Mudge, Anne W; Jazin, Elena; Cairns, Nigel J

    2004-03-17

    Insoluble beta-amyloid deposits in Alzheimer's disease (AD) brain are proteolytically derived from the membrane bound amyloid precursor protein (APP). The APP gene is differentially spliced to produce isoforms that can be classified into those containing a Kunitz-type serine protease inhibitor domain (K(+), APP(751), APP(770), APRP(365) and APRP(563)), and those without (K(-), APP(695) and APP(714)). Given the hypothesis that Abeta is a result of aberrant catabolism of APP, differential expression of mRNA isoforms containing protease inhibitors might play an active role in the pathology of AD. We took 513 cerebral cortex samples from 90 AD and 81 control brains and quantified the mRNA isoforms of APP with TaqMan real-time RT-PCR. After adjustment for age at death, brain pH and gender we found a change in the ratio of KPI(+) to KPI(-) mRNA isoforms of APP. Three separate probes, designed to recognise only KPI(+) mRNA species, gave increases of between 28% and 50% in AD brains relative to controls (p=0.002). There was no change in the mRNA levels of KPI-(APP 695) (p=0.898). Therefore, whilst KPI-mRNA levels remained stable the KPI(+) species increased specifically in the AD brains.

  11. Endothelin-1 is elevated in Alzheimer's disease brain microvessels and is neuroprotective.

    PubMed

    Luo, Jinhua; Grammas, Paula

    2010-01-01

    The vasoactive protein endothelin-1 (ET-1) is produced by vascular endothelial cells and participates in the regulation of vascular inflammation. We have previously documented that the cerebral microvasculature is a source of inflammatory proteins and a likely contributor to the pathogenesis of Alzheimer's disease (AD). In this study, we (a) compare expression of ET-1 in brain microvessels isolated from AD and control brains; (b) determine thrombin regulation of ET-1 synthesis and release in brain endothelial cells; and (c) assess the effects of ET-1 on neuronal viability in vitro. Western blot analysis indicates a significantly higher level of ET-1 in AD vessels compared to vessels from age-matched controls. ET-1 expression and secretion are both induced by the inflammatory and neurotoxic protein thrombin. Pretreatment of neuronal cultures with ET-1 significantly increases neuronal survival when cells are challenged with oxidative stress (H2O2) or thrombin. The protective effect of ET-1 is blocked by incubation with an inhibitor of the c-Jun kinase (JNK) cascade. These data demonstrate that in the brain microvasculature dysfunctional or stressed endothelial cells express ET-1 and that this protein promotes the survival of brain neurons exposed to injury.

  12. Altered DNA base excision repair profile in brain tissue and blood in Alzheimer's disease.

    PubMed

    Lillenes, Meryl S; Rabano, Alberto; Støen, Mari; Riaz, Tahira; Misaghian, Dorna; Møllersen, Linda; Esbensen, Ying; Günther, Clara-Cecilie; Selnes, Per; Stenset, Vidar T V; Fladby, Tormod; Tønjum, Tone

    2016-05-28

    Alzheimer's disease (AD) is a progressive, multifactorial neurodegenerative disorder that is the main cause of dementia globally. AD is associated with increased oxidative stress, resulting from imbalance in production and clearance of reactive oxygen species (ROS). ROS can damage DNA and other macromolecules, leading to genome instability and disrupted cellular functions. Base excision repair (BER) plays a major role in repairing oxidative DNA lesions. Here, we compared the expression of BER components APE1, OGG1, PARP1 and Polβ in blood and postmortem brain tissue from patients with AD, mild cognitive impairment (MCI) and healthy controls (HC). BER mRNA levels were correlated to clinical signs and cerebrospinal fluid biomarkers for AD. Notably, the expression of BER genes was higher in brain tissue than in blood samples. Polβ mRNA and protein levels were significantly higher in the cerebellum than in the other brain regions, more so in AD patients than in HC. Blood mRNA levels of OGG1 was low and PARP1 high in MCI and AD. These findings reflect the oxidative stress-generating energy-consumption in the brain and the importance of BER in repairing these damage events. The data suggest that alteration in BER gene expression is an event preceding AD. The results link DNA repair in brain and blood to the etiology of AD at the molecular level and can potentially serve in establishing novel biomarkers, particularly in the AD prodromal phase.

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

    PubMed Central

    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

  14. Caffeine suppresses amyloid-beta levels in plasma and brain of Alzheimer's disease transgenic mice.

    PubMed

    Cao, Chuanhai; Cirrito, John R; Lin, Xiaoyang; Wang, Li; Wang, Lilly; Verges, Deborah K; Dickson, Alexander; Mamcarz, Malgorzata; Zhang, Chi; Mori, Takashi; Arendash, Gary W; Holtzman, David M; Potter, Huntington

    2009-01-01

    Recent epidemiologic studies suggest that caffeine may be protective against Alzheimer's disease (AD). Supportive of this premise, our previous studies have shown that moderate caffeine administration protects/restores cognitive function and suppresses brain amyloid-beta (Abeta) production in AD transgenic mice. In the present study, we report that acute caffeine administration to both young adult and aged AD transgenic mice rapidly reduces Abeta levels in both brain interstitial fluid and plasma without affecting Abeta elimination. Long-term oral caffeine treatment to aged AD mice provided not only sustained reductions in plasma Abeta, but also decreases in both soluble and deposited Abeta in hippocampus and cortex. Irrespective of caffeine treatment, plasma Abeta levels did not correlate with brain Abeta levels or with cognitive performance in individual aged AD mice. Although higher plasma caffeine levels were strongly associated with lower plasma Abeta1-40 levels in aged AD mice, plasma caffeine levels were also not linked to cognitive performance. Plasma caffeine and theophylline levels were tightly correlated, both being associated with reduced inflammatory cytokine levels in hippocampus. Our conclusion is two-fold: first, that both plasma and brain Abeta levels are reduced by acute or chronic caffeine administration in several AD transgenic lines and ages, indicating a therapeutic value of caffeine against AD; and second, that plasma Abeta levels are not an accurate index of brain Abeta levels/deposition or cognitive performance in aged AD mice.

  15. Docosahexaenoic acid homeostasis, brain aging and Alzheimer's disease: Can we reconcile the evidence?

    PubMed

    Cunnane, Stephen C; Chouinard-Watkins, Raphael; Castellano, Christian A; Barberger-Gateau, Pascale

    2013-01-01

    A crossroads has been reached on research into docosahexaenoic acid (DHA) and Alzheimer's disease (AD). On the one hand, several prospective observational studies now clearly indicate a protective effect of higher fish and DHA intake against risk of AD. On the other hand, once AD is clinically evident, supplementation trials demonstrate essentially no benefit of DHA in AD. Despite apparently low DHA intake in AD, brain DHA levels are frequently the same as in controls, suggesting that low DHA intake results in low plasma DHA but does not necessarily reduce brain DHA in humans. Animal models involving dietary omega-3 fatty acid deficiency to deplete brain DHA may therefore not be appropriate in AD research. Studies in the healthy elderly suggest that DHA homeostasis changes during aging. Tracer methodology now permits estimation of DHA half-life in the human brain and whole body. Apolipoprotein E alleles have an important impact not only on AD but also on DHA homeostasis in humans. We therefore encourage further development of innovative approaches to the study of DHA metabolism and its role in human brain function. A better understanding of DHA metabolism in humans will hopefully help explain how higher habitual DHA intake protects against the risk of deteriorating cognition during aging and may eventually give rise to a breakthrough in the treatment of AD.

  16. Preliminary study of Alzheimer's Disease diagnosis based on brain electrical signals using wireless EEG

    NASA Astrophysics Data System (ADS)

    Handayani, N.; Akbar, Y.; Khotimah, S. N.; Haryanto, F.; Arif, I.; Taruno, W. P.

    2016-03-01

    This research aims to study brain's electrical signals recorded using EEG as a basis for the diagnosis of patients with Alzheimer's Disease (AD). The subjects consisted of patients with AD, and normal subjects are used as the control. Brain signals are recorded for 3 minutes in a relaxed condition and with eyes closed. The data is processed using power spectral analysis, brain mapping and chaos test to observe the level of complexity of EEG's data. The results show a shift in the power spectral in the low frequency band (delta and theta) in AD patients. The increase of delta and theta occurs in lobus frontal area and lobus parietal respectively. However, there is a decrease of alpha activity in AD patients where in the case of normal subjects with relaxed condition, brain alpha wave dominates the posterior area. This is confirmed by the results of brain mapping. While the results of chaos analysis show that the average value of MMLE is lower in AD patients than in normal subjects. The level of chaos associated with neural complexity in AD patients with lower neural complexity is due to neuronal damage caused by the beta amyloid plaques and tau protein in neurons.

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

    PubMed

    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.

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

    PubMed

    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.

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

    NASA Astrophysics Data System (ADS)

    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.

  20. Alzheimer's disease-like pathology has transient effects on the brain and blood metabolome.

    PubMed

    Pan, Xiaobei; Nasaruddin, Muhammad Bin; Elliott, Christopher T; McGuinness, Bernadette; Passmore, Anthony P; Kehoe, Patrick G; Hölscher, Christian; McClean, Paula L; Graham, Stewart F; Green, Brian D

    2016-02-01

    The pathogenesis of Alzheimer's disease (AD) is complex involving multiple contributing factors. The extent to which AD pathology affects the metabolome is still not understood nor is it known how disturbances change as the disease progresses. For the first time, we have profiled longitudinally (6, 8, 10, 12, and 18 months) both the brain and plasma metabolome of APPswe/PS1deltaE9 double transgenic and wild-type mice. A total of 187 metabolites were quantified using a targeted metabolomic methodology. Multivariate statistical analysis produced models that distinguished APPswe/PS1deltaE9 from wild-type mice at 8, 10, and 12 months. Metabolic pathway analysis found perturbed polyamine metabolism in both brain and blood plasma. There were other disturbances in essential amino acids, branched-chain amino acids, and also in the neurotransmitter serotonin. Pronounced imbalances in phospholipid and acylcarnitine homeostasis were evident in 2 age groups. AD-like pathology, therefore, affects greatly on both the brain and blood metabolomes, although there appears to be a clear temporal sequence whereby changes to brain metabolites precede those in blood.

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

    PubMed

    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.

  2. Oxidative modification of lipoic acid by HNE in Alzheimer disease brain.

    PubMed

    Hardas, Sarita S; Sultana, Rukhsana; Clark, Amy M; Beckett, Tina L; Szweda, Luke I; Murphy, M Paul; Butterfield, D Allan

    2013-01-01

    Alzheimer disease (AD) is an age-related neurodegenerative disease characterized by the presence of three pathological hallmarks: synapse loss, extracellular senile plaques (SP) and intracellular neurofibrillary tangles (NFTs). The major component of SP is amyloid β-peptide (Aβ), which has been shown to induce oxidative stress. The AD brain shows increased levels of lipid peroxidation products, including 4-hydroxy-2-nonenal (HNE). HNE can react covalently with Cys, His, or Lys residues on proteins, altering structure and function of the latter. In the present study we measured the levels of the HNE-modified lipoic acid in brain of subjects with AD and age-matched controls. Lipoic acid is a key co-factor for a number of proteins including pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, key complexes for cellular energetics. We observed a significant decrease in the levels of HNE-lipoic acid in the AD brain compared to that of age-matched controls. To investigate this phenomenon further, the levels and activity of lipoamide dehydrogenase (LADH) were measured in AD and control brains. Additionally, LADH activities were measured after in-vitro HNE-treatment to mice brains. Both LADH levels and activities were found to be significantly reduced in AD brain compared to age-matched control. HNE-treatment also reduced the LADH activity in mice brain. These data are consistent with a two-hit hypothesis of AD: oxidative stress leads to lipid peroxidation that, in turn, causes oxidative dysfunction of key energy-related complexes in mitochondria, triggering neurodegeneration. This study is consonant with the notion that lipoic acid supplementation could be a potential treatment for the observed loss of cellular energetics in AD and potentiate the antioxidant defense system to prevent or delay the oxidative stress in and progression of this devastating dementing disorder.

  3. Apolipoprotein E ε4 modulates functional brain connectome in Alzheimer's disease.

    PubMed

    Wang, Jinhui; Wang, Xiao; He, Yi; Yu, Xin; Wang, Huali; He, Yong

    2015-05-01

    The apolipoprotein E (APOE) ɛ4 allele is a well-established genetic risk factor for Alzheimer's disease (AD). Recent research has demonstrated an APOE ɛ4-mediated modulation of intrinsic functional brain networks in cognitively normal individuals. However, it remains largely unknown whether and how APOE ɛ4 affects the brain's functional network architecture in patients with AD. Using resting-state functional MRI and graph-theory approaches, we systematically investigated the topological organization of whole-brain functional networks in 16 APOE ɛ4 carriers and 26 matched noncarriers with AD at three levels: global whole-brain, intermediate module, and regional node/connection. Neuropsychological analysis showed that the APOE ɛ4 carriers performed worse on delayed memory but better on a late item generation of a verbal fluency task (associated with executive function) than noncarriers. Whole-brain graph analyses revealed that APOE ɛ4 significantly disrupted whole-brain topological organization as characterized by (i) reduced parallel information transformation efficiency; (ii) decreased intramodular connectivity within the posterior default mode network (pDMN) and intermodular connectivity of the pDMN and executive control network (ECN) with other neuroanatomical systems; and (iii) impaired functional hubs and their rich-club connectivities that primarily involve the pDMN, ECN, and sensorimotor systems. Further simulation analysis indicated that these altered connectivity profiles of the pDMN and ECN largely accounted for the abnormal global network topology. Finally, the changes in network topology exhibited significant correlations with the patients' cognitive performances. Together, our findings suggest that the APOE genotype modulates large-scale brain networks in AD and shed new light on the gene-connectome interaction in this disease.

  4. Protective Effects of Liquiritin on the Brain of Rats with Alzheimer's Disease

    PubMed Central

    Huang, X; Wang, Y; Ren, K

    2015-01-01

    ABSTRACT Background: Alzheimer's disease (AD) is a sort of nerve degenerative disease with clinical manifestation of memory damage and cognitive dysfunction. Its typical pathological change is the abnormal deposition of amyloid-beta (Aβ). Method: In this study, a rat AD model with liquiritin (LQ) interference was established to observe the effects of LQ on the AD rats’ behavioural memory and primary hippocampus cells. Results: Liquiritin had the effect of improving the rats’ learning and memory ability, enhancing the activity of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in rats’ brain tissues, increasing the antioxidant ability, protecting the primary cultured hippocampal neurons and inhibiting the apoptosis induced by Aβ25–35. Conclusion: The protective effects of LQ can be related to the enhancement of antioxidase activity and clearance of oxygen radicals. PMID:27399208

  5. Decrease of the immunophilin FKBP52 accumulation in human brains of Alzheimer's disease and FTDP-17.

    PubMed

    Giustiniani, Julien; Sineus, Marlène; Sardin, Elodie; Dounane, Omar; Panchal, Maï; Sazdovitch, Véronique; Duyckaerts, Charles; Chambraud, Béatrice; Baulieu, Etienne-Emile

    2012-01-01

    Human neurodegenerative diseases characterized by abnormal intraneuronal inclusions of the tau protein, or "tauopathies", include Alzheimer's disease (AD), Pick's disease, progressive supranuclear palsy, corticobasal degeneration as well as fronto-temporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Several abnormalities of tau may contribute to the pathological processes, yet the mechanisms involved in tau cellular toxicity remain unclear. Previously, we demonstrated an interaction between various isoforms of tau and the immunophilin FKBP52 (FK506-Binding Protein), suggesting a direct involvement of FKBP52 in tau function. Here we analyze the expression of FKBP52 in human brains of patients with different tauopathies, including AD. Immunohistofluorescence studies carried out on cerebral cortex in different tauopathies reveal that FKBP52 is not sequestered by filamentous tau inclusions while FKBP52 is colocalized with tau in the control case brains. We found that FKBP52 expression level is abnormally low in frontal cortex of AD and FTDP-17 brains, as compared to controls, despite no alteration in the FKBP52 mRNA expression level. The possible involvement of FKBP52 in pathological tau expression/function is discussed.

  6. Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease.

    PubMed

    Aliev, Gjumrakch; Palacios, Hector H; Walrafen, Brianna; Lipsitt, Amanda E; Obrenovich, Mark E; Morales, Ludis

    2009-10-01

    Alzheimer's disease (AD) and cerebrovascular accidents are two leading causes of age-related dementia. Increasing evidence supports the idea that chronic hypoperfusion is primarily responsible for the pathogenesis that underlies both disease processes. In this regard, hypoperfusion appears to induce oxidative stress (OS), which is largely due to reactive oxygen species (ROS), and over time initiates mitochondrial failure which is known as an initiating factor of AD. Recent evidence indicates that chronic injury stimulus induces hypoperfusion seen in vulnerable brain regions. This reduced regional cerebral blood flow (CBF) then leads to energy failure within the vascular endothelium and associated brain parenchyma, manifested by damaged mitochondrial ultrastructure (the formation of large number of immature, electron-dense "hypoxic" mitochondria) and by overproduction of mitochondrial DNA (mtDNA) deletions. Additionally, these mitochondrial abnormalities co-exist with increased redox metal activity, lipid peroxidation, and RNA oxidation. Interestingly, vulnerable neurons and glial cells show mtDNA deletions and oxidative stress markers only in the regions that are closely associated with damaged vessels, and, moreover, brain vascular wall lesions linearly correlate with the degree of neuronal and glial cell damage. We summarize the large body of evidence which indicates that sporadic, late-onset AD results from a vascular etiology by briefly reviewing mitochondrial damage and vascular risk factors associated with the disease and then we discuss the cerebral microvascular changes reason for the energy failure that occurs in normal aging and, to a much greater extent, AD.

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

    PubMed

    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.

  8. Detection of Conversion from Mild Cognitive Impairment to Alzheimer's Disease Using Longitudinal Brain MRI

    PubMed Central

    Sun, Zhuo; van de Giessen, Martijn; Lelieveldt, Boudewijn P. F.; Staring, Marius

    2017-01-01

    Mild Cognitive Impairment (MCI) is an intermediate stage between healthy and Alzheimer's disease (AD). To enable early intervention it is important to identify the MCI subjects that will convert to AD in an early stage. In this paper, we provide a new method to distinguish between MCI patients that either convert to Alzheimer's Disease (MCIc) or remain stable (MCIs), using only longitudinal T1-weighted MRI. Currently, most longitudinal studies focus on volumetric comparison of a few anatomical structures, thereby ignoring more detailed development inside and outside those structures. In this study we propose to exploit the anatomical development within the entire brain, as found by a non-rigid registration approach. Specifically, this anatomical development is represented by the Stationary Velocity Field (SVF) from registration between the baseline and follow-up images. To make the SVFs comparable among subjects, we use the parallel transport method to align them in a common space. The normalized SVF together with derived features are then used to distinguish between MCIc and MCIs subjects. This novel feature space is reduced using a Kernel Principal Component Analysis method, and a linear support vector machine is used as a classifier. Extensive comparative experiments are performed to inspect the influence of several aspects of our method on classification performance, specifically the feature choice, the smoothing parameter in the registration and the use of dimensionality reduction. The optimal result from a 10-fold cross-validation using 36 month follow-up data shows competitive results: accuracy 92%, sensitivity 95%, specificity 90%, and AUC 94%. Based on the same dataset, the proposed approach outperforms two alternative ones that either depends on the baseline image only, or uses longitudinal information from larger brain areas. Good results were also obtained when scans at 6, 12, or 24 months were used for training the classifier. Besides the

  9. Neuropharmacological effect of Mangiferin on brain cholinesterase and brain biogenic amines in the management of Alzheimer's disease.

    PubMed

    Biradar, Siddaruda M; Joshi, Hanumanthachar; Chheda, Tarak K

    2012-05-15

    The present study was conducted to evaluate the neuropharmacological effect of Mangiferin on brain cholinesterase and brain biogenic amines along with its antioxidant status. Scopolamine and natural aging were employed as an experimental amnesia inducing agents. The tested dose of Mangiferin (40, 20 and 10 mg/kg) significantly improved the learning ability and retention of learned memory in Elevated plus Maze and Passive Shock Avoidance exteroceptive behavioural models. Pre-treatment with Mangiferin restored increased whole brain acetylcholinestrease, lipid peroxidation and reduced glutathione due to scopolamine and natural aging. Whole brain increased dopamine and nor-adrenaline content in brain in the inducing groups were reversed by tested doses of Mangiferin insignificantly. Moreover the cerebroprotective effect of Mangiferin was well supported by photomicrographs of Hippocampus of brain, where as severity of cell damage, number of pyknotic black neurons, formation of karyorrhexis, karyolysis and number of neuronal cell death were less comparative to scopolamine group. The observed effects of Mangiferin claim that it would be worthwhile to utilize in the treatment of Alzheimer's disease.

  10. Demonstration of aluminum in amyloid fibers in the cores of senile plaques in the brains of patients with Alzheimer's disease.

    PubMed

    Yumoto, Sakae; Kakimi, Shigeo; Ohsaki, Akihiro; Ishikawa, Akira

    2009-11-01

    Aluminum (Al) exposure has been reported to be a risk factor for Alzheimer's disease (senile dementia of Alzheimer type), although the role of Al in the etiology of Alzheimer's disease remains controversial. We examined the presence of Al in the Alzheimer's brain using energy-dispersive X-ray spectroscopy combined with transmission electron microscopy (TEM-EDX). TEM-EDX analysis allows simultaneous imaging of subcellular structures with high spatial resolution and analysis of small quantities of elements contained in the same subcellular structures. We identified senile plaques by observation using TEM and detected Al in amyloid fibers in the cores of senile plaques located in the hippocampus and the temporal lobe by EDX. Phosphorus and calcium were also present in the amyloid fibers. No Al could be detected in the extracellular space in senile plaques or in the cytoplasm of nerve cells. In this study, we demonstrated colocalization of Al and beta-amyloid (Abeta) peptides in amyloid fibers in the cores of senile plaques. The results support the following possibilities in the brains of patients with Alzheimer's disease: Al could be involved in the aggregation of Abeta peptides to form toxic fibrils; Al might induce Abeta peptides into the beta-sheet structure; and Al might facilitate iron-mediated oxidative reactions, which cause severe damage to brain tissues.

  11. Use of neural networks in brain SPECT to diagnose Alzheimer's disease.

    PubMed

    Page, M P; Howard, R J; O'Brien, J T; Buxton-Thomas, M S; Pickering, A D

    1996-02-01

    The usefulness of artificial neural networks in the classification of 99mTc-HMPAO SPECT axial brain scans was investigated in a study group of Alzheimer's disease patients and age-matched normal subjects. The cortical circumferential profiling (CCP) technique was used to extract information regarding patterns of cortical perfusion. Traditional analysis of the CCP data, taken from slices at the level of the basal ganglia, indicated significant perfusion deficits for Alzheimer's disease patients relative to normals, particularly in the left temporo-parietal and left posterior frontal areas of the cortex. The compressed profiles were then used to train a neural-network classifier, the performance of which was compared with that of a number of more traditional statistical (discriminant function) techniques and that of two expert viewers. The optimal classification performance of the neural network (ROC area = 0.91) was better than that of the alternative statistical techniques (max. ROC area = 0.85) and that of the expert viewers (max. ROC area = 0.79). The CCP produces perfusion profiles which are well suited to automated classification methods, particularly those employing neural networks. The technique has the potential for wide application.

  12. Paired Helical Filaments from Alzheimer Disease Brain Induce Intracellular Accumulation of Tau Protein in Aggresomes*

    PubMed Central

    Santa-Maria, Ismael; Varghese, Merina; Ksiȩżak-Reding, Hanna; Dzhun, Anastasiya; Wang, Jun; Pasinetti, Giulio M.

    2012-01-01

    Abnormal folding of tau protein leads to the generation of paired helical filaments (PHFs) and neurofibrillary tangles, a key neuropathological feature in Alzheimer disease and tauopathies. A specific anatomical pattern of pathological changes developing in the brain suggests that once tau pathology is initiated it propagates between neighboring neuronal cells, possibly spreading along the axonal network. We studied whether PHFs released from degenerating neurons could be taken up by surrounding cells and promote spreading of tau pathology. Neuronal and non-neuronal cells overexpressing green fluorescent protein-tagged tau (GFP-Tau) were treated with isolated fractions of human Alzheimer disease-derived PHFs for 24 h. We found that cells internalized PHFs through an endocytic mechanism and developed intracellular GFP-Tau aggregates with attributes of aggresomes. This was particularly evident by the perinuclear localization of aggregates and redistribution of the vimentin intermediate filament network and retrograde motor protein dynein. Furthermore, the content of Sarkosyl-insoluble tau, a measure of abnormal tau aggregation, increased 3-fold in PHF-treated cells. An exosome-related mechanism did not appear to be involved in the release of GFP-Tau from untreated cells. The evidence that cells can internalize PHFs, leading to formation of aggresome-like bodies, opens new therapeutic avenues to prevent propagation and spreading of tau pathology. PMID:22496370

  13. Paired helical filaments from Alzheimer disease brain induce intracellular accumulation of Tau protein in aggresomes.

    PubMed

    Santa-Maria, Ismael; Varghese, Merina; Ksiezak-Reding, Hanna; Dzhun, Anastasiya; Wang, Jun; Pasinetti, Giulio M

    2012-06-08

    Abnormal folding of tau protein leads to the generation of paired helical filaments (PHFs) and neurofibrillary tangles, a key neuropathological feature in Alzheimer disease and tauopathies. A specific anatomical pattern of pathological changes developing in the brain suggests that once tau pathology is initiated it propagates between neighboring neuronal cells, possibly spreading along the axonal network. We studied whether PHFs released from degenerating neurons could be taken up by surrounding cells and promote spreading of tau pathology. Neuronal and non-neuronal cells overexpressing green fluorescent protein-tagged tau (GFP-Tau) were treated with isolated fractions of human Alzheimer disease-derived PHFs for 24 h. We found that cells internalized PHFs through an endocytic mechanism and developed intracellular GFP-Tau aggregates with attributes of aggresomes. This was particularly evident by the perinuclear localization of aggregates and redistribution of the vimentin intermediate filament network and retrograde motor protein dynein. Furthermore, the content of Sarkosyl-insoluble tau, a measure of abnormal tau aggregation, increased 3-fold in PHF-treated cells. An exosome-related mechanism did not appear to be involved in the release of GFP-Tau from untreated cells. The evidence that cells can internalize PHFs, leading to formation of aggresome-like bodies, opens new therapeutic avenues to prevent propagation and spreading of tau pathology.

  14. Alzheimer's Disease

    MedlinePlus

    ... people. Dementia is a brain disorder that seriously affects a person's ability to carry out daily activities. AD begins slowly. It first involves the parts of the brain that control thought, memory and language. People with AD may have trouble ...

  15. Regional and Gender Study of Neuronal Density in Brain during Aging and in Alzheimer's Disease

    PubMed Central

    Martínez-Pinilla, Eva; Ordóñez, Cristina; del Valle, Eva; Navarro, Ana; Tolivia, Jorge

    2016-01-01

    Background: Learning processes or language development are only some of the cognitive functions that differ qualitatively between men and women. Gender differences in the brain structure seem to be behind these variations. Indeed, this sexual dimorphism at neuroanatomical level is accompanied unequivocally by differences in the way that aging and neurodegenerative diseases affect men and women brains. Objective: The aim of this study is the analysis of neuronal density in four areas of the hippocampus, and entorhinal and frontal cortices to analyze the possible gender influence during normal aging and in Alzheimer's disease (AD). Methods: Human brain tissues of different age and from both sexes, without neurological pathology and with different Braak's stages of AD, were studied. Neuronal density was quantified using the optical dissector. Results: Our results showed the absence of a significant neuronal loss during aging in non-pathological brains in both sexes. However, we have demonstrated specific punctual significant variations in neuronal density related with the age and gender in some regions of these brains. In fact, we observed a higher neuronal density in CA3 and CA4 hippocampal areas of non-pathological brains of young men compared to women. During AD, we observed a negative correlation between Braak's stages and neuronal density in hippocampus, specifically in CA1 for women and CA3 for men, and in frontal cortex for both, men and women. Conclusion: Our data demonstrated a sexual dimorphism in the neuronal vulnerability to degeneration suggesting the need to consider the gender of the individuals in future studies, regarding neuronal loss in aging and AD, in order to avoid problems in interpreting data. PMID:27679571

  16. Scopolamine effects on functional brain connectivity: a pharmacological model of Alzheimer's disease.

    PubMed

    Bajo, R; Pusil, S; López, M E; Canuet, L; Pereda, E; Osipova, D; Maestú, F; Pekkonen, E

    2015-07-01

    Scopolamine administration may be considered as a psychopharmacological model of Alzheimer's disease (AD). Here, we studied a group of healthy elderly under scopolamine to test whether it elicits similar changes in brain connectivity as those observed in AD, thereby verifying a possible model of AD impairment. We did it by testing healthy elderly subjects in two experimental conditions: glycopyrrolate (placebo) and scopolamine administration. We then analyzed magnetoencephalographic (MEG) data corresponding to both conditions in resting-state with eyes closed. This analysis was performed in source space by combining a nonlinear frequency band-specific measure of functional connectivity (phase locking value, PLV) with network analysis methods. Under scopolamine, functional connectivity between several brain areas was significantly reduced as compared to placebo, in most frequency bands analyzed. Besides, regarding the two complex network indices studied (clustering and shortest path length), clustering significantly decreased in the alpha band while shortest path length significantly increased also in alpha band both after scopolamine administration. Overall our findings indicate that both PLV and graph analysis are suitable tools to measure brain connectivity changes induced by scopolamine, which causes alterations in brain connectivity apparently similar to those reported in AD.

  17. Automated detection of brain atrophy patterns based on MRI for the prediction of Alzheimer's disease

    PubMed Central

    Plant, Claudia; Teipel, Stefan J.; Oswald, Annahita; Böhm, Christian; Meindl, Thomas; Mourao-Miranda, Janaina; Bokde, Arun W.; Hampel, Harald; Ewers, Michael

    2010-01-01

    Subjects with mild cognitive impairment (MCI) have an increased risk to develop Alzheimer's disease (AD). Voxel-based MRI studies have demonstrated that widely distributed cortical and subcortical brain areas show atrophic changes in MCI, preceding the onset of AD-type dementia. Here we developed a novel data mining framework in combination with three different classifiers including support vector machine (SVM), Bayes statistics, and voting feature intervals (VFI) to derive a quantitative index of pattern matching for the prediction of the conversion from MCI to AD. MRI was collected in 32 AD patients, 24 MCI subjects and 18 healthy controls (HC). Nine out of 24 MCI subjects converted to AD after an average follow-up interval of 2.5 years. Using feature selection algorithms, brain regions showing the highest accuracy for the discrimination between AD and HC were identified, reaching a classification accuracy of up to 92%. The extracted AD clusters were used as a search region to extract those brain areas that are predictive of conversion to AD within MCI subjects. The most predictive brain areas included the anterior cingulate gyrus and orbitofrontal cortex. The best prediction accuracy, which was cross-validated via train-and-test, was 75% for the prediction of the conversion from MCI to AD. The present results suggest that novel multivariate methods of pattern matching reach a clinically relevant accuracy for the a priori prediction of the progression from MCI to AD. PMID:19961938

  18. Prefrontal hypometabolism in Alzheimer disease is related to longitudinal amyloid accumulation in remote brain regions.

    PubMed

    Klupp, Elisabeth; Grimmer, Timo; Tahmasian, Masoud; Sorg, Christian; Yakushev, Igor; Yousefi, Behrooz H; Drzezga, Alexander; Förster, Stefan

    2015-03-01

    In PET studies of patients with Alzheimer disease (AD), prominent hypometabolism can occur in brain regions without major amyloid load. These hypometabolism-only (HO) areas may not be explained easily as a consequence of local amyloid toxicity. The aim of this longitudinal multimodal imaging study was the investigation of locoregional and remote relationships between metabolism in HO areas and longitudinal amyloid increase in functionally connected brain areas, with a particular focus on intrinsic functional connectivity as a relevant linking mechanism between pathology and dysfunction. Fifteen AD patients underwent longitudinal examinations with (11)C-Pittsburgh compound B ((11)C-PiB) and (18)F-FDG PET (mean follow-up period, 2 y). The peak HO region was identified by the subtraction of equally thresholded statistical T maps (hypometabolism minus amyloid burden), resulting from voxel-based statistical parametric mapping group comparisons between the AD patients and 15 healthy controls. Then functionally connected and nonconnected brain networks were identified by means of seed-based intrinsic functional connectivity analysis of the resting-state functional MRI data of healthy controls. Finally, network-based, region-of-interest-based, and voxel-based correlations were calculated between longitudinal changes of normalized (11)C-PiB binding and (18)F-FDG metabolism. Positive voxel-based and region-of-interest-based correlations were demonstrated between longitudinal (11)C-PiB increases in the HO-connected network, encompassing bilateral temporoparietal and frontal brain regions, and metabolic changes in the peak HO region as well as locoregionally within several AD-typical brain regions. Our results indicate that in AD amyloid accumulation in remote but functionally connected brain regions may significantly contribute to longitudinally evolving hypometabolism in brain regions not strongly affected by local amyloid pathology, supporting the amyloid- and network

  19. Construction and Analysis of Weighted Brain Networks from SICE for the Study of Alzheimer's Disease

    PubMed Central

    Munilla, Jorge; Ortiz, Andrés; Górriz, Juan M.; Ramírez, Javier; Weiner, Michael W.

    2017-01-01

    Alzheimer's Disease (AD) is the most common neurodegenerative disease in elderly people, and current drugs, unfortunately, do not represent yet a cure but only slow down its progression. This is explained, at least in part, because the understanding of the neurodegenerative process is still incomplete, being sometimes mistaken, particularly at the first steps of the illness, with the natural aging process. A better identification of how the functional activity deteriorates is thus crucial to develop new and more effective treatments. Sparse inverse covariance estimates (SICE) have been recently employed for deriving functional connectivity patterns from Positron Emission Tomography (PET) of brains affected by Alzheimer's Disease. SICE, unlike the traditional covariance methods, allows to analyze the interdependencies between brain regions factoring out the influence of others. To analyze the effects of the illness, connectivity patterns of brains affected by AD are compared with those obtained for control groups. These comparisons are, however, carried out for binary (undirected and unweighted) adjacency matrices with the same number of arcs. Additionally, the effect of the number of subjects employed or the validity of the regularization parameter used to compute the SICE have been not hitherto analyzed. In this paper, we delve into the construction of connectivity patterns from PET using SICE. In particular, we describe the effect that the number of subjects employed has on the results and identify, based on the reconstruction error of linear regression systems, a range of valid values for the regularization parameter. The amount of arcs is also proved as a discriminant value, and we show that it is possible to pass from unweighted (binary) to weighted adjacency matrices, where the weight of a connection corresponding to the existence of a relationship between two brain areas can be correlated to the persistence of this relationship when computed for different

  20. Construction and Analysis of Weighted Brain Networks from SICE for the Study of Alzheimer's Disease.

    PubMed

    Munilla, Jorge; Ortiz, Andrés; Górriz, Juan M; Ramírez, Javier

    2017-01-01

    Alzheimer's Disease (AD) is the most common neurodegenerative disease in elderly people, and current drugs, unfortunately, do not represent yet a cure but only slow down its progression. This is explained, at least in part, because the understanding of the neurodegenerative process is still incomplete, being sometimes mistaken, particularly at the first steps of the illness, with the natural aging process. A better identification of how the functional activity deteriorates is thus crucial to develop new and more effective treatments. Sparse inverse covariance estimates (SICE) have been recently employed for deriving functional connectivity patterns from Positron Emission Tomography (PET) of brains affected by Alzheimer's Disease. SICE, unlike the traditional covariance methods, allows to analyze the interdependencies between brain regions factoring out the influence of others. To analyze the effects of the illness, connectivity patterns of brains affected by AD are compared with those obtained for control groups. These comparisons are, however, carried out for binary (undirected and unweighted) adjacency matrices with the same number of arcs. Additionally, the effect of the number of subjects employed or the validity of the regularization parameter used to compute the SICE have been not hitherto analyzed. In this paper, we delve into the construction of connectivity patterns from PET using SICE. In particular, we describe the effect that the number of subjects employed has on the results and identify, based on the reconstruction error of linear regression systems, a range of valid values for the regularization parameter. The amount of arcs is also proved as a discriminant value, and we show that it is possible to pass from unweighted (binary) to weighted adjacency matrices, where the weight of a connection corresponding to the existence of a relationship between two brain areas can be correlated to the persistence of this relationship when computed for different

  1. Brain structure and function related to depression in Alzheimer's disease: contributions from neuroimaging research.

    PubMed

    Brommelhoff, Jessica A; Sultzer, David L

    2015-01-01

    The development of minimally invasive in vivo methods for imaging the brain has allowed for unprecedented advancement in our understanding of brain-behavior relationships. Structural, functional, and multimodal neuroimaging techniques have become more sophisticated in detecting structural and physiological abnormalities that may underlie various affective disorders and neurological illnesses such as depression in Alzheimer's disease (AD). In general, neuroimaging studies of depression in AD investigate whether depression is associated with damage to structures in specific neural networks involving frontal and subcortical structures or with functional disruption of cortical neural systems. This review provides an overview of how various imaging modalities have contributed to our understanding of the neurobiology of depression in AD. At present, the literature does not conclusively support any specific pathogenesis for depression, and it is not clear whether patients with AD and depression have histopathological and neurochemical characteristics that contribute to mood symptoms that are different from cognitively intact individuals with depression. Neuroimaging studies suggest that atrophy of temporal or frontal structures, white matter lesions in frontal lobe or subcortical systems, reduced activity in dorsolateral frontal cortex, or small vessel cerebrovascular disease may be associated with depression in AD. Conceptual, clinical, and methodological challenges in studying this relationship are discussed. Further work is needed to understand the specific brain structures, relevant white matter tracts, and interactions among them that are most important. This review concludes with potential directions for future research.

  2. [Theoretic basis on the same therapeutic program for different degenerative brain diseases in terms of the Governor Vessel: Alzheimer's disease and Parkinson's disease].

    PubMed

    Wu, Junyan; Wang, Jie; Zhang, Junlong

    2015-05-01

    Through the consultation of TCM ancient classical theory, the relationship of kidney essence, marrow and brain is analyzed. It is discovered that the degenerative brain diseases, represented by Alzheimer's disease (AD) and Parkinson's disease (PD) share the same etiological basis as "kidney essence deficiency and brain marrow emptiness" and have the mutual pathological outcomes as yang qi declining. The Governor Vessel gathers yang qi of the whole body and maintains the normal functional activity of zangfu organs in the human body through the storage, regulation and invigoration of yang qi. It is viewed that the theory of the Governor Vessel is applied to treat the different degenerative brain diseases, which provides the theoretic support and practice guide for the thought of TCM as the same therapeutic program for the different diseases. As a result, the degenerative brain diseases can be retarded and the approach is provided to the effective prevention and treatment of degenerative diseases in central nerve system:

  3. Lipofuscin and Abeta42 exhibit distinct distribution patterns in normal and Alzheimer's disease brains.

    PubMed

    D'Andrea, Michael R; Nagele, Robert G; Gumula, Norah A; Reiser, Patti A; Polkovitch, Deborah A; Hertzog, Brenda M; Andrade-Gordon, Patricia

    2002-04-19

    Our recent study has provided evidence that Abeta42, a 42 amino acid fragment of the amyloid precursor protein, accumulates intracellularly in vulnerable neurons. This study appears to show that neurons lyse and form dense-core amyloid plaques in Alzheimer's disease (AD) entorhinal cortex. Previous studies have suggested that intracellular Abeta42 co-localizes with lipofuscin in neurons and those increased levels of lipofuscin and Abeta42 are associated with AD. Other studies have questioned this relationship and suggested that beta-amyloid and lipofuscin are not co-localized and that their levels are independent of one another in AD and age-matched control tissues. In an effort to resolve this controversy, we investigated the relative spatial relationship of intracellular Abeta42 and lipofuscin in AD brains tissue using a novel combined immunohistochemical:histochemical staining protocol. Our results show separate and distinct localization patterns of Abeta42 and lipofuscin in neurons and amyloid plaques.

  4. PSEN1 and PSEN2 gene expression in Alzheimer's disease brain: a new approach.

    PubMed

    Delabio, Roger; Rasmussen, Lucas; Mizumoto, Igor; Viani, Gustavo-Arruda; Chen, Elizabeth; Villares, João; Costa, Isabela-Bazzo; Turecki, Gustavo; Linde, Sandra Aparecido; Smith, Marilia Cardoso; Payão, Spencer-Luiz

    2014-01-01

    Presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes encode the major component of y-secretase, which is responsible for sequential proteolytic cleavages of amyloid precursor proteins and the subsequent formation of amyloid-β peptides. 150 RNA samples from the entorhinal cortex, auditory cortex and hippocampal regions of individuals with Alzheimer's disease (AD) and controls elderly subjects were analyzed with using real-time rtPCR. There were no differences between groups for PSEN1 expression. PSEN2 was significantly downregulated in the auditory cortex of AD patients when compared to controls and when compared to other brain regions of the patients. Alteration in PSEN2 expression may be a risk factor for AD.

  5. Developing drugs that can cross the blood-brain barrier: applications to Alzheimer's disease.

    PubMed

    Banks, William A

    2008-12-10

    Development of therapeutics for the central nervous system is one of the most challenging areas in drug development. This is primarily because, in addition to all of the other complications one faces in developing new drugs targeting peripheral sites, one must also negotiate the blood-brain barrier (BBB). There are dozens of strategies to overcome the obstacle of the BBB, but many of these are bound to fail, barring extreme serendipity, because they are based on an inaccurate or incomplete picture of the BBB. This article therefore starts with a brief review of the BBB as it pertains to drug development. It then examines some examples of the delivery of drugs to the central nervous system that are relevant to Alzheimer's disease, placing emphasis on peptides, antibodies, and antisense oligonucleotides.

  6. ERP-based detection of brain pathology in rat models for preclinical Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Nouriziabari, Seyed Berdia

    Early pathological features of Alzheimer's disease (AD) include the accumulation of hyperphosphorylated tau protein (HP-tau) in the entorhinal cortex and progressive loss of basal forebrain (BF) cholinergic neurons. These pathologies are known to remain asymptomatic for many years before AD is clinically diagnosed; however, they may induce aberrant brain processing which can be captured as an abnormality in event-related potentials (ERPs). Here, we examined cortical ERPs while a differential associative learning paradigm was applied to adult male rats with entorhinal HP-tau, pharmacological blockade of muscarinic acetylcholine receptors, or both conditions. Despite no impairment in differential associative and reversal learning, each pathological feature induced distinct abnormality in cortical ERPs to an extent that was sufficient for machine classifiers to accurately detect a specific type of pathology based on these ERP features. These results highlight a potential use of ERPs during differential associative learning as a biomarker for asymptomatic AD pathology.

  7. Sexually Dimorphic Expression of Reelin in the Brain of a Mouse Model of Alzheimer Disease.

    PubMed

    Palladino, Giampiero; Nicolia, Vincenzina; Kovacs, Gabor G; Canterini, Sonia; Ciraci, Viviana; Fuso, Andrea; Mangia, Franco; Scarpa, Sigfrido; Fiorenza, Maria Teresa

    2017-03-01

    Recent evidence highlights the protective role of reelin against amyloid β (Aβ)-induced synaptic dysfunction and cognitive impairment in Alzheimer disease (AD). In this study, exploiting TgCRND8 mice that overexpress a mutant form of amyloid β precursor protein (AβPP) and display an early onset of AD neuropathological signs, we addressed the question whether changes of reelin expression eventually precede the appearance of Aβ-plaques in a sex-dependent manner. We show that sex-associated and brain region-specific differences in reelin expression appear long before Aβ-plaque formation. However, in spite of a downregulation of reelin expression compared to males, TgCRND8 females display fewer Aβ-plaques, suggesting that additional factors, other than sex and reelin level, influence amyloidosis in this mouse model.

  8. A proposed strategy for international collaborative research in brain aging and Alzheimer's disease.

    PubMed

    Khachaturian, Z S; Radebaugh, T S

    1990-01-01

    A description and discussion are given of several of the programmes initiated by the United States' National Institute on Aging that could be expanded to facilitate multicentre collaboration studies. It includes: the Alzheimer's Disease Research Centers; the Alzheimer's Disease Patient Registry Program; the World Health Organization Special Programme for Research on Aging; and how collaborative links with scientists working on this disease in other countries may be established.

  9. Dysphagia in Alzheimer's disease.

    PubMed

    Seçil, Yaprak; Arıcı, Şehnaz; İncesu, Tülay Kurt; Gürgör, Nevin; Beckmann, Yeşim; Ertekin, Cumhur

    2016-06-01

    To investigate electrophysiological parameters of swallowing in all stages of Alzheimer's disease. Forty Alzheimer's disease patients, 20 age-matched normal controls and 20 young normal controls were included. Dysphagia limit (DL) and sequential water swallowing (SWS) tests were performed. Cardiac rhythm, respiration and sympathetic skin responses were concomitantly recorded. Dysphagia was found in 30/40 (75%) of Alzheimer's disease patients. Mean volume at the DL test was significantly reduced (16.5±1.0mL) in the Alzheimer's disease group. Swallowing and apnea times in the SWS test were significantly prolonged in elderly controls, but even longer in Alzheimer's disease patients. Alzheimer's disease patients had electrophysiological features of dysphagia, even in the early period of disease. The cortical involvement and severity of cognitive disorder can increase swallowing problems, but subclinical signs of dysphagia may be observed even in patients with mild or moderate Alzheimer's disease. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  10. Voxel-based discriminant map classification on brain ventricles for Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Wang, Jingnan; de Haan, Gerard; Unay, Devrim; Soldea, Octavian; Ekin, Ahmet

    2009-02-01

    One major hallmark of the Alzheimer's disease (AD) is the loss of neurons in the brain. In many cases, medical experts use magnetic resonance imaging (MRI) to qualitatively measure the neuronal loss by the shrinkage or enlargement of the structures-of-interest. Brain ventricle is one of the popular choices. It is easily detectable in clinical MR images due to the high contrast of the cerebro-spinal fluid (CSF) with the rest of the parenchyma. Moreover, atrophy in any periventricular structure will directly lead to ventricle enlargement. For quantitative analysis, volume is the common choice. However, volume is a gross measure and it cannot capture the entire complexity of the anatomical shape. Since most existing shape descriptors are complex and difficult-to-reproduce, more straightforward and robust ways to extract ventricle shape features are preferred in the diagnosis. In this paper, a novel ventricle shape based classification method for Alzheimer's disease has been proposed. Training process is carried out to generate two probability maps for two training classes: healthy controls (HC) and AD patients. By subtracting the HC probability map from the AD probability map, we get a 3D ventricle discriminant map. Then a matching coefficient has been calculated between each training subject and the discriminant map. An adjustable cut-off point of the matching coefficients has been drawn for the two classes. Generally, the higher the cut-off point that has been drawn, the higher specificity can be achieved. However, it will result in relatively lower sensitivity and vice versa. The benchmarked results against volume based classification show that the area under the ROC curves for our proposed method is as high as 0.86 compared with only 0.71 for volume based classification method.

  11. Loss of neprilysin alters protein expression in the brain of Alzheimer's disease model mice.

    PubMed

    Nilsson, Per; Loganathan, Krishnapriya; Sekiguchi, Misaki; Winblad, Bengt; Iwata, Nobuhisa; Saido, Takaomi C; Tjernberg, Lars O

    2015-10-01

    Alzheimer's disease (AD) is a neurodegenerative disease displaying extracellular plaques formed by the neurotoxic amyloid β-peptide (Aβ), and intracellular neurofibrillary tangles consisting of protein tau. However, how these pathologies relate to the massive neuronal death that occurs in AD brains remain elusive. Neprilysin is the major Aβ-degrading enzyme and a lack thereof increases Aβ levels in the brain twofold. To identify altered protein expression levels induced by increased Aβ levels, we performed a proteomic analysis of the brain of the AD mouse model APPsw and compared it to that of APPsw mice lacking neprilysin. To this end we established an LC-MS/MS method to analyze brain homogenate, using an (18) O-labeled internal standard to accurately quantify the protein levels. To distinguish between alterations in protein levels caused by increased Aβ levels and those induced by neprilysin deficiency independently of Aβ, the brain proteome of neprilysin deficient APPsw mice was also compared to that of neprilysin deficient mice. By this approach we identified approximately 600 proteins and the levels of 300 of these were quantified. Pathway analysis showed that many of the proteins with altered expression were involved in neurological disorders, and that tau, presenilin and APP were key regulators in the identified networks. The data have been deposited to the ProteomeXchange Consortium with identifiers PXD000968 and PXD001786 (http://proteomecentral.proteomexchange.org/dataset/PXD000968 and (http://proteomecentral.proteomexchange.org/dataset/PXD001786). Interestingly, the levels of several proteins, including some not previously reported to be linked to AD, were associated with increased Aβ levels. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. [Study on Brain Functional Connectivity Using Resting State Electroencephalogram Based on Synchronization Likelihood in Alzheimer's Disease].

    PubMed

    Li, Li; Chen, Jingjing; Zheng, Xuyuan

    2015-10-01

    Alzheimer's disease (AD) is the most common type of dementia and a neurodegenerative disease with progressive cognitive dysfunction as the main feature. How to identify the early changes of cognitive dysfunction and give appropriate treatments is of great significance to delay the onset of dementia. Some other researches have shown that AD is associated with abnormal changes of brain networks. To study human brain functional connectivity characteristics in AD, 16 channels electroencephalogram (EEG) were recorded under resting and eyes-closed condition in 15 AD patients and 15 subjects in the control group. The synchronization likelihood of the full-band and alpha-band (8-13 Hz) data were evaluated, which resulted in the synchronization likelihood coefficient matrices. Considering a threshold T, the matrices were converted into binary graphs. Then the graphs of two groups were measured by topological parameters including the clustering coefficient and global efficiency. The results showed that the global efficiency of the network in full-band EEG was significantly smaller in AD group for the values of T = 0.06 and T = 0.07, but there was no statistically significant difference in the clustering coefficients between the two groups for the values of T (0.05-0.07). However, the clustering coefficient and global efficiency were significantly lower in AD patients at alpha-band for the same threshold range than those of subjects in the control group. It suggests that there may be decreases of the brain connectivity strength in AD patients at alpha-band of the resting-state EEG. This study provides a support for quantifying functional brain state of AD from the brain network perspective.

  13. Cellular model studies of brain-mediated phototherapy on Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Zhu, Ling; Liu, Timon Cheng-Yi; Hu, Bina; Li, Xiao-Yun; Wang, Yong-Qing

    2008-12-01

    Alzheimer's disease (AD) is now the most common neurodegenerative disease. Despite approval of several drugs for AD, the disease continues to rob millions of their memories and their lives. We have studied the cellular models of brain-mediated phototherapy on AD, and the studies will be reviewed in this paper. Genetic studies have shown that dysfunction of amyloid β-protein (Aβ) or tau is sufficient to cause AD. Aβ or Aβ induced redox stress induced neuron apoptosis might be as a cellular model of AD. We found red light at 640+/-15 nm from light emitting diode array (RLED640) might inhibit Aβ 25-35 induced PC12 cell apoptosis, which is mediated by cyclic adenosine monophosphate, and it might inhibit hydrogen peroxide (H2O2) induced differentiated PC12 cell (dPC12) apoptosis, which is mediated by tyrosine hydroxylase. There is rhythm dysfunction in AD. We found low intensity 810 nm laser irradiation might rehabilitate TNF-alpha induced inhibition of clock gen expression of NIH 3T3 fibroblasts. Our studies provide a foundation for photobiomodulation on brain to rehabilitate AD.

  14. Three-Dimensional Eigenbrain for the Detection of Subjects and Brain Regions Related with Alzheimer's Disease.

    PubMed

    Zhang, Yudong; Wang, Shuihua; Phillips, Preetha; Yang, Jiquan; Yuan, Ti-Fei

    2016-01-01

    Considering that Alzheimer's disease (AD) is untreatable, early diagnosis of AD from the healthy elderly controls (HC) is pivotal. However, computer-aided diagnosis (CAD) systems were not widely used due to its poor performance. Inspired from the eigenface approach for face recognition problems, we proposed an eigenbrain to detect AD brains. Eigenface is only for 2D image processing and is not suitable for volumetric image processing since faces are usually obtained as 2D images. We extended the eigenbrain to 3D. This 3D eigenbrain (3D-EB) inherits the fundamental strategies in either eigenface or 2D eigenbrain (2D-EB). All the 3D brains were transferred to a feature space, which encoded the variation among known 3D brain images. The feature space was named as the 3D-EB, and defined as eigenvectors on the set of 3D brains. We compared four different classifiers: feed-forward neural network, support vector machine (SVM) with linear kernel, polynomial (Pol) kernel, and radial basis function kernel. The 50x10-fold stratified cross validation experiments showed that the proposed 3D-EB is better than the 2D-EB. SVM with Pol kernel performed the best among all classifiers. Our "3D-EB + Pol-SVM" achieved an accuracy of 92.81% ± 1.99% , a sensitivity of 92.07% ± 2.48% , a specificity of 93.02% ± 2.22% , and a precision of 79.03% ± 2.37% . Based on the most important 3D-EB U1, we detected 34 brain regions related with AD. The results corresponded to recent literature. We validated the effectiveness of the proposed 3D-EB by detecting subjects and brain regions related to AD.

  15. The hunt for brain Aβ oligomers by peripherally circulating multi-functional nanoparticles: Potential therapeutic approach for Alzheimer disease.

    PubMed

    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.

  16. Alzheimer Disease Alters the Relationship of Cardiorespiratory Fitness With Brain Activity During the Stroop Task

    PubMed Central

    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

  17. Fungal Enolase, β-Tubulin, and Chitin Are Detected in Brain Tissue from Alzheimer's Disease Patients.

    PubMed

    Pisa, Diana; Alonso, Ruth; Rábano, Alberto; Horst, Michael N; Carrasco, Luis

    2016-01-01

    Recent findings provide evidence that fungal structures can be detected in brain tissue from Alzheimer's disease (AD) patients using rabbit polyclonal antibodies raised against whole fungal cells. In the present work, we have developed and tested specific antibodies that recognize the fungal proteins, enolase and β-tubulin, and an antibody that recognizes the fungal polysaccharide chitin. Consistent with our previous studies, a number of rounded yeast-like and hyphal structures were detected using these antibodies in brain sections from AD patients. Some of these structures were intracellular and, strikingly, some were found to be located inside nuclei from neurons, whereas other fungal structures were detected extracellularly. Corporya amylacea from AD patients also contained enolase and β-tubulin as revealed by these selective antibodies, but were devoid of fungal chitin. Importantly, brain sections from control subjects were usually negative for staining with the three antibodies. However, a few fungal structures can be observed in some control individuals. Collectively, these findings indicate the presence of two fungal proteins, enolase and β-tubulin, and the polysaccharide chitin, in CNS tissue from AD patients. These findings are consistent with our hypothesis that AD is caused by disseminated fungal infection.

  18. Direct visualization of fungal infection in brains from patients with Alzheimer's disease.

    PubMed

    Pisa, Diana; Alonso, Ruth; Juarranz, Angeles; Rábano, Alberto; Carrasco, Luis

    2015-01-01

    Recently, we have reported the presence of fungal infections in patients with Alzheimer's disease (AD). Accordingly, fungal proteins and DNA were found in brain samples, demonstrating the existence of infection in the central nervous system. In the present work, we raised antibodies to specific fungal species and performed immunohistochemistry to directly visualize fungal components inside neurons from AD patients. Mice infected with Candida glabrata were initially used to assess whether yeast can be internalized in mammalian tissues. Using polyclonal rabbit antibodies against C. glabrata, rounded immunopositive cells could be detected in the cytoplasm of cells from liver, spleen, and brain samples in infected, but not uninfected, mice. Immunohistochemical analyses of tissue from the frontal cortex of AD patients revealed the presence of fungal material in a small percentage (~10%) of cells, suggesting the presence of infection. Importantly, this immunopositive material was absent in control samples. Confocal microscopy indicated that this fungal material had an intracellular localization. The specific morphology of this material varied between patients; in some instances, disseminated material was localized to the cytoplasm, whereas small punctate bodies were detected in other patients. Interestingly, fungal material could be revealed using different anti-fungal antibodies, suggesting multiple infections. In summary, fungal infection can only be observed using specific anti-fungal antibodies and only a small percentage of cells contain fungi. Our findings provide an explanation for the hitherto elusive detection of fungi in AD brains, and are consistent with the idea that fungal cells are internalized inside neurons.

  19. Conformational features of tau fibrils from Alzheimer's disease brain are faithfully propagated by unmodified recombinant protein.

    PubMed

    Morozova, Olga A; March, Zachary M; Robinson, Anne S; Colby, David W

    2013-10-08

    Fibrils composed of tau protein are a pathological hallmark of several neurodegenerative disorders including Alzheimer's disease (AD). Here we show that when recombinant tau protein is seeded with paired helical filaments (PHFs) isolated from AD brain, the amyloid formed shares many of the structural features of AD PHFs. In contrast, tau amyloids formed with heparin as an inducing agent-a common biochemical model of tau misfolding-are structurally distinct from brain-derived PHFs. Using ultrastructural analysis by electron microscopy, circular dichroism, and chemical denaturation, we found that AD seeded recombinant tau fibrils were not significantly different than tau fibrils isolated from AD brain tissue. Tau fibrils produced by incubating recombinant tau with heparin had significantly narrower fibrils with a longer periodicity, higher chemical stability, and distinct secondary structure compared to AD PHFs. The addition of heparin to the reaction of recombinant tau and AD PHFs also corrupted the templating process, resulting in a mixture of fibril conformations. Our results suggest that AD-isolated PHFs act as a conformational template for the formation of recombinant tau fibrils. Therefore, the use of AD PHFs as seeds to stimulate recombinant tau amyloid formation produces synthetic tau fibers that closely resemble those associated with AD pathology and provides a biochemical model of tau misfolding that may be of improved utility for structural studies and drug screening. These results also demonstrate that post-translational modifications such as phosphorylation are not a prerequisite for the propagation of the tau fibril conformation found in AD.

  20. A Spherical Brain Mapping of MR Images for the Detection of Alzheimer's Disease.

    PubMed

    Martinez-Murcia, F J; Górriz, J M; Ramírez, J; Ortiz, A; For The Alzheimer's Disease Neuroimaging Initiative

    2016-01-01

    Magnetic Resonance Imaging (MRI) is of fundamental importance in neuroscience, providing good contrast and resolution, as well as not being considered invasive. Despite the development of newer techniques involving radiopharmaceuticals, it is still a recommended tool in Alzheimer's Disease (AD) neurological practice to assess neurodegeneration, and recent research suggests that it could reveal changes in the brain even before the symptomatology appears. In this paper we propose a method that performs a Spherical Brain Mapping, using different measures to project the three-dimensional MR brain images onto two-dimensional maps revealing statistical characteristics of the tissue. The resulting maps could be assessed visually, but also perform a significant feature reduction that will allow further supervised or unsupervised processing, reducing the computational load while maintaining a large amount of the original information. We have tested our methodology against a MRI database comprising 180 AD affected patients and 180 normal controls, where some of the mappings have revealed as an optimum strategy for the automatic processing and characterization of AD patterns, achieving up to a 90.9% of accuracy, as well as significantly reducing the computational load. Additionally, our maps allow the visual analysis and interpretation of the images, which can be of great help in the diagnosis of this and other types of dementia.

  1. Alzheimer's disease: connecting findings from graph theoretical studies of brain networks.

    PubMed

    Tijms, Betty M; Wink, Alle Meije; de Haan, Willem; van der Flier, Wiesje M; Stam, Cornelis J; Scheltens, Philip; Barkhof, Frederik

    2013-08-01

    The interrelationships between pathological processes and emerging clinical phenotypes in Alzheimer's disease (AD) are important yet complicated to study, because the brain is a complex network where local disruptions can have widespread effects. Recently, properties in brain networks obtained with neuroimaging techniques have been studied in AD with tools from graph theory. However, the interpretation of graph alterations remains unclear, because the definition of connectivity depends on the imaging modality used. Here we examined which graph properties have been consistently reported to be disturbed in AD studies, using a heuristically defined "graph space" to investigate which theoretical models can best explain graph alterations in AD. Findings from structural and functional graphs point to a loss of highly connected areas in AD. However, studies showed considerable variability in reported group differences of most graph properties. This suggests that brain graphs might not be isometric, which complicates the interpretation of graph measurements. We highlight confounding factors such as differences in graph construction methods and provide recommendations for future research.

  2. Preserved pontine glucose metabolism in Alzheimer disease: A reference region for functional brain image (PET) analysis

    SciTech Connect

    Minoshima, Satoshi; Frey, K.A.; Foster, N.L.; Kuhl, D.W.

    1995-07-01

    Our goal was to examine regional preservation of energy metabolism in Alzheimer disease (AD) and to evaluate effects of PET data normalization to reference regions. Regional metabolic rates in the pons, thalamus, putamen, sensorimotor cortex, visual cortex, and cerebellum (reference regions) were determined stereotaxically and examined in 37 patients with probable AD and 22 normal controls based on quantitative {sup 18}FDG-PET measurements. Following normalization of metabolic rates of the parietotemporal association cortex and whole brain to each reference region, distinctions of the two groups were assessed. The pons showed the best preservation of glucose metabolism in AD. Other reference regions showed relatively preserved metabolism compared with the parietotemporal association cortex and whole brain, but had significant metabolic reduction. Data normalization to the pons not only enhanced statistical significance of metabolic reduction in the parietotemporal association cortex, but also preserved the presence of global cerebral metabolic reduction indicated in analysis of the quantitative data. Energy metabolism in the pons in probable AD is well preserved. The pons is a reliable reference for data normalization and will enhance diagnostic accuracy and efficiency of quantitative and nonquantitative functional brain imaging. 39 refs., 2 figs., 3 tabs.

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

    PubMed Central

    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

  4. The role of calsyntenin-3 in dystrophic neurite formation in Alzheimer's disease brain.

    PubMed

    Uchida, Yoko; Gomi, Fujiya

    2016-03-01

    β-Amyloid (Aβ) oligomers may play an important role in the early pathogenesis of Alzheimer's disease: cognitive impairment caused by synaptic dysfunction. Dystrophic neurites surrounding Aβ plaques, another pathological feature of Alzheimer's disease, are plaque-associated neuritic alterations preceding the appearance of synaptic loss. In the present review, we focus on the mechanism of dystrophic neurite formation by Aß oligomers, and discuss the neurotoxic role of Aβ-induced calsyntenin-3 in mediating dystrophic neurite formation.

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

    PubMed Central

    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

  6. Toward a brain-computer interface for Alzheimer's disease patients by combining classical conditioning and brain state classification.

    PubMed

    Liberati, Giulia; Dalboni da Rocha, Josué Luiz; van der Heiden, Linda; Raffone, Antonino; Birbaumer, Niels; Olivetti Belardinelli, Marta; Sitaram, Ranganatha

    2012-01-01

    Brain-computer interfaces (BCIs) provide alternative methods for communicating and acting on the world, since messages or commands are conveyed from the brain to an external device without using the normal output pathways of peripheral nerves and muscles. Alzheimer's disease (AD) patients in the most advanced stages, who have lost the ability to communicate verbally, could benefit from a BCI that may allow them to convey basic thoughts (e.g., "yes" and "no") and emotions. There is currently no report of such research, mostly because the cognitive deficits in AD patients pose serious limitations to the use of traditional BCIs, which are normally based on instrumental learning and require users to self-regulate their brain activation. Recent studies suggest that not only self-regulated brain signals, but also involuntary signals, for instance related to emotional states, may provide useful information about the user, opening up the path for so-called "affective BCIs". These interfaces do not necessarily require users to actively perform a cognitive task, and may therefore be used with patients who are cognitively challenged. In the present hypothesis paper, we propose a paradigm shift from instrumental learning to classical conditioning, with the aim of discriminating "yes" and "no" thoughts after associating them to positive and negative emotional stimuli respectively. This would represent a first step in the development of a BCI that could be used by AD patients, lending a new direction not only for communication, but also for rehabilitation and diagnosis.

  7. Unbiased Metabolomic Investigation of Alzheimer's Disease Brain Points to Dysregulation of Mitochondrial Aspartate Metabolism.

    PubMed

    Paglia, Giuseppe; Stocchero, Matteo; Cacciatore, Stefano; Lai, Steven; Angel, Peggi; Alam, Mohammad Tauqeer; Keller, Markus; Ralser, Markus; Astarita, Giuseppe

    2016-02-05

    Alzheimer's disease (AD) is the most common cause of adult dementia. Yet the complete set of molecular changes accompanying this inexorable, neurodegenerative disease remains elusive. Here we adopted an unbiased lipidomics and metabolomics approach to surveying frozen frontal cortex samples from clinically characterized AD patients (n = 21) and age-matched controls (n = 19), revealing marked molecular differences between them. Then, by means of metabolomic pathway analysis, we incorporated the novel molecular information into the known biochemical pathways and compared it with the results of a metabolomics meta-analysis of previously published AD research. We found six metabolic pathways of the central metabolism as well as glycerophospholipid metabolism predominantly altered in AD brains. Using targeted metabolomics approaches and MS imaging, we confirmed a marked dysregulation of mitochondrial aspartate metabolism. The altered metabolic pathways were further integrated with clinical data, showing various degrees of correlation with parameters of dementia and AD pathology. Our study highlights specific, altered biochemical pathways in the brains of individuals with AD compared with those of control subjects, emphasizing dysregulation of mitochondrial aspartate metabolism and supporting future venues of investigation.

  8. The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer's disease brain.

    PubMed

    Varnum, Megan M; Ikezu, Tsuneya

    2012-08-01

    Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline of cognitive function. There is no therapy that can halt or reverse its progression. Contemporary research suggests that age-dependent neuroinflammatory changes may play a significant role in the decreased neurogenesis and cognitive impairments in AD. The innate immune response is characterized by pro-inflammatory (M1) activation of macrophages and subsequent production of specific cytokines, chemokines, and reactive intermediates, followed by resolution and alternative activation for anti-inflammatory signaling (M2a) and wound healing (M2c). We propose that microglial activation phenotypes are analogous to those of macrophages and that their activation plays a significant role in regulating neurogenesis in the brain. Microglia undergo a switch from an M2- to an M1-skewed activation phenotype during aging. This review will assess the neuroimmunological studies that led to characterization of the different microglial activation states in AD mouse models. It will also discuss the roles of microglial activation on neurogenesis in AD and propose anti-inflammatory molecules as exciting therapeutic targets for research. Molecules such as interleukin-4 and CD200 have proven to be important anti-inflammatory mediators in the regulation of neuroinflammation in the brain, which will be discussed in detail for their therapeutic potential.

  9. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease

    PubMed Central

    Lipinski, Marta M.; Zheng, Bin; Lu, Tao; Yan, Zhenyu; Py, Bénédicte F.; Ng, Aylwin; Xavier, Ramnik J.; Li, Cheng; Yankner, Bruce A.; Scherzer, Clemens R.; Yuan, Junying

    2010-01-01

    Dysregulation of autophagy, a cellular catabolic mechanism essential for degradation of misfolded proteins, has been implicated in multiple neurodegenerative diseases. However, the mechanisms that lead to the autophagy dysfunction are still not clear. Based on the results of a genome-wide screen, we show that reactive oxygen species (ROS) serve as common mediators upstream of the activation of the type III PI3 kinase, which is critical for the initiation of autophagy. Furthermore, ROS play an essential function in the induction of the type III PI3 kinase and autophagy in response to amyloid β peptide, the main pathogenic mediator of Alzheimer's disease (AD). However, lysosomal blockage also caused by Aβ is independent of ROS. In addition, we demonstrate that autophagy is transcriptionally down-regulated during normal aging in the human brain. Strikingly, in contrast to normal aging, we observe transcriptional up-regulation of autophagy in the brains of AD patients, suggesting that there might be a compensatory regulation of autophagy. Interestingly, we show that an AD drug and an AD drug candidate have inhibitory effects on autophagy, raising the possibility that decreasing input into the lysosomal system may help to reduce cellular stress in AD. Finally, we provide a list of candidate drug targets that can be used to safely modulate levels of autophagy without causing cell death. PMID:20660724

  10. Diversity of Amyloid-beta Proteoforms in the Alzheimer's Disease Brain.

    PubMed

    Wildburger, Norelle C; Esparza, Thomas J; LeDuc, Richard D; Fellers, Ryan T; Thomas, Paul M; Cairns, Nigel J; Kelleher, Neil L; Bateman, Randall J; Brody, David L

    2017-08-25

    Amyloid-beta (Aβ) plays a key role in the pathogenesis of Alzheimer's disease (AD), but little is known about the proteoforms present in AD brain. We used high-resolution mass spectrometry to analyze intact Aβ from soluble aggregates and insoluble material in brains of six cases with severe dementia and pathologically confirmed AD. The soluble aggregates are especially relevant because they are believed to be the most toxic form of Aβ. We found a diversity of Aβ peptides, with 26 unique proteoforms including various N- and C-terminal truncations. N- and C-terminal truncations comprised 73% and 30%, respectively, of the total Aβ proteoforms detected. The Aβ proteoforms segregated between the soluble and more insoluble aggregates with N-terminal truncations predominating in the insoluble material and C- terminal truncations segregating into the soluble aggregates. In contrast, canonical Aβ comprised the minority of the identified proteoforms (15.3%) and did not distinguish between the soluble and more insoluble aggregates. The relative abundance of many truncated Aβ proteoforms did not correlate with post-mortem interval, suggesting they are not artefacts. This heterogeneity of Aβ proteoforms deepens our understanding of AD and offers many new avenues for investigation into pathological mechanisms of the disease, with implications for therapeutic development.

  11. Distinct brain networks underlie cognitive dysfunction in Parkinson and Alzheimer diseases.

    PubMed

    Mattis, Paul J; Niethammer, Martin; Sako, Wataru; Tang, Chris C; Nazem, Amir; Gordon, Marc L; Brandt, Vicky; Dhawan, Vijay; Eidelberg, David

    2016-11-01

    To determine whether cognitive impairment in Parkinson disease (PD) and Alzheimer disease (AD) derives from the same network pathology. We analyzed (18)F-fluorodeoxyglucose PET scans from 40 patients with AD and 40 age-matched healthy controls from the Alzheimer's Disease Neuroimaging Initiative and scanned an additional 10 patients with AD and 10 healthy controls at The Feinstein Institute for Medical Research to derive an AD-related metabolic pattern (ADRP) analogous to our previously established PD cognition-related pattern (PDCP) and PD motor-related pattern (PDRP). We computed individual subject expression values for ADRP and PDCP in 89 patients with PD and correlated summary scores for cognitive functioning with network expression. We also evaluated changes in ADRP and PDCP expression in a separate group of 15 patients with PD scanned serially over a 4-year period. Analysis revealed a significant AD-related metabolic topography characterized by covarying metabolic reductions in the hippocampus, parahippocampal gyrus, and parietal and temporal association regions. Expression of ADRP, but not PDCP, was elevated in both AD groups and correlated with worse cognitive summary scores. Patients with PD showed slight ADRP expression, due to topographic overlap with the network underlying PD motor-related pattern degeneration, but only their PDCP expression values increased as cognitive function and executive performance declined. Longitudinal data in PD disclosed an analogous dissociation of network expression. Cognitive dysfunction in PD is associated with a specific brain network that is largely spatially and functionally distinct from that seen in relation to AD. © 2016 American Academy of Neurology.

  12. A neuroprotective brain-penetrating endopeptidase fusion protein ameliorates Alzheimer disease pathology and restores neurogenesis.

    PubMed

    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.

  13. Anatomical connectivity mapping: a new tool to assess brain disconnection in Alzheimer's disease.

    PubMed

    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.

  14. Multifactorial causal model of brain (dis)organization and therapeutic intervention: Application to Alzheimer's disease.

    PubMed

    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

  15. Event-related potential markers of brain changes in preclinical familial Alzheimer disease

    PubMed Central

    Ally, B.A.; Celone, K.; McKeever, J.; Ruiz-Rizzo, A.L.; Lopera, F.; Stern, C.E.; Budson, A.E.

    2011-01-01

    Objectives: Event-related potentials (ERPs) can reflect differences in brain electrophysiology underlying cognitive functions in brain disorders such as dementia and mild cognitive impairment. To identify individuals at risk for Alzheimer disease (AD) we used high-density ERPs to examine brain physiology in young presymptomatic individuals (average age 34.2 years) who carry the E280A mutation in the presenilin-1 (PSEN1) gene and will go on to develop AD around the age of 45. Methods: Twenty-one subjects from a Colombian population with familial AD participated: 10 presymptomatic subjects positive for the PSEN1 mutation (carriers) and 11 siblings without the mutation (controls). Subjects performed a visual recognition memory test while 128-channel ERPs were recorded. Results: Despite identical behavioral performance, PSEN1 mutation carriers showed less positivity in frontal regions and more positivity in occipital regions, compared to controls. These differences were more pronounced during the 200–300 msec period. Discriminant analysis at this time interval showed promising sensitivity (72.7%) and specificity (81.8%) of the ERP measures to predict the presence of AD pathology. Conclusions: Presymptomatic PSEN1 mutation carriers show changes in brain physiology that can be detected by high-density ERPs. The relative differences observed showing greater frontal positivity in controls and greater occipital positivity in carriers indicates that control subjects may use frontally mediated processes to distinguish between studied and unstudied visual items, whereas carriers appear to rely more upon perceptual details of the items to distinguish between them. These findings also demonstrate the potential usefulness of ERP brain correlates as preclinical markers of AD. PMID:21775732

  16. Redox Proteomics Analysis to Decipher the Neurobiology of Alzheimer-like Neurodegeneration: Overlaps in Down Syndrome and Alzheimer Disease Brain

    PubMed Central

    Butterfield, D. Allan; Di Domenico, Fabio; Swomley, Aaron M.; Head, Elizabeth; Perluigi, Marzia

    2015-01-01

    Accumulation of oxidative damage is a common feature of neurodegeneration that together with mitochondrial dysfunction point to the fact that reactive oxygen species are major contributors to loss of neuronal homeostasis and cell death. Among several targets of oxidative stress, free radical-mediated damage to proteins is particularly important in aging and age-related neurodegenerative diseases. In the majority of cases, oxidative stress mediated post-translational modifications cause non-reversible modifications of protein structure that consistently lead to impaired function. Redox proteomics methods are powerful tools to unravel the complexity of neurodegeneration, by identifying brain proteins with oxidative post-translational modifications that are detrimental for protein function. The present review discusses the current literature showing evidence of impaired pathways linked to oxidative stress possibly involved in the neurodegenerative process leading to the development of Alzheimer-like dementia. In particular, we focus attention on dysregulated pathways that underlie neurodegeneration in both aging adults with Down syndrome (DS) and AD. Since AD pathology is age-dependent in DS and shows similarities with AD, identification of common oxidized proteins by redox proteomics in both DS and AD can improve our understanding of the overlapping mechanisms that lead from normal aging to development of AD. The most relevant proteomics findings highlight that disturbance of protein homeostasis and energy production are central mechanisms of neurodegeneration and overlap in aging DS and AD. Protein oxidation impacts crucial intracellular functions and may be considered a “leitmotif” of degenerating neurons. Therapeutic strategies aimed at preventing/reducing multiple components of processes leading to accumulation of oxidative damage will be critical in future studies. PMID:25242166

  17. Blood-brain barrier pathology in Alzheimer's and Parkinson's disease: implications for drug therapy.

    PubMed

    Desai, Brinda S; Monahan, Angela J; Carvey, Paul M; Hendey, Bill

    2007-01-01

    The blood-brain barrier (BBB) is a tightly regulated barrier in the central nervous system. Though the BBB is thought to be intact during neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD), recent evidence argues otherwise. Dysfunction of the BBB may be involved in disease progression, eliciting of peripheral immune response, and, most importantly, altered drug efficacy. In this review, we will give a brief overview of the BBB, its components, and their functions. We will critically evaluate the current literature in AD and PD BBB pathology resulting from insult, neuroinflammation, and neurodegeneration. Specifically, we will discuss alterations in tight junction, transport and endothelial cell surface proteins, and vascular density changes, all of which result in altered permeability. Finally, we will discuss the implications of BBB dysfunction in current and future therapeutics. Developing a better appreciation of BBB dysfunction in AD and PD may not only provide novel strategies in treatment, but will prove an interesting milestone in understanding neurodegenerative disease etiology and progression.

  18. Alzheimer disease: focus on computed tomography.

    PubMed

    Reynolds, April

    2013-01-01

    Alzheimer disease is the most common type of dementia, affecting approximately 5.3 million Americans. This debilitating disease is marked by memory loss, confusion, and loss of cognitive ability. The exact cause of Alzheimer disease is unknown although research suggests that it might result from a combination of factors. The hallmarks of Alzheimer disease are the presence of beta-amyloid plaques and neurofibrillary tangles in the brain. Radiologic imaging can help physicians detect these structural characteristics and monitor disease progression and brain function. Computed tomography and magnetic resonance imaging are considered first-line imaging modalities for the routine evaluation of Alzheimer disease.

  19. Genetics of Alzheimer's Disease

    PubMed Central

    Ridge, Perry G.; Ebbert, Mark T. W.; Kauwe, John S. K.

    2013-01-01

    Alzheimer's disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease-altering treatments. It is a complex disorder with environmental and genetic components. There are two major types of Alzheimer's disease, early onset and the more common late onset. The genetics of early-onset Alzheimer's disease are largely understood with variants in three different genes leading to disease. In contrast, while several common alleles associated with late-onset Alzheimer's disease, including APOE, have been identified using association studies, the genetics of late-onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset Alzheimer's disease. PMID:23984328

  20. Physical activity, body mass index, and brain atrophy in Alzheimer's disease.

    PubMed

    Boyle, Christina P; Raji, Cyrus A; Erickson, Kirk I; Lopez, Oscar L; Becker, James T; Gach, H Michael; Longstreth, W T; Teverovskiy, Leonid; Kuller, Lewis H; Carmichael, Owen T; Thompson, Paul M

    2015-01-01

    The purpose of this study was to use a novel imaging biomarker to assess associations between physical activity (PA), body mass index (BMI), and brain structure in normal aging, mild cognitive impairment, and Alzheimer's dementia. We studied 963 participants (mean age: 74.1 ± 4.4 years) from the multisite Cardiovascular Health Study including healthy controls (n = 724), Alzheimer's dementia patients (n = 104), and people with mild cognitive impairment (n = 135). Volumetric brain images were processed using tensor-based morphometry to analyze regional brain volumes. We regressed the local brain tissue volume on reported PA and computed BMI, and performed conjunction analyses using both variables. Covariates included age, sex, and study site. PA was independently associated with greater whole brain and regional brain volumes and reduced ventricular dilation. People with higher BMI had lower whole brain and regional brain volumes. A PA-BMI conjunction analysis showed brain preservation with PA and volume loss with increased BMI in overlapping brain regions. In one of the largest voxel-based cross-sectional studies to date, PA and lower BMI may be beneficial to the brain across the spectrum of aging and neurodegeneration.

  1. Identification of Differentially Expressed Genes through Integrated Study of Alzheimer's Disease Affected Brain Regions.

    PubMed

    Puthiyedth, Nisha; Riveros, Carlos; Berretta, Regina; Moscato, Pablo

    2016-01-01

    Alzheimer's disease (AD) is the most common form of dementia in older adults that damages the brain and results in impaired memory, thinking and behaviour. The identification of differentially expressed genes and related pathways among affected brain regions can provide more information on the mechanisms of AD. In the past decade, several studies have reported many genes that are associated with AD. This wealth of information has become difficult to follow and interpret as most of the results are conflicting. In that case, it is worth doing an integrated study of multiple datasets that helps to increase the total number of samples and the statistical power in detecting biomarkers. In this study, we present an integrated analysis of five different brain region datasets and introduce new genes that warrant further investigation. The aim of our study is to apply a novel combinatorial optimisation based meta-analysis approach to identify differentially expressed genes that are associated to AD across brain regions. In this study, microarray gene expression data from 161 samples (74 non-demented controls, 87 AD) from the Entorhinal Cortex (EC), Hippocampus (HIP), Middle temporal gyrus (MTG), Posterior cingulate cortex (PC), Superior frontal gyrus (SFG) and visual cortex (VCX) brain regions were integrated and analysed using our method. The results are then compared to two popular meta-analysis methods, RankProd and GeneMeta, and to what can be obtained by analysing the individual datasets. We find genes related with AD that are consistent with existing studies, and new candidate genes not previously related with AD. Our study confirms the up-regualtion of INFAR2 and PTMA along with the down regulation of GPHN, RAB2A, PSMD14 and FGF. Novel genes PSMB2, WNK1, RPL15, SEMA4C, RWDD2A and LARGE are found to be differentially expressed across all brain regions. Further investigation on these genes may provide new insights into the development of AD. In addition, we identified

  2. Alzheimer's disease and type 2 diabetes-related alterations in brain mitochondria, autophagy and synaptic markers.

    PubMed

    Carvalho, Cristina; Santos, Maria S; Oliveira, Catarina R; Moreira, Paula I

    2015-08-01

    We aimed to investigate mitochondrial function, biogenesis and autophagy in the brain of type 2 diabetes (T2D) and Alzheimer's disease (AD) mice. Isolated brain mitochondria and homogenates from cerebral cortex and hippocampus of wild-type (WT), triple transgenic AD (3xTg-AD) and T2D mice were used to evaluate mitochondrial functional parameters and protein levels of mitochondrial biogenesis, autophagy and synaptic integrity markers, respectively. A significant decrease in mitochondrial respiration, membrane potential and energy levels was observed in T2D and 3xTg-AD mice. Also, a significant decrease in the levels of autophagy-related protein 7 (ATG7) and glycosylated lysosomal membrane protein 1 (LAMP1) was observed in cerebral cortex and hippocampus of T2D and 3xTg-AD mice. Moreover, both brain regions of 3xTg-AD mice present lower levels of nuclear respiratory factor (NRF) 1 while the levels of NRF2 are lower in both brain regions of T2D and 3xTg-AD mice. A decrease in mitochondrial encoded, nicotinamide adenine dinucleotide dehydrogenase subunit 1 (ND1) was also observed in T2D and 3xTg-AD mice although only statistically significant in T2D cortex. Furthermore, a decrease in the levels of postsynaptic density protein 95 (PSD95) in the cerebral cortex of 3xTg-AD mice and in hippocampus of T2D and 3xTg-AD mice and a decrease in the levels of synaptosomal-associated protein 25 (SNAP 25) in the hippocampus of T2D and 3xTg-AD mice were observed suggesting synaptic integrity loss. These results support the idea that alterations in mitochondrial function, biogenesis and autophagy cause synaptic damage in AD and T2D.

  3. Multifunctional Roles of Enolase in Alzheimer Disease Brain: Beyond Altered Glucose Metabolism

    PubMed Central

    Butterfield, D. Allan; Bader Lange, Miranda L.

    2015-01-01

    Enolase enzymes are abundantly expressed, cytosolic carbon-oxygen lyases known for their role in glucose metabolism. Recently, enolase has been shown to possess a variety of different regulatory functions, beyond glycolysis and gluconeogenesis, associated with hypoxia, ischemia, and Alzheimer disease (AD). AD is an age-associated neurodegenerative disorder characterized pathologically by elevated oxidative stress and subsequent damage to proteins, lipids, and nucleic acids, appearance of neurofibrillary tangles and senile plaques, and loss of synapse and neuronal cells. It is unclear if development of a hypometabolic environment is a consequence of or contributes to AD pathology, since there is not only a significant decline in brain glucose levels in AD, but also there is an increase in proteomics identified oxidatively modified glycolytic enzymes that are rendered inactive, including enolase. Previously, our laboratory identified α-enolase as one the most frequently up-regulated and oxidatively modified proteins in amnestic mild cognitive impairment (MCI), early-onset AD (EOAD), and AD. However, the glycolytic conversion of 2-phosphoglycerate to phosphoenolpyruvate catalyzed by enolase does not directly produce ATP or NADH; therefore it is surprising that, among all glycolytic enzymes, α-enolase was one of only two glycolytic enzymes consistently up-regulated from MCI to AD. These findings suggest enolase is involved with more than glucose metabolism in AD brain, but may possess other functions, normally necessary to preserve brain function. This review examines potential altered function(s) of brain enolase in MCI, EOAD, and AD, alterations that may contribute to the biochemical, pathological, clinical characteristics, and progression of this dementing disorder. PMID:19780894

  4. Rab6 is increased in Alzheimer's disease brain and correlates with endoplasmic reticulum stress.

    PubMed

    Scheper, W; Hoozemans, J J M; Hoogenraad, C C; Rozemuller, A J M; Eikelenboom, P; Baas, F

    2007-10-01

    Alzheimer's disease (AD) is characterized by deposits of aggregated proteins. Accumulation of aggregation-prone proteins activates protein quality control mechanisms, such as the unfolded protein response (UPR) in the endoplasmic reticulum (ER). We previously reported upregulation of the UPR marker BiP in AD brain. In this study, we investigated the small GTPase Rab6, which is involved in retrograde Golgi-ER trafficking and may function as a post-ER quality control system. Using immunohistochemistry and semiquantitative Western blotting, the expression of Rab6 was analysed in hippocampus, entorhinal and temporal cortex of 10 AD patients and six nondemented control subjects. Rab6 is upregulated in AD temporal cortex from Braak stage 3/4, the same stage that UPR activation is found. We observe increased neuronal Rab6 immunoreactivity in all brain areas examined. Although some neurones show colocalization of immunoreactivity for Rab6 and hyperphosphorylated tau, strong Rab6 staining does not colocalize with tangles. We find a highly significant correlation between the Rab6 and BiP levels. In vitro data show that Rab6 is not upregulated as a result of UPR activation or proteasome inhibition indicating an independent regulatory mechanism. Our data suggest that ER and post-ER protein quality control mechanisms are activated early in the pathology of AD.

  5. Depletion of coagulation factor XII ameliorates brain pathology and cognitive impairment in Alzheimer disease mice.

    PubMed

    Chen, Zu-Lin; Revenko, Alexey S; Singh, Pradeep; MacLeod, A Robert; Norris, Erin H; Strickland, Sidney

    2017-05-04

    Vascular abnormalities and inflammation are found in many Alzheimer disease (AD) patients, but whether these changes play a causative role in AD is not clear. The factor XII (FXII) -initiated contact system can trigger both vascular pathology and inflammation and is activated in AD patients and AD mice. We have investigated the role of the contact system in AD pathogenesis. Cleavage of high-molecular-weight kininogen (HK), a marker for activation of the inflammatory arm of the contact system, is increased in a mouse model of AD, and this cleavage is temporally correlated with the onset of brain inflammation. Depletion of FXII in AD mice inhibited HK cleavage in plasma and reduced neuroinflammation, fibrinogen deposition, and neurodegeneration in the brain. Moreover, FXII-depleted AD mice showed better cognitive function than untreated AD mice. These results indicate that FXII-mediated contact system activation contributes to AD pathogenesis, and therefore this system may offer novel targets for AD treatment. © 2017 by The American Society of Hematology.

  6. Body mass index is associated with biological CSF markers of core brain pathology of Alzheimer's disease.

    PubMed

    Ewers, Michael; Schmitz, Susanne; Hansson, Oskar; Walsh, Cathal; Fitzpatrick, Annette; Bennett, David; Minthon, Lennart; Trojanowski, John Q; Shaw, Leslie M; Faluyi, Yetunde O; Vellas, Bruno; Dubois, Bruno; Blennow, Kaj; Buerger, Katharina; Teipel, Stefan J; Weiner, Michael; Hampel, Harald

    2012-08-01

    Weight changes are common in aging and Alzheimer's disease (AD) and postmortem findings suggest a relation between lower body mass index (BMI) and increased AD brain pathology. In the current multicenter study, we tested whether lower BMI is associated with higher core AD brain pathology as assessed by cerebrospinal fluid (CSF)-based biological markers of AD in 751 living subjects: 308 patients with AD, 296 subjects with amnestic mild cognitive impairment (MCI), and 147 elderly healthy controls (HC). Based upon a priori cutoff values on CSF concentration of total tau and beta-amyloid (Aβ(1-42)), subjects were binarized into a group with abnormal CSF biomarker signature (CSF+) and those without (CSF-). Results showed that BMI was significantly lower in the CSF+ when compared with the CSF- group (F = 27.7, df = 746, p < 0.001). There was no interaction between CSF signature and diagnosis or apolipoprotein E (ApoE) genotype. In conclusion, lower BMI is indicative of AD pathology as assessed with CSF-based biomarkers in demented and nondemented elderly subjects.

  7. Boosting diagnosis accuracy of Alzheimer's disease using high dimensional recognition of longitudinal brain atrophy patterns.

    PubMed

    Farzan, Ali; Mashohor, Syansiah; Ramli, Abd Rahman; Mahmud, Rozi

    2015-09-01

    Boosting accuracy in automatically discriminating patients with Alzheimer's disease (AD) and normal controls (NC), based on multidimensional classification of longitudinal whole brain atrophy rates and their intermediate counterparts in analyzing magnetic resonance images (MRI). Longitudinal percentage of brain volume changes (PBVC) in two-year follow up and its intermediate counterparts in early 6-month and late 18-month are used as features in supervised and unsupervised classification procedures based on K-mean, fuzzy clustering method (FCM) and support vector machine (SVM). The most relevant features for classification are selected using discriminative analysis (DA) of features and their principal components (PC). Accuracy of the proposed method is evaluated in a group of 30 patients with AD (16 males, 14 females, age±standard-deviation (SD)=75±1.36 years) and 30 normal controls (15 males, 15 females, age±SD=77±0.88 years) using leave-one-out cross-validation. Results indicate superiority of supervised machine learning techniques over unsupervised ones in diagnosing AD and withal, predominance of RBF kernel over lineal one. Accuracies of 83.3%, 83.3%, 90% and 91.7% are achieved in classification by K-mean, FCM, linear SVM and SVM with radial based function (RBF) respectively. Evidence that SVM classification of longitudinal atrophy rates may results in high accuracy is given. Additionally, it is realized that use of intermediate atrophy rates and their principal components improves diagnostic accuracy. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease.

    PubMed

    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.

  9. HNK-1 Carrier Glycoproteins Are Decreased in the Alzheimer's Disease Brain.

    PubMed

    García-Ayllón, María-Salud; Botella-López, Arancha; Cuchillo-Ibañez, Inmaculada; Rábano, Alberto; Andreasen, Niels; Blennow, Kaj; Ávila, Jesús; Sáez-Valero, Javier

    2017-01-01

    The human natural killer-1 (HNK-1), 3-sulfonated glucuronic acid, is a glycoepitope marker of cell adhesion that participates in cell-cell and cell-extracellular matrix interactions and in neurite growth. Very little is known about the regulation of the HNK-1 glycan in neurodegenerative disease, particularly in Alzheimer's disease (AD). In this study, we investigate changes in the levels of HNK-1 carrier glycoproteins in AD. We demonstrate an overall decrease in HNK-1 immunoreactivity in glycoproteins extracted from the frontal cortex of AD subjects, compared with levels from non-demented controls (NDC). Immunoblotting of ventricular post-mortem and lumbar ante-mortem cerebrospinal fluid with HNK-1 antibodies indicate similar levels of carrier glycoproteins in AD and NDC samples. Decrease in HNK-1 carrier glycoproteins were not paralleled by changes in messenger RNA (mRNA) levels of the enzymes involved in the synthesis of the glycoepitope, β-1,4-galactosyltransferase (β4GalT), glucuronyltransferases GlcAT-P and GlcAT-S, or sulfotransferase HNK-1ST. Over-expression of amyloid precursor protein in Tg2576 transgenic mice and in vitro treatment of SH-SY5Y neuroblastoma cells with the amyloidogenic Aβ42 peptide resulted in a decrease in HNK-1 immunoreactivity levels in brain and cellular extracts, whereas the levels of soluble HNK-1 glycoproteins detected in culture media were not affected by Aβ treatment. HNK-1 levels remain unaffected in the brain extracts of Tg-VLW mice, a model of mutant hyperphosphorylated tau, and in SH-SY5Y cells over-expressing hyperphosphorylated wild-type tau. These results provide evidence that cellular levels of HNK-1 carrier glycoforms are decreased in the brain of AD subjects, probably influenced by the β-amyloid protein.

  10. Multifunctional Liposomes Reduce Brain β-Amyloid Burden and Ameliorate Memory Impairment in Alzheimer's Disease Mouse Models

    PubMed Central

    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; Re, Francesca

    2014-01-01

    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 [11C]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. PMID:25319699

  11. Multifunctional liposomes reduce brain β-amyloid burden and ameliorate memory impairment in Alzheimer's disease mouse models.

    PubMed

    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.

  12. [Proceeding memory in Alzheimer's disease].

    PubMed

    Arroyo-Anlló, Eva Ma; Chamorro-Sánchez, Jorge; Díaz-Marta, Juan Poveda; Gil, Roger

    2013-01-01

    Procedural learning can acquire or develop skills through performance and repetition of a task unconsciously or unintentionally. Procedural skills are considered as the cornerstone in the neuropsychological rehabilitation to promote the autonomy of patients with brain damage, as those with Alzheimer's disease. This review presents data about procedural skills in Alzheimer's disease. Over the past three decades, we have found 40 articles studying various procedural skills in the Alzheimer's disease: motor, perceptual-motor, cognitive, perceptual-cognitive and those developed through serial reaction-time paradigm. We analyzed every study evaluating a procedural skill, indicating the used task and preservation or no preservation of procedural learning. Overall, most of the papers published describe conservation of learning procedures or relatively conserved in Alzheimer's disease, which could be used to promote patient autonomy.

  13. Rapidly progressive Alzheimer disease.

    PubMed

    Schmidt, Christian; Wolff, Martin; Weitz, Michael; Bartlau, Thomas; Korth, Carsten; Zerr, Inga

    2011-09-01

    Different rates of progression have been observed among patients with Alzheimer disease. Risk factors that accelerate deterioration have been identified and some are being discussed, such as genetics, comorbidity, and the early appearance of Alzheimer disease motor signs. Progressive forms of Alzheimer disease have been reported with rapid cognitive decline and disease duration of only a few years. This short review aims to provide an overview of the current knowledge of rapidly progressive Alzheimer disease. Furthermore, we suggest that rapid, in this context, should be defined as a Mini-Mental State Examination score decrease of 6 points per year.

  14. Ultrasound Delivery of an Anti-Aβ Therapeutic Agent to the Brain in a Mouse Model of Alzheimer's Disease

    NASA Astrophysics Data System (ADS)

    Jordão, Jessica F.; Ayala-Grosso, Carlos A.; Chopra, Rajiv; McLaurin, JoAnne; Aubert, Isabelle; Hynynen, Kullervo

    2009-04-01

    Plaques composed of amyloid-beta (Aβ) peptides represent a pathological hallmark in the brain of patients with Alzheimer's disease. Aβ oligomers are considered cytotoxic and several therapeutic approaches focus on reducing Aβ load in the brain of Alzheimer's patients. The efficacy of most anti-Aβ agents is significantly limited because they do not cross the blood-brain-barrier. Innovative technologies capable of enhancing the permeability of the blood-brain barrier, thereby allowing entry of therapeutic agents into the brain, show great promise in circumventing this problem. The application of low-intensity focused ultrasound in the presence of an ultrasound contrast agent causes localized and transient permeability of the blood-brain barrier. We demonstrate the value of this technology for the delivery of anti-Aβ antibodies to the brain of TgCRND8 mice, a mouse model of Alzheimer's disease exhibiting Aβ plaques. BAM-10, an anti-Aβ antibody, was injected into the tail vein simultaneously with exposure to MRI-guided, low-intensity focused ultrasound (FUS) to one hemisphere of TgCNRD8 mice. Four hours after treatment, antibodies were detected at significant amounts only in the brain of mice receiving FUS in addition to BAM-10. This data provides a proof-of-concept that FUS allows anti-Aβ therapeutics to efficiently enter the brain and target Aβ plaques. Four days following a single treatment with BAM-10 and MRI-guided FUS, a significant decrease in the number of Aβ plaques on the side of the treated hemisphere was observed in TgCRND8 mice. In conclusion low-intensity, focused ultrasound is effective in delivering Aβ antibodies to the brain. This technology has the potential to enhance current anti-Aβ treatments by allowing increased exposure of amyloid plaques to treatment agents.

  15. Traumatic brain injury history is associated with earlier age of onset of Alzheimer disease.

    PubMed

    LoBue, Christian; Wadsworth, Hannah; Wilmoth, Kristin; Clem, Matthew; Hart, John; Womack, Kyle B; Didehbani, Nyaz; Lacritz, Laura H; Rossetti, Heidi C; Cullum, C Munro

    2017-01-01

    This study examined whether a history of traumatic brain injury (TBI) is associated with earlier onset of Alzheimer disease (AD), independent of apolipoprotein ε4 status (Apoe4) and gender. Participants with a clinical diagnosis of AD (n = 7625) were obtained from the National Alzheimer's Coordinating Center Uniform Data Set, and categorized based on self-reported lifetime TBI with loss of consciousness (LOC) (TBI+ vs. TBI-) and presence of Apoe4. ANCOVAs, controlling for gender, race, and education were used to examine the association between history of TBI, presence of Apoe4, and an interaction of both risk factors on estimated age of AD onset. Estimated AD onset differed by TBI history and Apoe4 independently (p's < .001). The TBI+ group had a mean age of onset 2.5 years earlier than the TBI- group. Likewise, Apoe4 carriers had a mean age of onset 2.3 years earlier than non-carriers. While the interaction was non-significant (p = .34), participants having both a history of TBI and Apoe4 had the earliest mean age of onset compared to those with a TBI history or Apoe4 alone (MDifference = 2.8 and 2.7 years, respectively). These results remained unchanged when stratified by gender. History of self-reported TBI can be associated with an earlier onset of AD-related cognitive decline, regardless of Apoe4 status and gender. TBI may be related to an underlying neurodegenerative process in AD, but the implications of age at time of injury, severity, and repetitive injuries remain unclear.

  16. Type II fuzzy systems for amyloid plaque segmentation in transgenic mouse brains for Alzheimer's disease quantification

    NASA Astrophysics Data System (ADS)

    Khademi, April; Hosseinzadeh, Danoush

    2014-03-01

    Alzheimer's disease (AD) is the most common form of dementia in the elderly characterized by extracellular deposition of amyloid plaques (AP). Using animal models, AP loads have been manually measured from histological specimens to understand disease etiology, as well as response to treatment. Due to the manual nature of these approaches, obtaining the AP load is labourious, subjective and error prone. Automated algorithms can be designed to alleviate these challenges by objectively segmenting AP. In this paper, we focus on the development of a novel algorithm for AP segmentation based on robust preprocessing and a Type II fuzzy system. Type II fuzzy systems are much more advantageous over the traditional Type I fuzzy systems, since ambiguity in the membership function may be modeled and exploited to generate excellent segmentation results. The ambiguity in the membership function is defined as an adaptively changing parameter that is tuned based on the local contrast characteristics of the image. Using transgenic mouse brains with AP ground truth, validation studies were carried out showing a high degree of overlap and low degree of oversegmentation (0.8233 and 0.0917, respectively). The results highlight that such a framework is able to handle plaques of various types (diffuse, punctate), plaques with varying Aβ concentrations as well as intensity variation caused by treatment effects or staining variability.

  17. Brain metabolism in Alzheimer disease and vascular dementia assessed by in vivo proton magnetic resonance spectroscopy.

    PubMed

    Herminghaus, Sebastian; Frölich, Lutz; Gorriz, Corrina; Pilatus, Ullrich; Dierks, Thomas; Wittsack, Hans-Jörg; Lanfermann, Heinrich; Maurer, Konrad; Zanella, Friedhelm E

    2003-07-30

    Proton magnetic resonance spectroscopy (MRS) allows the assessment of various cerebral metabolites non-invasively in vivo. Among 1H MRS-detectable metabolites, N-acetyl-aspartate and N-acetyl-aspartyl-glutamate (tNAA), trimethylamines (TMA), creatine and creatine phosphate (tCr), inositol (Ins) and glutamate (Gla) are of particular interest, since these moieties can be assigned to specific neuronal and glial metabolic pathways, membrane constituents, and energy metabolism. In this study on 94 subjects from a memory clinic population, 1H MRS results (single voxel STEAM: TE 20 ms, TR 1500 ms) on the above metabolites were assessed for five different brain regions in probable vascular dementia (VD), probable Alzheimer's disease (AD), and age-matched healthy controls. In both VD and AD, ratios of tNAA/tCr were decreased, which may be attributed to neuronal atrophy and loss, and Ins/tCr-ratios were increased indicating either enhanced gliosis or alteration of the cerebral inositol metabolism. However, the topographical distribution of the metabolic alterations in both diseases differed, revealing a temporoparietal pattern for AD and a global, subcortically pronounced pattern for VD. Furthermore, patients suffering from vascular dementia (VD) had remarkably enhanced TMA/tCr ratios, potentially due to ongoing degradation of myelin. Thus, the metabolic alterations obtained by 1H MRS in vivo allow insights into the pathophysiology of the different dementias and may be useful for diagnostic classification.

  18. Blood-brain barrier dysfunction as a cause and consequence of Alzheimer's disease.

    PubMed

    Erickson, Michelle A; Banks, William A

    2013-10-01

    The blood-brain barrier (BBB) plays critical roles in the maintenance of central nervous system (CNS) homeostasis. Dysfunction of the BBB occurs in a number of CNS diseases, including Alzheimer's disease (AD). A prevailing hypothesis in the AD field is the amyloid cascade hypothesis that states that amyloid-β (Aβ) deposition in the CNS initiates a cascade of molecular events that cause neurodegeneration, leading to AD onset and progression. In this review, the participation of the BBB in the amyloid cascade and in other mechanisms of AD neurodegeneration will be discussed. We will specifically focus on three aspects of BBB dysfunction: disruption, perturbation of transporters, and secretion of neurotoxic substances by the BBB. We will also discuss the interaction of the BBB with components of the neurovascular unit in relation to AD and the potential contribution of AD risk factors to aspects of BBB dysfunction. From the results discussed herein, we conclude that BBB dysfunction contributes to AD through a number of mechanisms that could be initiated in the presence or absence of Aβ pathology.

  19. Microwaves and Alzheimer's disease

    PubMed Central

    Zhang, Xia; Huang, Wen-Juan; Chen, Wei-Wei

    2016-01-01

    Alzheimer's diseases (AD) is the most common type of dementia and a neurodegenerative disease that occurs when the nerve cells in the brain die. The cause and treatment of AD remain unknown. However, AD is a disease that affects the brain, an organ that controls behavior. Accordingly, anything that can interact with the brain may affect this organ positively or negatively, thereby protecting or encouraging AD. In this regard, modern life encompasses microwaves for all issues including industrial, communications, medical and domestic tenders, and among all applications, the cell phone wave, which directly exposes the brain, continues to be the most used. Evidence suggests that microwaves may produce various biological effects on the central nervous system (CNS) and many arguments relay the possibility that microwaves may be involved in the pathophysiology of CNS disease, including AD. By contrast, previous studies have reported some beneficial cognitive effects and that microwaves may protect against cognitive impairment in AD. However, although many of the beneficial effects of microwaves are derived from animal models, but can easily be extrapolated to humans, whether microwaves cause AD is an important issue that is to be addressed in the current review. PMID:27698682

  20. Microwaves and Alzheimer's disease.

    PubMed

    Zhang, Xia; Huang, Wen-Juan; Chen, Wei-Wei

    2016-10-01

    Alzheimer's diseases (AD) is the most common type of dementia and a neurodegenerative disease that occurs when the nerve cells in the brain die. The cause and treatment of AD remain unknown. However, AD is a disease that affects the brain, an organ that controls behavior. Accordingly, anything that can interact with the brain may affect this organ positively or negatively, thereby protecting or encouraging AD. In this regard, modern life encompasses microwaves for all issues including industrial, communications, medical and domestic tenders, and among all applications, the cell phone wave, which directly exposes the brain, continues to be the most used. Evidence suggests that microwaves may produce various biological effects on the central nervous system (CNS) and many arguments relay the possibility that microwaves may be involved in the pathophysiology of CNS disease, including AD. By contrast, previous studies have reported some beneficial cognitive effects and that microwaves may protect against cognitive impairment in AD. However, although many of the beneficial effects of microwaves are derived from animal models, but can easily be extrapolated to humans, whether microwaves cause AD is an important issue that is to be addressed in the current review.

  1. Intranasal nanoparticles of basic fibroblast growth factor for brain delivery to treat Alzheimer's disease.

    PubMed

    Zhang, Chi; Chen, Jie; Feng, Chengcheng; Shao, Xiayan; Liu, Qingfeng; Zhang, Qizhi; Pang, Zhiqing; Jiang, Xinguo

    2014-01-30

    Disabilities caused by neurodegeneration have become one of the main causes of mortality in elderly population, with drug distribution to the brain remaining one of the most difficult challenges in the treatment of the central nervous system (CNS) diseases due to the existence of blood-brain barrier. Lectins modified polyethylene glycol-polylactide-polyglycolide (PEG-PLGA) nanoparticles could enhance the drug delivery to the brain following intranasal administration. In this study, basic fibroblast growth factor (bFGF) was entrapped in nanoparticles conjugated with Solanum tuberosum lectin (STL), which selectively binds to N-acetylglucosamine on the nasal epithelial membrane for its brain delivery. The resulting nanoparticles had uniform particle size and negative zeta potential. The brain distribution of the formulations following intranasal administration was assessed using radioisotopic tracing method. The areas under the concentration-time curve of (125)I-bFGF in the olfactory bulb, cerebrum, and cerebellum of rats following nasal application of STL modified nanoparticles (STL-bFGF-NP) were 1.79-5.17 folds of that of rats with intravenous administration, and 0.61-2.21 and 0.19-1.07 folds higher compared with intranasal solution and unmodified nanoparticles, respectively. Neuroprotective effect was evaluated using Mirror water maze task in rats with intracerebroventricular injection of β-amyloid25-35 and ibotenic acid. The spatial learning and memory of Alzheimer's disease (AD) rats in STL-bFGF-NP group were significantly improved compared with AD model group, and were also better than other preparations. The results were consistent with the value of choline acetyltransferase activity of rat hippocampus as well as the histological observations of rat hippocampal region. The histopathology assays also confirmed the in vivo safety of STL-bFGF-NP. These results clearly indicated that STL-NP was a promising drug delivery system for peptide and protein drugs such as

  2. Effects of imaging modalities, brain atlases and feature selection on prediction of Alzheimer's disease.

    PubMed

    Ota, Kenichi; Oishi, Naoya; Ito, Kengo; Fukuyama, Hidenao

    2015-12-30

    The choice of biomarkers for early detection of Alzheimer's disease (AD) is important for improving the accuracy of imaging-based prediction of conversion from mild cognitive impairment (MCI) to AD. The primary goal of this study was to assess the effects of imaging modalities and brain atlases on prediction. We also investigated the influence of support vector machine recursive feature elimination (SVM-RFE) on predictive performance. Eighty individuals with amnestic MCI [40 developed AD within 3 years] underwent structural magnetic resonance imaging (MRI) and (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) scans at baseline. Using Automated Anatomical Labeling (AAL) and LONI Probabilistic Brain Atlas (LPBA40), we extracted features representing gray matter density and relative cerebral metabolic rate for glucose in each region of interest from the baseline MRI and FDG-PET data, respectively. We used linear SVM ensemble with bagging and computed the area under the receiver operating characteristic curve (AUC) as a measure of classification performance. We performed multiple SVM-RFE to compute feature ranking. We performed analysis of variance on the mean AUCs for eight feature sets. The interactions between atlas and modality choices were significant. The main effect of SVM-RFE was significant, but the interactions with the other factors were not significant. Multimodal features were found to be better than unimodal features to predict AD. FDG-PET was found to be better than MRI. Imaging modalities and brain atlases interact with each other and affect prediction. SVM-RFE can improve the predictive accuracy when using atlas-based features. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease.

    PubMed

    Lozano, Andres M; Fosdick, Lisa; Chakravarty, M Mallar; Leoutsakos, Jeannie-Marie; Munro, Cynthia; Oh, Esther; Drake, Kristen E; Lyman, Christopher H; Rosenberg, Paul B; Anderson, William S; Tang-Wai, David F; Pendergrass, Jo Cara; Salloway, Stephen; Asaad, Wael F; Ponce, Francisco A; Burke, Anna; Sabbagh, Marwan; Wolk, David A; Baltuch, Gordon; Okun, Michael S; Foote, Kelly D; McAndrews, Mary Pat; Giacobbe, Peter; Targum, Steven D; Lyketsos, Constantine G; Smith, Gwenn S

    2016-09-06

    Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown. To assess DBS of memory circuits as a treatment for patients with mild Alzheimer's disease (AD). We evaluated active "on" versus sham "off" bilateral DBS directed at the fornix-a major fiber bundle in the brain's memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation. Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the "on" versus "off" stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients <65 years old (n = 12) whose results trended toward being worse with DBS ON versus OFF, in patients≥65 (n = 30) DBS-f ON treatment was associated with a trend toward both benefit on clinical outcomes and a greater increase in cerebral glucose metabolism. DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.

  4. Differences in Aβ brain networks in Alzheimer's disease and healthy controls.

    PubMed

    Duan, Huoqiang; Jiang, Jiehui; Xu, Jun; Zhou, Hucheng; Huang, Zhemin; Yu, Zhihua; Yan, Zhuangzhi

    2017-01-15

    The prevailing β-amyloid (Aβ)-cascade hypothesis is the most classical Alzheimer's disease (AD) pathogenesis. In this hypothesis, excessive Aβ plaque deposition in human brain is considered to be the cause of AD. Carbon 11-labeled Pittsburgh compound B Positron emission tomography (11C-PiB PET) is the latest technology to detect Aβ plaques in vivo. Thus, it is possible to investigate the difference of Aβ brain networks between AD patients and Health Controls (HC) by analyzing 11C-PiB PET images. In this study, a graph-theoretical method was employed to investigate the topological properties of Aβ networks in 18 Chinese AD patients and 16 HC subjects from Huashan Hospital, Shanghai. The results showed that both groups demonstrated small-world property, and this property was more obvious in AD group. Additionally, the clustering coefficients and path lengths were significantly lower in AD group. The global efficiency was larger in AD than in HC. A direct comparison between with and without regression found that sex, age and weight had no significant effect on the Aβ network. Moreover, three altered regions in AD group were identified, including left cuneus (CUN.L), right caudate nucleus (CAU.R) and left superior frontal gyrus (SFGdor. L). A voxel-wise correlation analysis showed that in AD patients, the regions of strengthened connection with CUN.L were mainly located in frontal cortex and parietal cortex, the regions of strengthen connection with CAU.R were mainly located in temporal cortex. Finally, a machine learning based analysis demonstrated that the three regions could be better biomarkers than the whole brain for AD classification. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Aneuploidy and DNA replication in the normal human brain and Alzheimer's disease.

    PubMed

    Mosch, Birgit; Morawski, Markus; Mittag, Anja; Lenz, Dominik; Tarnok, Attila; Arendt, Thomas

    2007-06-27

    Reactivation of the cell cycle, including DNA replication, might play a major role in Alzheimer's disease (AD). A more than diploid DNA content in differentiated neurons might alternatively result from chromosome mis-segregation during mitosis in neuronal progenitor cells. It was our objective to distinguish between these two mechanisms for aneuploidy and to provide evidence for a functional cell cycle in AD. Using slide-based cytometry, chromogenic in situ hybridization, and PCR amplification of alu-repeats, we quantified the DNA amount of identified cortical neurons in normal human brain and AD and analyzed the link between a tetraploid DNA content and expression of the early mitotic marker cyclin B1. In the normal brain, the number of neurons with a more than diploid content amounts to approximately 10%. Less than 1% of neurons contains a tetraploid DNA content. These neurons do not express cyclin B1, most likely representing constitutional tetraploidy. This population of cyclin B1-negative tetraploid neurons, at a reduced number, is also present in AD. In addition, a population of cyclin B1-positive tetraploid neurons of approximately 2% of all neurons was observed in AD. Our results indicate that at least two different mechanisms need to be distinguished giving rise to a tetraploid DNA content in the adult brain. Constitutional aneuploidy in differentiated neurons might be more frequent than previously thought. It is, however, not elevated in AD. In addition, in AD some neurons have re-entered the cell cycle and entirely passed through a functional interphase with a complete DNA replication.

  6. Tau Pathology Distribution in Alzheimer's disease Corresponds Differentially to Cognition-Relevant Functional Brain Networks

    PubMed Central

    Hansson, Oskar; Grothe, Michel J.; Strandberg, Tor Olof; Ohlsson, Tomas; Hägerström, Douglas; Jögi, Jonas; Smith, Ruben; Schöll, Michael

    2017-01-01

    Neuropathological studies have shown that the typical neurofibrillary pathology of hyperphosphorylated tau protein in Alzheimer's disease (AD) preferentially affects specific brain regions whereas others remain relatively spared. It has been suggested that the distinct regional distribution profile of tau pathology in AD may be a consequence of the intrinsic network structure of the human brain. The spatially distributed brain regions that are most affected by the spread of tau pathology may hence reflect an interconnected neuronal system. Here, we characterized the brain-wide regional distribution profile of tau pathology in AD using 18F-AV 1451 tau-sensitive positron emission tomography (PET) imaging, and studied this pattern in relation to the functional network organization of the human brain. Specifically, we quantified the spatial correspondence of the regional distribution pattern of PET-evidenced tau pathology in AD with functional brain networks characterized by large-scale resting state functional magnetic resonance imaging (rs-fMRI) data in healthy subjects. Regional distribution patterns of increased PET-evidenced tau pathology in AD compared to controls were characterized in two independent samples of prodromal and manifest AD cases (the Swedish BioFINDER study, n = 44; the ADNI study, n = 35). In the BioFINDER study we found that the typical AD tau pattern involved predominantly inferior, medial, and lateral temporal cortical areas, as well as the precuneus/posterior cingulate, and lateral parts of the parietal and occipital cortex. This pattern overlapped primarily with the dorsal attention, and to some extent with higher visual, limbic and parts of the default-mode network. PET-evidenced tau pathology in the ADNI replication sample, which represented a more prodromal group of AD cases, was less pronounced but showed a highly similar spatial distribution profile, suggesting an earlier-stage snapshot of a consistently progressing regional pattern. In

  7. Tau Pathology Distribution in Alzheimer's disease Corresponds Differentially to Cognition-Relevant Functional Brain Networks.

    PubMed

    Hansson, Oskar; Grothe, Michel J; Strandberg, Tor Olof; Ohlsson, Tomas; Hägerström, Douglas; Jögi, Jonas; Smith, Ruben; Schöll, Michael

    2017-01-01

    Neuropathological studies have shown that the typical neurofibrillary pathology of hyperphosphorylated tau protein in Alzheimer's disease (AD) preferentially affects specific brain regions whereas others remain relatively spared. It has been suggested that the distinct regional distribution profile of tau pathology in AD may be a consequence of the intrinsic network structure of the human brain. The spatially distributed brain regions that are most affected by the spread of tau pathology may hence reflect an interconnected neuronal system. Here, we characterized the brain-wide regional distribution profile of tau pathology in AD using (18)F-AV 1451 tau-sensitive positron emission tomography (PET) imaging, and studied this pattern in relation to the functional network organization of the human brain. Specifically, we quantified the spatial correspondence of the regional distribution pattern of PET-evidenced tau pathology in AD with functional brain networks characterized by large-scale resting state functional magnetic resonance imaging (rs-fMRI) data in healthy subjects. Regional distribution patterns of increased PET-evidenced tau pathology in AD compared to controls were characterized in two independent samples of prodromal and manifest AD cases (the Swedish BioFINDER study, n = 44; the ADNI study, n = 35). In the BioFINDER study we found that the typical AD tau pattern involved predominantly inferior, medial, and lateral temporal cortical areas, as well as the precuneus/posterior cingulate, and lateral parts of the parietal and occipital cortex. This pattern overlapped primarily with the dorsal attention, and to some extent with higher visual, limbic and parts of the default-mode network. PET-evidenced tau pathology in the ADNI replication sample, which represented a more prodromal group of AD cases, was less pronounced but showed a highly similar spatial distribution profile, suggesting an earlier-stage snapshot of a consistently progressing regional pattern

  8. Multimodal Imaging of Brain Connectivity Using the MIBCA Toolbox: Preliminary Application to Alzheimer's Disease

    NASA Astrophysics Data System (ADS)

    Ribeiro, André Santos; Lacerda, Luís Miguel; Silva, Nuno André da; Ferreira, Hugo Alexandre

    2015-06-01

    The Multimodal Imaging Brain Connectivity Analysis (MIBCA) toolbox is a fully automated all-in-one connectivity analysis toolbox that offers both pre-processing, connectivity, and graph theory analysis of multimodal images such as anatomical, diffusion, and functional MRI, and PET. In this work, the MIBCA functionalities were used to study Alzheimer's Disease (AD) in a multimodal MR/PET approach. Materials and Methods: Data from 12 healthy controls, and 36 patients with EMCI, LMCI and AD (12 patients for each group) were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu), including T1-weighted (T1-w), Diffusion Tensor Imaging (DTI) data, and 18F-AV-45 (florbetapir) dynamic PET data from 40-60 min post injection (4x5 min). Both MR and PET data were automatically pre-processed for all subjects using MIBCA. T1-w data was parcellated into cortical and subcortical regions-of-interest (ROIs), and the corresponding thicknesses and volumes were calculated. DTI data was used to compute structural connectivity matrices based on fibers connecting pairs of ROIs. Lastly, dynamic PET images were summed, and the relative Standard Uptake Values calculated for each ROI. Results: An overall higher uptake of 18F-AV-45, consistent with an increased deposition of beta-amyloid, was observed for the AD group. Additionally, patients showed significant cortical atrophy (thickness and volume) especially in the entorhinal cortex and temporal areas, and a significant increase in Mean Diffusivity (MD) in the hippocampus, amygdala and temporal areas. Furthermore, patients showed a reduction of fiber connectivity with the progression of the disease, especially for intra-hemispherical connections. Conclusion: This work shows the potential of the MIBCA toolbox for the study of AD, as findings were shown to be in agreement with the literature. Here, only structural changes and beta-amyloid accumulation were considered. Yet, MIBCA is further able to

  9. Peroxisome proliferator-activated receptors and Alzheimer's disease: hitting the blood-brain barrier.

    PubMed

    Zolezzi, Juan M; Inestrosa, Nibaldo C

    2013-12-01

    The blood-brain barrier (BBB) is often affected in several neurodegenerative disorders, such as Alzheimer's disease (AD). Integrity and proper functionality of the neurovascular unit are recognized to be critical for maintenance of the BBB. Research has traditionally focused on structural integrity more than functionality, and BBB alteration has usually been explained more as a consequence than a cause. However, ongoing evidence suggests that at the early stages, the BBB of a diseased brain often shows distinct expression patterns of specific carriers such as members of the ATP-binding cassette (ABC) transport protein family, which alter BBB traffic. In AD, amyloid-β (Aβ) deposits are a pathological hallmark and, as recently highlighted by Cramer et al. (2012), Aβ clearance is quite fundamental and is a less studied approach. Current knowledge suggests that BBB traffic plays a more important role than previously believed and that pharmacological modulation of the BBB may offer new therapeutic alternatives for AD. Recent investigations carried out in our laboratory indicate that peroxisome proliferator-activated receptor (PPAR) agonists are able to prevent Aβ-induced neurotoxicity in hippocampal neurons and cognitive impairment in a double transgenic mouse model of AD. However, even when enough literature about PPAR agonists and neurodegenerative disorders is available, the problem of how they exert their functions and help to prevent and rescue Aβ-induced neurotoxicity is poorly understood. In this review, along with highlighting the main features of the BBB and its role in AD, we will discuss information regarding the modulation of BBB components, including the possible role of PPAR agonists as BBB traffic modulators.

  10. Clinical Evaluation of Brain Perfusion SPECT with Brodmann Areas Mapping in Early Diagnosis of Alzheimer's Disease.

    PubMed

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

    2015-01-01

    Early diagnosis of Alzheimer's disease (AD) based on clinical criteria alone may be problematic, while current and future treatments should be administered earlier in order to be more effective. Thus, various disease biomarkers could be used for early detection of AD. We evaluated brain perfusion with 99mTc-HMPAO single photon emission computed tomography (SPECT) and Brodmann areas (BAs) mapping in mild AD using an automated software (NeuroGam) for the semi-quantitative evaluation of perfusion in BAs and the comparison with the software's normal database. We studied 34 consecutive patients with mild AD: 9 men, 25 women, mean age 70.9 ± 8.1 years, mean Mini-Mental State Examination 22.6 ± 2.5. BAs 25L, 25R, 38L, 38R, 28L, 28R, 36L, and 36R had the lower mean perfusion values, while BAs 31L, 31R, 19R, 18L, 18R, 17L, and 17R had the higher mean values. Compared with healthy subjects of the same age, perfusion values in BAs 25L, 25R, 28R, 28L, 36L, and 36R had the greatest deviations from the healthy sample, while the lowest deviations were found in BAs 32L, 32R, 19R, 24L, 17L, 17R, 18L, and 18R. A percentage of ≥94% of patients had perfusion values more than -2SDs below the mean of healthy subjects in BAs 38R, 38L, 36L, 36R, 23L, 23R, 22L, 44L, 28L, 28R, 25L, and 25R. The corresponding proportion was less than 38% for BAs 11L, 19R, 32L, 32R, 18L, 18R, 24L, and 17R. In conclusion, brain SPECT studies with automated perfusion mapping could be useful as an ancillary tool in daily practice, revealing perfusion impairments in early AD.

  11. Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease

    PubMed Central

    Liao, Fan; Yoon, Hyejin; Kim, Jungsu

    2017-01-01

    Purpose of review APOE4 genotype is the strongest genetic risk factor for Alzheimer's disease. Prevailing evidence suggests that amyloid β plays a critical role in Alzheimer's disease. The objective of this article is to review the recent findings about the metabolism of apolipoprotein E (ApoE) and amyloid β and other possible mechanisms by which ApoE contributes to the pathogenesis of Alzheimer's disease. Recent findings ApoE isoforms have differential effects on amyloid β metabolism. Recent studies demonstrated that ApoE-interacting proteins, such as ATP-binding cassette A1 (ABCA1) and LDL receptor, may be promising therapeutic targets for Alzheimer's disease treatment. Activation of liver X receptor and retinoid X receptor pathway induces ABCA1 and other genes, leading to amyloid β clearance. Inhibition of the negative regulators of ABCA1, such as microRNA-33, also induces ABCA1 and decreases the levels of ApoE and amyloid β. In addition, genetic inactivation of an E3 ubiquitin ligase, myosin regulatory light chain interacting protein, increases LDL receptor levels and inhibits amyloid accumulation. Although amyloid β-dependent pathways have been extensively investigated, there have been several recent studies linking ApoE with vascular function, neuroinflammation, metabolism, synaptic plasticity, and transcriptional regulation. For example, ApoE was identified as a ligand for a microglial receptor, TREM2, and studies suggested that ApoE may affect the TREM2-mediated microglial phagocytosis. Summary Emerging data suggest that ApoE affects several amyloid β-independent pathways. These underexplored pathways may provide new insights into Alzheimer's disease pathogenesis. However, it will be important to determine to what extent each mechanism contributes to the pathogenesis of Alzheimer's disease. PMID:27922847

  12. The Effect of the APOE Genotype on Individual BrainAGE in Normal Aging, Mild Cognitive Impairment, and Alzheimer's Disease.

    PubMed

    Löwe, Luise Christine; Gaser, Christian; Franke, Katja

    2016-01-01

    In our aging society, diseases in the elderly come more and more into focus. An important issue in research is Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) with their causes, diagnosis, treatment, and disease prediction. We applied the Brain Age Gap Estimation (BrainAGE) method to examine the impact of the Apolipoprotein E (APOE) genotype on structural brain aging, utilizing longitudinal magnetic resonance image (MRI) data of 405 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We tested for differences in neuroanatomical aging between carrier and non-carrier of APOE ε4 within the diagnostic groups and for longitudinal changes in individual brain aging during about three years follow-up. We further examined whether a combination of BrainAGE and APOE status could improve prediction accuracy of conversion to AD in MCI patients. The influence of the APOE status on conversion from MCI to AD was analyzed within all allelic subgroups as well as for ε4 carriers and non-carriers. The BrainAGE scores differed significantly between normal controls, stable MCI (sMCI) and progressive MCI (pMCI) as well as AD patients. Differences in BrainAGE changing rates over time were observed for APOE ε4 carrier status as well as in the pMCI and AD groups. At baseline and during follow-up, BrainAGE scores correlated significantly with neuropsychological test scores in APOE ε4 carriers and non-carriers, especially in pMCI and AD patients. Prediction of conversion was most accurate using the BrainAGE score as compared to neuropsychological test scores, even when the patient's APOE status was unknown. For assessing the individual risk of coming down with AD as well as predicting conversion from MCI to AD, the BrainAGE method proves to be a useful and accurate tool even if the information of the patient's APOE status is missing.

  13. Data on amyloid precursor protein accumulation, spontaneous physical activity, and motor learning after traumatic brain injury in the triple-transgenic mouse model of Alzheimer׳s disease.

    PubMed

    Kishimoto, Yasushi; Shishido, Hajime; Sawanishi, Mayumi; Toyota, Yasunori; Ueno, Masaki; Kubota, Takashi; Kirino, Yutaka; Tamiya, Takashi; Kawai, Nobuyuki

    2016-12-01

    This data article contains supporting information regarding the research article entitled "Traumatic brain injury accelerates amyloid-β deposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer׳s disease" (H. Shishido, Y. Kishimoto, N. Kawai, Y. Toyota, M. Ueno, T. Kubota, Y. Kirino, T. Tamiya, 2016) [1]. Triple-transgenic (3×Tg)-Alzheimer׳s disease (AD) model mice exhibited significantly poorer spatial learning than sham-treated 3×Tg-AD mice 28 days after traumatic brain injury (TBI). Correspondingly, amyloid-β (Aβ) deposition within the hippocampus was significantly greater in 3×Tg-AD mice 28 days after TBI. However, data regarding the short-term and long-term influences of TBI on amyloid precursor protein (APP) accumulation in AD model mice remain limited. Furthermore, there is little data showing whether physical activity and motor learning are affected by TBI in AD model mice. Here, we provide immunocytochemistry data confirming that TBI induces significant increases in APP accumulation in 3×Tg-AD mice at both 7 days and 28 days after TBI. Furthermore, 3×Tg-AD model mice exhibit a reduced ability to acquire conditioned responses (CRs) during delay eyeblink conditioning compared to sham-treated 3×Tg-AD model mice 28 days after TBI. However, physical activity and motor performance are not significantly changed in TBI-treated 3×Tg-AD model mice.

  14. Role of methylglyoxal in Alzheimer's disease.

    PubMed

    Angeloni, Cristina; Zambonin, Laura; Hrelia, Silvana

    2014-01-01

    Alzheimer's disease is the most common and lethal neurodegenerative disorder. The major hallmarks of Alzheimer's disease are extracellular aggregation of amyloid β peptides and, the presence of intracellular neurofibrillary tangles formed by precipitation/aggregation of hyperphosphorylated tau protein. The etiology of Alzheimer's disease is multifactorial and a full understanding of its pathogenesis remains elusive. Some years ago, it has been suggested that glycation may contribute to both extensive protein cross-linking and oxidative stress in Alzheimer's disease. Glycation is an endogenous process that leads to the production of a class of compounds known as advanced glycation end products (AGEs). Interestingly, increased levels of AGEs have been observed in brains of Alzheimer's disease patients. Methylglyoxal, a reactive intermediate of cellular metabolism, is the most potent precursor of AGEs and is strictly correlated with an increase of oxidative stress in Alzheimer's disease. Many studies are showing that methylglyoxal and methylglyoxal-derived AGEs play a key role in the etiopathogenesis of Alzheimer's disease.

  15. Adrenomedullin Expression in Alzheimer's Brain.

    PubMed

    Fernandez, Ana Patricia; Masa, Julia Serrano; Guedan, María Atocha; Futch, Hunter S; Martínez-Murillo, Ricardo

    2016-01-01

    Adrenomedullin (AM) is a potent vasodilator peptide highly expressed throughout the brain and originally isolated from pheochromocytoma cells. In addition to its vasoactive properties, AM is considered a neuromodulator that possesses antiapoptotic and antioxidant properties that suggest that this peptide can protect the brain from damage. In a previous study, we found that AM exerts a neuroprotective action in the brain and that this effect may be mediated by regulation of nitric oxide synthases, matrix metalloproteases, and inflammatory mediators. AM upregulation contributes to neuroprotection, but understanding the precise roles played by AM and its receptor (RAMP2) in neurodegenerative diseases including Alzheimer's disease (AD), awaits further research. In search of Alzheimer's biomarkers, the expression levels of peptides with endothelial vasodilatory action, including AM, were found to be significantly altered in mild AD or during pre-dementia stage of mild cognitive impairment. These studies concluded that ratio of AM or its precursor fragment mid-regional proAM in blood hold promise as diagnostic marker for AD. We are now presenting a study regarding the hypothesis that the AMRAMP2 system might be implicated in the pathophysiology of AD.

  16. Effect of Transcranial Brain Stimulation for the Treatment of Alzheimer Disease: A Review

    PubMed Central

    Nardone, Raffaele; Bergmann, Jürgen; Christova, Monica; Caleri, Francesca; Tezzon, Frediano; Ladurner, Gunther; Trinka, Eugen; Golaszewski, Stefan

    2012-01-01

    Available pharmacological treatments for Alzheimer disease (AD) have limited effectiveness, are expensive, and sometimes induce side effects. Therefore, alternative or complementary adjuvant therapeutic strategies have gained increasing attention. The development of novel noninvasive methods of brain stimulation has increased the interest in neuromodulatory techniques as potential therapeutic tool for cognitive rehabilitation in AD. In particular, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are noninvasive approaches that induce prolonged functional changes in the cerebral cortex. Several studies have begun to therapeutically use rTMS or tDCS to improve cognitive performances in patients with AD. However, most of them induced short-duration beneficial effects and were not adequately powered to establish evidence for therapeutic efficacy. Therefore, TMS and tDCS approaches, seeking to enhance cognitive function, have to be considered still very preliminary. In future studies, multiple rTMS or tDCS sessions might also interact, and metaplasticity effects could affect the outcome. PMID:22114748

  17. Automated Classification to Predict the Progression of Alzheimer's Disease Using Whole-Brain Volumetry and DTI

    PubMed Central

    Jung, Won Beom; Lee, Young Min; Kim, Young Hoon

    2015-01-01

    Objective This study proposes an automated diagnostic method to classify patients with Alzheimer's disease (AD) of degenerative etiology using magnetic resonance imaging (MRI) markers. Methods Twenty-seven patients with subjective memory impairment (SMI), 18 patients with mild cognitive impairment (MCI), and 27 patients with AD participated. MRI protocols included three dimensional brain structural imaging and diffusion tensor imaging to assess the cortical thickness, subcortical volume and white matter integrity. Recursive feature elimination based on support vector machine (SVM) was conducted to determine the most relevant features for classifying abnormal regions and imaging parameters, and then a factor analysis for the top-ranked factors was performed. Subjects were classified using nonlinear SVM. Results Medial temporal regions in AD patients were dominantly detected with cortical thinning and volume atrophy compared with SMI and MCI patients. Damage to white matter integrity was also accredited with decreased fractional anisotropy and increased mean diffusivity (MD) across the three groups. The microscopic damage in the subcortical gray matter was reflected in increased MD. Classification accuracy between pairs of groups (SMI vs. MCI, MCI vs. AD, SMI vs. AD) and among all three groups were 84.4% (±13.8), 86.9% (±10.5), 96.3% (±4.6), and 70.5% (±11.5), respectively. Conclusion This proposed method may be a potential tool to diagnose AD pathology with the current clinical criteria. PMID:25670951

  18. Alzheimer's disease and brain infarcts in the elderly. Agreement with neuropathology.

    PubMed

    Zekry, Dina; Duyckaerts, Charles; Belmin, Joël; Geoffre, Caroline; Moulias, Robert; Hauw, Jean-Jacques

    2002-11-01

    Clarifying the etiology of dementia is one of the most difficult diagnostic challenges, especially in the elderly. We examined the accuracy of clinical criteria to distinguish Alzheimer's disease (AD) and dementia associated with infarcts of the brain, either isolated (vascular dementia) or associated with degenerative lesions (mixed dementia). We carried out a prospective clinico-neuropathological study in a selected series of hospitalized patients. We evaluated the clinical aspects of 33 patients aged over 75 years by use of the criteria and scores of DSMIII, NINCDS-ADRDA, Loeb and Gandolfo, ADDTC and NINDS-AIREN and the Hachinski Ischemic Score. The neuropathological diagnosis was considered to be the gold standard. When comparing clinical criteria and neuropathology, the agreement was moderate for Hachinski's score (0.50) and Loeb's score (0.43) and substantial for the ADDTC (0.63) and the NINDS-AIREN (0.67). When mixed dementias were excluded, the agreement between all clinical criteria and scores and the pathological diagnosis rose to 0.88. Hachinski's score was the most sensitive (0.89) and the NINDS-AIREN the most specific (0.86) for the diagnosis of vascular dementia. In conclusion, all sets of clinical criteria distinguished pure AD from vascular dementia with a high accuracy whereas mixed dementia was clinically under-recognized. The NINDS-AIREN criteria were the most discriminating for the accurate identification of patients with mixed dementia.

  19. Effect of transcranial brain stimulation for the treatment of Alzheimer disease: a review.

    PubMed

    Nardone, Raffaele; Bergmann, Jürgen; Christova, Monica; Caleri, Francesca; Tezzon, Frediano; Ladurner, Gunther; Trinka, Eugen; Golaszewski, Stefan

    2012-01-01

    Available pharmacological treatments for Alzheimer disease (AD) have limited effectiveness, are expensive, and sometimes induce side effects. Therefore, alternative or complementary adjuvant therapeutic strategies have gained increasing attention. The development of novel noninvasive methods of brain stimulation has increased the interest in neuromodulatory techniques as potential therapeutic tool for cognitive rehabilitation in AD. In particular, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are noninvasive approaches that induce prolonged functional changes in the cerebral cortex. Several studies have begun to therapeutically use rTMS or tDCS to improve cognitive performances in patients with AD. However, most of them induced short-duration beneficial effects and were not adequately powered to establish evidence for therapeutic efficacy. Therefore, TMS and tDCS approaches, seeking to enhance cognitive function, have to be considered still very preliminary. In future studies, multiple rTMS or tDCS sessions might also interact, and metaplasticity effects could affect the outcome.

  20. Redox Proteomic Analysis of Carbonylated Brain Proteins in Mild Cognitive Impairment and Early Alzheimer's Disease

    PubMed Central

    Sultana, Rukhsana; Perluigi, Marzia; Newman, Shelley F.; Pierce, William M.; Cini, Chiara; Coccia, Raffaella

    2010-01-01

    Abstract Previous studies indicated increased levels of protein oxidation in brain from subjects with Alzheimer's disease (AD), raising the question of whether oxidative damage is a late effect of neurodegeneration or precedes and contributes to the pathogenesis of AD. Hence, in the present study we used a parallel proteomic approach to identify oxidatively modified proteins in inferior parietal lobule (IPL) from subjects with mild cognitive impairment (MCI) and early stage-AD (EAD). By comparing to age-matched controls, we reasoned that such analysis could help in understanding potential mechanisms involved in upstream processes in AD pathogenesis. We have identified four proteins that showed elevated levels of protein carbonyls: carbonic anhydrase II (CA II), heat shock protein 70 (Hsp70), mitogen-activated protein kinase I (MAPKI), and syntaxin binding protein I (SBP1) in MCI IPL. In EAD IPL we identified three proteins: phosphoglycerate mutase 1 (PM1), glial fibrillary acidic protein, and fructose bisphospate aldolase C (FBA-C). Our results imply that some of the common targets of protein carbonylation correlated with AD neuropathology and suggest a possible involvement of protein modifications in the AD progression. Antioxid. Redox Signal. 12, 327–336. PMID:19686046

  1. Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer's disease mice.

    PubMed

    Arendash, Gary W; Mori, Takashi; Cao, Chuanhai; Mamcarz, Malgorzata; Runfeldt, Melissa; Dickson, Alexander; Rezai-Zadeh, Kavon; Tane, Jun; Citron, Bruce A; Lin, Xiaoyang; Echeverria, Valentina; Potter, Huntington

    2009-01-01

    We have recently shown that Alzheimer's disease (AD) transgenic mice given a moderate level of caffeine intake (the human equivalent of 5 cups of coffee per day) are protected from development of otherwise certain cognitive impairment and have decreased hippocampal amyloid-beta (Abeta) levels due to suppression of both beta-secretase (BACE1) and presenilin 1 (PS1)/gamma-secretase expression. To determine if caffeine intake can have beneficial effects in "aged" APPsw mice already demonstrating cognitive impairment, we administered caffeine in the drinking water of 18-19 month old APPsw mice that were impaired in working memory. At 4-5 weeks into caffeine treatment, those impaired transgenic mice given caffeine (Tg/Caff) exhibited vastly superior working memory compared to the continuing impairment of control transgenic mice. In addition, Tg/Caff mice had substantially reduced Abeta deposition in hippocampus (decrease 40%) and entorhinal cortex (decrease 46%), as well as correlated decreases in brain soluble Abeta levels. Mechanistically, evidence is provided that caffeine suppression of BACE1 involves the cRaf-1/NFkappaB pathway. We also determined that caffeine concentrations within human physiological range effectively reduce active and total glycogen synthase kinase 3 levels in SweAPP N2a cells. Even with pre-existing and substantial Abeta burden, aged APPsw mice exhibited memory restoration and reversal of AD pathology, suggesting a treatment potential of caffeine in cases of established AD.

  2. Lithium activates brain phospholipase A2 and improves memory in rats: implications for Alzheimer's disease.

    PubMed

    Mury, Fábio B; da Silva, Weber C; Barbosa, Nádia R; Mendes, Camila T; Bonini, Juliana S; Sarkis, Jorge Eduardo Souza; Cammarota, Martin; Izquierdo, Ivan; Gattaz, Wagner F; Dias-Neto, Emmanuel

    2016-10-01

    Phospholipase A2 (Pla2) is required for memory retrieval, and its inhibition in the hippocampus has been reported to impair memory acquisition in rats. Moreover, cognitive decline and memory deficits showed to be reduced in animal models after lithium treatment, prompting us to evaluate possible links between Pla2, lithium and memory. Here, we evaluated the possible modulation of Pla2 activity by a long-term treatment of rats with low doses of lithium and its impact in memory. Wistar rats were trained for the inhibitory avoidance task, treated with lithium for 100 days and tested for perdurability of long-term memory. Hippocampal samples were used for quantifying the expression of 19 brain-expressed Pla2 genes and for evaluating the enzymatic activity of Pla2 using group-specific radio-enzymatic assays. Our data pointed to a significant perdurability of long-term memory, which correlated with increased transcriptional and enzymatic activities of certain members of the Pla2 family (iPla2 and sPla2) after the chronic lithium treatment. Our data suggest new possible targets of lithium, add more information on its pharmacological activity and reinforce the possible use of low doses of lithium for the treatment of neurodegenerative conditions such as the Alzheimer's disease.

  3. Brain substrates of learning and retention in mild cognitive impairment diagnosis and progression to Alzheimer's disease.

    PubMed

    Chang, Yu-Ling; Bondi, Mark W; Fennema-Notestine, Christine; McEvoy, Linda K; Hagler, Donald J; Jacobson, Mark W; Dale, Anders M

    2010-04-01

    Understanding the underlying qualitative features of memory deficits in mild cognitive impairment (MCI) can provide critical information for early detection of Alzheimer's disease (AD). This study sought to investigate the utility of both learning and retention measures in (a) the diagnosis of MCI, (b) predicting progression to AD, and (c) examining their underlying brain morphometric correlates. A total of 607 participants were assigned to three MCI groups (high learning-low retention; low learning-high retention; low learning-low retention) and one control group (high learning-high retention) based on scores above or below a 1.5 SD cutoff on learning and retention indices of the Rey Auditory Verbal Learning Test. Our results demonstrated that MCI individuals with predominantly a learning deficit showed a widespread pattern of gray matter loss at baseline, whereas individuals with a retention deficit showed more focal gray matter loss. Moreover, either learning or retention measures provided good predictive value for longitudinal clinical outcome over two years, although impaired learning had modestly better predictive power than impaired retention. As expected, impairments in both measures provided the best predictive power. Thus, the conventional practice of relying solely on the use of delayed recall or retention measures in studies of amnestic MCI misses an important subset of older adults at risk of developing AD. Overall, our results highlight the importance of including learning measures in addition to retention measures when making a diagnosis of MCI and for predicting clinical outcome. (c) 2009 Elsevier Ltd. All rights reserved.

  4. Redox proteomic analysis of carbonylated brain proteins in mild cognitive impairment and early Alzheimer's disease.

    PubMed

    Sultana, Rukhsana; Perluigi, Marzia; Newman, Shelley F; Pierce, William M; Cini, Chiara; Coccia, Raffaella; Butterfield, D Allan

    2010-03-01

    Previous studies indicated increased levels of protein oxidation in brain from subjects with Alzheimer's disease (AD), raising the question of whether oxidative damage is a late effect of neurodegeneration or precedes and contributes to the pathogenesis of AD. Hence, in the present study we used a parallel proteomic approach to identify oxidatively modified proteins in inferior parietal lobule (IPL) from subjects with mild cognitive impairment (MCI) and early stage-AD (EAD). By comparing to age-matched controls, we reasoned that such analysis could help in understanding potential mechanisms involved in upstream processes in AD pathogenesis. We have identified four proteins that showed elevated levels of protein carbonyls: carbonic anhydrase II (CA II), heat shock protein 70 (Hsp70), mitogen-activated protein kinase I (MAPKI), and syntaxin binding protein I (SBP1) in MCI IPL. In EAD IPL we identified three proteins: phosphoglycerate mutase 1 (PM1), glial fibrillary acidic protein, and fructose bisphospate aldolase C (FBA-C). Our results imply that some of the common targets of protein carbonylation correlated with AD neuropathology and suggest a possible involvement of protein modifications in the AD progression.

  5. Voxel-based Morphometry of Brain MRI in Normal Aging and Alzheimer's Disease.

    PubMed

    Matsuda, Hiroshi

    2013-02-01

    Voxel-based morphometry (VBM) using structural brain MRI has been widely used for assessment of normal aging and Alzheimer's disease (AD). VBM of MRI data comprises segmentation into gray matter, white matter, and cerebrospinal fluid partitions, anatomical standardization of all the images to the same stereotactic space using linear affine transformation and further non-linear warping, smoothing, and finally performing a statistical analysis. Two techniques for VBM are commonly used, optimized VBM using statistical parametric mapping (SPM) 2 or SPM5 with non-linear warping based on discrete cosine transforms and SPM8 plus non-linear warping based on diffeomorphic anatomical registration using exponentiated Lie algebra (DARTEL). In normal aging, most cortical regions prominently in frontal and insular areas have been reported to show age-related gray matter atrophy. In contrast, specific structures such as amygdala, hippocampus, and thalamus have been reported to be preserved in normal aging. On the other hand, VBM studies have demonstrated progression of atrophy mapping upstream to Braak's stages of neurofibrillary tangle deposition in AD. The earliest atrophy takes place in medial temporal structures. Stand-alone VBM software using SPM8 plus DARTEL running on Windows has been newly developed as an adjunct to the clinical assessment of AD. This software provides a Z-score map as a consequence of comparison of a patient's MRI with a normal database.

  6. The pancreas-brain axis: insight into disrupted mechanisms associating type 2 diabetes and Alzheimer's disease.

    PubMed

    Desai, Gauri S; Zheng, Chen; Geetha, Thangiah; Mathews, Suresh T; White, B Douglas; Huggins, Kevin W; Zizza, Claire A; Broderick, Tom L; Babu, Jeganathan Ramesh

    2014-01-01

    Epidemiological and observational studies indicate a positive correlation between type 2 diabetes (T2DM) and dementia, with an increased risk of dementia and Alzheimer's disease (AD) associated with insulin-treated diabetes patients. The purpose of this review is to reveal the molecular mechanisms that connect physiological and pathological processes commonly observed in T2DM and AD. Conformational modifications in peptide residues, such as amyloid-β peptide in AD and amylin in T2DM have been shown to instigate formation of insoluble protein aggregates that get deposited in extracellular spaces of brain and pancreatic tissue thus disrupting their normal function. Impaired insulin signaling plays a critical role in AD pathogenesis by reducing IRS-associated PI3 kinase activity and increasing GSK-3β activity. GSK-3β has been suggested to be a component of the γ-secretase complex and is involved in amyloid-β protein precursor processing. GSK-3β along with CDK5 is responsible for hyperphosphorylation of tau leading to the formation of neurofibrillary tangles. In summary, there is evidence to believe that a molecular link connects AD and T2DM and has potential for further investigation toward development of an effective therapeutic target.

  7. Increased levels of 4-hydroxynonenal and acrolein in the brain in preclinical Alzheimer disease.

    PubMed

    Bradley, M A; Markesbery, W R; Lovell, M A

    2010-06-15

    Previous studies demonstrate increased levels of 4-hydroxynonenal (HNE) and acrolein in vulnerable brain regions of subjects with mild cognitive impairment and late-stage Alzheimer disease (LAD). Recently preclinical AD (PCAD) subjects, who demonstrate normal antemortem neuropsychological test scores but abundant AD pathology at autopsy, have become the focus of increased study. Levels of extractable HNE and acrolein were quantified by gas chromatography-mass spectrometry with negative chemical ionization, and protein-bound HNE and acrolein were quantified by dot-blot immunohistochemistry in the hippocampus/parahippocampal gyrus (HPG), superior and middle temporal gyri (SMTG), and cerebellum (CER) of 10 PCAD and 10 age-matched normal control (NC) subjects. Results of the analyses show a significant (P<0.05) increase in levels of extractable acrolein in the HPG of PCAD subjects compared to age-matched NC subjects and a significant decrease in extractable acrolein in PCAD CER. Significant increases in protein-bound HNE in HPG and a significant decrease in CER of PCAD subjects compared to NC subjects were observed. No significant alterations were observed in either extractable or protein-bound HNE or acrolein in the SMTG of PCAD subjects. Additionally, no significant differences in levels of protein carbonyls were observed in the HPG, SMTG, or CER of PCAD subjects compared to NC subjects.

  8. Alterations in brain leptin signalling in spite of unchanged CSF leptin levels in Alzheimer's disease.

    PubMed

    Maioli, Silvia; Lodeiro, Maria; Merino-Serrais, Paula; Falahati, Farshad; Khan, Wasim; Puerta, Elena; Codita, Alina; Rimondini, Roberto; Ramirez, Maria J; Simmons, Andrew; Gil-Bea, Francisco; Westman, Eric; Cedazo-Minguez, Angel

    2015-02-01

    Several studies support the relation between leptin and Alzheimer's disease (AD). We show that leptin levels in CSF are unchanged as subjects progress to AD. However, in AD hippocampus, leptin signalling was decreased and leptin localization was shifted, being more abundant in reactive astrocytes and less in neurons. Similar translocation of leptin was found in brains from Tg2576 and apoE4 mice. Moreover, an enhancement of leptin receptors was found in hippocampus of young Tg2576 mice and in primary astrocytes and neurons treated with Aβ₁₋₄₂. In contrast, old Tg2576 mice showed decreased leptin receptors levels. Similar findings to those seen in Tg2576 mice were found in apoE4, but not in apoE3 mice. These results suggest that leptin levels are intact, but leptin signalling is impaired in AD. Thus, Aβ accumulation and apoE4 genotype result in a transient enhancement of leptin signalling that might lead to a leptin resistance state over time. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  9. Support vector machine-based classification of Alzheimer's disease from whole-brain anatomical MRI.

    PubMed

    Magnin, Benoît; Mesrob, Lilia; Kinkingnéhun, Serge; Pélégrini-Issac, Mélanie; Colliot, Olivier; Sarazin, Marie; Dubois, Bruno; Lehéricy, Stéphane; Benali, Habib

    2009-02-01

    We present and evaluate a new automated method based on support vector machine (SVM) classification of whole-brain anatomical magnetic resonance imaging to discriminate between patients with Alzheimer's disease (AD) and elderly control subjects. We studied 16 patients with AD [mean age +/- standard deviation (SD) = 74.1 +/- 5.2 years, mini-mental score examination (MMSE) = 23.1 +/- 2.9] and 22 elderly controls (72.3 +/- 5.0 years, MMSE = 28.5 +/- 1.3). Three-dimensional T1-weighted MR images of each subject were automatically parcellated into regions of interest (ROIs). Based upon the characteristics of gray matter extracted from each ROI, we used an SVM algorithm to classify the subjects and statistical procedures based on bootstrap resampling to ensure the robustness of the results. We obtained 94.5% mean correct classification for AD and control subjects (mean specificity, 96.6%; mean sensitivity, 91.5%). Our method has the potential in distinguishing patients with AD from elderly controls and therefore may help in the early diagnosis of AD.

  10. Brain aging and late-onset Alzheimer's disease: many open questions.

    PubMed

    Behl, Christian

    2012-08-01

    Despite decades of research in the field of Alzheimer's disease (AD), a real understanding of its molecular pathophysiology and treatments relevant to the day-to-day lives of patients remain out of reach. Research has, with good reason, focused on certain key pathways and potential mechanisms, but sometimes this has been at the expense of work on other theories, which may be slowing down progress in this field. Interesting theories at present include oxidative stress and caloric restriction. Work on the Aβ cascade should continue but with a shift in focus to its intracellular effects and an awareness that additional pathogenetic factors and processes must be involved--most importantly, brain aging. Hyperphosphorylation of tau, for instance, provides another interesting pathway, with one old drug showing promise in this regard. Moreover, work in epigenetics and on protein homeostasis has produced interesting findings and both lines of investigation may reveal suitable targets for future intervention. Taken together, analysis of the biochemistry of aged neurons and the interplay with pathways of neurodegeneration may lead to a better understanding of AD and how to treat and prevent this condition.

  11. Brain-Derived Neurotrophic Factor in Alzheimer's Disease: Risk, Mechanisms, and Therapy.

    PubMed

    Song, Jing-Hui; Yu, Jin-Tai; Tan, Lan

    2015-12-01

    Brain-derived neurotrophic factor (BDNF) has a neurotrophic support on neuron of central nervous system (CNS) and is a key molecule in the maintenance of synaptic plasticity and memory storage in hippocampus. However, changes of BDNF level and expression have been reported in the CNS as well as blood of Alzheimer's disease (AD) patients in the last decade, which indicates a potential role of BDNF in the pathogenesis of AD. Therefore, this review aims to summarize the latest progress in the field of BDNF and its biological roles in AD pathogenesis. We will discuss the interaction between BDNF and amyloid beta (Aβ) peptide, the effect of BDNF on synaptic repair in AD, and the association between BDNF polymorphism and AD risk. The most important is, enlightening the detailed biological ability and complicated mechanisms of action of BDNF in the context of AD would provide a future BDNF-related remedy for AD, such as increment in the production or release of endogenous BDNF by some drugs or BDNF mimics.

  12. Lacosamide reduces HDAC levels in the brain and improves memory: Potential for treatment of Alzheimer's disease.

    PubMed

    Bang, Shraddha R; Ambavade, Shirishkumar D; Jagdale, Priti G; Adkar, Prafulla P; Waghmare, Arun B; Ambavade, Prashant D

    2015-07-01

    Lacosamide, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of epilepsy. Some HDAC inhibitors have been proven effective for the treatment of memory disorders. The present investigation was designed to evaluate the effect of lacosamide on memory and brain HDAC levels. The effect on memory was evaluated in animals with scopolamine-induced amnesia using the elevated plus maze, object recognition test, and radial arm maze. The levels of acetylcholinesterase and HDAC in the cerebral cortex were evaluated. Lacosamide at doses of 10 and 30mg/kg significantly reduced the transfer latency in the elevated plus maze. Lacosamide at a dose of 30mg/kg significantly increased the time spent with a familiar object in the object recognition test at the 24h interval and decreased the time spent in the baited arm. Moreover, at this dose, the number of errors in the radial arm maze at 3 and 24h intervals was minimized and a reduction in the level of HDAC1, but not acetylcholinesterase, was observed in the cerebral cortex. These effects of lacosamide are equivalent to those of piracetam at a dose of 300mg/kg. These results suggest that lacosamide at a 30mg/kg dose improves disrupted memory, possibly by inhibiting HDAC, and could be used to treat amnesic symptoms of Alzheimer's disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Optical fiber spectroscopy measures perfusion of the brain in a murine Alzheimer's disease model

    NASA Astrophysics Data System (ADS)

    Ahn, Hyung Jin; Strickland, Sidney; Krueger, James; Gareau, Daniel

    2014-02-01

    Optical fiber spectroscopy is a versatile tool for measuring diffuse reflectance and extracting absorption information that can noninvasively quantify the presence of chromophores such as oxyhemoglobin and deoxy-hemoglobin in tissues. Cerebrovascular abnormalities were widely recognized in Alzheimer's disease (AD) patients. We analyzed blood volume fraction and level of oxygenated hemoglobin in Tg6799 mice, which are transgenic mice expressing five different familial Alzheimer disease-associated mutations in the human amyloid precursor protein and presenilin-1 genes. Diffuse reflectance spectra were iteratively fit as weighted sums of oxy- and deoxy-hemoglobin. Our observations showed slightly hypoxic conditions and significantly increased blood volume in the Alzheimer's mice versus wild type. These results suggest that hyperperfusion of our AD mice may be a compensating mechanism for impaired cerebral vascular function and somehow relevant with early stage of AD patients. Ongoing work focuses on developing a cannula fixture that allows measurement in awake, behaving animals.

  14. Preventing schizophrenia and Alzheimer disease: comparative ethics.

    PubMed

    Post, S G

    2001-08-01

    Schizophrenia and Alzheimer disease are both diseases of the brain that involve genetic susceptibility factors and for which the prevention or delay of symptom onset are important research goals. This paper provides some comparisons between current preventive efforts in schizophrenia and Alzheimer disease, focusing on certain ethical features of these endeavors such as potential discrimination, misdiagnosis, and stigma.

  15. Curcumin ameliorates insulin signalling pathway in brain of Alzheimer's disease transgenic mice.

    PubMed

    Feng, Hui-Li; Dang, Hui-Zi; Fan, Hui; Chen, Xiao-Pei; Rao, Ying-Xue; Ren, Ying; Yang, Jin-Duo; Shi, Jing; Wang, Peng-Wen; Tian, Jin-Zhou

    2016-12-01

    Deficits in glucose, impaired insulin signalling and brain insulin resistance are common in the pathogenesis of Alzheimer's disease (AD); therefore, some scholars even called AD type 3 diabetes mellitus. Curcumin can reduce the amyloid pathology in AD. Moreover, it is a well-known fact that curcumin has anti-oxidant and anti-inflammatory properties. However, whether or not curcumin could regulate the insulin signal transduction pathway in AD remains unclear. In this study, we used APPswe/PS1dE9 double transgenic mice as the AD model to investigate the mechanisms and the effects of curcumin on AD. Immunohistochemical (IHC) staining and a western blot analysis were used to test the major proteins in the insulin signal transduction pathway. After the administration of curcumin for 6 months, the results showed that the expression of an insulin receptor (InR) and insulin receptor substrate (IRS)-1 decreased in the hippocampal CA1 area of the APPswe/PS1dE9 double transgenic mice, while the expression of phosphatidylinositol-3 kinase (PI3K), phosphorylated PI3K (p-PI3K), serine-threonine kinase (AKT) and phosphorylated AKT (p-AKT) increased. Among the curcumin groups, the medium-dose group was the most effective one. Thus, we believe that curcumin may be a potential therapeutic agent that can regulate the critical molecules in brain insulin signalling pathways. Furthermore, curcumin could be adopted as one of the AD treatments to improve a patient's learning and memory ability.

  16. Altered whole-brain white matter networks in preclinical Alzheimer's disease.

    PubMed

    Fischer, Florian Udo; Wolf, Dominik; Scheurich, Armin; Fellgiebel, Andreas

    2015-01-01

    Surrogates of whole-brain white matter (WM) networks reconstructed using diffusion tensor imaging (DTI) are novel markers of structural brain connectivity. Global connectivity of networks has been found impaired in clinical Alzheimer's disease (AD) compared to cognitively healthy aging. We hypothesized that network alterations are detectable already in preclinical AD and investigated major global WM network properties. Other structural markers of neurodegeneration typically affected in prodromal AD but seeming largely unimpaired in preclinical AD were also examined. 12 cognitively healthy elderly with preclinical AD as classified by florbetapir-PET (mean age 73.4 ± 4.9) and 31 age-matched controls without cerebral amyloidosis (mean age 73.1 ± 6.7) from the ADNI were included. WM networks were reconstructed from DTI using tractography and graph theory. Indices of network capacity and the established imaging markers of neurodegeneration hippocampal volume, and cerebral glucose utilization as measured by fludeoxyglucose-PET were compared between the two groups. Additionally, we measured surrogates of global WM integrity (fractional anisotropy, mean diffusivity, volume). We found an increase of shortest path length and a decrease of global efficiency in preclinical AD. These results remained largely unchanged when controlling for WM integrity. In contrast, neither markers of neurodegeneration nor WM integrity were altered in preclinical AD subjects. Our results suggest an impairment of WM networks in preclinical AD that is detectable while other structural imaging markers do not yet indicate incipient neurodegeneration. Moreover, these findings are specific to WM networks and cannot be explained by other surrogates of global WM integrity.

  17. Pomegranate from Oman Alleviates the Brain Oxidative Damage in Transgenic Mouse Model of Alzheimer's disease

    PubMed Central

    Subash, Selvaraju; Essa, Musthafa Mohamed; Al-Asmi, Abdullah; Al-Adawi, Samir; Vaishnav, Ragini; Braidy, Nady; Manivasagam, Thamilarasan; Guillemin, Gilles J.

    2014-01-01

    Oxidative stress may play a key role in Alzheimer's disease (AD) neuropathology. Pomegranates (石榴 Shí Liú) contain very high levels of antioxidant polyphenolic substances, as compared to other fruits and vegetables. Polyphenols have been shown to be neuroprotective in different model systems. Here, the effects of the antioxidant-rich pomegranate fruit grown in Oman on brain oxidative stress status were tested in the AD transgenic mouse. The 4-month-old mice with double Swedish APP mutation (APPsw/Tg2576) were purchased from Taconic Farm, NY, USA. Four-month-old Tg2576 mice were fed with 4% pomegranate or control diet for 15 months and then assessed for the influence of diet on oxidative stress. Significant increase in oxidative stress was found in terms of enhanced levels of lipid peroxidation (LPO) and protein carbonyls. Concomitantly, decrease in the activities of antioxidant enzymes was observed in Tg2576 mice treated with control diet. Supplementation with 4% pomegranate attenuated oxidative damage, as evidenced by decreased LPO and protein carbonyl levels and restoration in the activities of the antioxidant enzymes [superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione (GSH), and Glutathione S transferase (GST)]. The activities of membrane-bound enzymes [Na+ K+-ATPase and acetylcholinesterase (AChE)] were altered in the brain regions of Tg2576 mouse treated with control diet, and 4% pomegranate supplementation was able to restore the activities of enzymes to comparable values observed in controls. The results suggest that the therapeutic potential of 4% pomegranate in the treatment of AD might be associated with counteracting the oxidative stress by the presence of active phytochemicals in it. PMID:25379464

  18. Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

    PubMed Central

    Kokiko-Cochran, Olga; Ransohoff, Lena; Veenstra, Mike; Lee, Sungho; Saber, Maha; Sikora, Matt; Teknipp, Ryan; Xu, Guixiang; Bemiller, Shane; Wilson, Gina; Crish, Samuel; Bhaskar, Kiran; Lee, Yu-Shang; Ransohoff, Richard M.

    2016-01-01

    Abstract Traumatic brain injury (TBI) has acute and chronic sequelae, including an increased risk for the development of Alzheimer's disease (AD). TBI-associated neuroinflammation is characterized by activation of brain-resident microglia and infiltration of monocytes; however, recent studies have implicated beta-amyloid as a major manipulator of the inflammatory response. To examine neuroinflammation after TBI and development of AD-like features, these studies examined the effects of TBI in the presence and absence of beta-amyloid. The R1.40 mouse model of cerebral amyloidosis was used, with a focus on time points well before robust AD pathologies. Unexpectedly, in R1.40 mice, the acute neuroinflammatory response to TBI was strikingly muted, with reduced numbers of CNS myeloid cells acquiring a macrophage phenotype and decreased expression of inflammatory cytokines. At chronic time points, macrophage activation substantially declined in non-Tg TBI mice; however, it was relatively unchanged in R1.40 TBI mice. The persistent inflammatory response coincided with significant tissue loss between 3 and 120 days post-injury in R1.40 TBI mice, which was not observed in non-Tg TBI mice. Surprisingly, inflammatory cytokine expression was enhanced in R1.40 mice compared with non-Tg mice, regardless of injury group. Although R1.40 TBI mice demonstrated task-specific deficits in cognition, overall functional recovery was similar to non-Tg TBI mice. These findings suggest that accumulating beta-amyloid leads to an altered post-injury macrophage response at acute and chronic time points. Together, these studies emphasize the role of post-injury neuroinflammation in regulating long-term sequelae after TBI and also support recent studies implicating beta-amyloid as an immunomodulator. PMID:26414955

  19. Rey's Auditory Verbal Learning Test scores can be predicted from whole brain MRI in Alzheimer's disease.

    PubMed

    Moradi, Elaheh; Hallikainen, Ilona; Hänninen, Tuomo; Tohka, Jussi

    2017-01-01

    Rey's Auditory Verbal Learning Test (RAVLT) is a powerful neuropsychological tool for testing episodic memory, which is widely used for the cognitive assessment in dementia and pre-dementia conditions. Several studies have shown that an impairment in RAVLT scores reflect well the underlying pathology caused by Alzheimer's disease (AD), thus making RAVLT an effective early marker to detect AD in persons with memory complaints. We investigated the association between RAVLT scores (RAVLT Immediate and RAVLT Percent Forgetting) and the structural brain atrophy caused by AD. The aim was to comprehensively study to what extent the RAVLT scores are predictable based on structural magnetic resonance imaging (MRI) data using machine learning approaches as well as to find the most important brain regions for the estimation of RAVLT scores. For this, we built a predictive model to estimate RAVLT scores from gray matter density via elastic net penalized linear regression model. The proposed approach provided highly significant cross-validated correlation between the estimated and observed RAVLT Immediate (R = 0.50) and RAVLT Percent Forgetting (R = 0.43) in a dataset consisting of 806 AD, mild cognitive impairment (MCI) or healthy subjects. In addition, the selected machine learning method provided more accurate estimates of RAVLT scores than the relevance vector regression used earlier for the estimation of RAVLT based on MRI data. The top predictors were medial temporal lobe structures and amygdala for the estimation of RAVLT Immediate and angular gyrus, hippocampus and amygdala for the estimation of RAVLT Percent Forgetting. Further, the conversion of MCI subjects to AD in 3-years could be predicted based on either observed or estimated RAVLT scores with an accuracy comparable to MRI-based biomarkers.

  20. Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease.

    PubMed

    Kokiko-Cochran, Olga; Ransohoff, Lena; Veenstra, Mike; Lee, Sungho; Saber, Maha; Sikora, Matt; Teknipp, Ryan; Xu, Guixiang; Bemiller, Shane; Wilson, Gina; Crish, Samuel; Bhaskar, Kiran; Lee, Yu-Shang; Ransohoff, Richard M; Lamb, Bruce T

    2016-04-01

    Traumatic brain injury (TBI) has acute and chronic sequelae, including an increased risk for the development of Alzheimer's disease (AD). TBI-associated neuroinflammation is characterized by activation of brain-resident microglia and infiltration of monocytes; however, recent studies have implicated beta-amyloid as a major manipulator of the inflammatory response. To examine neuroinflammation after TBI and development of AD-like features, these studies examined the effects of TBI in the presence and absence of beta-amyloid. The R1.40 mouse model of cerebral amyloidosis was used, with a focus on time points well before robust AD pathologies. Unexpectedly, in R1.40 mice, the acute neuroinflammatory response to TBI was strikingly muted, with reduced numbers of CNS myeloid cells acquiring a macrophage phenotype and decreased expression of inflammatory cytokines. At chronic time points, macrophage activation substantially declined in non-Tg TBI mice; however, it was relatively unchanged in R1.40 TBI mice. The persistent inflammatory response coincided with significant tissue loss between 3 and 120 days post-injury in R1.40 TBI mice, which was not observed in non-Tg TBI mice. Surprisingly, inflammatory cytokine expression was enhanced in R1.40 mice compared with non-Tg mice, regardless of injury group. Although R1.40 TBI mice demonstrated task-specific deficits in cognition, overall functional recovery was similar to non-Tg TBI mice. These findings suggest that accumulating beta-amyloid leads to an altered post-injury macrophage response at acute and chronic time points. Together, these studies emphasize the role of post-injury neuroinflammation in regulating long-term sequelae after TBI and also support recent studies implicating beta-amyloid as an immunomodulator.

  1. Cholinergic modulation of visual and attentional brain responses in Alzheimer's disease and in health

    PubMed Central

    Bentley, P.; Driver, J.; Dolan, R.J.

    2008-01-01

    Visuo-attentional deficits occur early in Alzheimer's disease (AD) and are considered more responsive to pro-cholinergic therapy than characteristic memory disturbances. We hypothesised that neural responses in AD during visual attentional processing would be impaired relative to controls, yet partially susceptible to improvement with cholinesterase inhibition. We studied 16 mild AD patients and 17 age-matched healthy controls, using fMRI-scanning to enable within-subject placebo-controlled comparisons of the effects of physostigmine on stimulus- and attention-related brain activations, and to allow between-group comparisons for these. Subjects viewed stimuli comprising faces or buildings while performing a shallow judgement (colour of image) or a deep judgement (young/old age of depicted face or building). Behaviourally, AD subjects performed poorer than controls in both tasks, while physostigmine benefited AD patients for the more demanding age-judgement task. Stimulus-selective (face minus building, and vice versa) BOLD signals in precuneus and posterior parahippocampal cortex were attenuated in AD relative to controls but increased following physostigmine. By contrast, face-selective responses in fusiform cortex were not impaired in AD and showed decreases following physostigmine for both groups. Task-dependent responses in right parietal and prefrontal cortices were diminished in AD but improved following physostigmine. A similar pattern of group and treatment effects was observed in two extrastriate cortical regions that showed enhanced stimulus-selectivity for the deep versus shallow task. Finally, for the healthy group, physostigmine decreased task-dependent effects, partly due to an exaggeration of selectivity during the shallow relative to deep task. Our results demonstrate cholinergic-mediated improvements for both stimulus- and attention-dependent responses in functionally affected extrastriate and frontoparietal regions for AD. We also show that normal

  2. Frequency-specific alterations of large-scale functional brain networks in patients with Alzheimer's disease.

    PubMed

    Qin, Yuan-Yuan; Li, Ya-Peng; Zhang, Shun; Xiong, Ying; Guo, Lin-Ying; Yang, Shi-Qi; Yao, Yi-Hao; Li, Wei; Zhu, Wen-Zhen

    2015-03-05

    Previous studies have indicated that the cognitive deficits in patients with Alzheimer's disease (AD) may be due to topological deteriorations of the brain network. However, whether the selection of a specific frequency band could impact the topological properties is still not clear. Our hypothesis is that the topological properties of AD patients are also frequency-specific. Resting state functional magnetic resonance imaging data from 10 right-handed moderate AD patients (mean age: 64.3 years; mean mini mental state examination [MMSE]: 18.0) and 10 age and gender-matched healthy controls (mean age: 63.6 years; mean MMSE: 28.2) were enrolled in this study. The global efficiency, the clustering coefficient (CC), the characteristic path length (CpL), and "small-world" property were calculated in a wide range of thresholds and averaged within each group, at three different frequency bands (0.01-0.06 Hz, 0.06-0.11 Hz, and 0.11-0.25 Hz). At lower-frequency bands (0.01-0.06 Hz, 0.06-0.11 Hz), the global efficiency, the CC and the "small-world" properties of AD patients decreased compared to controls. While at higher-frequency bands (0.11-0.25 Hz), the CpL was much longer, and the "small-world" property was disrupted in AD, particularly at a higher threshold. The topological properties changed with different frequency bands, suggesting the existence of disrupted global and local functional organization associated with AD. This study demonstrates that the topological alterations of large-scale functional brain networks in AD patients are frequency dependent, thus providing fundamental support for optimal frequency selection in future related research.

  3. Consumption of grape seed extract prevents amyloid-beta deposition and attenuates inflammation in brain of an Alzheimer's disease mouse.

    PubMed

    Wang, Yan-Jiang; Thomas, Philip; Zhong, Jin-Hua; Bi, Fang-Fang; Kosaraju, Shantha; Pollard, Anthony; Fenech, Michael; Zhou, Xin-Fu

    2009-01-01

    Polyphenols extracted from grape seeds are able to inhibit amyloid-beta (Abeta) aggregation, reduce Abeta production and protect against Abeta neurotoxicity in vitro. We aimed to investigate the therapeutic effects of a polyphenol-rich grape seed extract (GSE) in Alzheimer's disease (AD) mice. APP(Swe)/PS1dE9 transgenic mice were fed with normal AIN-93G diet (control diet), AIN-93G diet with 0.07% curcumin or diet with 2% GSE beginning at 3 months of age for 9 months. Total phenolic content of GSE was 592.5 mg/g dry weight, including gallic acid (49 mg/g), catechin (41 mg/g), epicatechin (66 mg/g) and proanthocyanidins (436.6 mg catechin equivalents/g). Long-term feeding of GSE diet was well tolerated without fatality, behavioural abnormality, changes in food consumption, body weight or liver function. The Abeta levels in the brain and serum of the mice fed with GSE were reduced by 33% and 44%, respectively, compared with the Alzheimer's mice fed with the control diet. Amyloid plaques and microgliosis in the brain of Alzheimer's mice fed with GSE were also reduced by 49% and 70%, respectively. Curcumin also significantly reduced brain Abeta burden and microglia activation. Conclusively, polyphenol-rich GSE prevents the Abeta deposition and attenuates the inflammation in the brain of a transgenic mouse model, and this thus is promising in delaying development of AD.

  4. Cognitive and Brain Profiles Associated with Current Neuroimaging Biomarkers of Preclinical Alzheimer's Disease.

    PubMed

    Besson, Florent L; La Joie, Renaud; Doeuvre, Loïc; Gaubert, Malo; Mézenge, Florence; Egret, Stéphanie; Landeau, Brigitte; Barré, Louisa; Abbas, Ahmed; Ibazizene, Meziane; de La Sayette, Vincent; Desgranges, Béatrice; Eustache, Francis; Chételat, Gaël

    2015-07-22

    Neuroimaging biomarkers, namely hippocampal volume loss, temporoparietal hypometabolism, and neocortical β-amyloid (Aβ) deposition, are included in the recent research criteria for preclinical Alzheimer's disease (AD). However, how to use these biomarkers is still being debated, especially regarding their sequence. Our aim was to characterize the cognitive and brain profiles of elders classified as positive or negative for each biomarker to further our understanding of their use in the preclinical diagnosis of AD. Fifty-four cognitively normal individuals (age = 65.8 ± 8.3 years) underwent neuropsychological tests (structural MRI, FDG-PET, and Florbetapir-PET) and were dichotomized into positive or negative independently for each neuroimaging biomarker. Demographic, neuropsychological, and neuroimaging data were compared between positive and negative subgroups. The MRI-positive subgroup had lower executive performances and mixed patterns of lower volume and metabolism in AD-characteristic regions and in the prefrontal cortex. The FDG-positive subgroup showed only hypometabolism, predominantly in AD-sensitive areas extending to the whole neocortex, compared with the FDG-negative subgroup. The amyloid-positive subgroup was older and included more APOE ε4 carriers compared with the amyloid-negative subgroup. When considering MRI and/or FDG biomarkers together (i.e., the neurodegeneration-positive), there was a trend for an inverse relationship with Aβ deposition such that those with neurodegeneration tended to show less Aβ deposition and the reverse was true as well. Our findings suggest that: (1) MRI and FDG biomarkers provide complementary rather than redundant information and (2) relatively young cognitively normal elders tend to have either neurodegeneration or Aβ deposition, but not both, suggesting additive rather than sequential/causative links between AD neuroimaging biomarkers at this age. Significance statement: Neuroimaging biomarkers are included in

  5. Proteomic profiling of brain cortex tissues in a Tau transgenic mouse model of Alzheimer's disease

    SciTech Connect

    Chang, Seong-Hun; Jung, In-Soo; Han, Gi-Yeon; Kim, Nam-Hee; Kim, Hyun-Jung; Kim, Chan-Wha

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer A transgenic mouse model expressing NSE-htau23 was used. Black-Right-Pointing-Pointer 2D-gel electrophoresis to analyze the cortex proteins of transgenic mice was used. Black-Right-Pointing-Pointer Differentially expressed spots in different stages of AD were identified. Black-Right-Pointing-Pointer GSTP1 and CAII were downregulated with the progression of AD. Black-Right-Pointing-Pointer SCRN1 and ATP6VE1 were up regulated and down regulated differentially. -- Abstract: Alzheimer's disease (AD) involves regionalized neuronal death, synaptic loss, and an accumulation of intracellular neurofibrillary tangles and extracellular senile plaques. Although there have been numerous studies on tau proteins and AD in various stages of neurodegenerative disease pathology, the relationship between tau and AD is not yet fully understood. A transgenic mouse model expressing neuron-specific enolase (NSE)-controlled human wild-type tau (NSE-htau23), which displays some of the typical Alzheimer-associated pathological features, was used to analyze the brain proteome associated with tau tangle deposition. Two-dimensional electrophoresis was performed to compare the cortex proteins of transgenic mice (6- and 12-month-old) with those of control mice. Differentially expressed spots in different stages of AD were identified with ESI-Q-TOF (electrospray ionization quadruple time-of-flight) mass spectrometry and liquid chromatography/tandem mass spectrometry. Among the identified proteins, glutathione S-transferase P 1 (GSTP1) and carbonic anhydrase II (CAII) were down-regulated with the progression of AD, and secerin-1 (SCRN1) and V-type proton ATPase subunit E 1 (ATP6VE1) were up-regulated only in the early stages, and down-regulated in the later stages of AD. The proteins, which were further confirmed by RT-PCR at the mRNA level and with western blotting at the protein level, are expected to be good candidates as drug targets for AD. The study

  6. Brain Substrates of Learning and Retention in Mild Cognitive Impairment Diagnosis and Progression to Alzheimer's Disease

    ERIC Educational Resources Information Center

    Chang, Yu-Ling; Bondi, Mark W.; Fennema-Notestine, Christine; McEvoy, Linda K.; Hagler, Donald J., Jr.; Jacobson, Mark W.; Dale, Anders M.

    2010-01-01

    Understanding the underlying qualitative features of memory deficits in mild cognitive impairment (MCI) can provide critical information for early detection of Alzheimer's disease (AD). This study sought to investigate the utility of both learning and retention measures in (a) the diagnosis of MCI, (b) predicting progression to AD, and (c)…

  7. Brain Substrates of Learning and Retention in Mild Cognitive Impairment Diagnosis and Progression to Alzheimer's Disease

    ERIC Educational Resources Information Center

    Chang, Yu-Ling; Bondi, Mark W.; Fennema-Notestine, Christine; McEvoy, Linda K.; Hagler, Donald J., Jr.; Jacobson, Mark W.; Dale, Anders M.

    2010-01-01

    Understanding the underlying qualitative features of memory deficits in mild cognitive impairment (MCI) can provide critical information for early detection of Alzheimer's disease (AD). This study sought to investigate the utility of both learning and retention measures in (a) the diagnosis of MCI, (b) predicting progression to AD, and (c)…

  8. Hippocampal Sclerosis of Aging, a Common Alzheimer's Disease 'Mimic': Risk Genotypes are Associated with Brain Atrophy Outside the Temporal Lobe.

    PubMed

    Nho, Kwangsik; Saykin, Andrew J; Nelson, Peter T

    2016-01-01

    Hippocampal sclerosis of aging (HS-Aging) is a common brain disease in older adults with a clinical course that is similar to Alzheimer's disease. Four single-nucleotide polymorphisms (SNPs) have previously shown association with HS-Aging. The present study investigated structural brain changes associated with these SNPs using surface-based analysis. Participants from the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 1,239), with both MRI scans and genotype data, were used to assess the association between brain atrophy and previously identified HS-Aging risk SNPs in the following genes: GRN, TMEM106B, ABCC9, and KCNMB2 (minor allele frequency for each is >30%). A fifth SNP (near the ABCC9 gene) was evaluated in post-hoc analysis. The GRN risk SNP (rs5848_T) was associated with a pattern of atrophy in the dorsomedial frontal lobes bilaterally, remarkable since GRN is a risk factor for frontotemporal dementia. The ABCC9 risk SNP (rs704180_A) was associated with multifocal atrophy whereas a SNP (rs7488080_A) nearby (∼50 kb upstream) ABCC9 was associated with atrophy in the right entorhinal cortex. Neither TMEM106B (rs1990622_T), KCNMB2 (rs9637454_A), nor any of the non-risk alleles were associated with brain atrophy. When all four previously identified HS-Aging risk SNPs were summed into a polygenic risk score, there was a pattern of associated multifocal brain atrophy in a predominately frontal pattern. We conclude that common SNPs previously linked to HS-Aging pathology were associated with a distinct pattern of anterior cortical atrophy. Genetic variation associated with HS-Aging pathology may represent a non-Alzheimer's disease contribution to atrophy outside of the hippocampus in older adults.

  9. Application of triple immunohistochemistry to characterize amyloid plaque-associated inflammation in brains with Alzheimer's disease.

    PubMed

    Dandrea, M R; Reiser, P A; Gumula, N A; Hertzog, B M; Andrade-Gordon, P

    2001-03-01

    Inflammation, characterized by the presence of activated microglia and reactive astrocytes (gliosis), has been described in Alzheimer's disease (AD). We used our routine single immunohistochemical (IHC) labeling protocol to label amyloid plaques, an AD neuropathological hallmark, activated microglia, and reactive astrocytes in serial sections of AD hippocampus and entorhinal cortex of brain. Although most amyloid plaques were associated with inflammation throughout the serial sections, the extent of microglial and astrocytic activation varied among the amyloid plaques. We also observed a population of amyloid plaques that did not appear to coincide with immunolabeled microglia and astrocytes in serial sections, leading us to speculate that some amyloid plaques are not associated with inflammation. Because serial sectioning limited our ability to confirm these findings, we developed a triple IHC protocol to investigate the association of activated microglia and reactive astrocytes simultaneously with amyloid plaques in sections of AD brain entorhinal cortex and hippocampus. Unlike the potential errors of extrapolating descriptive information from routine IHC or histochemical staining methods on sectioned tissues, triple IHC allowed direct characterization of three differently colored antigens in situ. The success of the protocol depended on selection of distinguishable color schemes and resolution of other critical technical elements including the compatibility of the reagents and the sensitivity and sequence of the detection systems. The results of the triple IHC protocol clarified the spatial relation of microglia and astrocytes with amyloid plaques and provoked novel interpretations about the roles of inflammation in AD brain tissues. We categorized three distinct populations of amyloid plaques related to of inflammation: 1) Abeta42 immunoreactive (a marker of amyloid plaques) amyloid plaques without activated microglia or reactive astrocytes, 2) Abeta42-positive

  10. Brain imaging and cognitive predictors of stroke and Alzheimer disease in the Framingham Heart Study.

    PubMed

    Weinstein, Galit; Beiser, Alexa S; Decarli, Charles; Au, Rhoda; Wolf, Philip A; Seshadri, Sudha

    2013-10-01

    Exposure to vascular risk factors has a gradual deleterious effect on brain MRI and cognitive measures. We explored whether a pattern of these measures exists that predicts stroke and Alzheimer disease (AD) risk. A cognitive battery was administered to 1679 dementia and stroke-free Framingham offspring (age, >55 years; mean, 65.7±7.0) between 1999 and 2004; participants were also free of other neurological conditions that could affect cognition and >90% also had brain MRI examination. We related cognitive and MRI measures to risks of incident stroke and AD ≤10 years of follow-up. As a secondary analysis, we explored these associations in The Framingham Heart Study original cohort (mean age, 67.5±7.3 and 84.8±3.3 years at the cognitive assessment and MRI examination, respectively). A total of 55 Offspring participants sustained strokes and 31 developed AD. Offspring who scored <1.5 SD below predicted mean scores, for age and education, on an executive function test, had a higher risk of future stroke (hazard ratio [HR], 2.27; 95% confidence interval [CI], 1.06-4.85) and AD (HR, 3.60; 95% CI, 1.52-8.52); additional cognitive tests also predicted AD. Participants with low (<20 percentile) total brain volume and high (>20 percentile) white matter hyperintensity volume had a higher risk of stroke (HR, 1.97; 95% CI, 1.03-3.77 and HR, 2.74; 95% CI, 1.51-5.00, respectively) but not AD. Hippocampal volume at the bottom quintile predicted AD in the offspring and original cohorts (HR, 4.41; 95% CI, 2.00-9.72 and HR, 2.37; 95% CI, 1.12-5.00, respectively). A stepwise increase in stroke risk was apparent with increasing numbers of these cognitive and imaging markers. Specific patterns of cognitive and brain structural measures observed even in early aging predict stroke risk and may serve as biomarkers for risk prediction.

  11. Anti-brain spectrin immunoreactivity in Alzheimer's disease: degradation of spectrin in an animal model of cholinergic degeneration.

    PubMed

    Fernández-Shaw, C; Marina, A; Cazorla, P; Valdivieso, F; Vázquez, J

    1997-07-01

    In a previous work, we described the existence of anti-brain spectrin auto antibodies in Alzheimer's disease (AD) patients (J. Neuroimmunol. 68 (1996) 39-44). In this report, we further support our previous observations, showing that sera from 9 out of 18 AD patients, but none of 14 control subjects, immunoreacted with spectrin synthesized by PC12 cells. In addition, degradation of brain spectrin was found to be greatly enhanced in the frontal cortex of rats subjected to an animal model of cholinergic degeneration. Our data suggest that spectrin degradation and generation of anti-spectrin auto antibodies may be related to the cholinergic degeneration encountered in AD.

  12. Roles of brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) signalling in Alzheimer's disease.

    PubMed

    Zhang, Fang; Kang, Zhilong; Li, Wen; Xiao, Zhicheng; Zhou, Xinfu

    2012-07-01

    Alzheimer's disease (AD) is one of the most common causes of dementia in the elderly. It is characterized by extracellular deposition of the neurotoxic peptide, amyloid-beta (Aβ) peptide fibrils, and is accompanied by extensive loss of neurons in the brains of affected individuals. However, the pathogenesis of AD is not fully understood. The aim of this review is to discuss the possible role of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signalling in the development of AD, focusing on BDNF/TrkB signalling in the production of Aβ, tau hyperphosphorylation and cognition decline, and exploring new possibilities for AD intervention.

  13. Recent advances in the neuroimmunology of cell-surface CNS autoantibody syndromes, Alzheimer's disease, traumatic brain injury and schizophrenia.

    PubMed

    Needham, Ed; Zandi, Michael S

    2014-10-01

    In this update, we review recent advances in antibody-associated disorders of the central nervous system, and the immune mechanisms which may contribute to Alzheimer's disease, traumatic brain injury and schizophrenia. The field of neuroimmunology is rapidly developing and has concerned itself with an expanding portfolio of diseases. The core neuroimmunological diseases remain, multiple sclerosis, neuromyelitis optica, primary inflammatory and antibody-associated disorders of the central and peripheral nervous system (including Myasthenia Gravis and other disorders of neuromuscular junction and muscle, paraneoplastic syndromes, paraproteinaemic neuropathies), and the neurological involvement seen in systemic inflammatory diseases including lupus, sarcoidosis and vasculitis. But it is increasingly realised that immune mechanisms may contribute to the pathogenesis of degenerative diseases including Alzheimer's disease, traumatic brain disease and psychiatric diseases including schizophrenia and depression. These common and devastating disorders, often without effective disease-modifying therapies, are yet to be seen in a conventional neuroimmunology clinic, but the immune mechanisms identified have encouraged research into novel therapeutic approaches for them.

  14. Clinical application of 3D arterial spin-labeled brain perfusion imaging for Alzheimer disease: comparison with brain perfusion SPECT.

    PubMed

    Takahashi, H; Ishii, K; Hosokawa, C; Hyodo, T; Kashiwagi, N; Matsuki, M; Ashikaga, R; Murakami, T

    2014-05-01

    Alzheimer disease is the most common neurodegenerative disorder with dementia, and a practical and economic biomarker for diagnosis of Alzheimer disease is needed. Three-dimensional arterial spin-labeling, with its high signal-to-noise ratio, enables measurement of cerebral blood flow precisely without any extrinsic tracers. We evaluated the performance of 3D arterial spin-labeling compared with SPECT, and demonstrated the 3D arterial spin-labeled imaging characteristics in the diagnosis of Alzheimer disease. This study included 68 patients with clinically suspected Alzheimer disease who underwent both 3D arterial spin-labeling and SPECT imaging. Two readers independently assessed both images. Kendall W coefficients of concordance (K) were computed, and receiver operating characteristic analyses were performed for each reader. The differences between the images in regional perfusion distribution were evaluated by means of statistical parametric mapping, and the incidence of hypoperfusion of the cerebral watershed area, referred to as "borderzone sign" in the 3D arterial spin-labeled images, was determined. Readers showed K = 0.82/0.73 for SPECT/3D arterial spin-labeled imaging, and the respective areas under the receiver operating characteristic curve were 0.82/0.69 for reader 1 and 0.80/0.69 for reader 2. Statistical parametric mapping showed that the perisylvian and medial parieto-occipital perfusion in the arterial spin-labeled images was significantly higher than that in the SPECT images. Borderzone sign was observed on 3D arterial spin-labeling in 70% of patients misdiagnosed with Alzheimer disease. The diagnostic performance of 3D arterial spin-labeling and SPECT for Alzheimer disease was almost equivalent. Three-dimensional arterial spin-labeled imaging was more influenced by hemodynamic factors than was SPECT imaging. © 2014 by American Journal of Neuroradiology.

  15. Exploring Patterns of Alteration in Alzheimer's Disease Brain Networks: A Combined Structural and Functional Connectomics Analysis

    PubMed Central

    Palesi, Fulvia; Castellazzi, Gloria; Casiraghi, Letizia; Sinforiani, Elena; Vitali, Paolo; Gandini Wheeler-Kingshott, Claudia A. M.; D'Angelo, Egidio

    2016-01-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a severe derangement of cognitive functions, primarily memory, in elderly subjects. As far as the functional impairment is concerned, growing evidence supports the “disconnection syndrome” hypothesis. Recent investigations using fMRI have revealed a generalized alteration of resting state networks (RSNs) in patients affected by AD and mild cognitive impairment (MCI). However, it was unclear whether the changes in functional connectivity were accompanied by corresponding structural network changes. In this work, we have developed a novel structural/functional connectomic approach: resting state fMRI was used to identify the functional cortical network nodes and diffusion MRI to reconstruct the fiber tracts to give a weight to internodal subcortical connections. Then, local and global efficiency were determined for different networks, exploring specific alterations of integration and segregation patterns in AD and MCI patients compared to healthy controls (HC). In the default mode network (DMN), that was the most affected, axonal loss, and reduced axonal integrity appeared to compromise both local and global efficiency along posterior-anterior connections. In the basal ganglia network (BGN), disruption of white matter integrity implied that main alterations occurred in local microstructure. In the anterior insular network (AIN), neuronal loss probably subtended a compromised communication with the insular cortex. Cognitive performance, evaluated by neuropsychological examinations, revealed a dependency on integration and segregation of brain networks. These findings are indicative of the fact that cognitive deficits in AD could be associated not only with cortical alterations (revealed by fMRI) but also with subcortical alterations (revealed by diffusion MRI) that extend beyond the areas primarily damaged by neurodegeneration, toward the support of an emerging concept of AD as a

  16. Angiotensin Converting Enzyme Inhibitors Ameliorate Brain Inflammation Associated with Microglial Activation: Possible Implications for Alzheimer's Disease.

    PubMed

    Torika, Nofar; Asraf, Keren; Roasso, Ella; Danon, Abraham; Fleisher-Berkovich, Sigal

    2016-12-01

    Angiotensin converting enzyme (ACE) converts Angiotensin I to a potent vasoconstrictor angiotensin II (ANG II). ACE inhibitors (ACEIs) are widely used for the management of hypertension. All components of the renin-angiotensin system (RAS) have also been identified in the brain. In addition to cytokines, neuromodulators such as ANG II can induce neuroinflammation. Moreover, in Alzheimer's disease (AD) models, where neuroinflammation occurs and is thought to contribute to the propagation of the disease, increased levels of ANG II and ACE have been detected. However, the specific effect of ACEIs on neuroinflammation and AD remains obscure. The present study suggests that captopril and perindopril, centrally active ACEIs, may serve as modulators for microglial activation associated with AD. Our in vitro study investigated the effect of both ACEIs on nitric oxide (NO), tumor necrosis factor- α (TNF-α) release and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-induced BV2 microglia. Exposure of BV2 microglia to ACEIs significantly attenuated the LPS-induced NO and TNF-α release. In vivo, short term intranasal administration of perindopril or captopril to 5 Familial AD (5XFAD) mice significantly reduced amyloid burden and CD11b expression (a microglial marker) or only CD11b expression respectively, in the cortex of 5XFAD. Long-term intranasal administration of captopril to mice reduced amyloid burden with no effect on CD11b expression. We provide evidence that intranasal delivery of ACEI may serve as an efficient alternative for their systemic administration, as it results in the attenuation of microglial accumulation and even the reduction of Amyloid β (Aβ) plaques.

  17. Neuroserpin up-regulation in the Alzheimer's disease brain is associated with elevated thyroid hormone receptor-β1 and HuD expression.

    PubMed

    Subhadra, Bobban; Schaller, Kristin; Seeds, Nicholas W

    2013-11-01

    Neuroserpin, the major inhibitor of tissue plasminogen activator (tPA) in brain, has been shown to be up-regulated in Alzheimer's disease (AD). Inhibition of tPA activity leads to reduced brain levels of plasmin, one of the main enzymes responsible for the degradation and clearance of amyloid-beta and its plaques from the brain. Thyroid hormone is one of the few factors known to enhance expression of neuroserpin in neurons. Thyroid hormone acts on neurons by binding to its receptors THR1α and THR1β, which then function in the nucleus to up-regulate the expression of numerous genes including the RNA-binding protein HuD. HuD acts post-transcriptionally to enhance expression of numerous proteins including neuroserpin by stabilizing their mRNAs. A series of Alzheimer's disease brain tissues were compared to age-matched control brains for their expression of neuroserpin, THRβ1 and HuD by western blotting. Alzheimer's disease brain tissues with elevated neuroserpin protein also showed increased expression of THRβ1 and HuD. Pair-wise analyses showed significant correlation p-values between neuroserpin, THRβ1 and HuD levels; suggesting that the up-regulation of neuroserpin in Alzheimer's disease brain may result from an activation of the thyroid hormone response system in these individuals. These findings provide evidence for a potential relationship between thyroid hormone disorders and Alzheimer's disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Biomarkers for Alzheimer's Disease Diagnosis.

    PubMed

    Mantzavinosa, Vasileios; Alexiou, Athanasios; Greig, Nigel H; Kamal, Mohammad A

    2017-02-03

    The dramatic increase in the population with dementia expected in the next decades is accompanied by the establishment of novel and innovated methods that will offer accurate and efficient detection of the disease in its early stages. While Alzheimer's disease is the most common cause of dementia, by the time is typically diagnosed substantial neuronal loss and neuropathological lesions can damaged many brain regions. The aim of this study is to investigate the main risk factors that affect and increase Alzheimer's disease progression over time even in cases with no significant memory impairment present. Several potential markers are discussed such as oxidative stress, metal ions, vascular disorders, protein dysfunctions and alterations in the mitochondrial populations. A multiparametric model of Alzheimer's biomarkers is presented according to the latest classification of the disease.

  19. Integrating Genome-Wide Association Study and Brain Expression Data Highlights Cell Adhesion Molecules and Purine Metabolism in Alzheimer's Disease.

    PubMed

    Xiang, Zimin; Xu, Meiling; Liao, Mingzhi; Jiang, Yongshuai; Jiang, Qinghua; Feng, Rennan; Zhang, Liangcai; Ma, Guoda; Wang, Guangyu; Chen, Zugen; Zhao, Bin; Sun, Tiansheng; Li, Keshen; Liu, Guiyou

    2015-08-01

    Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly. Recently, genome-wide association studies (GWAS) have been used to investigate AD pathogenesis. However, a large proportion of AD heritability has yet to be explained. We previously identified the cell adhesion molecule (CAM) pathway as a consistent signal in two AD GWAS. However, it is unclear whether CAM is present in the Genetic and Environmental Risk for Alzheimer's Disease Consortium (GERAD) GWAS and brain expression GWAS. Meanwhile, we think integrating AD GWAS and AD brain expression datasets may provide complementary information to identify important pathways involved in AD. Here, we conducted a systems analysis using (1) KEGG pathways, (2) large-scale AD GWAS from GERAD (n = 11,789), (3) two brain expression GWAS datasets (n = 399) from the AD cerebellum and temporal cortex, and (4) previous results from pathway analysis of AD GWAS. Our results indicate that (1) CAM is a consistent signal in five AD GWAS; (2) CAM is the most significant signal in AD; (3) we confirmed previous AD risk pathways related to immune system and diseases, and cardiovascular disease, etc.; and (4) we highlighted the purine metabolism pathway in AD for the first time. We believe that our results may advance our understanding of AD mechanisms and will be very informative for future genetic studies in AD.

  20. Serum anti-GFAP and anti-S100 autoantibodies in brain aging, Alzheimer's disease and vascular dementia.

    PubMed

    Mecocci, P; Parnetti, L; Romano, G; Scarelli, A; Chionne, F; Cecchetti, R; Polidori, M C; Palumbo, B; Cherubini, A; Senin, U

    1995-03-01

    Autoantibodies against glial fibrillary acidic protein (GFAP) and S100 protein were measured in sera of patients suffering from vascular dementia (VD), presenile Alzheimer's disease (AD), senile Alzheimer's disease (SDAT) and aged healthy controls by means of ELISA test. VD and SDAT showed the highest levels of both autoantibodies, AD the lowest. From these results a relationship between autoantibody titers and aging seems possible. Dosage of anti-GFAP and anti-S100 autoantibodies does not appear useful for diagnostic purpose because of the overlap observed among groups. Rather, the presence of these antibodies seems to reflect an alteration of the blood-brain barrier that promotes the access of central nervous system antigens to immunocompetent cells.

  1. Heparan sulfate proteoglycan in diffuse plaques of hippocampus but not of cerebellum in Alzheimer's disease brain.

    PubMed

    Snow, A D; Sekiguchi, R T; Nochlin, D; Kalaria, R N; Kimata, K

    1994-02-01

    Previous studies have shown the basement membrane form of heparan sulfate proteoglycan (HSPG) known as perlecan, co-localized to beta-amyloid protein (A beta)-containing amyloid deposits in brains of patients with Alzheimer's disease (AD) and Down's syndrome. Although HSPG was localized to diffuse A beta plaques in hippocampus, amygdala, and neocortex, it is not known whether they are present in diffuse A beta plaques in cerebellum. In the present study, Alcian blue staining and immunocytochemical techniques were used to determine whether highly sulfated glycosaminoglycans (GAGs) and/or HSPG (perlecan) were also present in diffuse A beta plaques of cerebellum. Tissues from cases of AD were examined for the co-localization of highly sulfated GAGs, HSPGs, and A beta in diffuse plaques in cerebellum in comparison with hippocampus. Consecutive serial sections of AD brain tissue were stained or immunostained with 1) the modified Bielschowsky stain; 2) a polyclonal antibody directed against synthetic A beta (1-40); 3) Congo red; 4) Alcian blue (pH 5.7) with varying concentrations of magnesium chloride for identification of sulfated and highly sulfated GAGs; and 5) polyclonal and monoclonal antibodies recognizing either the core protein or a specific GAG epitope on perlecan. All cases (7 of 7) of AD contained diffuse A beta plaques in the cerebellum as identified by positive Bielschowsky staining and A beta immunoreactivity. None of these cases demonstrated positive Alcian blue staining (at 0.3 and 0.7 mol/L MgCl2), HSPG, or HS GAG immunoreactivity in the same diffuse cerebellar plaques on adjacent serial sections. However, Alcian blue staining, HSPG, and/or HS GAG immunoreactivity were observed in blood vessel walls, choroid plexus, and within Purkinje cells, suggesting that the techniques used were reliable and specific. In cerebellum, all plaques containing amyloid cores that were Congo red-positive were also positive for highly sulfated GAGs (by Alcian blue staining

  2. Impairment of biliverdin reductase-A promotes brain insulin resistance in Alzheimer disease: A new paradigm.

    PubMed

    Barone, Eugenio; Di Domenico, Fabio; Cassano, Tommaso; Arena, Andrea; Tramutola, Antonella; Lavecchia, Michele Angelo; Coccia, Raffaella; Butterfield, D Allan; Perluigi, Marzia

    2016-02-01

    Clinical studies suggest a link between peripheral insulin resistance and cognitive dysfunction. Interestingly, post-mortem analyses of Alzheimer disease (AD) subjects demonstrated insulin resistance in the brain proposing a role for cognitive deficits observed in AD. However, the mechanisms responsible for the onset of brain insulin resistance (BIR) need further elucidations. Biliverdin reductase-A (BVR-A) emerged as a unique Ser/Thr/Tyr kinase directly involved in the insulin signaling and represents an up-stream regulator of the insulin signaling cascade. Because we previously demonstrated the oxidative stress (OS)-induced impairment of BVR-A in human AD brain, we hypothesize that BVR-A dysregulation could be associated with the onset of BIR in AD. In the present work, we longitudinally analyze the age-dependent changes of (i) BVR-A protein levels and activation, (ii) total oxidative stress markers levels (PC, HNE, 3-NT) as well as (iii) IR/IRS1 levels and activation in the hippocampus of the triple transgenic model of AD (3xTg-AD) mice. Furthermore, ad hoc experiments have been performed in SH-SY5Y neuroblastoma cells to clarify the molecular mechanism(s) underlying changes observed in mice. Our results show that OS-induced impairment of BVR-A kinase activity is an early event, which starts prior the accumulation of Aβ and tau pathology or the elevation of TNF-α, and that greatly contribute to the onset of BIR along the progression of AD pathology in 3xTg-Ad mice. Based on these evidence we, therefore, propose a new paradigm for which: OS-induced impairment of BVR-A is firstly responsible for a sustained activation of IRS1, which then causes the stimulation of negative feedback mechanisms (i.e. mTOR) aimed to turn-off IRS1 hyper-activity and thus BIR. Similar alterations characterize also the normal aging process in mice, positing BVR-A impairment as a possible bridge in the transition from normal aging to AD. Copyright © 2015 Elsevier Inc. All rights

  3. Serotonin 1A receptors in the living brain of Alzheimer's disease patients

    PubMed Central

    Kepe, Vladimir; Barrio, Jorge R.; Huang, Sung-Cheng; Ercoli, Linda; Siddarth, Prabha; Shoghi-Jadid, Kooresh; Cole, Gregory M.; Satyamurthy, Nagichettiar; Cummings, Jeffrey L.; Small, Gary W.; Phelps, Michael E.

    2006-01-01

    4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide, a selective serotonin 1A (5-HT1A) molecular imaging probe, was used in conjunction with positron emission tomography (PET) for quantification of 5-HT1A receptor densities in the living brains of Alzheimer's disease patients (ADs) (n = 8), subjects with mild cognitive impairment (n = 6), and controls (n = 5). ADs had receptor densities significantly decreased in both hippocampi (binding potential: controls 1.62 ± 0.07; ADs 1.18 ± 0.26) and also in raphe nuclei (controls 0.63 ± 0.09; ADs 0.37 ± 0.20). When volume losses are included, 5-HT1A losses are even more severe (i.e., average mean decreases of 24% in mild cognitive impairment patients and 49% in ADs). A strong correlation of 5-HT1A receptor decreases in hippocampus with worsening of clinical symptoms (Mini Mental State Exam scores) was also found. Moreover, these decreases in 5-HT1A receptor measures correlate with decreased glucose utilization as measured with 2-deoxy-2-[F-18]fluoro-d-glucose PET in the brains of ADs (standardized uptake values; globally: controls 0.89 ± 0.04, ADs 0.72 ± 0.04; posterior cingulate gyrus: controls 1.05 ± 0.09, ADs 0.79 ± 0.11). They also inversely correlate with increased neuropathological loads measured with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile PET in several neocortical regions in the same subjects. The in vivo observations were confirmed independently by in vitro digital autoradiography with 4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide and 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile on brain tissue specimens from two ADs and three nondemented subjects. PMID:16407119

  4. Ibuprofen and Alzheimer's disease.

    PubMed

    Dokmeci, Dikmen

    2004-01-01

    There is epidemiological observation that long-term treatment of patients suffering from rheumatoid arthritis with ibuprofen results in reduced risk and delayed onset of Alzheimer's disease (AD). Chronic central nervous system inflammation in AD brain is implicated in the pathology, but how ibuprofen impacts the pathogenic AD pathways is unclear. Ibuprofen, a commonly used over-the-counter nonsteroidal anti-inflammatory drug (NSAID) that is a cyclooxygenase (COX)-1 and COX-2 inhibitor as well as a peroxisome proliferator-activated receptor (PPAR) agonist, decreases the production of nitric oxide (NO), protects neurons against glutamate toxicity and decreases the production of proinflammatory cytokines. Ibuprofen crosses the blood brain barrier and suppresses neuritic plaque pathology and inflammation in AD brain. Furthermore, ibuprofen is a potent free radical scavenger, and it could reduce lipid peroxidation and free radical generation. Because of neuroprotective activity, relative safety, and its long history of use, ibuprofen is currently being developed for clinical use in AD. Ibuprofen may be a promising new therapeutic avenue for the treatment of neurodegenerative diseases such as AD.

  5. Acute aerobic exercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer's disease.

    PubMed

    Coelho, Flávia Gomes de Melo; Vital, Thays Martins; Stein, Angelica Miki; Arantes, Franciel José; Rueda, André Veloso; Camarini, Rosana; Teodorov, Elizabeth; Santos-Galduróz, Ruth Ferreira

    2014-01-01

    Studies indicate the involvement of brain-derived neurotrophic factor (BDNF) in the pathogenesis of Alzheimer's disease (AD). Decreased BDNF levels may constitute a lack of trophic support and contribute to cognitive impairment in AD. The benefits of acute and chronic physical exercise on BDNF levels are well-documented in humans, however, exercise effects on BDNF levels have not been analyzed in older adults with AD. The aim of this study was to investigate the effects of acute aerobic exercise on BDNF levels in older adults with AD and to verify associations among BDNF levels, aerobic fitness, and level of physical activity. Using a controlled design, twenty-one patients with AD (76.3 ± 6.2 years) and eighteen healthy older adults (74.6 ± 4.7 years) completed an acute aerobic exercise. The outcomes included measures of BDNF plasma levels, aerobic fitness (treadmill grade, time to exhaustion, VO2, and maximal lactate) and level of physical activity (Baecke Questionnaire Modified for the Elderly). The independent t-test shows differences between groups with respect to the BDNF plasma levels at baseline (p = 0.04; t = 4.53; df = 37). In two-way ANOVA, a significant effect of time was found (p = 0.001; F = 13.63; df = 37), the aerobic exercise significantly increased BDNF plasma levels in AD patients and healthy controls. A significant correlation (p = 0.04; r = 0.33) was found between BDNF levels and the level of physical activity. The results of our study suggest that aerobic exercise increases BDNF plasma levels in patients with AD and healthy controls. In addition to that, BDNF levels had association with level of physical activity.

  6. Brain local and regional neuroglial alterations in Alzheimer's Disease: cell types, responses and implications.

    PubMed

    Toledano, Adolfo; Álvarez, María-Isabel; Toledano-Díaz, Adolfo; Merino, José-Joaquín; Rodríguez, José Julio

    2016-01-01

    From birth to death, neurons are dynamically accompanied by neuroglial cells in a very close morphological and functional relationship. Three families have been classically considered within the CNS: astroglia, oligodendroglia and microglia. Many types/subtypes (including NGR2+ cells), with a wide variety of physiological and pathological effects on neurons, have been described using morphological and immunocytochemical criteria. Glio-glial, glio-neuronal and neuro-glial cell signaling and gliotransmission are phenomena that are essential to support brain functions. Morphofunctional changes resulting from the plasticity of all the glial cell types parallel the plastic neuronal changes that optimize the functionality of neuronal circuits. Moreover, neuroglia possesses the ability to adopt a reactive status (gliosis) in which, generally, new functions arise to improve and restore if needed the neural functionality. All these features make neuroglial cells elements of paramount importance when attempting to explain any physiological or pathological processes in the CNS, because they are involved in both, neuroprotection/neurorepair and neurodegeneration. There exist diverse and profound, regional and local, neuroglial changes in all involutive processes (physiological and pathological aging; neurodegenerative disorders, including Alzheimer ´s disease -AD-), but today, the exact meaning of such modifications (the modifications of the different neuroglial types, in time and place), is not well understood. In this review we consider the different neuroglial cells and their responses in order to understand the possible role they fulfill in pathogenesis, diagnosis and treatment (preventive or palliative) of AD. The existence of differentiated and/or concurrent pathogenic and neuro-protective/neuro-restorative astroglial and microglial responses is highlighted.

  7. Concordance between brain (18)F-FDG PET and cerebrospinal fluid biomarkers in diagnosing Alzheimer's disease.

    PubMed

    Rubí, S; Noguera, A; Tarongí, S; Oporto, M; García, A; Vico, H; Espino, A; Picado, M J; Mas, A; Peña, C; Amer, G

    2017-06-20

    Cortical posterior hypometabolism on PET imaging with (18)F-FDG (FDG-PET), and altered levels of Aß1-42 peptide, total Tau (tTau) and phosphorylated Tau (pTau) proteins in cerebrospinal fluid (CSF) are established diagnostic biomarkers in Alzheimer's disease (AD). An evaluation has been made of the concordance and relationship between the results of FDG-PET and CSF biomarkers in symptomatic patients with suspected AD. A retrospective review was carried out on 120 patients with cognitive impairment referred to our Cognitive Neurology Unit, and who were evaluated by brain FDG-PET and a lumbar puncture for CSF biomarkers. In order to calculate their Kappa coefficient of concordance, the result of the FDG-PET and the set of the three CSF biomarkers in each patient was classified as normal, inconclusive, or AD-compatible. The relationship between the results of both methods was further assessed using logistic regression analysis, including the Aß1-42, tTau and pTau levels as quantitative predictors, and the FDG-PET result as the dependent variable. The weighted Kappa coefficient between FDG-PET and CSF biomarkers was 0.46 (95% CI: 0.35-0.57). Logistic regression analysis showed that the Aß1-42 and tTau values together were capable of discriminating an FDG-PET result metabolically suggestive of AD from one non-suggestive of AD, with a 91% sensitivity and 93% specificity at the cut-off line Aß1-42=44+1.3×tTau. The level of concordance between FDG-PET and CSF biomarkers was moderate, indicating their complementary value in diagnosing AD. The Aß1-42 and tTau levels in CSF help to predict the patient FDG-PET cortical metabolic status. Copyright © 2017 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

  8. Deep brain stimulation for Alzheimer disease: a decision and cost-effectiveness analysis.

    PubMed

    Mirsaeedi-Farahani, Keyvan; Halpern, C H; Baltuch, G H; Wolk, D A; Stein, S C

    2015-05-01

    Alzheimer disease (AD) is characterized by impairments in memory function. Standard AD treatment provides marginal improvements in this domain. Recent reports, however, suggested that deep brain stimulation (DBS) may result in improved memory. Given significant equipment costs and health expenses required for DBS surgery, we determine clinical and economic thresholds required for it to be as effective as standard AD treatment. Literature review yielded annual AD progression probabilities, health-related quality of life (QoL), and costs by AD stage. Our 5-year decision analysis model compared cumulative QoL in quality-adjusted life years (QALYs) and costs of standard therapy to theoretical DBS treatment of various success rates, using known complication rates and QoL data. The base case was a patient with mild-stage AD. DBS success was defined as regression to and maintenance of minimal stage AD, which was defined as midway between mild and no dementia, for the first year, and continuation of the natural course of AD for the remaining 4 years. Compared to standard treatment alone, DBS for mild-stage AD requires a success rate of 3% to overcome effects of possible surgical complications on QoL. If DBS can be delivered with success rates above 20% ($200 K/QALY) or 74% ($50 K/QALY) for mild AD, it can be considered cost-effective. Above a success rate of 80%, DBS treatment is both clinically more effective and more cost-effective than standard treatment. Our findings demonstrate that clinical and economic thresholds required for DBS to be cost-effective for AD are relatively low.

  9. Alzheimer's disease and blood-brain barrier function - Why have anti-β-amyloid therapies failed to prevent dementia progression?

    PubMed Central

    Pahnke, Jens; Walker, Lary C.; Scheffler, Katja; Krohn, Markus

    2009-01-01

    Proteopathies of the brain are defined by abnormal, disease-inducing protein deposition that leads to functional abrogation and death of neurons. Immunization trials targeting the removal of amyloid-β plaques in Alzheimer's disease have so far failed to stop the progression of dementia, despite autopsy findings of reduced plaque load. Here, we summarize current knowledge of the relationship between AD pathology and blood-brain barrier function, and propose that the activation of the excretion function of the blood-brain barrier might help to achieve better results in trials targeting the dissolution of cerebral amyloid-β aggregates. We further discuss a possible role of oligomers in limiting the efficacy of immunotherapy. PMID:19481107

  10. Multifunctional nanoliposomes with curcumin-lipid derivative and brain targeting functionality with potential applications for Alzheimer disease.

    PubMed

    Mourtas, Spyridon; Lazar, Adina N; Markoutsa, Eleni; Duyckaerts, Charles; Antimisiaris, Sophia G

    2014-06-10

    With the objective to formulate multifunctional nanosized liposomes to target amyloid deposits in Alzheimer Disease (AD) brains, a lipid-PEG-curcumin derivative was synthesized and characterized. Multifunctional liposomes incorporating the curcumin derivative and additionally decorated with a Blood Brain Barrier (BBB) transport mediator (anti-Transferin antibody) were prepared and characterized. The fluorescence intensity of curcumin derivative was found to increase notably when the curcumin moiety was in the form of a diisopropylethylamine (DIPEA) salt. Both curcumin-derivative liposomes and curcumin-derivative Anti-TrF liposomes showed a high affinity for the amyloid deposits, on post-mortem brains samples of AD patients. The ability of both liposomes to delay Aβ1-42 peptide aggregation was confirmed by Thioflavin assay. However, the decoration of the curcumin-derivative liposomes with the Anti-TrF improved significantly the intake by the BBB cellular model. Results verify that the attachment of an antibody on the curcumin-liposome surface does not block deposit staining or prevention of Aβ aggregation, while the presence of the curcumin-PEG-lipid conjugate does not reduce their brain-targeting capability substantially, proving the potential of such multifunctional NLs for application in Alzheimer disease treatment and diagnosis.

  11. Functional brain networks in Alzheimer's disease: EEG analysis based on limited penetrable visibility graph and phase space method

    NASA Astrophysics Data System (ADS)

    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.

  12. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease.

    PubMed

    Deane, Rashid; Singh, Itender; Sagare, Abhay P; Bell, Robert D; Ross, Nathan T; LaRue, Barbra; Love, Rachal; Perry, Sheldon; Paquette, Nicole; Deane, Richard J; Thiyagarajan, Meenakshisundaram; Zarcone, Troy; Fritz, Gunter; Friedman, Alan E; Miller, Benjamin L; Zlokovic, Berislav V

    2012-04-01

    In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40- and Aβ42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APPsw/0 mice overexpressing human Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aβ40 and Aβ42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APPsw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD.

  13. Melatonin in Alzheimer's disease.

    PubMed

    Lin, Li; Huang, Qiong-Xia; Yang, Shu-Sheng; Chu, Jiang; Wang, Jian-Zhi; Tian, Qing

    2013-07-12

    Alzheimer's disease (AD), an age-related neurodegenerative disorder with progressive cognition deficit, is characterized by extracellular senile plaques (SP) of aggregated β-amyloid (Aβ) and intracellular neurofibrillary tangles, mainly containing the hyperphosphorylated microtubule-associated protein tau. Multiple factors contribute to the etiology of AD in terms of initiation and progression. Melatonin is an endogenously produced hormone in the brain and decreases during aging and in patients with AD. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning and slows down the progression of cognitive impairment in AD patients. Melatonin efficiently protects neuronal cells from Aβ-mediated toxicity via antioxidant and anti-amyloid properties. It not only inhibits Aβ generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Aβ. Our studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting the cholinergic system and in anti-inflammation. The aim of this review is to stimulate interest in melatonin as a potentially useful agent in the prevention and treatment of AD.

  14. Association of Parkinson disease-related protein PINK1 with Alzheimer disease and multiple sclerosis brain lesions.

    PubMed

    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.

  15. Deciphering Alzheimer disease.

    PubMed

    Selkoe, Dennis; Mandelkow, Eckhard; Holtzman, David

    2012-01-01

    Alzheimer disease represents an insidious impairment of intellect and emotional well-being. However, recent advances in biochemical pathology and human genetics offer promise that effective therapeutic agents may soon be developed.

  16. Alzheimer's Disease - Multiple Languages

    MedlinePlus

    ... Supplements Videos & Tools You Are Here: Home → Multiple Languages → All Health Topics → Alzheimer's Disease URL of this page: https://medlineplus.gov/languages/alzheimersdisease.html Other topics A-Z Expand Section ...

  17. β-methylamino-L-alanine (BMAA) is not found in the brains of patients with confirmed Alzheimer's disease.

    PubMed

    Meneely, Julie P; Chevallier, Olivier P; Graham, Stewart; Greer, Brett; Green, Brian D; Elliott, Christopher T

    2016-11-08

    Controversy surrounds the proposed hypothesis that exposure to β-methylamino-L-alanine (BMAA) could play a role in various neurodegenerative conditions including Alzheimer's disease (AD). Here we present the results of the most comprehensive scientific study on BMAA detection ever undertaken on brain samples from patients pathologically confirmed to have suffered from AD, and those from healthy volunteers. Following the full validation of a highly accurate and sensitive mass spectrometric method, no trace of BMAA was detected in the diseased brain or in the control specimens. This contradicts the findings of other reports and calls into question the significance of this compound in neurodegenerative disease. We have attempted to explain the potential causes of misidentification of BMAA in these studies.

  18. Effects of traumatic brain injury and posttraumatic stress disorder on development of Alzheimer's disease in Vietnam Veterans using the Alzheimer's Disease Neuroimaging Initiative: Preliminary Report.

    PubMed

    Weiner, Michael W; Harvey, Danielle; Hayes, Jacqueline; Landau, Susan M; Aisen, Paul S; Petersen, Ronald C; Tosun, Duygu; Veitch, Dallas P; Jack, Clifford R; Decarli, Charles; Saykin, Andrew J; Grafman, Jordan; Neylanthe, Thomas C

    2017-06-01

    Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) have previously been reported to be associated with increased risk of Alzheimer's disease (AD). We are using biomarkers to study Vietnam Veterans with/without mild cognitive impairment with a history of at least one TBI and/or ongoing PTSD to determine whether these contribute to the development of AD. Potential subjects identified by Veterans Administration records underwent an initial telephone screen. Consented subjects underwent clinical evaluation, lumbar puncture, structural MRI and amyloid PET scans. We observed worse cognitive functioning in PTSD and TBI + PTSD groups, worse global cognitive functioning in the PTSD group, lower superior parietal volume in the TBI + PTSD group, and lower amyloid positivity in the PTSD group, but not the TBI group compared to controls without TBI/PTSD. Medial temporal lobe atrophy was not increased in the PTSD and/or TBI groups. Preliminary results do not indicate that TBI or PTSD increase the risk for AD measured by amyloid PET. Additional recruitment, longitudinal follow-up, and tau PET scans will provide more information in the future.

  19. Interlaboratory comparison of assessments of Alzheimer disease-related lesions: a study of the BrainNet Europe Consortium.

    PubMed

    Alafuzoff, Irina; Pikkarainen, Maria; Al-Sarraj, Safa; Arzberger, Thomas; Bell, Jeanne; Bodi, Istvan; Bogdanovic, Nenad; Budka, Herbert; Bugiani, Orso; Ferrer, Isidro; Gelpi, Ellen; Giaccone, Giorgio; Graeber, Manuel B; Hauw, Jean-Jacques; Kamphorst, Wouter; King, Andrew; Kopp, Nicolas; Korkolopoulou, Penelope; Kovács, Gábor G; Meyronet, David; Parchi, Piero; Patsouris, Efstratios; Preusser, Matthias; Ravid, Rivka; Roggendorf, Wolfgang; Seilhean, Danielle; Streichenberger, Nathalie; Thal, Dietmar R; Kretzschmar, Hans

    2006-08-01

    This interlaboratory study evaluated the reproducibility of the assessments of neuritic plaques and neurofibrillary tangles (NFTs)--the hallmark lesions of Alzheimer disease--and compared the staining between the BrainNet Europe centers. To reduce the topography-related inconsistencies in assessments, we used a 2-mm tissue microarray (TMA) technique. The TMA block included 42 core samples taken from 21 paraffin blocks. The assessments were done on Bielschowsky and Gallyas silver stains using an immunohistochemical (IHC) method with antibodies directed to beta-amyloid (IHC/Abeta) and hyperphosphorylated tau (IHC/HPtau). The staining quality and the assessments differed between the participants, being most diverse with Bielschowsky (good/acceptable stain in 53% of centers) followed by Gallyas (good/acceptable stain in 57%) and IHC/Abeta (good/acceptable stain in 71%). The most uniform staining quality and assessment was obtained with the IHC/HPtau method (good/acceptable stain in 94% of centers). The neuropathologic diagnostic protocol (Consortium to Establish a Registry for Alzheimer Disease, Braak and Braak, and the National Institute of Aging and Reagan [NIA-Reagan] Institute) that was used significantly influenced the agreement, being highest with NIA-Reagan (54%) recommendations. This agreement was improved by visualization of NFTs using the IHC/HPtau method. Therefore, the IHC/HPtau methodology to visualize NFTs and neuropil threads should be considered as a method of choice in a future diagnostic protocol for Alzheimer disease.

  20. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease.

    PubMed

    Cunnane, Stephen C; Courchesne-Loyer, Alexandre; St-Pierre, Valérie; Vandenberghe, Camille; Pierotti, Tyler; Fortier, Mélanie; Croteau, Etienne; Castellano, Christian-Alexandre

    2016-03-01

    Brain glucose uptake is impaired in Alzheimer's disease (AD). A key question is whether cognitive decline can be delayed if this brain energy defect is at least partly corrected or bypassed early in the disease. The principal ketones (also called ketone bodies), β-hydroxybutyrate and acetoacetate, are the brain's main physiological alternative fuel to glucose. Three studies in mild-to-moderate AD have shown that, unlike with glucose, brain ketone uptake is not different from that in healthy age-matched controls. Published clinical trials demonstrate that increasing ketone availability to the brain via moderate nutritional ketosis has a modest beneficial effect on cognitive outcomes in mild-to-moderate AD and in mild cognitive impairment. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet, by supplements providing 20-70 g/day of medium-chain triglycerides containing the eight- and ten-carbon fatty acids octanoate and decanoate, or by ketone esters. Given the acute dependence of the brain on its energy supply, it seems reasonable that the development of therapeutic strategies aimed at AD mandates consideration of how the underlying problem of deteriorating brain fuel supply can be corrected or delayed. © 2016 New York Academy of Sciences.

  1. Differential effects of ischemic vascular disease and Alzheimer's disease on brain atrophy and cognition.

    PubMed

    Zheng, Ling; Vinters, Harry V; Mack, Wendy J; Weiner, Michael W; Chui, Helena C

    2016-01-01

    We previously reported that pathologic measures of arteriosclerosis (AS), cerebral infarction, and Alzheimer’s disease (AD) are independently correlated with cortical gray matter (CGM) atrophy measured by in vivo magnetic resonance imaging (MRI). Here, we use path analyses to model the associations between these three pathology measures and cognitive impairment, as mediated by CGM atrophy, after controlling for age and education. In this sample of 116 elderly persons followed longitudinally to autopsy (ischemic vascular disease (IVD) program project), differential patterns were observed between AS and atrophy/cognition versus AD and atrophy/cognition. The total effect of AD pathology on global cognition (β = -0.61, s.e. = 0.06) was four times stronger than that of AS (β = -0.15, s.e. = 0.08). The effect of AS on cognition appears to occur through cerebral infarction and CGM atrophy (β = -0.13, s.e. = 0.04). In contrast, the effects of AD pathology on global cognition (β = -0.50, s.e. = 0.07) occur through a direct pathway that is five times stronger than the indirect pathway acting through CGM atrophy (β = -0.09, s.e. = 0.03). The strength of this direct AD pathway was not significantly mitigated by adding hippocampal volume to the model. AD pathology affects cognition not only through brain atrophy, but also via an unmeasured pathway that could be related to synaptic dysfunction before the development of cortical atrophy.

  2. Epigenomics of Alzheimer's disease.

    PubMed

    Bennett, David A; Yu, Lei; Yang, Jingyun; Srivastava, Gyan P; Aubin, Cristin; De Jager, Philip L

    2015-01-01

    Alzheimer's disease (AD) is a large and growing public health problem. It is characterized by the accumulation of amyloid β peptides and abnormally phosphorylated tau proteins that are associated with cognitive decline and dementia. Much has been learned about the genomics of AD from linkage analyses and, more recently, genome-wide association studies. Several but not all aspects of the genomic landscape are involved in amyloid β metabolism. The moderate concordance of disease among twins suggests other factors, potentially epigenomic factors, are related to AD. We are at the earliest stages of examining the relation of the epigenome to the clinical and pathologic phenotypes that characterize AD. Our literature review suggests that there is some evidence of age-related changes in human brain methylation. Unfortunately, studies of AD have been relatively small with limited coverage of methylation sites and microRNA, let alone other epigenomic marks. We are in the midst of 2 large studies of human brains including coverage of more than 420,000 autosomal cytosine-guanine dinucleotides with the Illumina Infinium HumanMethylation450 BeadArray, and histone acetylation with chromatin immunoprecipitation sequencing. We present descriptive data to help inform other researchers what to expect from these approaches to better design and power their studies. We then discuss future directions to inform on the epigenomic architecture of AD.

  3. What causes alzheimer's disease?

    PubMed

    Armstrong, R A

    2013-01-01

    Since the earliest descriptions of Alzheimer's disease (AD), many theories have been advanced as to its cause. These include: (1) exacerbation of aging, (2) degeneration of anatomical pathways, including the cholinergic and cortico-cortical pathways, (3) an environmental factor such as exposure to aluminium, head injury, or malnutrition, (4) genetic factors including mutations of amyloid precursor protein (APP) and presenilin (PSEN) genes and allelic variation in apolipoprotein E (Apo E), (5) mitochondrial dysfunction, (6) a compromised blood brain barrier, (7) immune system dysfunction, and (8) infectious agents. This review discusses the evidence for and against each of these theories and concludes that AD is a multifactorial disorder in which genetic and environmental risk factors interact to increase the rate of normal aging ('allostatic load'). The consequent degeneration of neurons and blood vessels results in the formation of abnormally aggregated 'reactive' proteins such as β-amyloid (Aβ) and tau. Gene mutations influence the outcome of age-related neuronal degeneration to cause early onset familial AD (EO-FAD). Where gene mutations are absent and a combination of risk factors present, Aβ and tau only slowly accumulate not overwhelming cellular protection systems until later in life causing late-onset sporadic AD (LO-SAD). Aβ and tau spread through the brain via cell to cell transfer along anatomical pathways, variation in the pathways of spread leading to the disease heterogeneity characteristic of AD.

  4. Nanotechnology for Alzheimer Disease.

    PubMed

    Leszek, Jerzy; Tse, Wai Hei; Zhang, Jin; Ávila-Rodriguez, Marco Fidel; Tarasov, Vadim V; Barreto, George E; Bachurin, Sergey O; Aliev, Gjumrakch

    2017-02-03

    Dementia of Alzheimer disease (AD) type affects memory, thinking and behavior. Researchers believe that changes in the brain may begin 10-20 years before symptoms appear and AD is diagnosed. The need to diagnose and treat the devastating disease at an early stage is critical to manage and treat AD. Unfortunately, the lack of validated biomarkers limits the possibility of the earlier stages of AD. The advance of nanotechnology could offer huge opportunities in early-stage diagnosis and well treatment of AD. Biocompatible nanoparticles with diameter in the range of 1-100 nm could be used as targeted delivery system for drugs (e.g. Rivastigmine) to overcome the blood-brain barrier (BBB), and to minimize the side effects caused by over-dosage. In addition, biocompatible nanomaterials with enhanced optical and magnetic properties may allow them being excellent alternative contrast agents for early-stage diagnosis. With more studies on using nanomaterials and nanotechnology in complex biochemical environment of the central nervous system, it is most likely that nanomaterials and nanotechnology can be give significant impact on the early-stage diagnosis and treatment of AD. In this review we discuss the challenges of current treatment and diagnosis of AD and the development on biocompatible nanoparticles, and provide the rational and potentials of using nanoparticles for both drug carrier and imaging contrast agent for diagnosis and treatment of AD. . Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Antioxidants for Alzheimer Disease

    PubMed Central

    Galasko, Douglas R.; Peskind, Elaine; Clark, Christopher M.; Quinn, Joseph F.; Ringman, John M.; Jicha, Gregory A.; Cotman, Carl; Cottrell, Barbara; Montine, Thomas J.; Thomas, Ronald G.; Aisen, Paul

    2013-01-01

    Objective To evaluate whether antioxidant supplements presumed to target specific cellular compartments affected cerebrospinal fluid (CSF) biomarkers. Design Double-blind, placebo-controlled clinical trial. Setting Academic medical centers. Participants Subjects with mild to moderate Alzheimer disease. Intervention Random assignment to treatment for 16 weeks with 800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d of α-lipoic acid (E/C/ALA); 400 mg of coenzyme Q 3 times/d; or placebo. Main Outcome Measures Changes from baseline to 16 weeks in CSF biomarkers related to Alzheimer disease and oxidative stress, cognition (Mini-Mental State Examination), and function (Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale). Results Seventy-eight subjects were randomized; 66 provided serial CSF specimens adequate for biochemical analyses. Study drugs were well tolerated, but accelerated decline in Mini-Mental State Examination scores occurred in the E/C/ALA group, a potential safety concern. Changes in CSF Aβ42, tau, and P-tau181 levels did not differ between the 3 groups. Cerebrospinal fluid F2-isoprostane levels, an oxidative stress biomarker, decreased on average by 19% from baseline to week 16 in the E/C/ALA group but were unchanged in the other groups. Conclusions Antioxidants did not influence CSF biomarkers related to amyloid or tau pathology. Lowering of CSF F2-isoprostane levels in the E/C/ALA group suggests reduction of oxidative stress in the brain. However, this treatment raised the caution of faster cognitive decline, which would need careful assessment if longer-term clinical trials are conducted. Trial Registration clinicaltrials.gov Identifier: NCT00117403 PMID:22431837

  6. Brain expression of Kv3 subunits during development, adulthood and aging and in a murine model of Alzheimer's disease.

    PubMed

    Boda, Enrica; Hoxha, Eriola; Pini, Alessandro; Montarolo, Francesca; Tempia, Filippo

    2012-03-01

    In neurons, voltage-dependent Kv3 potassium channels are essential for the generation of action potentials at high frequency. A dysregulation of the Kv3.1 and Kv3.4 channel subunits has been suggested to contribute to neuronal and glial alterations in Alzheimer's disease, but a quantitative evaluation of these subunits in a mouse model of the pathology is still lacking. We analysed the profile of expression of the four Kv3 subunits by quantitative reverse transcription PCR and Western blot in the whole mouse brain and in dissected brain regions (olfactory bulb, septum, neocortex, hippocampus, brainstem and cerebellum) from 14 days after conception to 18 months after birth. In addition, we measured the levels of Kv3.1 and Kv3.4 messenger RNAs (mRNAs) and proteins in neocortex and hippocampus of APPPS1 mice, a transgenic model of Alzheimer's disease. Although all Kv3 transcripts were significantly expressed in embryonic age in whole brain extracts, only Kv3.1, Kv3.2 and Kv3.4 subunit proteins were present, suggesting a novel role for Kv3 channels at this developmental stage. With the exception of Kv3.4, during postnatal development, Kv3 transcripts and proteins showed a progressive increase in expression and reached an asymptote in adulthood, suggesting that the increase in Kv3 expression during development might contribute to the maturation of the electrical activity of neurons. During aging, Kv3 expression was rather stable. In contrast, in the neocortex of aged APPPS1 mice, Kv3.1 mRNA and protein levels were significantly lower compared to wild type, suggesting that a decrease in Kv3 currents could play a role in the cognitive symptoms of Alzheimer's disease.

  7. Nanomedicine as a promising approach for the treatment and diagnosis of brain diseases: the example of Alzheimer's disease.

    PubMed

    Andrieux, K; Couvreur, P

    2013-07-01

    Targeting of the central nervous system (CNS) in order to treat disorders is actually challenging due to the necessity to cross the blood brain barrier (BBB). This review aims to show how nanomedicine can propose new approach for the treatment and the diagnosis of CNS diseases focusing on Alzheimer's disease (AD). AD is a neurodegenerative disorder prevalent in the senile population. It is characterized by severe neuronal loss and proliferation of plaques composed of β-amyloid peptide (Aβ) and Tau protein deposites. An imbalance between production and clearance leading to the aggregation of Aβ peptides especially in neurotoxic forms, may be the initiating factor in AD. The absence of an effective therapeutic approach nowadays could be, in part, due to the bad knowledge of AD physiopathology and the lack of early diagnosis. Many drawbacks such as poor bioavailability or limited BBB arising of tested molecules in the current or new therapeutic strategies explain their failure but can be resolved by the use of nanotechnology. Examples of recently published works using nanoparticles for improving diagnosis and therapy of AD are presented. Ideal nanocarriers for this aim must be able to pass through the BBB and to interact with an AD marker as soluble extracellular Aβ forms which are known as the most toxic ones. These first results, even if many ones were obtained in vitro, brought to light the potential of nanoparticles for this challenging issue.

  8. Glucagon-Like Peptide-1-Mediated Modulation of Inflammatory Pathways in the Diabetic Brain: Relevance to Alzheimer's Disease.

    PubMed

    Qin, LiMei; Chong, Thomas; Rodriguez, Richard; Pugazhenthi, Subbiah

    2016-01-01

    Neuroinflammation has emerged as an important cause of cognitive decline during aging and in Alzheimer's disease (AD). Chronic low-grade inflammation is observed in obesity and diabetes, which are important risk factors for AD. Therefore, we examined the markers of inflammation in the brain hippocampal samples of Zucker diabetic fatty (ZDF) rats. Pathway-specific gene expression profiling revealed significant increases in the expression of oxidative stress and inflammatory genes. Western blot analysis further showed the activation of NF-kB, defective CREB phosphorylation, and decreases in the levels of neuroprotective CREB target proteins, including Bcl-2, BDNF, and BIRC3 in the diabetic rat brain samples, all of which are related to AD pathology. As therapies based on glucagon-like peptide-1 (GLP-1) are effective in controlling blood glucose levels in type 2 diabetic patients, we tested the in vivo actions of GLP-1 in the diabetic brain by a 10-wk treatment of ZDF rats with alogliptin, an inhibitor of dipeptidyl peptidase. Alogliptin increased the circulating levels of GLP-1 by 125% and decreased blood glucose in diabetic rats by 59%. Normalization of defective signaling to CREB in the hippocampal samples of treated diabetic rats resulted in the increased expression of CREB targets. Dual actions of GLP-1 in the pancreatic beta cells and in the brain suggest that incretin therapies may reduce cognitive decline in the aging diabetic patients and also have the potential to be used in treating Alzheimer's patients.

  9. Label-free imaging and quantitative chemical analysis of Alzheimer's disease brain samples with multimodal multiphoton nonlinear optical microspectroscopy.

    PubMed

    Lee, Jang Hyuk; Kim, Dae Hwan; Song, Woo Keun; Oh, Myoung-Kyu; Ko, Do-Kyeong

    2015-05-01

    We developed multimodal multiphoton microspectroscopy using a small-diameter probe with gradient-index lenses and applied it to unstained Alzheimer's disease (AD) brain samples. Our system maintained the image quality and spatial resolution of images obtained using an objective lens of similar numerical aperture. Multicolor images of AD brain samples were obtained simultaneously by integrating two-photon excited fluorescence and second-harmonic generation on a coherent anti-Stokes Raman scattering (CARS) microendoscope platform. Measurements of two hippocampal regions, the cornus ammonis-1 and dentate gyrus, revealed more lipids, amyloid fibers, and collagen in the AD samples than in the normal samples. Normal and AD brains were clearly distinguished by a large spectral difference and quantitative analysis of the CH mode using CARS microendoscope spectroscopy. We expect this system to be an important diagnosis tool in AD research

  10. Label-free imaging and quantitative chemical analysis of Alzheimer's disease brain samples with multimodal multiphoton nonlinear optical microspectroscopy

    NASA Astrophysics Data System (ADS)

    Lee, Jang Hyuk; Kim, Dae Hwan; Song, Woo Keun; Oh, Myoung-Kyu; Ko, Do-Kyeong

    2015-05-01

    We developed multimodal multiphoton microspectroscopy using a small-diameter probe with gradient-index lenses and applied it to unstained Alzheimer's disease (AD) brain samples. Our system maintained the image quality and spatial resolution of images obtained using an objective lens of similar numerical aperture. Multicolor images of AD brain samples were obtained simultaneously by integrating two-photon excited fluorescence and second-harmonic generation on a coherent anti-Stokes Raman scattering (CARS) microendoscope platform. Measurements of two hippocampal regions, the cornus ammonis-1 and dentate gyrus, revealed more lipids, amyloid fibers, and collagen in the AD samples than in the normal samples. Normal and AD brains were clearly distinguished by a large spectral difference and quantitative analysis of the CH mode using CARS microendoscope spectroscopy. We expect this system to be an important diagnosis tool in AD research.

  11. [Brain imaging of Alzheimer' disease: state of the art and perspectives for clinicians].

    PubMed

    Trombella, Sara; Assal, Frédéric; Zekry, Dina; Gold, Gabriel; Giannakopoulos, Panteleimon; Garibotto, Valentina; Démonet, Jean-François; Frisoni, Giovanni B

    2016-04-20

    To improve the clinical detection of Alzheimer's disease (AD) new diagnostic criteria have been proposed, based on biomarkers of synaptic dysfunction, AD-related neurodegeneration, and Aβ cerebral amyloidosis. Magnetic resonance imaging (MRI) and position emission tomography (PET) neuroimaging can be configured as powerful means for the detection of medial-temporal atrophy, reduced uptake of 18F-FDG PET or and increased retention of Aβ amyloid protein by amyloïd-PET. In this review, we will discuss these promising techniques that allow assessing in vivo AD pathology and help clinicians to better diagnose and follow-up patients, particularly in clinical trials using disease-modifying treatments.

  12. Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer's disease.

    PubMed

    Huang, Xiao-Tian; Qian, Zhong-Ming; He, Xuan; Gong, Qi; Wu, Ka-Chun; Jiang, Li-Rong; Lu, Li-Na; Zhu, Zhou-Jing; Zhang, Hai-Yan; Yung, Wing-Ho; Ke, Ya

    2014-05-01

    Huperzine A (HupA), a natural inhibitor of acetylcholinesterase derived from a plant, is a licensed anti-Alzheimer's disease (AD) drug in China and a nutraceutical in the United States. In addition to acting as an acetylcholinesterase inhibitor, HupA possesses neuroprotective properties. However, the relevant mechanism is unknown. Here, we showed that the neuroprotective effect of HupA was derived from a novel action on brain iron regulation. HupA treatment reduced insoluble and soluble beta amyloid levels, ameliorated amyloid plaques formation, and hyperphosphorylated tau in the cortex and hippocampus of APPswe/PS1dE9 transgenic AD mice. Also, HupA decreased beta amyloid oligomers and amyloid precursor protein levels, and increased A Disintegrin And Metalloprotease Domain 10 (ADAM10) expression in these treated AD mice. However, these beneficial effects of HupA were largely abolished by feeding the animals with a high iron diet. In parallel, we found that HupA decreased iron content in the brain and demonstrated that HupA also has a role to reduce the expression of transferrin-receptor 1 as well as the transferrin-bound iron uptake in cultured neurons. The findings implied that reducing iron in the brain is a novel mechanism of HupA in the treatment of Alzheimer's disease. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Autotoxicity and Alzheimer disease.

    PubMed

    McGeer, P L; McGeer, E G

    2000-06-01

    I mmunological responses are considered to be either humoral, resulting from cloning of B lymphocytes, or cell mediated, resulting from cloning of T lymphocytes. Autoimmune diseases occur when the cloned products attack host tissue. Inflammation is considered a nonspecific response to injury, characterized by exudation of serum into damaged tissue, and identified by the cardinal signs of rubor, calor, dolor, and tumor. However, these classic mechanisms do not fit pathological observations of Alzheimer disease (AD)-affected brain tissue. Although many of the components prominently associated with peripheral immunological and inflammatory states are present in AD lesions, there are no identifiable B lymphocytes or antibodies, and T cells are sparse. Furthermore, the blood-brain barrier is intact, excluding exudation of exogenous serum proteins. Although "neuroinflammation" is the term commonly used to describe the pathological changes, it fails to define adequately the process that is taking place. The reaction is neither a nonspecific response to injury, as classically implied for inflammatory reactions, nor an autoimmune reaction, despite the directed attack against plaques and extracellular tangles. It is most appropriately defined as an innate immunoreaction. The fact that such a reaction can be mounted by brain, an organ frequently described as being immunologically privileged, suggests that a reevaluation is required of the dimensions of the innate immune system, including how it operates at the tissue level. The innate immune system is primitive, while the adaptive immune system, which is directed by peripheral immune organs, is an invention of vertebrates. Even in vertebrates, however, the innate immune system is the first line of defense. Much more needs to be learned about the operation of the innate immune system in health and disease. Arch Neurol. 2000.

  14. The starving brain: Overfed meets undernourished in the pathology of mild cognitive impairment (MCI) and Alzheimer's disease (AD).

    PubMed

    Gibas, Kelly J

    2017-09-09

    Type II Diabetes affects 400 million people worldwide (IDF, 2013). The pathology is paradoxical: internal starvation activated by overfeeding. Hyperinsulinemic impairments of glucose homeostasis are treated with anti-hyperglycemics exacerbating cell starvation, inducing hypoglycemia and raising respiratory quotient. Reductions in hyperglycemia are achieved at the expense of glucose dependency and metabolic inflexibility (Gibas & Gibas, 2017). The brain is not immune from these cycles of starvation. The bioenergetic model characterizes propagation of late-onset, sporadic Alzheimer's disease as loss of molecular fidelity and compromised energy originating in brain networks with highest metabolic demand. Impaired networks function as hubs of connectivity with other "at risk" regions causing propagation of disease to neighboring cells and compensatory up-regulation in protein synthesis, including amyloid precursor protein (Demetrius et al., 2014). Impaired brain circuits are hypo-metabolic. Cerebral energy declines after stages of quasi-stable, hyper-metabolism. Elevated insulin with low bioavailable glucose cross the BBB hyper-activating neurons to preserve brain function, thereby overloading the astrocyte-neuron lactate shuttle. Sustained deficits reprogram the neural phenotype toward lactate driven, OXPHOS. Increased OXPHOS fosters competition between normal and "metabolically charged" neurons for limited fuel. Cerebral starvation causes apoptosis of healthy neurons due to selective disadvantage. The neuroenergetic model defines late-onset neural decline as symptomatic of "brain starvation" resulting from a physiological paradox, concurrent hyperinsulinemia and hypoglycemia, without an evolved cellular response. Catabolic degeneration occurs on a spectrum linear to energy deficit ranging from mild cognitive impairment (MCI) to Alzheimer's disease (AD); this pathology of cerebral starvation is known as Type III diabetes. Copyright © 2017. Published by Elsevier Ltd.

  15. Alpha1-chimaerin, a Rac1 GTPase-activating protein, is expressed at reduced mRNA levels in the brain of Alzheimer's disease patients

    PubMed Central

    Kato, Tomoko; Konishi, Yoshihiro; Shimohama, Shun; Beach, Thomas G.; Akatsu, Hiroyasu; Tooyama, Ikuo

    2015-01-01

    Alpha1-chimaerin is a GTPase-activating protein (GAP) for Rac1, a member of the Rho small GTPase family, whose action leads to the inactivation of Rac1. Rac1 activity is upregulated in Alzheimer's disease, but little is known about the role of α1-chimaerin. In this study, we investigated the expression and localization of α1-chimaerin mRNA in postmortem human brains from patients with Alzheimer's disease and control subjects. In situ hybridization studies demonstrated that α1-chimaerin was expressed by neurons in the neo-cortex of the temporal lobe and the hippocampus of both controls and Alzheimer's disease cases, with the signal intensity dramatically decreased in patients with Alzheimer's disease. Real-time PCR analysis confirmed a significant reduction of α1-chimaerin mRNA expression in the temporal cortex of Alzheimer's disease cases. In contrast, α2-chimaerin mRNA levels showed no significant difference between the groups. The present study showed reduced α1-chimaerin expression in the brain of Alzheimer's disease cases, suggesting a role in the upregulation of Rac1 activity during the disease process. PMID:25676811

  16. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer's disease brain

    PubMed Central

    Takeda, Shuko; Wegmann, Susanne; Cho, Hansang; DeVos, Sarah L.; Commins, Caitlin; Roe, Allyson D.; Nicholls, Samantha B.; Carlson, George A.; Pitstick, Rose; Nobuhara, Chloe K.; Costantino, Isabel; Frosch, Matthew P.; Müller, Daniel J.; Irimia, Daniel; Hyman, Bradley T.

    2015-01-01

    Tau pathology is known to spread in a hierarchical pattern in Alzheimer's disease (AD) brain during disease progression, likely by trans-synaptic tau transfer between neurons. However, the tau species involved in inter-neuron propagation remains unclear. To identify tau species responsible for propagation, we examined uptake and propagation properties of different tau species derived from postmortem cortical extracts and brain interstitial fluid of tau-transgenic mice, as well as human AD cortices. Here we show that PBS-soluble phosphorylated high-molecular-weight (HMW) tau, though very low in abundance, is taken up, axonally transported, and passed on to synaptically connected neurons. Our findings suggest that a rare species of soluble phosphorylated HMW tau is the endogenous form of tau involved in propagation and could be a target for therapeutic intervention and biomarker development. PMID:26458742

  17. Currents of memory: recent progress, translational challenges, and ethical considerations in fornix deep brain stimulation trials for Alzheimer's disease.

    PubMed

    Viaña, John Noel M; Vickers, James C; Cook, Mark J; Gilbert, Frederic

    2017-03-11

    The serendipitous discovery of triggered autobiographical memories and eventual memory improvement in an obese patient who received fornix deep brain stimulation in 2008 paved the way for several phase I and phase II clinical trials focused on the safety and efficacy of this potential intervention for people with Alzheimer's disease. In this article, we summarize clinical trials and case reports on fornix deep brain stimulation for Alzheimer's disease and review experiments on animal models evaluating the physiological or behavioral effects of this intervention. Based on information from these reports and studies, we identify potential translational challenges of this approach and determine practical and ethical considerations for clinical trials, focusing on issues regarding selection criteria, trial design, and outcome evaluation. Based on initial results suggesting greater benefit for those with milder disease stage, we find it essential that participant expectations are carefully managed to avoid treatment disenchantment and/or frustration from participants and caregivers. Finally, we urge for collaboration between centers to establish proper clinical standards and to promote better trial results comparison.

  18. Aberrant Functional Connectivity Architecture in Alzheimer's Disease and Mild Cognitive Impairment: A Whole-Brain, Data-Driven Analysis.

    PubMed

    Zhou, Bo; Yao, Hongxiang; Wang, Pan; Zhang, Zengqiang; Zhan, Yafeng; Ma, Jianhua; Xu, Kaibin; Wang, Luning; An, Ningyu; Liu, Yong; Zhang, Xi

    2015-01-01

    The purpose of our study was to investigate whether the whole-brain functional connectivity pattern exhibits disease severity-related alterations in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Resting-state functional magnetic resonance imaging data were acquired in 27 MCI subjects, 35 AD patients, and 27 age- and gender-matched subjects with normal cognition (NC). Interregional functional connectivity was assessed based on a predefined template which parcellated the brain into 90 regions. Altered whole-brain functional connectivity patterns were identified via connectivity comparisons between the AD and NC subjects. Finally, the relationship between functional connectivity strength and cognitive ability according to the mini-mental state examination (MMSE) was evaluated in the MCI and AD groups. Compared with the NC group, the AD group exhibited decreased functional connectivities throughout the brain. The most significantly affected regions included several important nodes of the default mode network and the temporal lobe. Moreover, changes in functional connectivity strength exhibited significant associations with disease severity-related alterations in the AD and MCI groups. The present study provides novel evidence and will facilitate meta-analysis of whole-brain analyses in AD and MCI, which will be critical to better understand the neural basis of AD.

  19. Brain-targeted co-delivery of therapeutic gene and peptide by multifunctional nanoparticles in Alzheimer's disease mice.

    PubMed

    Liu, Yang; An, Sai; Li, Jianfeng; Kuang, Yuyang; He, Xi; Guo, Yubo; Ma, Haojun; Zhang, Yu; Ji, Bin; Jiang, Chen

    2016-02-01

    Multifunctional nanocarriers are increasingly promising for disease treatment aimed to regulate multiple pathological dysfunctions and overcome barriers in drug delivery. Here we develop a multifunctional nanocarrier for Alzheimer's disease (AD) treatment by achieving therapeutic gene and peptide co-delivery to brain based on PEGylated dendrigraft poly-l-lysines (DGLs) via systemic administration. The dendritic amine-rich structure of DGLs provides plenty reaction sites and positive charge for drug loading. Successful co-delivery of drugs overcoming the blood-brain barrier by brain-targeted ligand modification was demonstrated both in vitro and in vivo. The pharmacodynamics study of the system following multiple-dosing treatment was verified in transgenic AD mice. Down-regulation of the key enzyme in amyloid-β formation was achieved by delivering non-coding RNA plasmid. Simultaneous delivery of the therapeutic peptide into brain leads to reduction of neurofibrillary tangles. Meanwhile, memory loss rescue in AD mice was also observed. Taken together, the multifunctional nanocarrier provides an excellent drug co-delivery platform for brain diseases.

  20. Evaluation of whole brain health in aging and Alzheimer's disease: a standard procedure for scoring an MRI-based brain atrophy and lesion index.

    PubMed

    Guo, Hui; Song, Xiaowei; Schmidt, Matthias H; Vandorpe, Robert; Yang, Zhan; LeBlanc, Emily; Zhang, Jing; Beyea, Steven; Zhang, Yunting; Rockwood, Kenneth

    2014-01-01

    The Brain Atrophy and Lesion Index (BALI), a semi-quantitative rating scale, has been developed to evaluate whole brain structural changes in aging and Alzheimer's disease (AD). This study describes a standard procedure to score the BALI and train new raters for reliable BALI evaluation following this procedure. Structural MRI of subjects in the Alzheimer's Disease Neuroimaging Initiative dataset who had 3.0T, T1, and T2 weighted MRI scans at baseline and at 6, 12, and 24 month follow-ups were retrieved (n = 122, including 24 AD, 51 mild cognitive impairment patients, and 47 healthy control subjects). Images were evaluated by four raters following training with a step-by-step BALI process. Seven domains of structural brain changes were evaluated, and a total score was calculated as the sum of the sub-scores. New raters achieved >90% accuracy after two weeks of training. Reliability was shown in both intra-rater correlation coefficients (ICC ≥ 0.92, p < 0.001) and inter-rater correlation coefficients (ICC ≥0.88, p < 0.001). Mean BALI total scores differed by diagnosis (F ≥ 2.69, p ≤ 0.049) and increased consistently over two years. The BALI can be introduced using a standard procedure that allows new users to achieve highly reliable evaluation of structural brain changes. This can advance its potential as a robust method for assessing global brain health in aging, AD, and mild cognitive impairment.

  1. Influence of drug transporters and stereoselectivity on the brain penetration of pioglitazone as a potential medicine against Alzheimer's disease

    PubMed Central

    Chang, Kai Lun; Pee, Hai Ning; Yang, Shili; Ho, Paul C.

    2015-01-01

    Pioglitazone is currently undergoing clinical trials for treatment of Alzheimer's disease (AD). However, poor brain penetration remains an obstacle to development of the drug for such intended clinical uses. In this study, we demonstrate that the inhibition of P-glycoprotein (P-gp) significantly increases brain penetration of pioglitazone, whereas inhibition of breast cancer resistance protein (BCRP) has little effect. We also investigate the stereoselectivity of pioglitazone uptake in the brain. When mice were dosed with racemic pioglitazone, the concentration of (+)-pioglitazone was 46.6% higher than that of (-)-pioglitazone in brain tissue and 67.7% lower than that of (-)-pioglitazone in plasma. Dosing mice with pure (+)-pioglitazone led to a 76% increase in brain exposure levels compared to those from an equivalent dose of racemic pioglitazone. Pure (+)-pioglitazone was also shown to have comparable amyloid-lowering capabilities to the racemic pioglitazone in an in vitro AD model. These results suggest that P-gp may act as a stereoselective barrier to prevent pioglitazone entry into the brain. Dosing with (+)-pioglitazone instead of the racemic mixture may result in higher levels of brain exposure to pioglitazone, thus potentially improving the development of pioglitazone treatment of AD. PMID:25760794

  2. Epidemiology of Alzheimer disease

    PubMed Central

    Reitz, Christiane; Brayne, Carol; Mayeux, Richard

    2012-01-01

    The global prevalence of dementia is estimated to be as high as 24 million, and is predicted to double every 20 years through to 2040, leading to a costly burden of disease. Alzheimer disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory. Before death, individuals with this disorder have usually become dependent on caregivers. The neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques—which are frequently surrounded by dystrophic neurites—and intracellular neurofibrillary tangles. These hallmark pathologies are often accompanied by the presence of reactive microgliosis and the loss of neurons, white matter and synapses. The etiological mechanisms underlying the neuropathological changes in AD remain unclear, but are probably affected by both environmental and genetic factors. Here, we provide an overview of the criteria used in the diagnosis of AD, highlighting how this disease is related to, but distinct from, normal aging. We also summarize current information relating to AD prevalence, incidence and risk factors, and review the biomarkers that may be used for risk assessment and in diagnosis. PMID:21304480

  3. Treatment of Alzheimer disease.

    PubMed

    Winslow, Bradford T; Onysko, Mary K; Stob, Christian M; Hazlewood, Kathleen A

    2011-06-15

    Alzheimer disease is the most common form of dementia, affecting nearly one-half [corrected] of Americans older than 85 years. It is characterized by progressive memory loss and cognitive decline. Amyloid plaque accumulation, neurofibrillary tau tangles, and depletion of acetylcholine are among the pathologic manifestations of Alzheimer disease. Although there are no proven modalities for preventing Alzheimer disease, hypertension treatment, omega-3 fatty acid supplementation, physical activity, and cognitive engagement demonstrate modest potential. Acetylcholinesterase inhibitors are first-line medications for the treatment of Alzheimer disease, and are associated with mild improvements in cognitive function, behavior, and activities of daily living; however, the clinical relevance of these effects is unclear. The most common adverse effects of acetylcholinesterase inhibitors are nausea, vomiting, diarrhea, dizziness, confusion, and cardiac arrhythmias. Short-term use of the N-methyl-D-aspartate receptor antagonist memantine can modestly improve measures of cognition, behavior, and activities of daily living in patients with moderate to severe Alzheimer disease. Memantine can also be used in combination with acetylcholinesterase inhibitors. Memantine is generally well tolerated, but whether its benefits produce clinically meaningful improvement is controversial. Although N-methyl-D-aspartate receptor antagonists and acetylcholinesterase inhibitors can slow the progression of Alzheimer disease, no pharmacologic agents can reverse the progression. Atypical antipsychotics can improve some behavioral symptoms, but have been associated with increased mortality rates in older patients with dementia. There is conflicting evidence about the benefit of selegiline, testosterone, and ginkgo for the treatment of Alzheimer disease. There is no evidence supporting the beneficial effects of vitamin E, estrogen, or nonsteroidal anti-inflammatory drug therapy.

  4. Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer's and Parkinson's diseases.

    PubMed

    Chen, Xuesong; Ghribi, Othman; Geiger, Jonathan D

    2010-01-01

    Sporadic Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common neurodegenerative diseases and as such they represent major public health problems. Finding effective treatments for AD and PD represents an unmet and elusive goal largely because these diseases are chronic and progressive, and have a complicated and ill-understood pathogenesis. Although the underlying mechanisms are not fully understood, caffeine, the most commonly ingested psychoactive drug in the world, has been shown in human and animal studies to be protective against AD and PD. One mechanism implicated in the pathogenesis of AD and PD is blood-brain barrier (BBB) dysfunction and we reported recently that caffeine exerts protective effects against AD and PD at least in part by keeping the BBB intact. The present review focuses on the role of BBB dysfunction in the pathogenesis of AD and PD, caffeine's protective effects against AD and PD, and potential mechanisms whereby caffeine protects against BBB leakage.

  5. Breakdown of brain connectivity between normal aging and Alzheimer's disease: a structural k-core network analysis.

    PubMed

    Daianu, Madelaine; Jahanshad, Neda; Nir, Talia M; Toga, Arthur W; Jack, Clifford R; Weiner, Michael W; Thompson, Paul M

    2013-01-01

    Brain connectivity analyses show considerable promise for understanding how our neural pathways gradually break down in aging and Alzheimer's disease (AD). Even so, we know very little about how the brain's networks change in AD, and which metrics are best to evaluate these changes. To better understand how AD affects brain connectivity, we analyzed anatomical connectivity based on 3-T diffusion-weighted images from 111 subjects (15 with AD, 68 with mild cognitive impairment, and 28 healthy elderly; mean age, 73.7±7.6 SD years). We performed whole brain tractography based on the orientation distribution functions, and compiled connectivity matrices showing the proportions of detected fibers interconnecting 68 cortical regions. We computed a variety of measures sensitive to anatomical network topology, including the structural backbone--the so-called "k-core"--of the anatomical network, and the nodal degree. We found widespread network disruptions, as connections were lost in AD. Among other connectivity measures showing disease effects, network nodal degree, normalized characteristic path length, and efficiency decreased with disease, while normalized small-worldness increased, in the whole brain and left and right hemispheres individually. The normalized clustering coefficient also increased in the whole brain; we discuss factors that may cause this effect. The proportions of fibers intersecting left and right cortical regions were asymmetrical in all diagnostic groups. This asymmetry may intensify as disease progressed. Connectivity metrics based on the k-core may help understand brain network breakdown as cognitive impairment increases, revealing how degenerative diseases affect the human connectome.

  6. Investigating Focal Connectivity Deficits in Alzheimer's Disease Using Directional Brain Networks Derived from Resting-State fMRI

    PubMed Central

    Zhao, Sinan; Rangaprakash, D; Venkataraman, Archana; Liang, Peipeng; Deshpande, Gopikrishna

    2017-01-01

    Connectivity analysis of resting-state fMRI has been widely used to identify biomarkers of Alzheimer's disease (AD) based on brain network aberrations. However, it is not straightforward to interpret such connectivity results since our understanding of brain functioning relies on regional properties (activations and morphometric changes) more than connections. Further, from an interventional standpoint, it is easier to modulate the activity of regions (using brain stimulation, neurofeedback, etc.) rather than connections. Therefore, we employed a novel approach for identifying focal directed connectivity deficits in AD compared to healthy controls. In brief, we present a model of directed connectivity (using Granger causality) that characterizes the coupling among different regions in healthy controls and Alzheimer's disease. We then characterized group differences using a (between-subject) generative model of pathology, which generates latent connectivity variables that best explain the (within-subject) directed connectivity. Crucially, our generative model at the second (between-subject) level explains connectivity in terms of local or regionally specific abnormalities. This allows one to explain disconnections among multiple regions in terms of regionally specific pathology; thereby offering a target for therapeutic intervention. Two foci were identified, locus coeruleus in the brain stem and right orbitofrontal cortex. Corresponding disrupted connectivity network associated with the foci showed that the brainstem is the critical focus of disruption in AD. We further partitioned the aberrant connectomic network into four unique sub-networks, which likely leads to symptoms commonly observed in AD. Our findings suggest that fMRI studies of AD, which have been largely cortico-centric, could in future investigate the role of brain stem in AD. PMID:28729831

  7. p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer's disease.

    PubMed

    Yao, X-Q; Jiao, S-S; Saadipour, K; Zeng, F; Wang, Q-H; Zhu, C; Shen, L-L; Zeng, G-H; Liang, C-R; Wang, J; Liu, Y-H; Hou, H-Y; Xu, X; Su, Y-P; Fan, X-T; Xiao, H-L; Lue, L-F; Zeng, Y-Q; Giunta, B; Zhong, J-H; Walker, D G; Zhou, H-D; Tan, J; Zhou, X-F; Wang, Y-J

    2015-11-01

    In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.

  8. p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer's disease

    PubMed Central

    Yao, X-Q; Jiao, S-S; Saadipour, K; Zeng, F; Wang, Q-H; Zhu, C; Shen, L-L; Zeng, G-H; Liang, C-R; Wang, J; Liu, Y-H; Hou, H-Y; Xu, X; Su, Y-P; Fan, X-T; Xiao, H-L; Lue, L-F; Zeng, Y-Q; Giunta, B; Zhong, J-H; Walker, D G; Zhou, H-D; Tan, J; Zhou, X-F; Wang, Y-J

    2015-01-01

    In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD. PMID:25917367

  9. Proteomic analysis of neurons microdissected from formalin-fixed, paraffin-embedded Alzheimer's disease brain tissue.

    PubMed

    Drummond, Eleanor S; Nayak, Shruti; Ueberheide, Beatrix; Wisniewski, Thomas

    2015-10-21

    The vast majority of human tissue specimens are formalin-fixed, paraffin embedded (FFPE) archival samples, making this type of tissue a potential gold mine for medical research. It is now accepted that proteomics can be done using FFPE tissue and can generate similar results as snap-frozen tissue. However, the current methodology requires a large amount of starting protein, limiting the questions that can be answered in these types of proteomics studies and making cell-type specific proteomics studies difficult. Cell-type specific proteomics has the potential to greatly enhance understanding of cell functioning in both normal and disease states. Therefore, here we describe a new method that allows localized proteomics on individual cell populations isolated from FFPE tissue sections using laser capture microdissection. To demonstrate this technique we microdissected neurons from archived tissue blocks of the temporal cortex from patients with Alzheimer's disease. Using this method we identified over 400 proteins in microdissected neurons; on average 78% that were neuronal and 50% that were associated with Alzheimer's disease. Therefore, this technique is able to provide accurate and meaningful data and has great potential for any future study that wishes to perform localized proteomics using very small amounts of archived FFPE tissue.

  10. Fungal infection in patients with Alzheimer's disease.

    PubMed

    Alonso, Ruth; Pisa, Diana; Marina, Ana Isabel; Morato, Esperanza; Rábano, Alberto; Carrasco, Luis

    2014-01-01

    Alzheimer's disease is a progressive neurodegenerative disorder that leads to dementia mainly among the elderly. This disease is characterized by the presence in the brain of amyloid plaques and neurofibrillary tangles that provoke neuronal cell death, vascular dysfunction, and inflammatory processes. In the present work, we have analyzed the existence of fungal infection in Alzheimer's disease patients. A proteomic analysis provides compelling evidence for the existence of fungal proteins in brain samples from Alzheimer's disease patients. Furthermore, PCR analysis reveals a variety of fungal species in these samples, dependent on the patient and the tissue tested. DNA sequencing demonstrated that several fungal species can be found in brain samples. Together, these results show that fungal macromolecules can be detected in brain from Alzheimer's disease patients. To our knowledge these findings represent the first evidence that fungal infection is detectable in brain samples from Alzheimer's disease patients. The possibility that this may represent a risk factor or may contribute to the etiological cause of Alzheimer's disease is discussed.

  11. Alzheimer disease and its management: a review.

    PubMed

    Samanta, Malay K; Wilson, B; Santhi, K; Kumar, K P Sampath; Suresh, B

    2006-01-01

    Alzheimer disease is a progressive degenerative disorder of the brain characterized by a slow, progressive decline in cognitive function and behavior. As the disease advances, persons with Alzheimer disease have tough time with daily usage of things like using the phone, cooking, handling money, or driving the car. The disease is more common in elder population. It is estimated that Alzheimer disease affects 15 million people worldwide and approximately 4 million Americans. The clinical features of Alzheimer disease overlaps with common signs of aging, and other types of dementia, hence the diagnosis remains difficult. The neuropathologic hallmarks of the disorder are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. Drugs approved for treating Alzheimer disease include acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonist. Caregivers not getting adequate information about Alzheimer disease may believe that nothing can be done to manage its symptoms. Understanding the extent of Alzheimer disease related knowledge can assist disease management that result in improved disease management and reduced care costs. This article attempts to focus on some of the important recent developments in understanding and management of Alzheimer disease.

  12. Brain in situ hybridization maps as a source for reverse-engineering transcriptional regulatory networks: Alzheimer's disease insights

    SciTech Connect

    Acquaah-Mensah, George K.; Taylor, Ronald C.

    2016-07-01

    Microarray data have been a valuable resource for identifying transcriptional regulatory relationships among genes. As an example, brain region-specific transcriptional regulatory events have the potential of providing etiological insights into Alzheimer Disease (AD). However, there is often a paucity of suitable brain-region specific expression data obtained via microarrays or other high throughput means. The Allen Brain Atlas in situ hybridization (ISH) data sets (Jones et al., 2009) represent a potentially valuable alternative source of high-throughput brain region-specific gene expression data for such purposes. In this study, Allen BrainAtlasmouse ISH data in the hippocampal fields were extracted, focusing on 508 genes relevant to neurodegeneration. Transcriptional regulatory networkswere learned using three high-performing network inference algorithms. Only 17% of regulatory edges from a network reverse-engineered based on brain region-specific ISH data were also found in a network constructed upon gene expression correlations inmousewhole brain microarrays, thus showing the specificity of gene expression within brain sub-regions. Furthermore, the ISH data-based networks were used to identify instructive transcriptional regulatory relationships. Ncor2, Sp3 and Usf2 form a unique three-party regulatory motif, potentially affecting memory formation pathways. Nfe2l1, Egr1 and Usf2 emerge among regulators of genes involved in AD (e.g. Dhcr24, Aplp2, Tia1, Pdrx1, Vdac1, andSyn2). Further, Nfe2l1, Egr1 and Usf2 are sensitive to dietary factors and could be among links between dietary influences and genes in the AD etiology. Thus, this approach of harnessing brain region-specific ISH data represents a rare opportunity for gleaning unique etiological insights for diseases such as AD.

  13. Brain in situ hybridization maps as a source for reverse-engineering transcriptional regulatory networks: Alzheimer's disease insights.

    PubMed

    Acquaah-Mensah, George K; Taylor, Ronald C

    2016-07-15

    Microarray data have been a valuable resource for identifying transcriptional regulatory relationships among genes. As an example, brain region-specific transcriptional regulatory events have the potential of providing etiological insights into Alzheimer Disease (AD). However, there is often a paucity of suitable brain-region specific expression data obtained via microarrays or other high throughput means. The Allen Brain Atlas in situ hybridization (ISH) data sets (Jones et al., 2009) represent a potentially valuable alternative source of high-throughput brain region-specific gene expression data for such purposes. In this study, Allen Brain Atlas mouse ISH data in the hippocampal fields were extracted, focusing on 508 genes relevant to neurodegeneration. Transcriptional regulatory networks were learned using three high-performing network inference algorithms. Only 17% of regulatory edges from a network reverse-engineered based on brain region-specific ISH data were also found in a network constructed upon gene expression correlations in mouse whole brain microarrays, thus showing the specificity of gene expression within brain sub-regions. Furthermore, the ISH data-based networks were used to identify instructive transcriptional regulatory relationships. Ncor2, Sp3 and Usf2 form a unique three-party regulatory motif, potentially affecting memory formation pathways. Nfe2l1, Egr1 and Usf2 emerge among regulators of genes involved in AD (e.g. Dhcr24, Aplp2, Tia1, Pdrx1, Vdac1, and Syn2). Further, Nfe2l1, Egr1 and Usf2 are sensitive to dietary factors and could be among links between dietary influences and genes in the AD etiology. Thus, this approach of harnessing brain region-specific ISH data represents a rare opportunity for gleaning unique etiological insights for diseases such as AD.

  14. Graded perturbations of metabolism in multiple regions of human brain in Alzheimer's disease: Snapshot of a pervasive metabolic disorder

    PubMed Central

    Xu, Jingshu; Begley, Paul; Church, Stephanie J.; Patassini, Stefano; Hollywood, Katherine A.; Jüllig, Mia; Curtis, Maurice A.; Waldvogel, Henry J.; Faull, Richard L.M.; Unwin, Richard D.; Cooper, Garth J.S.

    2016-01-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disorder that displays pathological characteristics including senile plaques and neurofibrillary tangles. Metabolic defects are also present in AD-brain: for example, signs of deficient cerebral glucose uptake may occur decades before onset of cognitive dysfunction and tissue damage. There have been few systematic studies of the metabolite content of AD human brain, possibly due to scarcity of high-quality brain tissue and/or lack of reliable experimental methodologies. Here we sought to: 1) elucidate the molecular basis of metabolic defects in human AD-brain; and 2) identify endogenous metabolites that might guide new approaches for therapeutic intervention, diagnosis or monitoring of AD. Brains were obtained from nine cases with confirmed clinical/neuropathological AD and nine controls matched for age, sex and post-mortem delay. Metabolite levels were measured in post-mortem tissue from seven regions: three that undergo severe neuronal damage (hippocampus, entorhinal cortex and middle-temporal gyrus); three less severely affected (cingulate gyrus, sensory cortex and motor cortex); and one (cerebellum) that is relatively spared. We report a total of 55 metabolites that were altered in at least one AD-brain region, with different regions showing alterations in between 16 and 33 metabolites. Overall, we detected prominent global alterations in metabolites from several pathways involved in glucose clearance/utilization, the urea cycle, and amino-acid metabolism. The finding that potentially toxigenic molecular perturbations are widespread throughout all brain regions including the cerebellum is consistent with a global brain disease process rather than a localized effect of AD on regional brain metabolism. PMID:26957286

  15. Region-specific metabolic alterations in the brain of the APP/PS1 transgenic mice of Alzheimer's disease.

    PubMed

    González-Domínguez, Raúl; García-Barrera, Tamara; Vitorica, Javier; Gómez-Ariza, José Luis

    2014-12-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide, but its etiology is still not completely understood. The identification of underlying pathological mechanisms is becoming increasingly important for the discovery of biomarkers and therapies, for which metabolomics presents a great potential. In this work, we studied metabolic alterations in different brain regions of the APP/PS1 mice by using a high-throughput metabolomic approach based on the combination of gas chromatography-mass spectrometry and ultra-high performance liquid chromatography-mass spectrometry. Multivariate statistics showed that metabolomic perturbations are widespread, affecting mainly the hippocampus and the cortex, but are also present in regions not primarily associated with AD such as the striatum, cerebellum and olfactory bulbs. Multiple metabolic pathways could be linked to the development of AD-type disorders in this mouse model, including abnormal purine metabolism, bioenergetic failures, dyshomeostasis of amino acids and disturbances in membrane lipids, among others. Interestingly, region-specific alterations were observed for some of the potential markers identified, associated with abnormal fatty acid composition of phospholipids and sphingomyelins, or differential regulation of neurotransmitter amino acids (e.g. glutamate, glycine, serine, N-acetyl-aspartate), not previously described to our knowledge. Therefore, these findings could provide a new insight into brain pathology in Alzheimer's disease.

  16. MS4A6A genotypes are associated with the atrophy rates of Alzheimer's disease related brain structures

    PubMed Central

    Tan, Lin; Wang, Hui-Fu; Wan, Yu; Sun, Fu-Rong; Tan, Chen-Chen; Yu, Jin-Tai; Tan, Lan

    2016-01-01

    Membrane-spanning 4-domains, subfamily A, member 6A (MS4A6A) has been identified as susceptibility loci of Alzheimer's disease (AD) by several recent genome-wide association studies (GWAS), whereas little is known about the potential roles of these variants in the brain structure and function of AD. In this study, we included a total of 812 individuals from the Alzheimer's disease Neuroimaging Initiative (ADNI) database. Using multiple linear regression models, we found MS4A6A genotypes were strongly related to atrophy rate of left middle temporal (rs610932: Pc = 0.017, rs7232: Pc = 0.022), precuneus (rs610932: Pc = 0.015) and entorhinal (rs610932, Pc = 0.022) on MRI in the entire group. In the subgroup analysis, MS4A6A SNPs were significantly accerlated the percentage of volume loss of middle temporal, precuneus and entorhinal, especially in the MCI subgroup. These findings reveal that MS4A6A genotypes affect AD specific brain structures which supported the possible role of MS4A6A polymorphisms in influencing AD-related neuroimaging phenotypes. PMID:27244883

  17. NMF-SVM based CAD tool applied to functional brain images for the diagnosis of Alzheimer's disease.

    PubMed

    Padilla, P; López, M; Górriz, J M; Ramírez, J; Salas-González, D; Álvarez, I

    2012-02-01

    This paper presents a novel computer-aided diagnosis (CAD) technique for the early diagnosis of the Alzheimer's disease (AD) based on nonnegative matrix factorization (NMF) and support vector machines (SVM) with bounds of confidence. The CAD tool is designed for the study and classification of functional brain images. For this purpose, two different brain image databases are selected: a single photon emission computed tomography (SPECT) database and positron emission tomography (PET) images, both of them containing data for both Alzheimer's disease (AD) patients and healthy controls as a reference. These databases are analyzed by applying the Fisher discriminant ratio (FDR) and nonnegative matrix factorization (NMF) for feature selection and extraction of the most relevant features. The resulting NMF-transformed sets of data, which contain a reduced number of features, are classified by means of a SVM-based classifier with bounds of confidence for decision. The proposed NMF-SVM method yields up to 91% classification accuracy with high sensitivity and specificity rates (upper than 90%). This NMF-SVM CAD tool becomes an accurate method for SPECT and PET AD image classification.

  18. T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer's Disease: Potential Pools of New Biomarkers

    PubMed Central

    Mietelska-Porowska, Anna

    2017-01-01

    Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the main cause of dementia. The disease is among the leading medical concerns of the modern world, because only symptomatic therapies are available, and no reliable, easily accessible biomarkers exist for AD detection and monitoring. Therefore extensive research is conducted to elucidate the mechanisms of AD pathogenesis, which seems to be heterogeneous and multifactorial. Recently much attention has been given to the neuroinflammation and activation of glial cells in the AD brain. Reports also highlighted the proinflammatory role of T lymphocytes infiltrating the AD brain. However, in AD molecular and cellular alterations involving T cells and immune mediators occur not only in the brain, but also in the blood and the cerebrospinal fluid (CSF). Here we review alterations concerning T lymphocytes and related immune mediators in the AD brain, CSF, and blood and the mechanisms by which peripheral T cells cross the blood brain barrier and the blood-CSF barrier. This knowledge is relevant for better AD therapies and for identification of novel biomarkers for improved AD diagnostics in the blood and the CSF. The data will be reviewed with the special emphasis on possibilities for development of AD biomarkers. PMID:28293644

  19. Intra-Arterially Delivered Mesenchymal Stem Cells Are Not Detected in the Brain Parenchyma in an Alzheimer's Disease Mouse Model.

    PubMed

    Lee, Na Kyung; Yang, Jehoon; Chang, Eun Hyuk; Park, Sang Eon; Lee, Jeongmin; Choi, Soo Jin; Oh, Wonil; Chang, Jong Wook; Na, Duk L

    2016-01-01

    Mesenchymal stem cells (MSCs) have a promising role as a therapeutic agent for neurodegenerative diseases such as Alzheimer's disease (AD). Prior studies suggested that intra-arterially administered MSCs are engrafted into the brain in stroke or traumatic brain injury (TBI) animal models. However, a controversial standpoint exists in terms of the integrity of the blood brain barrier (BBB) in transgenic AD mice. The primary goal of this study was to explore the feasibility of delivering human umbilical cord-blood derived mesenchymal stem cells (hUCB-MSCs) into the brains of non-transgenic WT (C3H/C57) and transgenic AD (APP/PS1) mice through the intra-arterial (IA) route. Through two experiments, mice were infused with hUCB-MSCs via the right internal carotid artery and were sacrificed at two different time points: 6 hours (experiment 1) or 5 minutes (experiment 2) after infusion. In both experiments, no cells were detected in the brain parenchyma while MSCs were detected in the cerebrovasculature in experiment 2. The results from this study highlight that intra-arterial delivery of MSCs is not the most favorable route to be implemented as a potential therapeutic approach for AD.

  20. Trends in brain oxygenation during mental and physical exercise measured using near-infrared spectroscopy (NIRS): potential for early detection of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Allen, Monica S.; Allen, Jeffery W.; Mikkilineni, Shweta; Liu, Hanli

    2005-04-01

    Motivation: Early diagnosis of Alzheimer's disease (AD) is crucial because symptoms respond best to available treatments in the initial stages of the disease. Recent studies have shown that marked changes in brain oxygenation during mental and physical tasks can be used for noninvasive functional brain imaging to detect Alzheimer"s disease. The goal of our study is to explore the possibility of using near infrared spectroscopy (NIRS) and mapping (NIRM) as a diagnostic tool for AD before the onset of significant morphological changes in the brain. Methods: A 16-channel NIRS brain imager was used to noninvasively measure spatial and temporal changes in cerebral hemodynamics induced during verbal fluency task and physical activity. The experiments involved healthy subjects (n = 10) in the age range of 25+/-5 years. The NIRS signals were taken from the subjects' prefrontal cortex during the activities. Results and Conclusion: Trends of oxygenated and deoxygenated hemoglobin in the prefrontal cortex of the brain were observed. During the mental stimulation, the subjects showed significant increase in oxygenated hemoglobin [HbO2] with a simultaneous decrease in deoxygenated hemoglobin [Hb]. However, physical exercise caused a rise in levels of HbO2 with small variations in Hb. This study basically demonstrates that NIRM taken from the prefrontal cortex of the human brain is sensitive to both mental and physical tasks and holds potential to serve as a diagnostic means for early detection of Alzheimer's disease.

  1. Intranasal delivery of nanoparticle encapsulated tarenflurbil: A potential brain targeting strategy for Alzheimer's disease.

    PubMed

    Muntimadugu, Eameema; Dhommati, Raju; Jain, Anjali; Challa, Venu Gopala Swami; Shaheen, M; Khan, Wahid

    2016-09-20

    Poor brain penetration of tarenflurbil (TFB) was one of the major reasons for its failure in phase III clinical trials conducted on Alzheimer's patients. Thus there is a tremendous need of developing efficient delivery systems for TFB. This study was designed with the aim of improving drug delivery to brain through intranasally delivered nanocarriers. TFB was loaded into two different nanocarriers i.e., poly (lactide-co-glycolide) nanoparticles (TFB-NPs) and solid lipid nanoparticles (TFB-SLNs). Particle size of both the nanocarriers (<200nm) as determined by dynamic light scattering technique and transmission electron microscopy, assured transcellular transport across olfactory axons whose diameter was ≈200nm and then paving a direct path to brain. TFB-NPs and TFB-SLNs resulted in 64.11±2.21% and 57.81±5.32% entrapment efficiencies respectively which again asserted protection of drug from chemical and biological degradation in nasal cavity. In vitro release studies proved the sustained release of TFB from TFB-NPs and TFB-SLNs in comparison with pure drug, indicating prolonged residence times of drug at targeting site. Pharmacokinetics suggested improved circulation behavior of nanoparticles and the absolute bioavailabilities followed this order: TFB-NPs (i.n.)>TFB-SLNs (i.n.)>TFB solution (i.n.)>TFB suspension (oral). Brain targeting efficiency was determined in terms of %drug targeting efficiency (%DTE) and drug transport percentage (DTP). The higher %DTE (287.24) and DTP (65.18) were observed for TFB-NPs followed by TFB-SLNs (%DTE: 183.15 and DTP: 45.41) among all other tested groups. These encouraging results proved that therapeutic concentrations of TFB could be transported directly to brain via olfactory pathway after intranasal administration of polymeric and lipidic nanoparticles. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. [Biomarkers in Alzheimer's disease].

    PubMed

    García-Ribas, G; López-Sendón Moreno, J L; García-Caldentey, J

    2014-04-01

    The new diagnostic criteria for Alzheimer's disease (AD) include brain imaging and cerebrospinal fluid (CSF) biomarkers, with the aim of increasing the certainty of whether a patient has an ongoing AD neuropathologic process or not. Three CSF biomarkers, Aß42, total tau, and phosphorylated tau, reflect the core pathological features of AD. It is already known that these pathological processes of AD starts decades before the first symptoms, so these biomarkers may provide means of early disease detection. At least three stages of AD could be identified: preclinical AD, mild cognitive impairment due to AD, and dementia due to AD. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review the actual research on blood-based biomarkers. Recent studies on healthy elderly subjects and on carriers of dominantly inherited AD mutations have also found biomarker changes that allow separate groups in these preclinical stages. These studies may aid for segregate populations in clinical trials and objectively evaluate if there are changes over the pathological processes of AD. Limits to widespread use of CSF biomarkers, apart from the invasive nature of the process itself, is the higher coefficient of variation for the analyses between centres. It requires strict pre-analytical and analytical procedures that may make feasible multi-centre studies and global cut-off points for the different stages of AD.

  3. Neuronutrition and Alzheimer's Disease

    PubMed Central

    Ramesh, Balenahalli N.; Rao, T.S. Sathyanarayana; Prakasam, Annamalai; Sambamurti, Kumar; Rao, K.S. Jagannatha

    2010-01-01

    Alzheimer's disease (AD) is a complex neurological disorder with several unequivocally identified genetic risk factors. Among the several environmental factors proposed for AD, dietary protective and risk factors have been most compelling. In particular, diets rich in saturated fatty acids and alcohol, and deficient in antioxidants and vitamins appear to promote the onset of the disease, while diets rich in unsaturated fatty acids, vitamins, antioxidants, and wine likely suppress its onset. Evidence suggests that diets rich in polyphenols and some spices suppress the onset of AD by scavenging free radicals and preventing oxidative damage. Metal ions are known to catalyze the production of free radicals and induce mental retardation or dementia. Several studies have also identified metals such as Pb, Fe, Al, Cu and Zn in AD pathogenesis. While specific chelators have been tested for therapy, they have not been very successful probably due to late administration after brain damage has been triggered. Since several dietary polyphenols are known to chelate metals, their routine use may also be protective against the onset of AD. PMID:20308778

  4. Neurogenesis in Alzheimer's disease

    PubMed Central

    Rodríguez, José J; Verkhratsky, Alexei

    2011-01-01

    It is widely acknowledged that neural stem cells generate new neurons through the process of neurogenesis in the adult brain. In mammals, adult neurogenesis occurs in two areas of the CNS: the subventricular zone and the subgranular zone of the dentate gyrus of the hippocampus. The newly generated cells display neuronal morphology, generate action potentials and receive functional synaptic inputs, their properties being equivalent to those of mature neurons. Alzheimer's disease (AD) is the widespread cause of dementia, and is an age-related, progressive and irreversible neurodegenerative disease that results in massive neuronal death and deterioration of cognitive functions. Here, we overview the relations between adult neurogenesis and AD, and try to analyse the controversies in the field. We also summarise recent data obtained in the triple transgenic model of AD that show time- and region-specific impairment of neurogenesis, which may account for the early changes in synaptic plasticity and cognitive impairments that develop prior to gross neurodegenerative alterations and that could underlie new rescue therapies. PMID:21323664

  5. Disrupted Small-World Brain Networks in Moderate Alzheimer's Disease: A Resting-State fMRI Study

    PubMed Central

    Wang, Xiangbin; Liu, Bing; Xi, Qian; Guo, Qihao; Jiang, Hong; Jiang, Tianzi; Wang, Peijun

    2012-01-01

    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. PMID:22457774

  6. Ganglioside metabolism in a transgenic mouse model of Alzheimer's disease: expression of Chol-1α antigens in the brain.

    PubMed

    Ariga, Toshio; Yanagisawa, Makoto; Wakade, Chandramohan; Ando, Susumu; Buccafusco, Jerry J; McDonald, Michael P; Yu, Robert K

    2010-10-04

    The accumulation of Aβ (amyloid β-protein) is one of the major pathological hallmarks in AD (Alzheimer's disease). Gangliosides, sialic acid-containing glycosphingolipids enriched in the nervous system and frequently used as biomarkers associated with the biochemical pathology of neurological disorders, have been suggested to be involved in the initial aggregation of Aβ. In the present study, we have examined ganglioside metabolism in the brain of a double-Tg (transgenic) mouse model of AD that co-expresses mouse/human chimaeric APP (amyloid precursor protein) with the Swedish mutation and human presenilin-1 with a deletion of exon 9. Although accumulation of Aβ was confirmed in the double-Tg mouse brains and sera, no statistically significant change was detected in the concentration and composition of major ganglio-N-tetraosyl-series gangliosides in the double-Tg brain. Most interestingly, Chol-1α antigens (cholinergic neuron-specific gangliosides), such as GT1aα and GQ1bα, which are minor species in the brain, were found to be increased in the double-Tg mouse brain. We interpret that the occurrence of these gangliosides may represent evidence for generation of cholinergic neurons in the AD brain, as a result of compensatory neurogenesis activated by the presence of Aβ.

  7. [Study on distribution of neural stem cells in the brain of Alzheimer disease transgenic mice through caudal vein transplantation].

    PubMed

    Zhan, Yan-qiang; Wang, Fu-rong; Li, Feng-guang; Xing, Bian-zhi; Fang, Xin; Zhang, Su-ming

    2007-07-03

    To observe whether neural stem cells (NSCs) can successfully permeate into the brain through the blood-brain barrier (BBB) of Alzheimer disease (AD) transgenic mice and explore the methods of distribution and migration. NSCs were isolated from 12-day-old fetal mice, cultured, labeled with enhanced green fluorescent protein (eGFP) and then transplanted into 10 AD transgenic mice and normal mice as controls through caudal vein. The mice were killed 48 h, 1 w, 2 w, and 4 w after transplantation respectively. The brains of the mice were made into continual frozen sections, the distribution and migration of the eGFP-labeled NSCs were studied under fluorescence microscope. At different time points after transplantation the eGFP-labeled NSCs were diffusely distributed in the brain: distributed around the blood vessels in the first 48 h, and then migrated gradually towards the hippocampus and cortex until 4 weeks later. There were no obvious abnormal complications occurring after transplantation. NSCs can successfully permeate into the brain through the BBB of AD transgenic mice, and migrate into the brain parenchyma gradually.

  8. Preservation of Neuronal Number Despite Age-Related Cortical Brain Atrophy In Elderly Subjects Without Alzheimer Disease

    PubMed Central

    Freeman, Stefanie H.; Kandel, Ruth; Cruz, Luis; Rozkalne, Anete; Newell, Kathy; Frosch, Matthew P.; Hedley-Whyte, E. Tessa; Locascio, Joseph J.; Lipsitz, Lewis; Hyman, Bradley T.

    2009-01-01

    Cerebral volume loss has long been associated with normal aging but whether this is due to aging itself or to age-related diseases including incipient Alzheimer disease (AD) is uncertain. To understand the changes that occur in the aging brain, we examined the cerebral cortex of 27 normal individuals ranging in age from 56 to 103 years. None fulfilled the criteria for the neuropathological diagnosis of AD or other neurodegenerative disease. Seventeen of the elderly participants had cognitive testing an average of 6.7 months prior to death. We used quantitative approaches to analyze cortical thickness, neuronal number, and density. Frontal and temporal neocortical regions had clear evidence of cortical thinning with age but total neuronal numbers in frontal and temporal neocortical regions remained relatively constant over a 50-year age range. These data suggest that loss of neuronal and dendritic architecture, rather than loss of neurons, underlies neocortical volume loss with increasing age in the absence of AD. PMID:19018241

  9. Smoking is associated with reduced cortical regional gray matter density in brain regions associated with incipient Alzheimer disease.

    PubMed

    Almeida, Osvaldo P; Garrido, Griselda J; Lautenschlager, Nicola T; Hulse, Gary K; Jamrozik, Konrad; Flicker, Leon

    2008-01-01

    The results of observational studies suggest that smoking increases the risk of Alzheimer disease (AD). The authors designed this study to determine if older people who smoke have decreased gray matter density in brain regions associated with incipient AD. The authors recruited 39 pairs (N = 78) of smokers/never-smokers 70 to 83 years of age who were matched for age, sex, education, and handedness. Participants were free of clinically significant cognitive impairment, depression, stroke, or other serious medical conditions. Gray matter density was determined by voxel-based morphometry using statistical parametric mapping of T1-weighted magnetic resonance images. Smokers had decreased gray matter density in the posterior cingulum and precuneus (bilateral), right thalamus, and frontal cortex (bilateral) compared with never-smokers. Smoking is associated with decreased gray matter density in brain regions previously associated with incipient AD. Longitudinal investigations are required to clarify whether these changes are progressive in nature.

  10. APP and PS-1 mutations induce brain oxidative stress independent of dietary cholesterol: implications for Alzheimer's disease.

    PubMed

    Mohmmad Abdul, Hafiz; Wenk, Gary L; Gramling, McGann; Hauss-Wegrzyniak, Beatrice; Butterfield, D Allan

    2004-09-23

    Epidemiological and biochemical studies strongly implicate a role for cholesterol in the pathogenesis of Alzheimer's disease (AD). Mutation in the PS-1 and APP genes, which increases production of the highly amyloidogenic amyloid beta-peptide (Abeta42), is the major cause of familial AD. The AD brain is under significant oxidative stress, including protein oxidation and lipid peroxidation. In the present study, protein oxidation and lipid peroxidation were compared in the brain homogenates from knock-in mice expressing mutant human PS-1 and APP in relation to the intake of dietary cholesterol. The APP and PS-1 mice displayed increased oxidative stress as measured by protein oxidation and lipid peroxidation, independent of dietary cholesterol. These results are discussed with reference to proposed therapeutic strategies of AD.

  11. Altered beta-secretase enzyme kinetics and levels of both BACE1 and BACE2 in the Alzheimer's disease brain.

    PubMed

    Stockley, John H; Ravid, Rivka; O'Neill, Cora

    2006-12-11

    beta-Secretase is the rate limiting enzymatic activity in the production of amyloid-beta peptide, the primary component of senile plaque pathology in Alzheimer's disease (AD). This study performed the first comparative analysis of beta-secretase enzyme kinetics in AD and control brain tissue. Results found V(max) values for beta-secretase to be significantly increased, and K(m) values unchanged in AD temporal cortex compared to matched control temporal cortex. The increased V(max) in AD cases, did not correlate with levels of BACE1, and decreased BACE1 and BACE2 levels correlated with the severity of neurofibrillary pathology (I-VI), and synaptic loss in AD. These results indicate that increased V(max) for beta-secretase is a feature of AD pathogenesis and this increase does not correlate directly with levels of BACE1, the principal beta-secretase in brain.

  12. Potential neuroimaging biomarkers of pathologic brain changes in Mild Cognitive Impairment and Alzheimer's disease: a systematic review.

    PubMed

    Ruan, Qingwei; D'Onofrio, Grazia; Sancarlo, Daniele; Bao, Zhijun; Greco, Antonio; Yu, Zhuowei

    2016-05-16

    Neuroimaging-biomarkers of Mild Cognitive Impairment (MCI) allow an early diagnosis in preclinical stages of Alzheimer's disease (AD). The goal in this paper was to review of biomarkers for Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD), with emphasis on neuroimaging biomarkers. A systematic review was conducted from existing literature that draws on markers and evidence for new measurement techniques of neuroimaging in AD, MCI and non-demented subjects. Selection criteria included: 1) age ≥ 60 years; 2) diagnosis of AD according to NIAAA criteria, 3) diagnosis of MCI according to NIAAA criteria with a confirmed progression to AD assessed by clinical follow-up, and 4) acceptable clinical measures of cognitive impairment, disability, quality of life, and global clinical assessments. Seventy-two articles were included in the review. With the development of new radioligands of neuroimaging, today it is possible to measure different aspects of AD neuropathology, early diagnosis of MCI and AD become probable from preclinical stage of AD to AD dementia and non-AD dementia. The panel of noninvasive neuroimaging-biomarkers reviewed provides a set methods to measure brain structural and functional pathophysiological changes in vivo, which are closely associated with preclinical AD, MCI and non-AD dementia. The dynamic measures of these imaging biomarkers are used to predict the disease progression in the early stages and improve the assessment of therapeutic efficacy in these diseases in future clinical trials.

  13. Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer's disease

    PubMed Central

    Ho, Lap; Ferruzzi, Mario G.; Janle, Elsa M.; Wang, Jun; Gong, Bing; Chen, Tzu-Ying; Lobo, Jessica; Cooper, Bruce; Wu, Qing Li; Talcott, Stephen T.; Percival, Susan S.; Simon, James E.; Pasinetti, Giulio Maria

    2013-01-01

    Epidemiological and preclinical studies indicate that polyphenol intake from moderate consumption of red wines may lower the relative risk for developing Alzheimer's disease (AD) dementia. There is limited information regarding the specific biological activities and cellular and molecular mechanisms by which wine polyphenolic components might modulate AD. We assessed accumulations of polyphenols in the rat brain following oral dosage with a Cabernet Sauvignon red wine and tested brain-targeted polyphenols for potential beneficial AD disease-modifying activities. We identified accumulations of select polyphenolic metabolites in the brain. We demonstrated that, in comparison to vehicle-control treatment, one of the brain-targeted polyphenol metabolites, quercetin-3-O-glucuronide, significantly reduced the generation of β-amyloid (Aβ) peptides by primary neuron cultures generated from the Tg2576 AD mouse model. Another brain-targeted metabolite, malvidin-3-O-glucoside, had no detectable effect on Aβ generation. Moreover, in an in vitro analysis using the photo-induced cross-linking of unmodified proteins (PICUP) technique, we found that quercetin-3-O-glucuronide is also capable of interfering with the initial protein-protein interaction of Aβ1–40 and Aβ1–42 that is necessary for the formation of neurotoxic oligomeric Aβ species. Lastly, we found that quercetin-3-O-glucuronide treatment, compared to vehicle-control treatment, significantly improved AD-type deficits in hippocampal formation basal synaptic transmission and long-term potentiation, possibly through mechanisms involving the activation of the c-Jun N-terminal kinases and the mitogen-activated protein kinase signaling pathways. Brain-targeted quercetin-3-O-glucuronide may simultaneously modulate multiple independent AD disease-modifying mechanisms and, as such, may contribute to the benefits of dietary supplementation with red wines as an effective intervention for AD.—Ho, L., Ferruzzi, M. G

  14. The clinical significance of brain microbleeds in patients with Alzheimer's disease: Preliminary study

    PubMed Central

    Heo, Jae-Hyeok; Im, Dong-Gyu; Lee, Seung-Hyeon; Ahn, Jin-Young

    2016-01-01

    Background: Microbleeds (MBs) are observed frequently in Alzheimer's disease (AD) and suggested to play a crucial role in the pathophysiology, but their clinical significance remains unclear. Materials and Methods: The study recruited 100 patients with AD who were diagnosed at the memory clinic in Seoul Medical Center in 2014. For each patient, baseline characteristics, neuropsychological tests, cerebrovascular risk factors, medial temporal lobe atrophy (MTLA), and severity of small vessel disease (SVD) according to the existence of MBs were evaluated. Results: The prevalence of MBs in patients with AD was 33%. The percentage of male gender, the severity of SVD and MTLA were significantly increased in MB(+) group. The MB(+) group showed more severe MTLA and SVD than MB(−) group. Conclusions: These results suggested that MBs might reflect the burden of amyloid and ischemic vascular pathology. PMID:27994360

  15. β-Amyloid precursor protein: function in stem cell development and Alzheimer's disease brain.

    PubMed

    Small, David H; Hu, Yanling; Bolós, Marta; Dawkins, Edgar; Foa, Lisa; Young, Kaylene M

    2014-01-01

    Stem cell therapy may be a suitable approach for the treatment of many neurodegenerative diseases. However, one major impediment to the development of successful cell-based therapies is our limited understanding of the mechanisms that instruct neural stem cell behaviour, such as proliferation and cell fate specification. The β-amyloid precursor protein (APP) of Alzheimer's disease (AD) may play an important role in neural stem cell proliferation and differentiation. Our recent work shows that in vitro, APP stimulates neural stem or progenitor cell proliferation and neuronal differentiation. The effect on proliferation is mediated by an autocrine factor that we have identified as cystatin C. As cystatin C expression is also reported to inhibit the development of amyloid pathology in APP transgenic mice, our finding has implications for the possible use of cystatin C for the therapy of AD.

  16. Alzheimer's disease markers from structural MRI and FDG-PET brain images

    NASA Astrophysics Data System (ADS)

    Chincarini, Andrea; Bosco, Paolo; Gemme, Gianluca; Morbelli, Silvia; Arnaldi, Dario; Sensi, Francesco; Solano, Ilaria; Amoroso, Nicola; Tangaro, Sabina; Longo, Renata; Squarcia, Sandro; Nobili, Flavio

    2012-11-01

    Despite the widespread use of neuroimaging tools (morphological and functional) in the routine diagnostic of cerebral diseases, the information available by the end user -the clinician- remains largely limited to qualitative visual analysis. This restriction greatly reduces the diagnostic impact of neuroimaging in routine clinical practice and increases the risk of misdiagnosis. In this context, researches are focussing on the development of sophisticated automatic analyses able to extract clinically relevant information from the captured data. The identification of biological markers at early stages of Alzheimer's disease (AD) contributes to diagnostic accuracy and adds prognostic value. However, in spite of recent developments, results of structural and functional imaging studies on predicting conversion to AD are not uniform. We provide here an overview of analysis methods and approaches, discussing their contribution to clinical assessment.

  17. Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment.

    PubMed

    Mattsson, Niklas; Tosun, Duygu; Insel, Philip S; Simonson, Alix; Jack, Clifford R; Beckett, Laurel A; Donohue, Michael; Jagust, William; Schuff, Norbert; Weiner, Michael W

    2014-05-01

    Patients with Alzheimer's disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-β pathology. Using 182 subjects from the Alzheimer's Disease Neuroimaging Initiative we tested associations of amyloid-β with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer's disease with dementia (n = 24). Based on the theory that Alzheimer's disease starts with amyloid-β accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-β-negative controls and -positive subjects in different diagnostic groups, and if amyloid-β had different associations with cerebral blood flow and grey matter volume. Global amyloid-β load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-β load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-β-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-β with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-β being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-β pathology affects cerebral blood flow across the span from controls to

  18. CSF and Brain Indices of Insulin Resistance, Oxidative Stress and Neuro-Inflammation in Early versus Late Alzheimer's Disease.

    PubMed

    Lee, Sarah; Tong, Ming; Hang, Steven; Deochand, Chetram; de la Monte, Suzanne

    2013-10-31

    Alzheimer's disease (AD) is characterized by progressive impairments in cognitive and behavioral functions with deficits in learning, memory and executive reasoning. Growing evidence points toward brain insulin and insulin-like growth factor (IGF) resistance-mediated metabolic derangements as critical etiologic factors in AD. This suggests that indices of insulin/IGF resistance and their consequences, i.e. oxidative stress, neuro-inflammation, and reduced neuronal plasticity, should be included in biomarker panels for AD. Herein, we examine a range of metabolic, inflammatory, stress, and neuronal plasticity related proteins in early AD, late AD, and aged control postmortem brain, postmortem ventricular fluid (VF), and clinical cerebrospinal fluid (CSF) samples. In AD brain, VF, and CSF samples the trends with respect to alterations in metabolic, neurotrophin, and stress indices were similar, but for pro-inflammatory cytokines, the patterns were discordant. With the greater severities of dementia and neurodegeneration, the differences from control were more pronounced for late AD (VF and brain) than early or moderate AD (brain, VF and CSF). The findings suggest that the inclusion of metabolic, neurotrophin, stress biomarkers in AβPP-Aβ+pTau CSF-based panels could provide more information about the status and progression of neurodegeneration, as well as aid in predicting progression from early- to late-stage AD. Furthermore, standardized multi-targeted molecular assays of neurodegeneration could help streamline postmortem diagnoses, including assessments of AD severity and pathology.

  19. Experimental traumatic brain injury induces rapid aggregation and oligomerization of amyloid-beta in an Alzheimer's disease mouse model.

    PubMed

    Washington, Patricia M; Morffy, Nicholas; Parsadanian, Maia; Zapple, David N; Burns, Mark P

    2014-01-01

    Soluble amyloid-beta (Aβ) oligomers are hypothesized to be the pathogenic species in Alzheimer's disease (AD), and increased levels of oligomers in the brain subsequent to traumatic brain injury (TBI) may exacerbate secondary injury pathways and underlie increased risk of developing AD in later life. To determine whether TBI causes Aβ aggregation and oligomerization in the brain, we exposed triple transgenic AD model mice to controlled cortical impact injury and measured levels of soluble, insoluble, and oligomeric Aβ by enzyme-linked immunosorbent assay (ELISA) at 1, 3, and 7 days postinjury. TBI rapidly increased levels of both soluble and insoluble Aβ40 and Aβ42 in the injured cortex at 1 day postinjury. We confirmed previous findings that identified damaged axons as a major site of Aβ accumulation using both immunohistochemistry and biochemistry. We also report that soluble Aβ oligomers were significantly increased in the injured cortex, as demonstrated by both ELISA and Western blot. Interestingly, the mouse brain is able to rapidly clear trauma-induced Aβ, with both soluble and insoluble Aβ species returning to sham levels by 7 days postinjury. In conclusion, we demonstrate that TBI causes acute accumulation and aggregation of Aβ in the brain, including the formation of low- and high-molecular-weight Aβ oligomers. The formation and aggregation of Aβ into toxic species acutely after injury may play a role in secondary injury cascades after trauma and, chronically, may contribute to increased risk of developing AD in later life.

  20. P3 beta-amyloid peptide has a unique and potentially pathogenic immunohistochemical profile in Alzheimer's disease brain.

    PubMed Central

    Higgins, L. S.; Murphy, G. M.; Forno, L. S.; Catalano, R.; Cordell, B.

    1996-01-01

    The presence of beta-amyloid in brain tissue is characteristic of Alzheimer's disease (AD). A naturally occurring derivative of the beta-amyloid peptide, p3, possesses all of the structural determinants required for fibril assembly and neurotoxicity. p3-specific antibodies were used to examine the distribution of this peptide in brain. p3 reactivity was absent or sparse in aged non-AD brains but was prevalent in selected areas of AD brain in diffuse deposits and in a subset of dystrophic neurites. p3-reactive dystrophic neurites were found both independent in the neuropil and associated with plaques. Little or no reactivity was observed to amyloid cores in classical plaques or to amyloid in the cerebral vasculature. The exclusive appearance of p3 reactivity in AD brain plus the selective localization of p3 reactivity to abnormal structures in the temporal lobe limbic system suggests that p3 may be a contributing factor to AD pathology. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8701997

  1. Experimental Traumatic Brain Injury Induces Rapid Aggregation and Oligomerization of Amyloid-Beta in an Alzheimer's Disease Mouse Model

    PubMed Central

    Washington, Patricia M.; Morffy, Nicholas; Parsadanian, Maia; Zapple, David N.

    2014-01-01

    Abstract Soluble amyloid-beta (Aβ) oligomers are hypothesized to be the pathogenic species in Alzheimer's disease (AD), and increased levels of oligomers in the brain subsequent to traumatic brain injury (TBI) may exacerbate secondary injury pathways and underlie increased risk of developing AD in later life. To determine whether TBI causes Aβ aggregation and oligomerization in the brain, we exposed triple transgenic AD model mice to controlled cortical impact injury and measured levels of soluble, insoluble, and oligomeric Aβ by enzyme-linked immunosorbent assay (ELISA) at 1, 3, and 7 days postinjury. TBI rapidly increased levels of both soluble and insoluble Aβ40 and Aβ42 in the injured cortex at 1 day postinjury. We confirmed previous findings that identified damaged axons as a major site of Aβ accumulation using both immunohistochemistry and biochemistry. We also report that soluble Aβ oligomers were significantly increased in the injured cortex, as demonstrated by both ELISA and Western blot. Interestingly, the mouse brain is able to rapidly clear trauma-induced Aβ, with both soluble and insoluble Aβ species returning to sham levels by 7 days postinjury. In conclusion, we demonstrate that TBI causes acute accumulation and aggregation of Aβ in the brain, including the formation of low- and high-molecular-weight Aβ oligomers. The formation and aggregation of Aβ into toxic species acutely after injury may play a role in secondary injury cascades after trauma and, chronically, may contribute to increased risk of developing AD in later life. PMID:24050316

  2. The proteins BACE1 and BACE2 and beta-secretase activity in normal and Alzheimer's disease brain.

    PubMed

    Stockley, J H; O'Neill, C

    2007-06-01

    The insidious progression of AD (Alzheimer's disease) is believed to be linked closely to the production, accumulation and aggregation of the approximately 4.5 kDa protein fragment called Abeta (amyloid beta-peptide). Abeta is produced by sequential cleavage of the amyloid precursor protein by two enzymes referred to as beta- and gamma-secretase. beta-Secretase is of central importance, as it catalyses the rate-limiting step in the production of Abeta and was identified 7 years ago as BACE1 (beta-site APP-cleaving enzyme 1). Soon afterwards, its homologue BACE2 was discovered, and both proteins represent a new subclass of the aspartyl protease family. Studies examining the regulation and function of beta-secretase in the normal and AD brain are central to the understanding of excessive production of Abeta in AD, and in targeting and normalizing this beta-secretase process if it has gone awry in the disease. Several reports indicate this, showing increased beta-secretase activity in AD, with recent findings by our group showing changes in beta-secretase enzyme kinetics in AD brain caused by an increased V(max). This article gives a brief review of studies which have examined BACE1 protein levels and beta-secretase activity in control and AD brain, considering further the expression of BACE2 in the human brain.

  3. Astrocytic Disruption in Traumatic Brain Injury and Alzheimer’s Disease

    DTIC Science & Technology

    2014-10-01

    AWARD NUMBER: W81XWH-13-1-0243 TITLE: Astrocytic Disruption in Traumatic Brain Injury and Alzheimer’s Disease PRINCIPAL INVESTIGATOR: John...Unlimited The views, opinions and/or findings contained in this report are those of the author( s ) and should not be construed as an official Department of...Disruption in Traumatic Brain Injury and Alzheimer’s Disease 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-13-1-0243 5c. PROGRAM ELEMENT NUMBER

  4. Perturbed iron distribution in Alzheimer's disease serum, cerebrospinal fluid, and selected brain regions: a systematic review and meta-analysis.

    PubMed

    Tao, Yunlong; Wang, Yu; Rogers, Jack T; Wang, Fudi

    2014-01-01

    The homeostasis and physiological role of iron in Alzheimer's disease (AD) has been debated for decades. Overall, it has been difficult to reach a consensus to prove marked disease-associated changes in the iron content of the AD brain, blood, or cerebrospinal fluid (CSF). We sought to contribute to resolve this issue by quantifying the iron content in serum, CSF, and sub-regions of the AD brain. We conducted a comprehensive systematic meta-analysis and review of multiple observational studies till October 2013 that investigated the iron content in AD serum, CSF, or brain tissue. 2,556 publications were screened. Forty-three eligible studies with 1,813 AD patients and 2,401 healthy controls were identified. Twenty-one studies investigated the serum iron in AD while seven and nineteen studies investigated the CSF iron and various brain regions iron respectively. Our meta-analysis showed that serum iron was significant lower in AD than healthy controls. CSF iron appeared not to be affected by AD although more studies are required due to the relative small number of CSF studies reported to date. We critically analyzed iron content in twelve selective brain regions by separated meta-analyses using cross-referenced statistical methods. We found that eight specific brain regions had higher iron concentrations that correlated with the clinical diagnosis of AD in a statistically validated manner. These data provided rigorous statistical support for the model that iron homeostasis was changed in AD patients, including the finding of lower iron in their serum and evidence for iron overload in several specific brain regions.

  5. The mechanical cause of age-related dementia (Alzheimer's disease): the brain is destroyed by the pulse.

    PubMed

    Stone, Jonathan; Johnstone, Daniel M; Mitrofanis, John; O'Rourke, Michael

    2015-01-01

    This review traces evidence that age-related dementia (Alzheimer's disease) results from the destructive impact of the pulse on cerebral vasculature. Evidence is reviewed that the neuropathology of the dementia is caused by the breakdown of small cerebral vessels (silent microbleeds), that the microbleeds result from pulse-induced damage to the cerebral vessels, and that pulse becomes increasingly destructive with age, because of the age-related stiffening of the aorta and great arteries, which causes an increase in the intensity of the pressure pulse. Implications for therapy are discussed, and evidence is reviewed that pulse-induced destruction of the brain, and of another highly vascular organ, the kidney, are becoming the default forms of death, the way we die if we survive the infections, cardiovascular disease, and malignancies, which still, for a decreasing minority, inflict the tragedy of early death.

  6. Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer's disease.

    PubMed

    Ho, Lap; Ferruzzi, Mario G; Janle, Elsa M; Wang, Jun; Gong, Bing; Chen, Tzu-Ying; Lobo, Jessica; Cooper, Bruce; Wu, Qing Li; Talcott, Stephen T; Percival, Susan S; Simon, James E; Pasinetti, Giulio Maria

    2013-02-01

    Epidemiological and preclinical studies indicate that polyphenol intake from moderate consumption of red wines may lower the relative risk for developing Alzheimer's disease (AD) dementia. There is limited information regarding the specific biological activities and cellular and molecular mechanisms by which wine polyphenolic components might modulate AD. We assessed accumulations of polyphenols in the rat brain following oral dosage with a Cabernet Sauvignon red wine and tested brain-targeted polyphenols for potential beneficial AD disease-modifying activities. We identified accumulations of select polyphenolic metabolites in the brain. We demonstrated that, in comparison to vehicle-control treatment, one of the brain-targeted polyphenol metabolites, quercetin-3-O-glucuronide, significantly reduced the generation of β-amyloid (Aβ) peptides by primary neuron cultures generated from the Tg2576 AD mouse model. Another brain-targeted metabolite, malvidin-3-O-glucoside, had no detectable effect on Aβ generation. Moreover, in an in vitro analysis using the photo-induced cross-linking of unmodified proteins (PICUP) technique, we found that quercetin-3-O-glucuronide is also capable of interfering with the initial protein-protein interaction of Aβ(1-40) and Aβ(1-42) that is necessary for the formation of neurotoxic oligomeric Aβ species. Lastly, we found that quercetin-3-O-glucuronide treatment, compared to vehicle-control treatment, significantly improved AD-type deficits in hippocampal formation basal synaptic transmission and long-term potentiation, possibly through mechanisms involving the activation of the c-Jun N-terminal kinases and the mitogen-activated protein kinase signaling pathways. Brain-targeted quercetin-3-O-glucuronide may simultaneously modulate multiple independent AD disease-modifying mechanisms and, as such, may contribute to the benefits of dietary supplementation with red wines as an effective intervention for AD.

  7. Synchronizing an aging brain: can entraining circadian clocks by food slow Alzheimer's disease?

    PubMed

    Kent, Brianne A

    2014-01-01

    Alzheimer's disease (AD) is a global epidemic. Unfortunately, we are still without effective treatments or a cure for this disease, which is having devastating consequences for patients, their families, and societies around the world. Until effective treatments are developed, promoting overall health may hold potential for delaying the onset or preventing neurodegenerative diseases such as AD. In particular, chronobiological concepts may provide a useful framework for identifying the earliest signs of age-related disease as well as inexpensive and noninvasive methods for promoting health. It is well reported that AD is associated with disrupted circadian functioning to a greater extent than normal aging. However, it is unclear if the central circadian clock (i.e., the suprachiasmatic nucleus) is dysfunctioning, or whether the synchrony between the central and peripheral clocks that control behavior and metabolic processes are becoming uncoupled. Desynchrony of rhythms can negatively affect health, increasing morbidity and mortality in both animal models and humans. If the uncoupling of rhythms is contributing to AD progression or exacerbating symptoms, then it may be possible to draw from the food-entrainment literature to identify mechanisms for re-synchronizing rhythms to improve overall health and reduce the severity of symptoms. The following review will briefly summarize the circadian system, its potential role in AD, and propose using a feeding-related neuropeptide, such as ghrelin, to synchronize uncoupled rhythms. Synchronizing rhythms may be an inexpensive way to promote healthy aging and delay the onset of neurodegenerative disease such as AD.

  8. NMF-Based Analysis of SPECT Brain Images for the Diagnosis of Alzheimer's Disease

    NASA Astrophysics Data System (ADS)

    Padilla, Pablo; Górriz, Juan-Manuel; Ramírez, Javier; Lang, Elmar; Chaves, Rosa; Segovia, Fermin; Álvarez, Ignacio; Salas-González, Diego; López, Miriam

    This paper offers a computer-aided diagnosis (CAD) technique for early diagnosis of Alzheimer's disease (AD) by means of single photon emission computed tomography (SPECT) image classification. The SPECT database for different patients is analyzed by applying the Fisher discriminant ratio (FDR) and non-negative matrix factorization (NMF) for the selection and extraction of the most significative features of each patient SPECT data, in order to reduce the large dimensionality of the input data and the problem of the curse of dimensionality, extracting score features. The NMF-transformed set of data, with reduced number of features, is classified by means of support vector machines (SVM) classification. The proposed NMF+SVM method yields up to 94% classification accuracy, thus becoming an accurate method for SPECT image classification. For the sake of completeness, comparison between conventional PCA+SVM method and the proposed method is also provided.

  9. Quantitative EEG After Brain Stimulation and Cognitive Training in Alzheimer Disease.

    PubMed

    Gandelman-Marton, Revital; Aichenbaum, Sergio; Dobronevsky, Evgenya; Khaigrekht, Michael; Rabey, Jose M

    2017-01-01

    Medications are the currently accepted symptomatic treatment of Alzheimer disease (AD), but their impact on delaying the progression of cognitive deficits and functional impairment is limited. The authors aimed to explore long-term electrophysiological effects of repetitive transcranial magnetic stimulation interlaced with cognitive training on quantitative electroencephalography (EEG) in patients with AD. Quantitative EEG was assessed on non-repetitive transcranial magnetic stimulation interlaced with cognitive training treatment days before treatment and after each treatment phase in seven patients with mild AD. After 4.5 months (54 sessions) of treatment, a significant increase of delta activity over the temporal region was found compared with pretreatment values. Nonsignificant increases of the log EEG power were found for alpha band over the frontal and temporal regions, beta band over the frontal region, theta band over the frontal, temporal, and parieto-occipital regions, and delta band over the frontal and parieto-occipital regions. Nonsignificant decreases were found for alpha over the parieto-occipital region, and for beta over the temporal and parieto-occipital regions. A positive correlation was found between log alpha power over the frontal and temporal regions at 6 weeks and Mini-Mental State Examination (MMSE) scores at 6 weeks and 4.5 months, and between log alpha power over the parieto-occipital regions and MMSE scores at 6 weeks. A negative correlation was found between log alpha power over the frontal and temporal regions at 6 weeks and baseline Alzheimer's Disease Assessment Scale-cognitive subscale scores. Repetitive transcranial magnetic stimulation interlaced with cognitive training has long-term effects on quantitative EEG in patients with mild AD. Further research on the quantitative EEG long-term effects of transcranial magnetic stimulation interlaced with cognitive training is required to confirm the authors' data.

  10. Alzheimer's Disease Information Page

    MedlinePlus

    ... treat moderate to severe AD symptoms. View Full Treatment Information Definition Alzheimer's disease (AD) is an age-related, non-reversible ... that are developing and testing new and novel therapies that can relieve the symptoms of ... Alzheimer’s Plan . U.S. Secretary of Health and Human Services ...

  11. Alzheimer's Disease and Depression.

    ERIC Educational Resources Information Center

    Teri, Linda; Wagner, Amy

    1992-01-01

    Reviews research on depression in Alzheimer's disease (AD). Discusses evidence suggesting that depression affects many AD patients and can have profound effects on patient long-term functioning and caregiver well-being. Notes that field is dominated by studies of prevalence, as opposed to studies of etiology, association with other aspects of…

  12. Alzheimer's Disease and Depression.

    ERIC Educational Resources Information Center

    Teri, Linda; Wagner, Amy

    1992-01-01

    Reviews research on depression in Alzheimer's disease (AD). Discusses evidence suggesting that depression affects many AD patients and can have profound effects on patient long-term functioning and caregiver well-being. Notes that field is dominated by studies of prevalence, as opposed to studies of etiology, association with other aspects of…

  13. CNF1 Increases Brain Energy Level, Counteracts Neuroinflammatory Markers and Rescues Cognitive Deficits in a Murine Model of Alzheimer's Disease

    PubMed Central

    Travaglione, Sara; Fabbri, Alessia; Guidotti, Marco; Ferri, Alberto; Campana, Gabriele; Fiorentini, Carla

    2013-01-01

    Overexpression of pro-inflammatory cytokines and cellular energy failure are associated with neuroinflammatory disorders, such as Alzheimer's disease. Transgenic mice homozygous for human ApoE4 gene, a well known AD and atherosclerosis animal model, show decreased levels of ATP, increased inflammatory cytokines level and accumulation of beta amyloid in the brain. All these findings are considered responsible for triggering cognitive decline. We have demonstrated that a single administration of the bacterial E. coli protein toxin CNF1 to aged apoE4 mice, beside inducing a strong amelioration of both spatial and emotional memory deficits, favored the cell energy restore through an increment of ATP content. This was accompanied by a modulation of cerebral Rho and Rac1 activity. Furthermore, CNF1 decreased the levels of beta amyloid accumulation and interleukin-1β expression in the hippocampus. Altogether, these data suggest that the pharmacological modulation of Rho GTPases by CNF1 can improve memory performances in an animal model of Alzheimer's disease via a control of neuroinflammation and a rescue of systemic energy homeostasis. PMID:23738020

  14. CNF1 increases brain energy level, counteracts neuroinflammatory markers and rescues cognitive deficits in a murine model of Alzheimer's disease.

    PubMed

    Loizzo, Stefano; Rimondini, Roberto; Travaglione, Sara; Fabbri, Alessia; Guidotti, Marco; Ferri, Alberto; Campana, Gabriele; Fiorentini, Carla

    2013-01-01

    Overexpression of pro-inflammatory cytokines and cellular energy failure are associated with neuroinflammatory disorders, such as Alzheimer's disease. Transgenic mice homozygous for human ApoE4 gene, a well known AD and atherosclerosis animal model, show decreased levels of ATP, increased inflammatory cytokines level and accumulation of beta amyloid in the brain. All these findings are considered responsible for triggering cognitive decline. We have demonstrated that a single administration of the bacterial E. coli protein toxin CNF1 to aged apoE4 mice, beside inducing a strong amelioration of both spatial and emotional memory deficits, favored the cell energy restore through an increment of ATP content. This was accompanied by a modulation of cerebral Rho and Rac1 activity. Furthermore, CNF1 decreased the levels of beta amyloid accumulation and interleukin-1β expression in the hippocampus. Altogether, these data suggest that the pharmacological modulation of Rho GTPases by CNF1 can improve memory performances in an animal model of Alzheimer's disease via a control of neuroinflammation and a rescue of systemic energy homeostasis.

  15. Emerging concepts in Alzheimer's disease.

    PubMed

    Vinters, Harry V

    2015-01-01

    Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) is the most common neuropathologic substrate of dementia. It is characterized by synapse loss (predominantly within neocortex) as well as deposition of certain distinctive lesions (the result of protein misfolding) throughout the brain. The latter include senile plaques, composed mainly of an amyloid (Aβ) core and a neuritic component; neurofibrillary tangles, composed predominantly of hyperphosphorylated tau; and cerebral amyloid angiopathy, a microangiopathy affecting both cerebral cortical capillaries and arterioles and resulting from Aβ deposition within their walls or (in the case of capillaries) immediately adjacent brain parenchyma. In this article, I discuss the hypothesized role these lesions play in causing cerebral dysfunction, as well as CSF and neuroimaging biomarkers (for dementia) that are especially relevant as immunotherapeutic approaches are being developed to remove Aβ from the brain parenchyma. In addition, I address the role of neuropathology in characterizing the sequelae of new AD/SDAT therapies and helping to validate CSF and neuroimaging biomarkers of disease. Comorbidity of AD/SDAT and various types of cerebrovascular disease is a major theme in dementia research, especially as cognitive impairment develops in the oldest old, who are especially vulnerable to ischemic and hemorrhagic brain lesions.

  16. Novel role of red wine-derived polyphenols in the prevention of Alzheimer's disease dementia and brain pathology: experimental approaches and clinical implications.

    PubMed

    Pasinetti, Giulio Maria

    2012-10-01

    Recent studies suggest that by the middle of this century, as many as 14 million Americans will have Alzheimer's disease, creating an enormous strain on families, the health care system and the federal budget. There are still widespread misconceptions about issues related to the prevention and/or treatment of disease pathogenesis, leaving us unprepared to deal with the disease. To address these challenges, several therapeutic approaches are currently under investigation, mainly in an attempt to delay disease onset and eventually slow down its progression. Recent epidemiological evidence has implicated the protective role of dietary polyphenols from grape products against Alzheimer's disease. Furthermore, experimental evidence supports the hypothesis that certain bioactive grape-derived polyphenols may protect against Alzheimer's disease-type cognitive deterioration, in part by interfering with the generation and assembly of β-amyloid peptides into neurotoxic oligomeric aggregated species. Brain-targeting polyphenols have been shown to significantly reduce the generation of β-amyloid peptides in primary cortico-hippocampal neuron cultures, and preliminary results indicate that they may influence neuronal synaptic plasticity. Recent evidence has also implicated the role of certain grape-derived preparations in beneficially modulating tau neuropathology, including reducing tau aggregation. Studies suggest that dietary polyphenolics may benefit Alzheimer's disease by modulating multiple disease-modifying modalities, both β-amyloid-dependent and independent mechanisms, and provide impetus for the development of polyphenolic compounds for Alzheimer's disease prevention and/or therapy.

  17. Reflections on Alzheimer's disease.

    PubMed

    Kushnir, S L

    1982-02-01

    As longevity increases, society will face a silent epidemic of idiopathic dementias. The concept, Alzheimer's disease, reflects a cumbersome and vaguely-defined cluster of signs, symptoms and other variables which might more appropriately be labelled as the idiopathic dementias, Alzheimer-type or IDAT. Diagnosis, which is made by exclusion and treatment, primarily custodial, demonstrates the complex nature and unfortunate prognosis of the problem. Dramatic progress, nevertheless, has been made in various scientific aspects of the issue, namely, in histology, genetics and neurochemistry. The resulting evidence warrants further speculation on the role of central cholinergic neurotransmission in cognitive functioning.

  18. Design, synthesis and biological evaluation of trimethine cyanine dyes as fluorescent probes for the detection of tau fibrils in Alzheimer's disease brain and olfactory epithelium.

    PubMed

    Gu, Jiamin; Anumala, Upendra Rao; Heyny-von Haußen, Roland; Hölzer, Jana; Goetschy-Meyer, Valérie; Mall, Gerhard; Hilger, Ingrid; Czech, Christian; Schmidt, Boris

    2013-06-01

    Shedding light on grey matter: Fluorescent trimethine cyanines were evaluated as imaging probes for neurofibrillary tangles in post-mortem brain sections of Alzheimer's disease patients. These probes bind to neurofibrillary tangles with high contrast and selectivity over amyloid β plaques.

  19. In vivo detection of microstructural correlates of brain pathology in preclinical and early Alzheimer Disease with magnetic resonance imaging.

    PubMed

    Zhao, Yue; Raichle, Marcus E; Wen, Jie; Benzinger, Tammie L; Fagan, Anne M; Hassenstab, Jason; Vlassenko, Andrei G; Luo, Jie; Cairns, Nigel J; Christensen, Jon J; Morris, John C; Yablonskiy, Dmitriy A

    2017-03-01

    Alzheimer disease (AD) affects at least 5 million individuals in the USA alone stimulating an intense search for disease prevention and treatment therapies as well as for diagnostic techniques allowing early identification of AD during a long pre-symptomatic period that can be used for the initiation of prevention trials of disease-modifying therapies in asymptomatic individuals. Our approach to developing such techniques is based on the Gr