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  1. [Alzheimer's disease and human memory].

    Science.gov (United States)

    Eustache, F; Giffard, B; Rauchs, G; Chételat, G; Piolino, P; Desgranges, B

    2006-10-01

    Memory disorders observed in Alzheimer's disease gave rise, from the eighties, to a detailed analysis into the framework of cognitive neuropsychology which aimed at describing the deficits of very specific processes. Beyond their clinical interest, these studies contributed to the modelisation of human memory thanks to the characterization of different memory systems and their relationships. The first part of this paper gives an overview of the memory deficits in Alzheimer's disease and insists on particular cognitive phenomena. Hence, several examples are developed in the domains of semantic memory (such as hyperpriming and hypopriming effects) and autobiographical memory. Recent results highlight the existence of severe autobiographical amnesia observed in all neurodegenerative diseases, though with contrasting profiles: Ribot's gradient in Alzheimer's disease (showing that remote memories are better preserved than recent ones), reverse gradient in semantic dementia and no clear gradient in the frontal variant of frontotemporal dementia. The second part of this article presents advances in cognitive neuroscience searching to disclose the cerebral substrates of these cognitive deficits in Alzheimer's disease. The studies using functional imaging techniques are the most informative regarding this problematic. While showing the dysfunctions of an extended network, they emphasize the selectivity of cerebral damages that are at the root of very specific cognitive dysfunctions, coming close in that way to the conceptions of cognitive neuropsychology. These neuroimaging studies unravel the existence of compensatory mechanisms, which until recently were clearly missing in the literature on neurodegenerative diseases. These different researches lead to a wide conception of human memory, not just limited to simple instrumental processes (encoding, storage, retrieval), but necessarily covering models of identity and continuity of the subject, which interact in a dynamic way

  2. Alzheimer Disease

    Science.gov (United States)

    ... Emergency Room? What Happens in the Operating Room? Alzheimer Disease KidsHealth > For Kids > Alzheimer Disease A A A ... slow it down. When Someone You Love Has Alzheimer Disease You might feel sad or angry — or both — ...

  3. Interneurons in the human olfactory system in Alzheimer's disease.

    Science.gov (United States)

    Saiz-Sanchez, Daniel; Flores-Cuadrado, Alicia; Ubeda-Bañon, Isabel; de la Rosa-Prieto, Carlos; Martinez-Marcos, Alino

    2016-02-01

    The principal olfactory structures display Alzheimer's disease (AD) related pathology at early stages of the disease. Consequently, olfactory deficits are among the earliest symptoms. Reliable olfactory tests for accurate clinical diagnosis are rarely made. In addition, neuropathological analysis postmortem of olfactory structures is often not made. Therefore, the relationship between the clinical features and the underlying pathology is poorly defined. Traditionally, research into Alzheimer's disease has focused on the degeneration of cortical temporal projection neurons and cholinergic neurons. Recent evidence has demonstrated the neurodegeneration of interneuron populations in AD. This review provides an updated overview of the pathological involvement of interneuron populations in the human olfactory system in Alzheimer's disease.

  4. Alzheimer's Disease

    Science.gov (United States)

    ... to note that Alzheimer's disease is not a normal part of aging. What Is Alzheimer's Disease? Video length: 2 min 29 sec Click to watch this video The course of Alzheimer’s disease—which symptoms appear and how quickly changes occur—varies from person to person. The time ...

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

    Science.gov (United States)

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

    2015-01-01

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

  6. Genetic control of human brain transcript expression in Alzheimer disease.

    Science.gov (United States)

    Webster, Jennifer A; Gibbs, J Raphael; Clarke, Jennifer; Ray, Monika; Zhang, Weixiong; Holmans, Peter; Rohrer, Kristen; Zhao, Alice; Marlowe, Lauren; Kaleem, Mona; McCorquodale, Donald S; Cuello, Cindy; Leung, Doris; Bryden, Leslie; Nath, Priti; Zismann, Victoria L; Joshipura, Keta; Huentelman, Matthew J; Hu-Lince, Diane; Coon, Keith D; Craig, David W; Pearson, John V; Heward, Christopher B; Reiman, Eric M; Stephan, Dietrich; Hardy, John; Myers, Amanda J

    2009-04-01

    We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We have now analyzed additional samples with a confirmed pathologic diagnosis of late-onset Alzheimer disease (LOAD; final n = 188 controls, 176 cases). Nine percent of the cortical transcripts that we analyzed had expression profiles correlated with their genotypes in the combined cohort, and approximately 5% of transcripts had SNP-transcript relationships that could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate-gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power for discovering risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease.

  7. Treatments for Alzheimer's Disease

    Science.gov (United States)

    ... 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 ...

  8. Diagnosis of Alzheimer's disease based on disease-specific autoantibody profiles in human sera.

    Directory of Open Access Journals (Sweden)

    Eric Nagele

    Full Text Available After decades of Alzheimer's disease (AD research, the development of a definitive diagnostic test for this disease has remained elusive. The discovery of blood-borne biomarkers yielding an accurate and relatively non-invasive test has been a primary goal. Using human protein microarrays to characterize the differential expression of serum autoantibodies in AD and non-demented control (NDC groups, we identified potential diagnostic biomarkers for AD. The differential significance of each biomarker was evaluated, resulting in the selection of only 10 autoantibody biomarkers that can effectively differentiate AD sera from NDC sera with a sensitivity of 96.0% and specificity of 92.5%. AD sera were also distinguishable from sera obtained from patients with Parkinson's disease and breast cancer with accuracies of 86% and 92%, respectively. Results demonstrate that serum autoantibodies can be used effectively as highly-specific and accurate biomarkers to diagnose AD throughout the course of the disease.

  9. Alzheimer's Disease Facts and Figures

    Medline Plus

    Full Text Available ... without Alzheimer's — a rate twice as high. Invest in a world without Alzheimer's. Donate Caregivers In 2016, ... COMMITMENT TO RESEARCH. Read More Alzheimer's Disease Facts in Each State The 2017 Alzheimer's Disease Facts and ...

  10. Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer disease.

    Science.gov (United States)

    Lurain, Nell S; Hanson, Barbara A; Martinson, Jeffrey; Leurgans, Sue E; Landay, Alan L; Bennett, David A; Schneider, Julie A

    2013-08-15

    Serum, cerebrospinal fluid (CSF), and cryopreserved lymphocytes from subjects in the Rush Alzheimer's Disease Center Religious Orders Study were analyzed for associations between cytomegalovirus (CMV) infection and clinical and pathological markers of Alzheimer disease. CMV antibody levels were associated with neurofibrillary tangles (NFTs). CSF interferon γ was only detected in seropositive subjects and was significantly associated with NFTs. The percentage of senescent T cells (CD4+ or CD8+CD28-CD57+) was significantly higher for CMV-seropositive as compared to CMV-seronegative subjects and was marginally associated with the pathologic diagnosis of Alzheimer disease (CD4+) or amyloid-β (CD8+). Immunocytochemical analysis showed induction of amyloid-β in human foreskin fibroblasts (HFFs) infected with each of 3 clinical CMV strains. In the same subjects, there was no association of herpes simplex virus type 1 (HSV-1) antibody levels with CMV antibody levels or clinical or pathological markers of Alzheimer disease. HSV-1 infection of HFFs did not induce amyloid-β. These data support an association between CMV and the development of Alzheimer disease.

  11. Being human: The role of pluripotent stem cells in regenerative medicine and humanizing Alzheimer's disease models.

    Science.gov (United States)

    Sproul, Andrew A

    2015-01-01

    Human pluripotent stem cells (PSCs) have the capacity to revolutionize medicine by allowing the generation of functional cell types such as neurons for cell replacement therapy. However, the more immediate impact of PSCs on treatment of Alzheimer's disease (AD) will be through improved human AD model systems for mechanistic studies and therapeutic screening. This review will first briefly discuss different types of PSCs and genome-editing techniques that can be used to modify PSCs for disease modeling or for personalized medicine. This will be followed by a more in depth analysis of current AD iPSC models and a discussion of the need for more complex multicellular models, including cell types such as microglia. It will finish with a discussion on current clinical trials using PSC-derived cells and the long-term potential of such strategies for treating AD.

  12. Genetics Home Reference: Alzheimer disease

    Science.gov (United States)

    ... Me Understand Genetics Home Health Conditions Alzheimer disease Alzheimer disease Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Alzheimer disease is a degenerative disease of the brain ...

  13. Rapidly progressive Alzheimer disease.

    Science.gov (United States)

    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. Calcium channel blockers and Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Yi Tan; Yulin Deng; Hong Qing

    2012-01-01

    Alzheimer's disease is characterized by two pathological hallmarks: amyloid plaques and neurofi-brillary tangles. In addition, calcium homeostasis is disrupted in the course of human aging. Recent research shows that dense plaques can cause functional alteration of calcium signals in mice with Alzheimer's disease. Calcium channel blockers are effective therapeutics for treating Alzheimer's disease. This review provides an overview of the current research of calcium channel blockers in-volved in Alzheimer's disease therapy.

  15. Familial Alzheimer's disease: genetic analysis related to disease heterogeneity, Down syndrome and human brain evolution.

    Science.gov (United States)

    Schapiro, M B; Rapoport, S I

    1989-01-01

    Etiologically heterogeneous subgroups of patients with Alzheimer's disease (AD) exist and need to be distinguished so as to better identify genetic causes of familial cases. Furthermore, the presence of AD neuropathology in Down syndrome (trisomy 21) subjects older than 35 years suggests that AD in some cases is caused by dysregulation of expression of genes on chromosome 21. Cerebral metabolic abnormalities in life, and the distribution of AD neuropathology in the post-mortem brain, indicate that AD involves the association neocortices and subcortical regions with which they evolved during evolution of the human brain. Accordingly, understanding the molecular basis of this evolution should elucidate the genetic basis of AD, whereas knowing the genetics of AD should be informative about the genomic changes which promoted brain evolution.

  16. mNos2 deletion and human NOS2 replacement in Alzheimer disease models.

    Science.gov (United States)

    Colton, Carol A; Wilson, Joan G; Everhart, Angela; Wilcock, Donna M; Puoliväli, Jukka; Heikkinen, Taneli; Oksman, Juho; Jääskeläinen, Olli; Lehtimäki, Kimmo; Laitinen, Teemu; Vartiainen, Nina; Vitek, Michael P

    2014-08-01

    Understanding the pathophysiologic mechanisms underlying Alzheimer disease relies on knowledge of disease onset and the sequence of development of brain pathologies. We present a comprehensive analysis of early and progressive changes in a mouse model that demonstrates a full spectrum of characteristic Alzheimer disease-like pathologies. This model demonstrates an altered immune redox state reminiscent of the human disease and capitalizes on data indicating critical differences between human and mouse immune responses, particularly in nitric oxide levels produced by immune activation of the NOS2 gene. Using the APPSwDI(+)/(+)mNos2(-/-) (CVN-AD) mouse strain, we show a sequence of pathologic events leading to neurodegeneration,which include pathologically hyperphosphorylated tau in the perforant pathway at 6 weeks of age progressing to insoluble tau, early appearance of β-amyloid peptides in perivascular deposits around blood vessels in brain regions known to be vulnerable to Alzheimer disease, and progression to damage and overt loss in select vulnerable neuronal populations in these regions. The role of species differences between hNOS2 and mNos2 was supported by generating mice in which the human NOS2 gene replaced mNos2. When crossed with CVN-AD mice, pathologic characteristics of this new strain (APPSwDI(+)/(-)/HuNOS2(tg+)/(+)/mNos2(-/-)) mimicked the pathologic phenotypes found in the CVN-AD strain.

  17. Alzheimer's disease in a dish: promises and challenges of human stem cell models.

    Science.gov (United States)

    Young, Jessica E; Goldstein, Lawrence S B

    2012-10-15

    Human pluripotent stem cells can differentiate into disease-relevant cell types, which capture the unique genome of an individual patient and provide insight into pathological mechanisms of human disease. Recently, human stem cell models for Alzheimer's disease (AD), the most common neurodegenerative dementia, have been described. Stem cell-derived neurons from patients with familial and sporadic AD and Down's syndrome recapitulate human disease phenotypes such as amyloid β peptide production, hyperphosphorylation of tau protein and endosomal abnormalities. Treatment of human neurons with small molecules can modulate these phenotypes, demonstrating the utility of this system for drug development and screening. This review will highlight the current AD stem cell models and discuss the remaining challenges and potential future directions of this field.

  18. Neuroinflammation in Alzheimer's disease

    DEFF Research Database (Denmark)

    Heneka, Michael T; Carson, Monica J; Khoury, Joseph El

    2015-01-01

    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...... therapeutic or preventive strategies for Alzheimer's disease....

  19. High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer's Disease in Human Cerebrospinal Fluid.

    Directory of Open Access Journals (Sweden)

    Ronald C Hendrickson

    Full Text Available Disease modifying treatments for Alzheimer's disease (AD constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001 and SME-2 (p = 0.0004 for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR, in AD were 21% (p = 0.039 and 17% (p = 0.026 lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic.

  20. Alzheimer's Disease Facts and Figures

    Science.gov (United States)

    ... Alzheimer's >> Home Text size: A A A 2017 Alzheimer's Disease Facts and Figures Download the Full Report: ... twice as high. Invest in a world without Alzheimer's. Donate Caregivers In 2016, 15.9 million family ...

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

    Science.gov (United States)

    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.

  2. Neuroinflammation in Alzheimer's disease

    NARCIS (Netherlands)

    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, Stephane; Joseph, Bertrand; Deigendesch, Nikolaus; Garaschuk, Olga; Boddeke, Erik; Dinarello, Charles A.; Breitner, John C.; Cole, Greg M.; Golenbock, Douglas T.; Kummer, Markus P.

    2015-01-01

    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 trigg

  3. Alzheimer disease: An interactome of many diseases

    Directory of Open Access Journals (Sweden)

    Balaji S Rao

    2014-01-01

    Full Text Available Alzheimer Disease (AD is an outcome as well as source of many diseases. Alzheimer is linked with many other diseases like Diabetes type 2, cholesterolemia, hypertension and many more. But how each of these diseases affecting other is still unknown to scientific community. Signaling Pathways of one disease is interlinked with other disease. But to what extent healthy brain is affected when any signaling in human body is disturbed is the question that matters. There is a need of Pathway analysis, Protein-Protein interaction (PPI and the conserved interactome study in AD and linked diseases. It will be helpful in finding the potent drug or vaccine target in conscious manner. In the present research the Protein-Protein interaction of all the proteins involved in Alzheimer Disease is analyzed using ViSANT and osprey tools and pathway analysis further reveals the significant genes/proteins linking AD with other diseases.

  4. Treatment of Alzheimer disease.

    Science.gov (United States)

    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.

  5. Cerebrolysin in Alzheimer's disease.

    Science.gov (United States)

    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.

  6. Cultured cells of the nervous system, including human neurones, in the study of the neuro-degenerative disorder, Alzheimer's disease: an overview.

    Science.gov (United States)

    De Boni, U

    1985-01-01

    Human nervous-system cells in culture are a suitable model for the study of the degenerative changes associated with Alzheimer's disease. Alzheimer-diseased brain contains a factor which induces the formation of paired helical filaments (PHF) in cultured cells, similar to that seen in Alzheimer's disease. The excitotoxic amino acids, glutamate and aspartate, induce similar PHE formation in cultured cells. The neurotoxic element aluminium is present in high concentrations in the brain in several human neurological disorders, including Alzheimer's disease. In cultured-cell systems, aluminium interacts with acidic nuclear proteins, decreases steroid binding, produces a form of neurofibrillary degeneration and alters nucleoside metabolism.

  7. The therapeutic effects of human adipose-derived stem cells in Alzheimer's disease mouse models.

    Science.gov (United States)

    Chang, Keun-A; Kim, Hee Jin; Joo, Yuyoung; Ha, Sungji; Suh, Yoo-Hun

    2014-01-01

    Alzheimer's disease (AD) is an irreversible neurodegenerative disease, still lacking proper clinical treatment. Therefore, many researchers have focused on the possibility of therapeutic use of stem cells for AD. Adipose-derived stem cells (ASCs), mesenchymal stem cells (MSCs) isolated from adipose tissue, are well known for their pluripotency and their ability to differentiate into multiple tissue types and have immune modulatory properties similar to those of MSCs from other origins. Because of their biological properties, ASCs can be considered for cell therapy and neuroregeneration. Our recent results clearly showed the therapeutic potential of these cells after transplantation into Tg2576 mice (an AD mouse model). Intravenously or intracerebrally transplanted human ASCs (hASCs) greatly improved the memory impairment and the neuropathology, suggesting that hASCs have a high therapeutic potential for AD.

  8. Alzheimer's Disease Facts and Figures

    Medline Plus

    Full Text Available ... for someone with Alzheimer's? Get Resources Cost to Nation The costs of health care and long-term ... of this disease in every state across the nation. Click below to see the effect that Alzheimer's ...

  9. Down Syndrome and Alzheimer's Disease

    Science.gov (United States)

    ... A A A Share Plus on Google Plus Alzheimer's & Dementia alz.org | IHaveAlz Overview What Is Dementia ... chapter Join our online community Down Syndrome and Alzheimer's Disease As they age, those affected by Down ...

  10. Alzheimer's Disease Facts and Figures

    Medline Plus

    Full Text Available ... advances a biomarker-based method for diagnosis and treatment at the earliest stages of Alzheimer's disease, we ... on the latest news and advances in Alzheimer's treatments, care and research. Get tips for living with ...

  11. Neuroinflammation in Alzheimer's disease

    OpenAIRE

    Heneka, MT; Carson, MJ; Khoury, JE; Landreth, GE; Brosseron, F.; Feinstein, Dl; Jacobs, AH; Wyss-Coray, T; Vitorica, J; Ransohoff, RM; Herrup, K; Frautschy, SA; Finsen, B.; Brown, GC; Verkhratsky, A.

    2015-01-01

    © 2015 Elsevier Ltd. 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 severa...

  12. Modeling Alzheimer's disease with human induced pluripotent stem (iPS) cells.

    Science.gov (United States)

    Mungenast, Alison E; Siegert, Sandra; Tsai, Li-Huei

    2016-06-01

    In the last decade, induced pluripotent stem (iPS) cells have revolutionized the utility of human in vitro models of neurological disease. The iPS-derived and differentiated cells allow researchers to study the impact of a distinct cell type in health and disease as well as performing therapeutic drug screens on a human genetic background. In particular, clinical trials for Alzheimer's disease (AD) have been failing. Two of the potential reasons are first, the species gap involved in proceeding from initial discoveries in rodent models to human studies, and second, an unsatisfying patient stratification, meaning subgrouping patients based on the disease severity due to the lack of phenotypic and genetic markers. iPS cells overcome this obstacles and will improve our understanding of disease subtypes in AD. They allow researchers conducting in depth characterization of neural cells from both familial and sporadic AD patients as well as preclinical screens on human cells. In this review, we briefly outline the status quo of iPS cell research in neurological diseases along with the general advantages and pitfalls of these models. We summarize how genome-editing techniques such as CRISPR/Cas9 will allow researchers to reduce the problem of genomic variability inherent to human studies, followed by recent iPS cell studies relevant to AD. We then focus on current techniques for the differentiation of iPS cells into neural cell types that are relevant to AD research. Finally, we discuss how the generation of three-dimensional cell culture systems will be important for understanding AD phenotypes in a complex cellular milieu, and how both two- and three-dimensional iPS cell models can provide platforms for drug discovery and translational studies into the treatment of AD.

  13. Recent developments in Alzheimer's disease therapeutics

    Directory of Open Access Journals (Sweden)

    Aisen Paul S

    2009-02-01

    Full Text Available Abstract Alzheimer's disease is a devastating neurological disorder that affects more than 37 million people worldwide. The economic burden of Alzheimer's disease is massive; in the United States alone, the estimated direct and indirect annual cost of patient care is at least $100 billion. Current FDA-approved drugs for Alzheimer's disease do not prevent or reverse the disease, and provide only modest symptomatic benefits. Driven by the clear unmet medical need and a growing understanding of the molecular pathophysiology of Alzheimer's disease, the number of agents in development has increased dramatically in recent years. Truly *disease-modifying' therapies that target the underlying mechanisms of Alzheimer's disease have now reached late stages of human clinical trials. Primary targets include beta-amyloid, whose presence and accumulation in the brain is thought to contribute to the development of Alzheimer's disease, and tau protein which, when hyperphosphorylated, results in the self-assembly of tangles of paired helical filaments also believed to be involved in the pathogenesis of Alzheimer's disease. In this review, we briefly discuss the current status of Alzheimer's disease therapies under study, as well the scientific context in which they have been developed.

  14. Human Development in the Context of Aging and Chronic Illness: The Role of Attachment in Alzheimer's Disease and Stroke.

    Science.gov (United States)

    Wright, Lore K.; And Others

    1995-01-01

    Examines two illness trajectories, Alzheimer's disease and stroke, to illustrate emerging changes in human development over each course of illness and the increasing importance of attachment behavior among ill elders and their family members. Argues that attachment links ailing older people to their environment, and that attachment is vital if…

  15. Normal aging in rats and pathological aging in human Alzheimer's disease decrease FAAH activity: modulation by cannabinoid agonists.

    Science.gov (United States)

    Pascual, A C; Martín-Moreno, A M; Giusto, N M; de Ceballos, M L; Pasquaré, S J

    2014-12-01

    Anandamide is an endocannabinoid involved in several physiological functions including neuroprotection. Anandamide is synthesized on demand and its endogenous level is regulated through its degradation, where fatty acid amide hydrolase plays a major role. The aim of this study was to characterize anandamide breakdown in physiological and pathological aging and its regulation by CB1 and CB2 receptor agonists. Fatty acid amide hydrolase activity was analyzed in an independent cohort of human cortical membrane samples from control and Alzheimer's disease patients, and in membrane and synaptosomes from adult and aged rat cerebral cortex. Our results demonstrate that fatty acid amide hydrolase activity decreases in the frontal cortex from human patients with Alzheimer's disease and this effect is mimicked by Aβ(1-40) peptide. This activity increases and decreases in aged rat cerebrocortical membranes and synaptosomes, respectively. Also, while the presence of JWH-133, a CB2 selective agonist, slightly increases anandamide hydrolysis in human controls, it decreases this activity in adults and aged rat cerebrocortical membranes and synaptosomes. In the presence of WIN55,212-2, a mixed CB1/CB2 agonist, anandamide hydrolysis increases in Alzheimer's disease patients but decreases in human controls as well as in adult and aged rat cerebrocortical membranes and synaptosomes. Although a similar profile is observed in fatty acid amide hydrolase activity between aged rat synaptic endings and human Alzheimer's disease brains, it is differently modulated by CB1/CB2 agonists. This modulation leads to a reduced availability of anandamide in Alzheimer's disease and to an increased availability of this endocannabinoid in aging.

  16. Biodistribution of Infused Human Umbilical Cord Blood Cells in Alzheimer's Disease-Like Murine Model.

    Science.gov (United States)

    Ehrhart, Jared; Darlington, Donna; Kuzmin-Nichols, Nicole; Sanberg, Cyndy D; Sawmiller, Darrell R; Sanberg, Paul R; Tan, Jun

    2016-01-01

    Human umbilical cord blood cells (HUCBCs), a prolific source of non-embryonic or adult stem cells, have emerged as effective and relatively safe immunomodulators and neuroprotectors, reducing behavioral impairment in animal models of Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, and stroke. In this report, we followed the bioavailability of HUCBCs in AD-like transgenic PSAPP mice and nontransgenic Sprague-Dawley rats. HUCBCs were injected into tail veins of mice or rats at a single dose of 1 × 10(6) or 2.2 × 10(6) cells, respectively, prior to harvesting of tissues at 24 h, 7 days, and 30 days after injection. For determination of HUCBC distribution, tissues from both species were subjected to total DNA isolation and polymerase chain reaction (PCR) amplification of the gene for human glycerol-3-phosphate dehydrogenase. Our results show a relatively similar biodistribution and retention of HUCBCs in both mouse and rat organs. HUCBCs were broadly detected both in the brain and several peripheral organs, including the liver, kidney, and bone marrow, of both species, starting within 7 days and continuing up to 30 days posttransplantation. No HUCBCs were recovered in the peripheral circulation, even at 24 h posttransplantation. Therefore, HUCBCs reach several tissues including the brain following a single intravenous treatment, suggesting that this route can be a viable method of administration of these cells for the treatment of neurodegenerative diseases.

  17. Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Brew Bruce J

    2009-12-01

    Full Text Available Abstract The excitotoxin quinolinic acid (QUIN is synthesized through the kynurenine pathway (KP by activated monocyte lineage cells. QUIN is likely to play a role in the pathogenesis of several major neuroinflammatory diseases including Alzheimer's disease (AD. The presence of reactive astrocytes, astrogliosis, increased oxidative stress and inflammatory cytokines are important pathological hallmarks of AD. We assessed the stimulatory effects of QUIN at low physiological to high excitotoxic concentrations in comparison with the cytokines commonly associated with AD including IFN-γ and TNF-α on primary human astrocytes. We found that QUIN induces IL-1β expression, a key mediator in AD pathogenesis, in human astrocytes. We also explored the effect of QUIN on astrocyte morphology and functions. At low concentrations, QUIN treatment induced concomitantly a marked increase in glial fibrillary acid protein levels and reduction in vimentin levels compared to controls; features consistent with astrogliosis. At pathophysiological concentrations QUIN induced a switch between structural protein expressions in a dose dependent manner, increasing VIM and concomitantly decreasing GFAP expression. Glutamine synthetase (GS activity was used as a functional metabolic test for astrocytes. We found a significant dose-dependent reduction in GS activity following QUIN treatment. All together, this study showed that QUIN is an important factor for astroglial activation, dysregulation and cell death with potential relevance to AD and other neuroinflammatory diseases.

  18. Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease

    OpenAIRE

    Bateman, R. J.; Aisen, P.S.; De Strooper, B.; Fox, N C.; Lemere, C. A.; Ringman, J.M.; Salloway, S.; Sperling, R. A.; Windisch, M.; Xiong, C.

    2011-01-01

    Autosomal-dominant Alzheimer's disease has provided significant understanding of the pathophysiology of Alzheimer's disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimer's disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimer's disease and the more common sporadic form of Alzheimer's disease. Current developments in autosomal-dominant Alzheimer's disease are...

  19. In vivo imaging of human adipose-derived stem cells in Alzheimer's disease animal model

    Science.gov (United States)

    Ha, Sungji; Ahn, Sangzin; Kim, Saeromi; Joo, Yuyoung; Chong, Young Hae; Suh, Yoo-Hun; Chang, Keun-A.

    2014-05-01

    Stem cell therapy is a promising tool for the treatment of diverse conditions, including neurodegenerative diseases such as Alzheimer's disease (AD). To understand transplanted stem cell biology, in vivo imaging is necessary. Nanomaterial has great potential for in vivo imaging and several noninvasive methods are used, such as magnetic resonance imaging, positron emission tomography, fluorescence imaging (FI) and near-infrared FI. However, each method has limitations for in vivo imaging. To overcome these limitations, multimodal nanoprobes have been developed. In the present study, we intravenously injected human adipose-derived stem cells (hASCs) that were labeled with a multimodal nanoparticle, LEO-LIVE™-Magnoxide 675 or 797 (BITERIALS, Seoul, Korea), into Tg2576 mice, an AD mouse model. After sequential in vivo tracking using Maestro Imaging System, we found fluorescence signals up to 10 days after injection. We also found strong signals in the brains extracted from hASC-transplanted Tg2576 mice up to 12 days after injection. With these results, we suggest that in vivo imaging with this multimodal nanoparticle may provide a useful tool for stem cell tracking and understanding stem cell biology in other neurodegenerative diseases.

  20. Transcriptional regulation of human FE65, a ligand of Alzheimer's disease amyloid precursor protein, by Sp1.

    LENUS (Irish Health Repository)

    Yu, Hoi-Tin

    2010-03-01

    FE65 is a neuronal-enriched adaptor protein that binds to the Alzheimer\\'s disease amyloid precursor protein (APP). FE65 forms a transcriptionally active complex with the APP intracellular domain (AICD). The precise gene targets for this complex are unclear but several Alzheimer\\'s disease-linked genes have been proposed. Additionally, evidence suggests that FE65 influences APP metabolism. The mechanism by which FE65 expression is regulated is as yet unknown. To gain insight into the regulatory mechanism, we cloned a 1.6 kb fragment upstream of the human FE65 gene and found that it possesses particularly strong promoter activity in neurones. To delineate essential regions in the human FE65 promoter, a series of deletion mutants were generated. The minimal FE65 promoter was located between -100 and +5, which contains a functional Sp1 site. Overexpression of the transcription factor Sp1 potentiates the FE65 promoter activity. Conversely, suppression of the FE65 promoter was observed in cells either treated with an Sp1 inhibitor or in which Sp1 was knocked down. Furthermore, reduced levels of Sp1 resulted in downregulation of endogenous FE65 mRNA and protein. These findings reveal that Sp1 plays a crucial role in transcriptional control of the human FE65 gene.

  1. Caregiving for Alzheimer's Disease or Other Dementia

    Science.gov (United States)

    ... What's this? Submit Button Caregiving for Person with Alzheimer's Disease or a related Dementia Recommend on Facebook Tweet Share Compartir What is Alzheimer's Disease? Alzheimer's disease is the most common form ...

  2. Alzheimer disease update.

    Science.gov (United States)

    Matthews, Brandy R

    2010-04-01

    Alzheimer disease (AD) is a progressive neurodegenerative disorder affecting more than 37 million people worldwide and increasing in incidence based on its primary risk factor, advancing age. A growing body of knowledge regarding amyloid and tau neuropathology, genetic and environmental risk modifiers, early and atypical clinical presentations, and the use of symptom-modifying medical and psychosocial therapies is available to aid in the diagnosis and management of patients with AD. Exciting recent advances in neurobiology render the areas of genetic susceptibility, biomarkers for early disease detection and assessment of disease progression, and novel therapeutic strategies to modify the natural history of the disease compelling, but in need of further study before implementation into routine clinical practice is feasible.

  3. Aluminum, the genetic apparatus of the human CNS and Alzheimer's disease (AD).

    Science.gov (United States)

    Pogue, A I; Lukiw, W J

    2016-06-01

    The genomes of eukaryotes orchestrate their expression to ensure an effective, homeostatic and functional gene signaling program, and this includes fundamentally altered patterns of transcription during aging, development, differentiation and disease. These actions constitute an extremely complex and intricate process as genetic operations such as transcription involve the very rapid translocation and polymerization of ribonucleotides using RNA polymerases, accessory transcription protein complexes and other interrelated chromatin proteins and genetic factors. As both free ribonucleotides and polymerized single-stranded RNA chains, ribonucleotides are highly charged with phosphate, and this genetic system is extremely vulnerable to disruption by a large number of electrostatic forces, and primarily by cationic metals such as aluminum. Aluminum has been shown by independent researchers to be particularly genotoxic to the genetic apparatus, and it has become reasonably clear that aluminum disturbs genetic signaling programs in the CNS that bear a surprising resemblance to those observed in Alzheimer's disease (AD) brain. This paper will focus on a discussion of two molecular-genetic aspects of aluminum genotoxicity: (1) the observation that micro-RNA (miRNA)-mediated global gene expression patterns in aluminum-treated transgenic animal models of AD (Tg-AD) strongly resemble those found in AD; and (2) the concept of "human biochemical individuality" and the hypothesis that individuals with certain gene expression patterns may be especially sensitive and perhaps predisposed to aluminum genotoxicity.

  4. The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer's disease.

    Science.gov (United States)

    Lee, Hyun Ju; Lee, Jong Kil; Lee, Hyun; Shin, Ji-woong; Carter, Janet E; Sakamoto, Toshiro; Jin, Hee Kyung; Bae, Jae-sung

    2010-08-30

    The neuropathological hallmarks of Alzheimer's disease (AD) include the presence of extracellular amyloid-beta peptide (Abeta) in the form of amyloid plaques in the brain parenchyma and neuronal loss. The mechanism associated with neuronal death by amyloid plaques is unclear but oxidative stress and glial activation has been implicated. Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) are being scrutinized as a potential therapeutic tool to prevent various neurodegenerative diseases including AD. However, the therapeutic impact of hUCB-MSCs in AD has not yet been reported. Here we undertook in vitro work to examine the potential impact of hUCB-MSCs treatment on neuronal loss using a paradigm of cultured hippocampal neurons treated with Abeta. We confirmed that hUCB-MSCs co-culture reduced the hippocampal apoptosis induced by Abeta treatment. Moreover, in an acute AD mouse model to directly test the efficacy of hUCB-MSCs treatment on AD-related cognitive and neuropathological outcomes, we demonstrated that markers of glial activation, oxidative stress and apoptosis levels were decreased in AD mouse brain. Interestingly, hUCB-MSCs treated AD mice demonstrated cognitive rescue with restoration of learning/memory function. These data suggest that hUCB-MSCs warrant further investigation as a potential therapeutic agent in AD.

  5. P-glycoprotein expression and amyloid accumulation in human aging and Alzheimer's disease: preliminary observations.

    Science.gov (United States)

    Chiu, Catherine; Miller, Miles C; Monahan, Renée; Osgood, Doreen P; Stopa, Edward G; Silverberg, Gerald D

    2015-09-01

    P-glycoprotein (P-gp), part of the blood-brain barrier, limits drug access to the brain and is the target for therapies designed to improve drug penetration. P-gp also extrudes brain amyloid-beta (Aβ). Accumulation of Aβ is a hallmark of Alzheimer's disease (AD). Aβ accumulates in normal aging and in AD primarily due to decreased Aβ clearance. This is a preliminary report on the relative protein and messenger RNA expression of P-gp in human brains, ages 20-100 years, including AD subjects. In these preliminary studies, cortical endothelial P-gp expression decreased in AD compared with controls (p P-gp expression in human aging are similar to aging rats. Microvessel P-gp messenger RNA remained unchanged with aging and AD. Aβ plaques were found in 42.8% of normal subjects (54.5% of those older than 50 years). A qualitative analysis showed that P-gp expression is lower than the group mean in subjects older than 75 years but increased if younger. Decreased P-gp expression may be related to Aβ plaques in aging and AD. Downregulating P-gp to allow pharmaceuticals into the central nervous system may increase Aβ accumulation.

  6. 77 FR 11116 - Draft National Plan To Address Alzheimer's Disease

    Science.gov (United States)

    2012-02-24

    ... HUMAN SERVICES Draft National Plan To Address Alzheimer's Disease AGENCY: Office of the Assistant.... SUMMARY: HHS is soliciting public input on the draft National Plan to Address Alzheimer's Disease, which... . Background On January 4, 2011, President Barack Obama signed into law the National Alzheimer's Project...

  7. Should Alzheimer's disease be equated with human brain ageing? A maladaptive interaction between brain evolution and senescence.

    Science.gov (United States)

    Neill, David

    2012-01-01

    In this review Alzheimer's disease is seen as a maladaptive interaction between human brain evolution and senescence. It is predicted to occur in everyone although does not necessarily lead to dementia. The pathological process is initiated in relation to a senescence mediated functional down-regulation in the posteromedial cortex (Initiation Phase). This leads to a loss of glutamatergic excitatory input to layer II entorhinal cortex neurons. A human specific maladaptive neuroplastic response is initiated in these neurons leading to neuronal dysfunction, NFT formation and death. This leads to further loss of glutamatergic excitatory input and propagation of the maladaptive response along excitatory pathways linking evolutionary progressed vulnerable neurons (Propagation Phase). Eventually neurons are affected in many brain areas resulting in dementia. Possible therapeutic approaches include enhancing glutamatergic transmission. The theory may have implications with regards to how Alzheimer's disease is classified.

  8. Alzheimer's disease and stigmatization

    Directory of Open Access Journals (Sweden)

    Dimitrios Kosmidis

    2012-04-01

    Full Text Available Aim: The main objective of the study was to explore social bias experienced by patients with Alzheimer's disease and to investigate the knowledge of a sample of the general population regarding this particular disease. Method: The sample consisted of 91 individuals who were first degree relatives of members of three Centers of Open Protection for the Elderly, who did not suffer from dementia as they have recently undergone screening for Alzheimer's disease. A survey design was adopted using a face-to-face questionnaire which apart from the demographical data and two open-ended questions, was based on a 5-point lickert scale, looking at knowledge, attitudes and stigma towards the disease. Data was analyzed through SPSS software using descriptive statistics while results were regarded significant at p<0,05 level of significance Results: For the quantitave questions, cronbach's a was a=0,75 and the average discrete index 0,31. Stigma was explored through a series of direct and in-direct questions and while 70 (77% persons distinguish dementia from mental illness, 9(9,9% people did not answer these questions. The majority (62,6% did not stigmatize the patient as 57 persons said that the patient is not to blame for the disease. Conclusions: from the distribution of results it becomes evident that there is a need for education, training and multifaceted enlightenment of the general population on issues concerning mental health. Answers that implied tendencies of marginalization of patients with dementia emanated mainly came from individuals in the sample with limited knowledge of the illness and relatively low educational background.

  9. Leptin Dysfunction and Alzheimer's Disease: Evidence from Cellular, Animal, and Human Studies.

    Science.gov (United States)

    McGuire, Matthew J; Ishii, Makoto

    2016-03-01

    There is accumulating evidence from epidemiological studies that changes in body weight are associated with Alzheimer's disease (AD) from mid-life obesity increasing the risk of developing AD to weight loss occurring at the earliest stages of AD. Therefore, factors that regulate body weight are likely to influence the development and progression of AD. The adipocyte-derived hormone leptin has emerged as a major regulator of body weight mainly by activating hypothalamic neural circuits. Leptin also has several pleotropic effects including regulating cognitive function and having neuroprotective effects, suggesting a potential link between leptin and AD. Here, we will examine the relationship between leptin and AD by reviewing the recent evidence from cellular and animal models to human studies. We present a model where leptin has a bidirectional role in AD. Not only can alterations in leptin levels and function worsen cognitive decline and progression of AD pathology, but AD pathology, in of itself, can disrupt leptin signaling, which together would lead to a downward spiral of progressive neurodegeneration and worsening body weight and systemic metabolic deficits. Collectively, these studies serve as a framework to highlight the importance of understanding the molecular mechanisms underlying the body weight and systemic metabolic deficits in AD, which has the potential to open new avenues that may ultimately lead to novel therapeutic targets and diagnostic tools.

  10. Characterization of L-[3H]nicotine binding in human cerebral cortex: comparison between Alzheimer's disease and the normal.

    Science.gov (United States)

    Flynn, D D; Mash, D C

    1986-12-01

    Putative nicotine receptors in the human cerebral cortex were characterized with L-[3H]nicotine, L-[3H]Nicotine binding was enhanced by the addition of Ca2+ and abolished in the presence of Na3EDTA. Association and dissociation of the ligand were rapid at 25 degrees C with t1/2 values of 2 and 3 min, respectively. Saturation binding analysis revealed an apparent single class of sites with a dissociation constant of 5.6 nM and a Hill coefficient of 1.05. There was no effect of postmortem interval on the density of binding sites assayed up to 24 h in rat frontoparietal cortex. Nicotine binding in human cortical samples was also unaltered by increasing sampling delay. In human cortical membranes, binding site density decreased with normal aging. Receptor affinity and concentration in samples of frontal cortex (Brodmann area 10) from patients with Alzheimer's disease were comparable to age-matched control values. Samples of infratemporal cortex (Brodmann area 38) from patients with Alzheimer's disease had a 50% reduction in the number of L-[3H]nicotine sites. Choline acetyltransferase activity was significantly decreased in both cortical areas. Enzyme activities in the temporal pole were reduced to 20% of control values. These data indicate that postsynaptic nicotine receptors are spared in the frontal cortex in Alzheimer's disease. In the infratemporal cortex, significant numbers of receptors remain despite the severe reduction in choline acetyltransferase activity. Replacement therapy directed at these sites may be warranted in Alzheimer's disease.

  11. A Combination Cocktail Improves Spatial Attention in a Canine Model of Human Aging and Alzheimer's disease

    Science.gov (United States)

    Head, Elizabeth; Murphey, Heather L.; Dowling, Amy L.S.; McCarty, Katie L.; Bethel, Samuel R.; Nitz, Jonathan A.; Pleiss, Melanie; Vanrooyen, Jenna; Grossheim, Mike; Smiley, Jeffery R.; Murphy, M. Paul; Beckett, Tina L.; Pagani, Dieter; Bresch, Frederick; Hendrix, Curt

    2014-01-01

    Alzheimer's disease (AD) involves multiple pathological processes in the brain, including increased inflammation and oxidative damage, as well as the accumulation of beta-amyloid (Aβ) plaques. We hypothesized that a combinatorial therapeutic approach to target these multiple pathways may provide cognitive and neuropathological benefits for AD patients. To test this hypothesis, we used a canine model of human aging and AD. Aged dogs naturally develop learning and memory impairments, human-type Aβ deposits and oxidative damage in the brain. Thus, 9 aged beagles (98-115 months) were treated with a medical food cocktail containing (1) an extract of turmeric containing 95% curcuminoids; (2) an extract of green tea containing 50% epigallocatechingallate; (3) N-acetyl cysteine; (4) R-alpha lipoic acid; and (5) an extract of black pepper containing 95% piperine. Nine similarly aged dogs served as placebo-treated controls. After 3 months of treatment, 13 dogs completed a variable distance landmark task used as a measure of spatial attention. As compared to placebo-treated animals, dogs receiving the medical food cocktail had significantly lower error scores (t(11)=4.3, p=0.001) and were more accurate across all distances (F(1,9)=20.7, p=0.001), suggesting an overall improvement in spatial attention. Measures of visual discrimination learning, executive function and spatial memory, and levels of brain and CSF Aβ were unaffected by the cocktail. Our results indicate that this medical food cocktail may be beneficial for improving spatial attention and motivation deficits associated with impaired cognition in aging and AD. PMID:22886019

  12. Alzheimer's Disease Facts and Figures

    Medline Plus

    Full Text Available ... serve our health care needs. The arc of scientific progress is now requiring a change in how we diagnose Alzheimer's disease. Both the National Institute on Aging – Alzheimer's Association (NIA-AA) 2011 workgroup and the International Work Group (IWG) have proposed guidelines that use detectable ...

  13. Immunotherapy for Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Weihua Wang; Liangfeng Fan; De'en Xu; Zhongmin Wen; Rong Yu; Quanhong Ma

    2012-01-01

    Alzheimer's disease (AD) is characterized by β-amyloid (Aβ) plaques consisted primarily of aggregated Aβ proteins and neurofibrillary tangles formed by hyperphosphorylated tau protein.Both Aβ and hyperphosphorylated tau are toxic both in vivo and in vitro.Immunotherapy targeting Aβ seems to provide a promising approach to reduce the toxic species in the brain.However,there is little evidence from clinical trials so far indicating the efficacy of Aβ immunotherapy in cognitive improvement.Immunization with tau peptides or anti-tau antibodies could remove the tau aggregates and improve the cognitive function in preclinical study,which provides a novel strategy of AD therapy.In this article,we will summarize the immunotherapeutic strategies targeting either Aβ or tau.

  14. Treatment for Alzheimer's diseases

    Directory of Open Access Journals (Sweden)

    Nina Arkadyevna Tyuvina

    2015-01-01

    Full Text Available The paper gives an update on the epidemiology, etiology, pathogenesis, prevention, and treatment of Alzheimer's disease (AD. It points out the role of acetylcholine and glutamatergic components of neurotransmission in the pathogenesis of the disease, as well as their interactions, which is important to keep in mind to have a potentiated response to therapy that includes both these components. Different approaches to AD therapy are considered on the basis of the current ideas on the pathogenetic mechanisms of a degenerative process and with regard to the clinical features of the disease (the nature of the psychopathological symptoms of the disease and its stage. Particular emphasis is placed on compensatory therapy for deficient cholinergic and glutamatergic neurotransmission. Whether psychopharmacological agents may be used and psychotherapeutic work with the relatives of patients with AD should be done are also highlighted. Data on the efficiency of replacement therapy for different dementia stages, which promotes a delay in degenerative processes and a definite stabilization of the mental status, are presented.

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

    Science.gov (United States)

    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…

  16. Study on Alzheimer's disease model

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    It is well known that the main brain lesion in Alzheimer's disease (AD) brain is neurofibrillary tangles (NFT) and senile plaques (SP). The amount of NFT is positively correlated with clinical degree of dementia in AD. It is also well studied that the major component of NFT is abnormally hyperphosphorylated microtubule associated protein tau that is caused by an imbalance of protein kinase and protein phosphatase (PP). To reconstitute a specific AD model based on the above hypothesis, we have injected separately calcium calmodulin dependent protein kinase (CaMKKII) activator, bradykinin and PP-2B inhibitor, cyclosporin A into rat hippocampus in the present study. The results showed that the injection of bradykinin caused learning and memory deficient in rats as well as Alzheimer-like tau phosphorylation, including Ser-262/356, Thr-231/235 and Ser-396/404. On the other hand, the injection of cyclosporin A induced the same phosphorylation sites as above except Ser-262/356, however, it did not mimic rat behavior abnormality as bradykinin injection did. The data suggested that activating of CaMKII and the phosphorylation of Ser-262/356 at tau might responsible for the lesion of learning and memory in our model rats. We also incubated PP-2A and PP-1 inhibitor, okadaic acid with human neuroblastoma cell line (SH-SY5Y), and found that (1) inhibition of above PPs induced Alzheimer-like phosphorylation and accumulation of neurofilaments, and Alzheimer-like microtubule disruption, (2) melatonin showed certain protection of the cell from okadaic acid toxicity. The data obtained from this study is significant in AD specific model study.

  17. Metallostasis in Alzheimer's disease.

    Science.gov (United States)

    Ayton, Scott; Lei, Peng; Bush, Ashley I

    2013-09-01

    2012 has been another year in which multiple large-scale clinical trials for Alzheimer's disease (AD) have failed to meet their clinical endpoints. With the social and financial burden of this disease increasing every year, the onus is now on the field of AD researchers to investigate alternative ideas to deliver outcomes for patients. Although several major clinical trials targeting Aβ have failed, three smaller clinical trials targeting metal interactions with Aβ have all shown benefit for patients. Here we review the genetic, pathological, biochemical, and pharmacological evidence that underlies the metal hypothesis of AD. The AD-affected brain suffers from metallostasis, or fatigue of metal trafficking, resulting in redistribution of metals into inappropriate compartments. The metal hypothesis is built upon a triad of transition elements: iron, copper, and zinc. The hypothesis has matured from early investigations showing amyloidogenic and oxidative stress consequences of these metals; recently, disease-related proteins, APP, tau, and presenilin, have been shown to have major roles in metal regulation, which provides insight into the pathway of neurodegeneration in AD and illuminates potential new therapeutic avenues.

  18. Multifunctional liposomes interact with Abeta in human biological fluids: Therapeutic implications for Alzheimer's disease.

    Science.gov (United States)

    Conti, Elisa; Gregori, Maria; Radice, Isabella; Da Re, Fulvio; Grana, Denise; Re, Francesca; Salvati, Elisa; Masserini, Massimo; Ferrarese, Carlo; Zoia, Chiara Paola; Tremolizzo, Lucio

    2017-02-23

    The accumulation of extracellular amyloid beta (Abeta42) both in brain and in cerebral vessels characterizes Alzheimer's disease (AD) pathogenesis. Recently, the possibility to functionalize nanoparticles (NPs) surface with Abeta42 binding molecules, making them suitable tools for reducing Abeta42 burden has been shown effective in models of AD. Aim of this work consisted in proving that NPs might be effective in sequestering Abeta42 in biological fluids, such as CSF and plasma. This demonstration is extremely important considering that these Abeta42 pools are in continuum with the brain parenchyma with drainage of Abeta from interstitial brain tissue to blood vessel and plasma. In this work, liposomes (LIP) were functionalized as previously shown in order to promote high-affinity Abeta binding, i.e., either with, phosphatidic acid (PA), or a modified Apolipoprotein E-derived peptide (mApo), or with a curcumin derivative (TREG); Abeta42 levels were determined by ELISA in CSF and plasma samples. mApo-PA-LIP (25 and 250 μM) mildly albeit significantly sequestered Abeta42 proteins in CSF samples obtained from healthy subjects (p < 0.01). Analogously a significant binding (∼20%) of Abeta42 (p < 0.001) was demonstrated following exposure to all functionalized liposomes in plasma samples obtained from selected AD or Down's syndrome patients expressing high levels of Abeta42. The same results were obtained by quantifying Abeta42 content after removal of liposome-bound Abeta by using gel filtration chromatography or ultracentrifugation on a discontinuous sucrose density gradient. In conclusion, we demonstrate that functionalized liposomes significantly sequester Abeta42 in human biological fluids. These data may be critical for future in vivo administration tests using NPs for promoting sink effect.

  19. Alzheimer's Disease Facts and Figures

    Medline Plus

    Full Text Available ... action. Become an advocate SPECIAL REPORT — ALZHEIMER'S DISEASE: THE NEXT FRONTIER In the history of medicine, one ... physician I am a researcher Message boards Get the facts 10 warning signs & symptoms What is dementia ...

  20. [Biomarkers in Alzheimer's disease].

    Science.gov (United States)

    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.

  1. Neuroinhibitory molecules in Alzheimer's disease.

    Science.gov (United States)

    Larner, A J; Keynes, R J

    2006-09-01

    Aberrant neurite growth is one of the neuropathological signatures of the Alzheimer's disease brain, both around amyloid plaques and in the cortical neuropil. Disruption of neuroinhibitory or repulsive growth and guidance signals, as well as of neurotrophic or permissive signals, may contribute to this dystrophic growth. Hence, therapeutic efforts directed exclusively at restoring neurotrophic activity are unlikely to meet with success. The molecular species responsible for neuroinhibitory effects in the Alzheimer's disease brain are beginning to be elucidated.

  2. Quiz: Alzheimer's Disease Quiz | Alzheimer's disease | NIH MedlinePlus the Magazine

    Science.gov (United States)

    ... of this page please turn Javascript on. Feature: Alzheimer's Disease Quiz: Alzheimer's Disease Quiz Past Issues / Fall 2010 Table of ... How many people in the United States have Alzheimer's disease? as many as 5.1 million as ...

  3. MRI morphometry in Alzheimer's disease.

    Science.gov (United States)

    Matsuda, Hiroshi

    2016-09-01

    MRI based evaluation of brain atrophy is regarded as a valid method to stage the disease and to assess progression in Alzheimer's disease (AD). Volumetric software programs have made it possible to quantify gray matter in the human brain in an automated fashion. At present, voxel based morphometry (VBM) is easily applicable to the routine clinical procedure with a short execution time. The importance of the VBM approach is that it is not biased to one particular structure and is able to assess anatomical differences throughout the brain. Stand-alone VBM software running on Windows, Voxel-based Specific Regional analysis system for AD (VSRAD), has been widely used in the clinical diagnosis of AD in Japan. On the other hand, recent application of graph theory to MRI has made it possible to analyze changes in structural connectivity in AD.

  4. [Music therapy and Alzheimer disease].

    Science.gov (United States)

    Tromeur, Emilie

    2014-01-01

    Music therapy and Alzheimer's dementia. Dementia such as Alzheimer's leads to the deterioration of the patient's global capacities. The cognitive disorders associated with it are disabling and affect every area of the patient's life. Every therapy's session undertaken with and by patients can act as a mirror of the progress of their disease and help to feel better, as described in this article on music therapy.

  5. Alzheimer's Disease | NIH MedlinePlus the Magazine

    Science.gov (United States)

    ... of this page please turn JavaScript on. Feature: Alzheimer's Disease Living with Alzheimer's Disease Past Issues / Winter 2015 Table of Contents ... delay or prevent the disease. Free Guide for Alzheimer's Caregivers Caring for a person with Alzheimer's disease ...

  6. Resilience in caregivers of persons with Alzheimer's disease: A human condition to overcome caregiver vulnerability

    Directory of Open Access Journals (Sweden)

    Bernardino Fernández-Calvo

    Full Text Available Abstract In general, the experience of providing assistance to and dealing with the complications experienced by a person with Alzheimer's disease puts caregivers in a situation of high risk, vulnerability, and stress, causing serious physical and emotional problems. However, some caregivers adopt a resilient mindset, which helps them to experience and express positive feelings as well as lower their burden in relation to the care. This positive experience occurs because caregivers perceive the process of caring as less adverse. They face the situation of care with a more positive mindset and are able to resist and maintain adaptive functioning. The objective of the present narrative literature review was to emphasize the need to develop intervention programs for caregivers based on salutogenic models of resilience, resistance, and personal growth to promote positive individual, family, and community resources.

  7. Context memory in Alzheimer's disease

    NARCIS (Netherlands)

    El Haj, M.; Kessels, R.P.C.

    2013-01-01

    Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by a gradual loss of memory. Specifically, context aspects of memory are impaired in AD. Our review sheds light on the neurocognitive mechanisms of this memory component that forms the core of episodic memory function.

  8. The modeling of Alzheimer's disease by the overexpression of mutant Presenilin 1 in human embryonic stem cells.

    Science.gov (United States)

    Honda, Makoto; Minami, Itsunari; Tooi, Norie; Morone, Nobuhiro; Nishioka, Hisae; Uemura, Kengo; Kinoshita, Ayae; Heuser, John E; Nakatsuji, Norio; Aiba, Kazuhiro

    2016-01-15

    Cellular disease models are useful tools for Alzheimer's disease (AD) research. Pluripotent stem cells, including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), are promising materials for creating cellular models of such diseases. In the present study, we established cellular models of AD in hESCs that overexpressed the mutant Presenilin 1 (PS1) gene with the use of a site-specific gene integration system. The overexpression of PS1 did not affect the undifferentiated status or the neural differentiation ability of the hESCs. We found increases in the ratios of amyloid-β 42 (Aβ42)/Aβ40 and Aβ43/Aβ40. Furthermore, synaptic dysfunction was observed in a cellular model of AD that overexpressed mutant PS1. These results suggest that the AD phenotypes, in particular, the electrophysiological abnormality of the synapses in our AD models might be useful for AD research and drug discovery.

  9. MicroRNAs and their therapeutic potential for human diseases: aberrant microRNA expression in Alzheimer's disease brains.

    Science.gov (United States)

    Satoh, Jun-ichi

    2010-01-01

    MicroRNAs (miRNAs) are a group of small noncoding RNAs that regulate translational repression of multiple target mRNAs. The miRNAs in a whole cell regulate greater than 30% of all protein-coding genes. The vast majority of presently identified miRNAs are expressed in the brain in a spatially and temporally controlled manner. They play a key role in neuronal development, differentiation, and synaptic plasticity. However, at present, the pathological implications of deregulated miRNA expression in neurodegenerative diseases remain largely unknown. This review will briefly summarize recent studies that focus attention on aberrant miRNA expression in Alzheimer's disease brains.

  10. [Aluminum, hypothetic cause of Alzheimer disease].

    Science.gov (United States)

    Pailler, F M; Bequet, D; Corbé, H; Giudicelli, C P

    1995-03-11

    A great deal of research has focused on aluminium as a putative causative factor in Alzheimer's disease. We measured by atomic absorption spectrophotometry aluminium levels in blood, urine and cerebrospinal fluid from 15 patients with Alzheimer's disease, compared with 20 control individuals. There were no statistically significant differences between the two groups. This suggests that aluminium is not a causative factor for Alzheimer's disease.

  11. Neuronal differentiation of human mesenchymal stem cells: changes in the expression of the Alzheimer's disease-related gene seladin-1.

    Science.gov (United States)

    Benvenuti, Susanna; Saccardi, Riccardo; Luciani, Paola; Urbani, Serena; Deledda, Cristiana; Cellai, Ilaria; Francini, Fabio; Squecco, Roberta; Rosati, Fabiana; Danza, Giovanna; Gelmini, Stefania; Greeve, Isabell; Rossi, Matteo; Maggi, Roberto; Serio, Mario; Peri, Alessandro

    2006-08-01

    Seladin-1 (SELective Alzheimer's Disease INdicator-1) is an anti-apoptotic gene, which is down-regulated in brain regions affected by Alzheimer's disease (AD). In addition, seladin-1 catalyzes the conversion of desmosterol into cholesterol. Disruption of cholesterol homeostasis in neurons may increase cell susceptibility to toxic agents. Because the hippocampus and the subventricular zone, which are affected in AD, are the unique regions containing stem cells with neurogenic potential in the adult brain, it might be hypothesized that this multipotent cell compartment is the predominant source of seladin-1 in normal brain. In the present study, we isolated and characterized human mesenchymal stem cells (hMSC) as a model of cells with the ability to differentiate into neurons. hMSC were then differentiated toward a neuronal phenotype (hMSC-n). These cells were thoroughly characterized and proved to be neurons, as assessed by molecular and electrophysiological evaluation. Seladin-1 expression was determined and found to be significantly reduced in hMSC-n compared to undifferentiated cells. Accordingly, the total content of cholesterol was decreased after differentiation. These original results demonstrate for the first time that seladin-1 is abundantly expressed by stem cells and appear to suggest that reduced expression in AD might be due to an altered pool of multipotent cells.

  12. Genome instability in Alzheimer disease

    DEFF Research Database (Denmark)

    Hou, Yujun; Song, Hyundong; Croteau, Deborah L

    2017-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Autosomal dominant, familial AD (fAD) is very rare and caused by mutations in amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2 (PSEN-2) genes. The pathogenesis...

  13. Alzheimer's Disease Facts and Figures

    Medline Plus

    Full Text Available ... An estimated 5.5 million Americans of all ages have Alzheimer's disease. Of the estimated 5.5 ... in 2017, an estimated 5.3 million are age 65 and older and approximately 200,000 individuals ...

  14. Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer's disease.

    Science.gov (United States)

    Berchtold, Nicole C; Coleman, Paul D; Cribbs, David H; Rogers, Joseph; Gillen, Daniel L; Cotman, Carl W

    2013-06-01

    Synapses are essential for transmitting, processing, and storing information, all of which decline in aging and Alzheimer's disease (AD). Because synapse loss only partially accounts for the cognitive declines seen in aging and AD, we hypothesized that existing synapses might undergo molecular changes that reduce their functional capacity. Microarrays were used to evaluate expression profiles of 340 synaptic genes in aging (20-99 years) and AD across 4 brain regions from 81 cases. The analysis revealed an unexpectedly large number of significant expression changes in synapse-related genes in aging, with many undergoing progressive downregulation across aging and AD. Functional classification of the genes showing altered expression revealed that multiple aspects of synaptic function are affected, notably synaptic vesicle trafficking and release, neurotransmitter receptors and receptor trafficking, postsynaptic density scaffolding, cell adhesion regulating synaptic stability, and neuromodulatory systems. The widespread declines in synaptic gene expression in normal aging suggests that function of existing synapses might be impaired, and that a common set of synaptic genes are vulnerable to change in aging and AD.

  15. LDLR expression and localization are altered in mouse and human cell culture models of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Jose F Abisambra

    Full Text Available BACKGROUND: Alzheimer's disease (AD is a chronic neurodegenerative disorder and the most common form of dementia. The major molecular risk factor for late-onset AD is expression of the epsilon-4 allele of apolipoprotein E (apoE, the major cholesterol transporter in the brain. The low-density lipoprotein receptor (LDLR has the highest affinity for apoE and plays an important role in brain cholesterol metabolism. METHODOLOGY/PRINCIPAL FINDINGS: Using RT-PCR and western blotting techniques we found that over-expression of APP caused increases in both LDLR mRNA and protein levels in APP transfected H4 neuroglioma cells compared to H4 controls. Furthermore, immunohistochemical experiments showed aberrant localization of LDLR in H4-APP neuroglioma cells, Abeta-treated primary neurons, and in the PSAPP transgenic mouse model of AD. Finally, immunofluorescent staining of LDLR and of gamma- and alpha-tubulin showed a change in LDLR localization preferentially away from the plasma membrane that was paralleled by and likely the result of a disruption of the microtubule-organizing center and associated microtubule network. CONCLUSIONS/SIGNIFICANCE: These data suggest that increased APP expression and Abeta exposure alters microtubule function, leading to reduced transport of LDLR to the plasma membrane. Consequent deleterious effects on apoE uptake and function will have implications for AD pathogenesis and/or progression.

  16. Alzheimer's disease: analyzing the missing heritability.

    Directory of Open Access Journals (Sweden)

    Perry G Ridge

    Full Text Available Alzheimer's disease (AD is a complex disorder influenced by environmental and genetic factors. Recent work has identified 11 AD markers in 10 loci. We used Genome-wide Complex Trait Analysis to analyze >2 million SNPs for 10,922 individuals from the Alzheimer's Disease Genetics Consortium to assess the phenotypic variance explained first by known late-onset AD loci, and then by all SNPs in the Alzheimer's Disease Genetics Consortium dataset. In all, 33% of total phenotypic variance is explained by all common SNPs. APOE alone explained 6% and other known markers 2%, meaning more than 25% of phenotypic variance remains unexplained by known markers, but is tagged by common SNPs included on genotyping arrays or imputed with HapMap genotypes. Novel AD markers that explain large amounts of phenotypic variance are likely to be rare and unidentifiable using genome-wide association studies. Based on our findings and the current direction of human genetics research, we suggest specific study designs for future studies to identify the remaining heritability of Alzheimer's disease.

  17. Glycation in Parkinson's disease and Alzheimer's disease.

    Science.gov (United States)

    Vicente Miranda, Hugo; El-Agnaf, Omar M A; Outeiro, Tiago Fleming

    2016-06-01

    Glycation is a spontaneous age-dependent posttranslational modification that can impact the structure and function of several proteins. Interestingly, glycation can be detected at the periphery of Lewy bodies in the brain in Parkinson's disease. Moreover, α-synuclein can be glycated, at least under experimental conditions. In Alzheimer's disease, glycation of amyloid β peptide exacerbates its toxicity and contributes to neurodegeneration. Recent studies establish diabetes mellitus as a risk factor for several neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. However, the mechanisms underlying this connection remain unclear. We hypothesize that hyperglycemia might play an important role in the development of these disorders, possibly by also inducing protein glycation and thereby dysfunction, aggregation, and deposition. Here, we explore protein glycation as a common player in Parkinson's and Alzheimer's diseases and propose it may constitute a novel target for the development of strategies for neuroprotective therapeutic interventions. © 2016 International Parkinson and Movement Disorder Society.

  18. Turning principles into practice in Alzheimer's disease

    OpenAIRE

    Lindesay, James; Bullock, Roger; Daniels, Hugo; Emre, Murat; Förstl, Hans; Frölich, Lutz; Gabryelewicz, Tomasz; Martínez-Lage, Pablo; Monsch, Andreas; Tsolaki, Magda; van Laar, Teus

    2010-01-01

    Abstract The prevalence of dementia is reaching epidemic proportions globally, but there remain a number of issues that prevent people with dementia, their families and caregivers, from taking control of their condition. In 2008, Alzheimer?s Disease International (ADI) launched a Global Alzheimer?s Disease Charter, which comprises six principles that underscore the urgency for a more ambitious approach to diagnosis, treatment and care. This review highlights some of the most import...

  19. The discovery of Alzheimer's disease

    OpenAIRE

    Hippius, Hanns; Neundörfer, Gabriele

    2003-01-01

    On Novembers, 1306, a clinical psychiatrist and neuroanatomist, Alois Alzheimer, reported “A peculiar severe disease process of the cerebral cortex” to the 37th Meeting of South-West German Psychiatrists in Tubingen, He described a 50-year-old woman whom he had followed from her admission for paranoia, progressive sleep and memory disturbance, aggression, and confusion, until her death 5 years later. His report noted distinctive plaques and neurofibrillary tangles in the brain histology. It e...

  20. Cellular basis of Alzheimer's disease.

    Science.gov (United States)

    Bali, Jitin; Halima, Saoussen Ben; Felmy, Boas; Goodger, Zoe; Zurbriggen, Sebastian; Rajendran, Lawrence

    2010-12-01

    Alzheimer's disease (AD) is the most common form of neurodegenerative disease. A characteristic feature of the disease is the presence of amyloid-β (Aβ) which either in its soluble oligomeric form or in the plaque-associated form is causally linked to neurodegeneration. Aβ peptide is liberated from the membrane-spanning -amyloid precursor protein by sequential proteolytic processing employing β- and γ-secretases. All these proteins involved in the production of Aβ peptide are membrane associated and hence, membrane trafficking and cellular compartmentalization play important roles. In this review, we summarize the key cellular events that lead to the progression of AD.

  1. Human olfactory bulb neural stem cells expressing hNGF restore cognitive deficit in Alzheimer's disease rat model.

    Science.gov (United States)

    Marei, Hany E S; Farag, Amany; Althani, Asma; Afifi, Nahla; Abd-Elmaksoud, Ahmed; Lashen, Samah; Rezk, Shaymaa; Pallini, Roberto; Casalbore, Patrizia; Cenciarelli, Carlo

    2015-01-01

    In this study, we aim to demonstrate the fate of allogenic adult human olfactory bulb neural stem/progenitor cells (OBNSC/NPCs) transplanted into the rat hippocampus treated with ibotenic acid (IBO), a neurotoxicant specific to hippocampal cholinergic neurons that are lost in Alzheimer's disease. We assessed their possible ability to survive, integrate, proliferate, and differentiate into different neuronal and glial elements: we also evaluate their possible therapeutic potential, and the mechanism(s) relevant to neuroprotection following their engraftment into the CNS milieu. OBNSC/NPCs were isolated from adult human olfactory bulb patients, genetically engineered to express GFP and human nerve growth factor (hNGF) by lentivirus-mediated infection, and stereotaxically transplanted into the hippocampus of IBO-treated animals and controls. Stereological analysis of engrafted OBNSCs eight weeks post transplantation revealed a 1.89 fold increase with respect to the initial cell population, indicating a marked ability for survival and proliferation. In addition, 54.71 ± 11.38%, 30.18 ± 6.00%, and 15.09 ± 5.38% of engrafted OBNSCs were identified by morphological criteria suggestive of mature neurons, oligodendrocytes and astrocytes respectively. Taken together, this work demonstrated that human OBNSCs expressing NGF ameliorate the cognitive deficiencies associated with IBO-induced lesions in AD model rats, and the improvement can probably be attributed primarily to neuronal and glial cell replacement as well as the trophic influence exerted by the secreted NGF.

  2. Complement 3 and factor h in human cerebrospinal fluid in Parkinson's disease, Alzheimer's disease, and multiple-system atrophy.

    Science.gov (United States)

    Wang, Yu; Hancock, Aneeka M; Bradner, Joshua; Chung, Kathryn A; Quinn, Joseph F; Peskind, Elaine R; Galasko, Douglas; Jankovic, Joseph; Zabetian, Cyrus P; Kim, Hojoong M; Leverenz, James B; Montine, Thomas J; Ginghina, Carmen; Edwards, Karen L; Snapinn, Katherine W; Goldstein, David S; Shi, Min; Zhang, Jing

    2011-04-01

    Complement activation, a key component of neuroinflammation, has been reported in both Parkinson's disease (PD) and Alzheimer's disease (AD). However, it is unclear whether complement activation and neuroinflammation in general are distinctly different from each another in major neurodegenerative disorders. In the present study, cerebrospinal fluid complement 3 (C3) and factor H (FH) were measured and evaluated together with amyloid-β(42) (Aβ(42)), which in recent investigations was decreased in patients with PD, in particular those with cognitive impairment. The study included 345 participants: 126 patients with PD at various stages with or without cognitive impairment, 50 with AD, and 32 with multiple-system atrophy, and 137 healthy control individuals. In addition to changes in Aβ(42) concentrations, there were clear differences in the patterns of complement profiles among neurodegenerative disorders. The C3/FH ratio demonstrated high sensitivity and specificity in differentiating patients with multiple-system atrophy from those with AD or PD and control individuals. In addition, the C3/Aβ(42) and FH/Aβ(42) ratios not only correlated with PD severity approximated using the Unified Parkinson's Disease Rating Scale but also with the presence of cognitive impairment or dementia in PD. Both C3 and FH correlated with the severity of impairment in AD as indicated using Mini-Mental State Examination scores.

  3. Imaging the earliest stages of Alzheimer's disease.

    Science.gov (United States)

    Wu, William; Small, Scott A

    2006-12-01

    Historical progress in medicine can be charted along the lines of technical innovations that have visualized the invisible. One hundred years ago, Alois Alzheimer exploited newly developed histological stains to visualize his eponymonous disease in dead tissue under the microscope. Now, as we are entering the second century of Alzheimer's disease research, technical innovation has endowed us with a range of in vivo imaging techniques that promise to visualize Alzheimer' disease in living people. The earliest stage of Alzheimer's disease is characterized by cell-sickness, not cell-death, and can occur before the deposition of amyloid plaques or neurofibrillary tangles. In principle, 'functional' imaging techniques might be able to detect this early stage of the disease, a stage that was invisible to Alzheimer himself. Here, we will first define the neurobiological meaning of 'function' and then review the different approaches that measure brain dysfunction in Alzheimer' disease.

  4. Memory and consciousness in Alzheimer's disease.

    Science.gov (United States)

    Souchay, C; Moulin, C J A

    2009-06-01

    Human memory can be split into familiarity and recollection processes which contribute to different aspects of memory function. These separate processes result in different experiential states. In this review, we examine how this dominant theoretical framework can explain the subjective experience of people with Alzheimer's disease, the profile of their memory impairments and their inability to reflect on their performance metacognitively. We conclude with a brief overview of the brain regions supporting conscious experience of memory, and propose that the memory and awareness deficits seen in Alzheimer's disease could be conceived of as a deficit in autonoetic consciousness. A future priority for research is to take these robust constructs into research programmes examining rehabilitation and pharmacological intervention.

  5. Relation between nicotine intake and Alzheimer's disease.

    OpenAIRE

    1991-01-01

    OBJECTIVE--To study the association between Alzheimer's disease and nicotine intake through smoking. DESIGN--Population based case-control study. SETTING--City of Rotterdam and four northern provinces of The Netherlands. SUBJECTS--198 patients with early onset Alzheimer's disease, 198 controls matched for age and sex, and families of 17 patients in whom Alzheimer's disease was apparently inherited as an autosomal dominant disorder. MAIN OUTCOME MEASURES--Age of onset of dementia, relative ris...

  6. Alzheimer's disease and periodontitis - an elusive link

    Directory of Open Access Journals (Sweden)

    Abhijit N. Gurav

    2014-01-01

    Full Text Available Alzheimer's disease is the preeminent cause and commonest form of dementia. It is clinically characterized by a progressive descent in the cognitive function, which commences with deterioration in memory. The exact etiology and pathophysiologic mechanism of Alzheimer's disease is still not fully understood. However it is hypothesized that, neuroinflammation plays a critical role in the pathogenesis of Alzheimer's disease. Alzheimer's disease is marked by salient inflammatory features, characterized by microglial activation and escalation in the levels of pro-inflammatory cytokines in the affected regions. Studies have suggested a probable role of systemic infection conducing to inflammatory status of the central nervous system. Periodontitis is common oral infection affiliated with gram negative, anaerobic bacteria, capable of orchestrating localized and systemic infections in the subject. Periodontitis is known to elicit a "low grade systemic inflammation" by release of pro-inflammatory cytokines into systemic circulation. This review elucidates the possible role of periodontitis in exacerbating Alzheimer's disease. Periodontitis may bear the potential to affect the onset and progression of Alzheimer's disease. Periodontitis shares the two important features of Alzheimer's disease namely oxidative damage and inflammation, which are exhibited in the brain pathology of Alzheimer's disease. Periodontitis can be treated and hence it is a modifiable risk factor for Alzheimer's disease.

  7. Recent progress of PET in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Na NIU

    2014-03-01

    Full Text Available Alzheimer's disease is the most common cause of dementia in the current elderly population. PET can detect pathophysiological changes in Alzheimer's disease with different radiotracers. This paper will focus on evaluating the value of 18F-FDG, amyloid and tau protein PET imaging in Alzheimer's disease. PET has been demonstrated to play an important role in the research of etiology, early diagnosis, differential dignosis, prognosis and medical treatment of Alzheimer's disease. doi: 10.3969/j.issn.1672-6731.2014.03.007

  8. Alzheimer's Disease: Symptoms, Diagnosis and Treatment

    Science.gov (United States)

    ... page please turn Javascript on. Feature: Alzheimer's Disease Symptoms, Diagnosis and Treatment Past Issues / Fall 2010 Table of Contents Symptoms Scientists believe that changes in the brain may ...

  9. Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer's Disease.

    Science.gov (United States)

    McGinley, Lisa M; Sims, Erika; Lunn, J Simon; Kashlan, Osama N; Chen, Kevin S; Bruno, Elizabeth S; Pacut, Crystal M; Hazel, Tom; Johe, Karl; Sakowski, Stacey A; Feldman, Eva L

    2016-03-01

    Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder and a leading cause of dementia. Current treatment fails to modify underlying disease pathologies and very little progress has been made to develop effective drug treatments. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional single-target approaches. In amyotrophic lateral sclerosis, we have shown that transplanted spinal neural stem cells (NSCs) integrate into the spinal cord, form synapses with the host, improve inflammation, and reduce disease-associated pathologies. Our current goal is to develop a similar "best in class" cellular therapy for AD. Here, we characterize a novel human cortex-derived NSC line modified to express insulin-like growth factor-I (IGF-I), HK532-IGF-I. Because IGF-I promotes neurogenesis and synaptogenesis in vivo, this enhanced NSC line offers additional environmental enrichment, enhanced neuroprotection, and a multifaceted approach to treating complex AD pathologies. We show that autocrine IGF-I production does not impact the cell secretome or normal cellular functions, including proliferation, migration, or maintenance of progenitor status. However, HK532-IGF-I cells preferentially differentiate into gamma-aminobutyric acid-ergic neurons, a subtype dysregulated in AD; produce increased vascular endothelial growth factor levels; and display an increased neuroprotective capacity in vitro. We also demonstrate that HK532-IGF-I cells survive peri-hippocampal transplantation in a murine AD model and exhibit long-term persistence in targeted brain areas. In conclusion, we believe that harnessing the benefits of cellular and IGF-I therapies together will provide the optimal therapeutic benefit to patients, and our findings support further preclinical development of HK532-IGF-I cells into a disease-modifying intervention for AD.

  10. Asymmetric dimethylarginine exacerbates Aβ-induced toxicity and oxidative stress in human cell and Caenorhabditis elegans models of Alzheimer disease.

    Science.gov (United States)

    Luo, Yunfeng; Yue, Wenhui; Quan, Xin; Wang, Yue; Zhao, Baolu; Lu, Zhongbing

    2015-02-01

    Growing evidence suggests a strong association between cardiovascular risk factors and incidence of Alzheimer disease (AD). Asymmetric dimethylarginine (ADMA), the endogenous nitric oxide synthase inhibitor, has been identified as an independent cardiovascular risk factor and is also increased in plasma of patients with AD. However, whether ADMA is involved in the pathogenesis of AD is unknown. In this study, we found that ADMA content was increased in a transgenic Caenorhabditis elegans β-amyloid (Aβ) overexpression model, strain CL2006, and in human SH-SY5Y cells overexpressing the Swedish mutant form of human Aβ precursor protein (APPsw). Moreover, ADMA treatment exacerbated Aβ-induced paralysis and oxidative stress in CL2006 worms and further elevated oxidative stress and Aβ secretion in APPsw cells. Knockdown of type 1 protein arginine N-methyltransferase to reduce ADMA production failed to show a protective effect against Aβ toxicity, but resulted in more paralysis in CL2006 worms as well as increased oxidative stress and Aβ secretion in APPsw cells. However, overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1) to promote ADMA degradation significantly attenuated oxidative stress and Aβ secretion in APPsw cells. Collectively, our data support the hypothesis that elevated ADMA contributes to the pathogenesis of AD. Our findings suggest that strategies to increase DDAH1 activity in neuronal cells may be a novel approach to attenuating AD development.

  11. Quiz: Alzheimer's Disease | NIH MedlinePlus the Magazine

    Science.gov (United States)

    ... of this page please turn JavaScript on. Feature: Alzheimer's Disease Quiz: Alzheimer's Disease Past Issues / Winter 2015 Table of Contents ... How many Americans over age 65 may have Alzheimer's disease? as many as 5 million as many ...

  12. Molecular profiling reveals diversity of stress signal transduction cascades in highly penetrant Alzheimer's disease human skin fibroblasts.

    Directory of Open Access Journals (Sweden)

    Graziella Mendonsa

    Full Text Available The serious and growing impact of the neurodegenerative disorder Alzheimer's disease (AD as an individual and societal burden raises a number of key questions: Can a blanket test for Alzheimer's disease be devised forecasting long-term risk for acquiring this disorder? Can a unified therapy be devised to forestall the development of AD as well as improve the lot of present sufferers? Inflammatory and oxidative stresses are associated with enhanced risk for AD. Can an AD molecular signature be identified in signaling pathways for communication within and among cells during inflammatory and oxidative stress, suggesting possible biomarkers and therapeutic avenues? We postulated a unique molecular signature of dysfunctional activity profiles in AD-relevant signaling pathways in peripheral tissues, based on a gain of function in G-protein-coupled bradykinin B2 receptor (BKB2R inflammatory stress signaling in skin fibroblasts from AD patients that results in tau protein Ser hyperphosphorylation. Such a signaling profile, routed through both phosphorylation and proteolytic cascades activated by inflammatory and oxidative stresses in highly penetrant familial monogenic forms of AD, could be informative for pathogenesis of the complex multigenic sporadic form of AD. Comparing stimulus-specific cascades of signal transduction revealed a striking diversity of molecular signaling profiles in AD human skin fibroblasts that express endogenous levels of mutant presenilins PS-1 or PS-2 or the Trisomy 21 proteome. AD fibroblasts bearing the PS-1 M146L mutation associated with highly aggressive AD displayed persistent BKB2R signaling plus decreased ERK activation by BK, correctible by gamma-secretase inhibitor Compound E. Lack of these effects in the homologous PS-2 mutant cells indicates specificity of presenilin gamma-secretase catalytic components in BK signaling biology directed toward MAPK activation. Oxidative stress revealed a JNK-dependent survival

  13. Why industry propaganda and political interference cannot disguise the inevitable role played by human exposure to aluminum in neurodegenerative diseases, including Alzheimer's disease.

    Science.gov (United States)

    Exley, Christopher

    2014-01-01

    In the aluminum age, it is clearly unpalatable for aluminum, the globe's most successful metal, to be implicated in human disease. It is unpalatable because for approximately 100 years human beings have reaped the rewards of the most abundant metal of the Earth's crust without seriously considering the potential consequences for human health. The aluminum industry is a pillar of the developed and developing world and irrespective of the tyranny of human exposure to aluminum it cannot be challenged without significant consequences for businesses, economies, and governments. However, no matter how deep the dependency or unthinkable the withdrawal, science continues to document, if not too slowly, a burgeoning body burden of aluminum in human beings. Herein, I will make the case that it is inevitable both today and in the future that an individual's exposure to aluminum is impacting upon their health and is already contributing to, if not causing, chronic diseases such as Alzheimer's disease. This is the logical, if uncomfortable, consequence of living in the aluminum age.

  14. Brain Imaging in Alzheimer Disease

    Science.gov (United States)

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

    2012-01-01

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

  15. Turning principles into practice in Alzheimer's disease

    NARCIS (Netherlands)

    Lindesay, J.; Bullock, R.; Daniels, H.; Emre, M.; Foerstl, H.; Froelich, L.; Gabryelewicz, T.; Martinez-Lage, P.; Monsch, A. U.; Tsolaki, M.; van Laar, T.

    2010-01-01

    P>The prevalence of dementia is reaching epidemic proportions globally, but there remain a number of issues that prevent people with dementia, their families and caregivers, from taking control of their condition. In 2008, Alzheimer's Disease International (ADI) launched a Global Alzheimer's Disease

  16. Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease.

    Science.gov (United States)

    Zeineh, Michael M; Chen, Yuanxin; Kitzler, Hagen H; Hammond, Robert; Vogel, Hannes; Rutt, Brian K

    2015-09-01

    Although amyloid plaques and neurofibrillary pathology play important roles in Alzheimer disease (AD), our understanding of AD is incomplete, and the contribution of microglia and iron to neurodegeneration is unknown. High-field magnetic resonance imaging (MRI) is exquisitely sensitive to microscopic iron. To explore iron-associated neuroinflammatory AD pathology, we studied AD and control human brain specimens by (1) performing ultra-high resolution ex vivo 7 Tesla MRI, (2) coregistering the MRI with successive histologic staining for iron, microglia, amyloid beta, and tau, and (3) quantifying the relationship between magnetic resonance signal intensity and histological staining. In AD, we identified numerous small MR hypointensities primarily within the subiculum that were best explained by the combination of microscopic iron and activated microglia (p = 0.025), in contradistinction to the relatively lesser contribution of tau or amyloid. Neuropathologically, this suggests that microglial-mediated neurodegeneration may occur in the hippocampal formation in AD and is detectable by ultra-high resolution MRI.

  17. Lycopene attenuates Aβ1-42 secretion and its toxicity in human cell and Caenorhabditis elegans models of Alzheimer disease.

    Science.gov (United States)

    Chen, Wei; Mao, Liuqun; Xing, Huanhuan; Xu, Lei; Fu, Xiang; Huang, Liyingzi; Huang, Dongling; Pu, Zhijun; Li, Qinghua

    2015-11-03

    Growing evidence suggests concentration of lycopene was reduced in plasma of patients with Alzheimer disease (AD). Lycopene, a member of the carotenoid family, has been identified as an antioxidant to attenuate oxidative damage and has neuroprotective role in several AD models. However, whether lycopene is involved in the pathogenesis of AD and molecular underpinnings are elusive. In this study, we found that lycopene can significantly delay paralysis in the Aβ1-42-transgenic Caenorhabditis elegans strain GMC101. Lycopene treatment reduced Aβ1-42 secretion in SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw). Next, we found lycopene can down-regulate expression level of β-amyloid precursor protein(APP) in APPsw cells. Moreover, lycopene treatment can not change endogenous reactive oxygen species level and apoptosis in APPsw cells. However, lycopene treatment protected against H2O2-induced oxidative stress and copper-induced damage in APPsw cells. Collectively, our data support that elevated lycopene contributes to the lower pathogenesis of AD. Our findings suggest that increasing lycopene in neurons may be a novel approach to attenuate onset and development of AD.

  18. The Importance of Adipokines in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Seyid Ahmet Ay

    2015-06-01

    Full Text Available Dementia and Alzheimers disease are characterized by disturbances in brain function and structure. Similarly, body mass index and obesity are associated with certain brain pathologies, including Alzheimers disease and dementia. In fact, there is mounting evidence linking metabolic dysfunction with dementia and Alzheimers disease. Major endocrine axes constitute links between brain and peripheral tissues, especially adipose tissue. Adipose tissue is metabolically very active and produces a variety of adipokines known to affect both peripheral and central nervous system processes. Experimental studies suggest that changes in adipokine function may contribute to the pathogenesis of Alzheimers disease. Herein, we review the adipokines leptin and adiponectin which are associated with morbidities related to obesity as well as dementia and Alzheimers disease. [Dis Mol Med 2015; 3(2.000: 22-28

  19. 7 Warning Signs of Alzheimer's | Alzheimer's disease | NIH MedlinePlus the Magazine

    Science.gov (United States)

    ... of this page please turn Javascript on. Feature: Alzheimer's Disease 7 Warning Signs of Alzheimer's Past Issues / Fall 2010 Table of Contents The ... Suncoast Gerontology Center, University of South Florida. How Alzheimer's Changes the Brain The only definite way to ...

  20. APP processing in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Zhang Yun-wu

    2011-01-01

    Full Text Available Abstract An important pathological feature of Alzheimer's disease (AD is the presence of extracellular senile plaques in the brain. Senile plaques are composed of aggregations of small peptides called β-amyloid (Aβ. Multiple lines of evidence demonstrate that overproduction/aggregation of Aβ in the brain is a primary cause of AD and inhibition of Aβ generation has become a hot topic in AD research. Aβ is generated from β-amyloid precursor protein (APP through sequential cleavages first by β-secretase and then by γ-secretase complex. Alternatively, APP can be cleaved by α-secretase within the Aβ domain to release soluble APPα and preclude Aβ generation. Cleavage of APP by caspases may also contribute to AD pathologies. Therefore, understanding the metabolism/processing of APP is crucial for AD therapeutics. Here we review current knowledge of APP processing regulation as well as the patho/physiological functions of APP and its metabolites.

  1. Lipofuscin hypothesis of Alzheimer's disease.

    Science.gov (United States)

    Giaccone, Giorgio; Orsi, Laura; Cupidi, Chiara; Tagliavini, Fabrizio

    2011-01-01

    The primary culprit responsible for Alzheimer's disease (AD) remains unknown. Aβ protein has been identified as the main component of amyloid of senile plaques, the hallmark lesion of AD, but it is not definitively established whether the formation of extracellular Aβ deposits is the absolute harbinger of the series of pathological events that hit the brain in the course of sporadic AD. The aim of this paper is to draw attention to a relatively overlooked age-related product, lipofuscin, and advance the hypothesis that its release into the extracellular space following the death of neurons may substantially contribute to the formation of senile plaques. The presence of intraneuronal Aβ, similarities between AD and age-related macular degeneration, and the possible explanation of some of the unknown issues in AD suggest that this hypothesis should not be discarded out of hand.

  2. Advances in the study of Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Angue Nkoghe Francoise; Yunman Li

    2005-01-01

    Alzheimer's disease (AD) is the most common cause of dementia, and the only treatment currently available for the disease is acetylcholinesterase inhibitors. Recent progress in understanding the molecular and cellular pathophysiology of Alzheimer's disease has suggested possible pharmacological interventions, including acetylcholineseterase inhibitors; secretase inhibitors; cholesterol lowering drugs; metal chelators and amyloid immunization. The objective of this paper is to review the main drugs possibly used for AD and their future therapeutic effects.

  3. High field magnetic resonance microscopy of the human hippocampus in Alzheimer's disease: quantitative imaging and correlation with iron.

    Science.gov (United States)

    Antharam, Vijay; Collingwood, Joanna F; Bullivant, John-Paul; Davidson, Mark R; Chandra, Saurav; Mikhaylova, Albina; Finnegan, Mary E; Batich, Christopher; Forder, John R; Dobson, Jon

    2012-01-16

    We report R(2) and R(2) in human hippocampus from five unfixed post-mortem Alzheimer's disease (AD) and three age-matched control cases. Formalin-fixed tissues from opposing hemispheres in a matched AD and control were included for comparison. Imaging was performed in a 600MHz (14T) vertical bore magnet at MR microscopy resolution to obtain R(2) and R(2) (62 μm×62 μm in-plane, 80 μm slice thickness), and R(1) at 250 μm isotropic resolution. R(1), R(2) and R(2) maps were computed for individual slices in each case, and used to compare subfields between AD and controls. The magnitudes of R(2) and R(2) changed very little between AD and control, but their variances in the Cornu Ammonis and dentate gyrus were significantly higher in AD compared for controls (piron and MRI parameters, each tissue block was cryosectioned at 30 μm in the imaging plane, and iron distribution was mapped using synchrotron microfocus X-ray fluorescence spectroscopy. A positive correlation of R(2) and R(2)* with iron was demonstrated. While studies with fixed tissues are more straightforward to conduct, fixation can alter iron status in tissues, making measurement of unfixed tissue relevant. To our knowledge, these data represent an advance in quantitative imaging of hippocampal subfields in unfixed tissue, and the methods facilitate direct analysis of the relationship between MRI parameters and iron. The significantly increased variance in AD compared for controls warrants investigation at lower fields and in-vivo, to determine if this parameter is clinically relevant.

  4. Biological markers of Alzheimer?s disease

    Directory of Open Access Journals (Sweden)

    Leonardo Cruz de Souza

    2014-03-01

    Full Text Available The challenges for establishing an early diagnosis of Alzheimer’s disease (AD have created a need for biomarkers that reflect the core pathology of the disease. The cerebrospinal fluid (CSF levels of total Tau (T-tau, phosphorylated Tau (P-Tau and beta-amyloid peptide (Aβ42 reflect, respectively, neurofibrillary tangle and amyloid pathologies and are considered as surrogate markers of AD pathophysiology. The combination of low Aβ42 and high levels of T-tau and P-Tau can accurately identify patients with AD at early stages, even before the development of dementia. The combined analysis of the CSF biomarkers is also helpful for the differential diagnosis between AD and other degenerative dementias. The development of these CSF biomarkers has evolved to a novel diagnostic definition of the disease. The identification of a specific clinical phenotype combined with the in vivo evidence of pathophysiological markers offers the possibility to make a diagnosis of AD before the dementia stage with high specificity.

  5. The economic costs of Alzheimer's disease.

    Science.gov (United States)

    Hay, J W; Ernst, R L

    1987-09-01

    This paper estimates the economic costs of Alzheimer's Disease to individuals and to society, based on review of published Alzheimer's Disease-related research. The analysis is derived from epidemiological projections and cost information for the United States population in 1983. Estimated costs include both direct medical care and social support costs, as well as indirect costs, such as support services provided by family or volunteers, and the value of lost economic productivity in Alzheimer's Disease patients. Mid-range estimates of net annual expected costs for an Alzheimer's Disease patient, excluding the value of lost productivity, are $18,517 in the first year and $17,643 in subsequent years, with direct medical and social services comprising about half of these costs. Under base case assumptions, the total cost of disease per patient in 1983, was $48,544 to $493,277, depending upon patient's age at disease onset. The estimated present value of total net costs to society for all persons first diagnosed with Alzheimer's Disease in 1983 was $27.9-31.2 billion. Development of a public or private insurance market for the economic burdens of Alzheimer's Disease would fill some of the gaps in the current US system of financing long-term chronic disease care.

  6. Diazepam-binding inhibitor. A brain neuropeptide present in human spinal fluid: studies in depression, schizophrenia, and Alzheimer's disease.

    Science.gov (United States)

    Barbaccia, M L; Costa, E; Ferrero, P; Guidotti, A; Roy, A; Sunderland, T; Pickar, D; Paul, S M; Goodwin, F K

    1986-12-01

    Diazepam-binding inhibitor is a novel peptide purified to homogeneity from rat and human brain. Diazepam-binding inhibitor is present, though not exclusively, in gamma-aminobutyric acid (GABA)-containing neurons where it is believed to inhibit GABAergic neurotransmission mediated by GABA by binding to the benzodiazepine-GABA receptor complex. Since an impairment of central GABAergic tone has been postulated to be associated with a number of neuropsychiatric disorders, we measured human diazepam-binding inhibitor immunoreactivity in the cerebrospinal fluid (CSF) of patients suffering from endogenous depression, schizophrenia, and dementia of the Alzheimer's type. Patients with major depression had significantly higher concentrations of human diazepam-binding inhibitor immunoreactivity in CSF when compared with age- and sex-matched normal volunteers, while no difference in CSF diazepam-binding inhibitor immunoreactivity was found in schizophrenics or patients with dementia of the Alzheimer's type when compared with controls. The possibility is discussed that the increased CSF human diazepam-binding inhibitor immunoreactivity observed in depressed patients may represent a functional disinhibition of GABAergic neurotransmission associated with depression.

  7. Education and the risk for Alzheimer's disease

    DEFF Research Database (Denmark)

    Letenneur, L; Launer, L J; Andersen, K

    2000-01-01

    The hypothesis that a low educational level increases the risk for Alzheimer's disease remains controversial. The authors studied the association of years of schooling with the risk for incident dementia and Alzheimer's disease by using pooled data from four European population-based follow......-up studies. Dementia cases were identified in a two-stage procedure that included a detailed diagnostic assessment of screen-positive subjects. Dementia and Alzheimer's disease were diagnosed by using international research criteria. Educational level was categorized by years of schooling as low (...), middle (8-11), or high (> or =12). Relative risks (95% confidence intervals) were estimated by using Poisson regression, adjusting for age, sex, study center, smoking status, and self-reported myocardial infarction and stroke. There were 493 (328) incident cases of dementia (Alzheimer's disease) and 28...

  8. Lithium May Fend off Alzheimer's Disease

    Institute of Scientific and Technical Information of China (English)

    Helen Pilcher; 夏红

    2004-01-01

    @@ Lithium, a common treatment for manic depression, might also help to stave off②Alzheimer's disease. Patients who take the drug to stabilize their mood disorder are less likely to succumb to dementia③, a study reveals.

  9. Ferric cycle activity and Alzheimer disease.

    Science.gov (United States)

    Dwyer, Barney E; Takeda, Atsushi; Zhu, Xiongwei; Perry, George; Smith, Mark A

    2005-07-01

    Elevated plasma homocysteine is an independent risk factor for the development of Alzheimer disease, however, the precise mechanisms underlying this are unclear. In this article, we expound on a novel hypothesis depicting the involvement of homocysteine in a vicious circle involving iron dysregulation and oxidative stress designated as the ferric cycle (Dwyer et al., 2004). Moreover, we suspect that the development of a critical heme deficiency in vulnerable neurons is an additional consequence of ferric cycle activity. Oxidative stress and heme deficiency are consistent with many pathological changes found in Alzheimer disease including mitochondrial abnormalities and impaired energy metabolism, cell cycle and cell signaling abnormalities, neuritic pathology, and other features of the disease involving alterations in iron homeostasis such as the abnormal expression of heme oxygenase-1 and iron response protein 2. Based on the ferric cycle concept, we have developed a model of Alzheimer disease development and progression, which offers an explanation for why sporadic Alzheimer disease is different than normal aging and why familial Alzheimer disease and sporadic Alzheimer disease could have different etiologies but a common end-stage.

  10. Periodontitis and Cognitive Decline in Alzheimer's Disease.

    Directory of Open Access Journals (Sweden)

    Mark Ide

    Full Text Available Periodontitis is common in the elderly and may become more common in Alzheimer's disease because of a reduced ability to take care of oral hygiene as the disease progresses. Elevated antibodies to periodontal bacteria are associated with an increased systemic pro-inflammatory state. Elsewhere raised serum pro-inflammatory cytokines have been associated with an increased rate of cognitive decline in Alzheimer's disease. We hypothesized that periodontitis would be associated with increased dementia severity and a more rapid cognitive decline in Alzheimer's disease. We aimed to determine if periodontitis in Alzheimer's disease is associated with both increased dementia severity and cognitive decline, and an increased systemic pro inflammatory state. In a six month observational cohort study 60 community dwelling participants with mild to moderate Alzheimer's Disease were cognitively assessed and a blood sample taken for systemic inflammatory markers. Dental health was assessed by a dental hygienist, blind to cognitive outcomes. All assessments were repeated at six months. The presence of periodontitis at baseline was not related to baseline cognitive state but was associated with a six fold increase in the rate of cognitive decline as assessed by the ADAS-cog over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state over the six month follow up period. Our data showed that periodontitis is associated with an increase in cognitive decline in Alzheimer's Disease, independent to baseline cognitive state, which may be mediated through effects on systemic inflammation.

  11. Periodontitis and Cognitive Decline in Alzheimer's Disease.

    Science.gov (United States)

    Ide, Mark; Harris, Marina; Stevens, Annette; Sussams, Rebecca; Hopkins, Viv; Culliford, David; Fuller, James; Ibbett, Paul; Raybould, Rachel; Thomas, Rhodri; Puenter, Ursula; Teeling, Jessica; Perry, V Hugh; Holmes, Clive

    2016-01-01

    Periodontitis is common in the elderly and may become more common in Alzheimer's disease because of a reduced ability to take care of oral hygiene as the disease progresses. Elevated antibodies to periodontal bacteria are associated with an increased systemic pro-inflammatory state. Elsewhere raised serum pro-inflammatory cytokines have been associated with an increased rate of cognitive decline in Alzheimer's disease. We hypothesized that periodontitis would be associated with increased dementia severity and a more rapid cognitive decline in Alzheimer's disease. We aimed to determine if periodontitis in Alzheimer's disease is associated with both increased dementia severity and cognitive decline, and an increased systemic pro inflammatory state. In a six month observational cohort study 60 community dwelling participants with mild to moderate Alzheimer's Disease were cognitively assessed and a blood sample taken for systemic inflammatory markers. Dental health was assessed by a dental hygienist, blind to cognitive outcomes. All assessments were repeated at six months. The presence of periodontitis at baseline was not related to baseline cognitive state but was associated with a six fold increase in the rate of cognitive decline as assessed by the ADAS-cog over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state over the six month follow up period. Our data showed that periodontitis is associated with an increase in cognitive decline in Alzheimer's Disease, independent to baseline cognitive state, which may be mediated through effects on systemic inflammation.

  12. [Western diet and Alzheimer's disease].

    Science.gov (United States)

    Berrino, Franco

    2002-01-01

    Alzheimer Disease, characterised by a global impairment of cognitive functions, is more and more common in Western societies, both because of longer life expectancy and, probably, because of increasing incidence. Several hints suggest that this degenerative disease is linked to western diet, characterised by excessive dietary intake of sugar, refined carbohydrates (with high glycaemic index), and animal product (with high content of saturated fats), and decreased intake of unrefined seeds--cereals, legumes, and oleaginous seeds--and other vegetables (with high content of fibres, vitamins, polyphenols and other antioxidant substances, phytoestrogens) and, in several populations, of sea food (rich in n-3 fatty acids). It has been hypothesised, in fact, that AD, may be promoted by insulin resistance, decreased endothelial production of nitric oxide, free radical excess, inflammatory metabolites, homocysteine, and oestrogen deficiency. AD, therefore, could theoretically be prevented (or delayed) by relatively simple dietary measures aimed at increasing insulin sensitivity (trough reduction of refined sugars and saturated fats from meat and dairy products), the ratio between n-3 and n-6 fatty acids (e.g. from fish and respectively seed oils), antioxidant vitamins, folic acid, vitamin B6, phytoestrogens (vegetables, whole cereals, and legumes, including soy products), vitamin B12 (bivalve molluscs, liver), and Cr, K, Mg, and Si salts. This comprehensive improvement of diet would fit with all the mechanistic hypotheses cited above. Several studies, on the contrary, are presently exploring monofactorial preventive strategies with specific vitamin supplementation or hormonal drugs, without, however, appreciable results.

  13. Does prevention for Alzheimer's disease exist?

    OpenAIRE

    Sonia Maria Dozzi Brucki

    2009-01-01

    Abstract The prevention of Alzheimer's disease is a growing public health concern amidst an ageing population. Meanwhile, there is no effective or curative treatment available where prevention could greatly reduce health costs. This review was based on reports of potential preventive factors, including modifiable lifestyle factors, as well as preventive pharmacological strategies. Although the present review was not systematic, the reports selected from PubMed using "Alzheimer's disease" and ...

  14. Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Goldsteins Gundars

    2010-12-01

    Full Text Available Abstract Background Purified intravenous immunoglobulin (IVIG obtained from the plasma of healthy humans is indicated for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity. IVIG contains naturally occurring auto-antibodies, including antibodies (Abs against β-amyloid (Aβ peptides accumulating in the brains of Alzheimer's disease (AD patients. IVIG has been shown to alleviate AD pathology when studied with mildly affected AD patients. Although its mechanisms-of-action have been broadly studied, it remains unresolved how IVIG affects the removal of natively formed brain Aβ deposits by primary astrocytes and microglia, two major cell types involved in the neuroinflammatory responses. Methods We first determined the effect of IVIG on Aβ toxicity in primary neuronal cell culture. The mechanisms-of-action of IVIG in reduction of Aβ burden was analyzed with ex vivo assay. We studied whether IVIG solubilizes natively formed Aβ deposits from brain sections of APP/PS1 mice or promotes Aβ removal by primary glial cells. We determined the role of lysosomal degradation pathway and Aβ Abs in the IVIG-promoted reduction of Aβ. Finally, we studied the penetration of IVIG into the brain parenchyma and interaction with brain deposits of human Aβ in a mouse model of AD in vivo. Results IVIG was protective against Aβ toxicity in a primary mouse hippocampal neuron culture. IVIG modestly inhibited the fibrillization of synthetic Aβ1-42 but did not solubilize natively formed brain Aβ deposits ex vivo. IVIG enhanced microglia-mediated Aβ clearance ex vivo, with a mechanism linked to Aβ Abs and lysosomal degradation. The IVIG-enhanced Aβ clearance appears specific for microglia since IVIG did not affect Aβ clearance by astrocytes. The cellular mechanisms of Aβ clearance we observed have potential relevance in vivo since after peripheral administration IVIG penetrated to mouse brain tissue reaching highest

  15. Molecular imaging of Alzheimer disease pathology.

    Science.gov (United States)

    Kantarci, K

    2014-06-01

    Development of molecular imaging agents for fibrillar β-amyloid positron-emission tomography during the past decade has brought molecular imaging of Alzheimer disease pathology into the spotlight. Large cohort studies with longitudinal follow-up in cognitively normal individuals and patients with mild cognitive impairment and Alzheimer disease indicate that β-amyloid deposition can be detected many years before the onset of symptoms with molecular imaging, and its progression can be followed longitudinally. The utility of β-amyloid PET in the differential diagnosis of Alzheimer disease is greatest when there is no pathologic overlap between 2 dementia syndromes, such as in frontotemporal lobar degeneration and Alzheimer disease. However β-amyloid PET alone may be insufficient in distinguishing dementia syndromes that commonly have overlapping β-amyloid pathology, such as dementia with Lewy bodies and vascular dementia, which represent the 2 most common dementia pathologies after Alzheimer disease. The role of molecular imaging in Alzheimer disease clinical trials is growing rapidly, especially in an era when preventive interventions are designed to eradicate the pathology targeted by molecular imaging agents.

  16. 2016 Alzheimer's disease facts and figures.

    Science.gov (United States)

    2016-04-01

    This report describes the public health impact of Alzheimer's disease, including incidence and prevalence, mortality rates, costs of care, and the overall impact on caregivers and society. It also examines in detail the financial impact of Alzheimer's on families, including annual costs to families and the difficult decisions families must often make to pay those costs. An estimated 5.4 million Americans have Alzheimer's disease. By mid-century, the number of people living with Alzheimer's disease in the United States is projected to grow to 13.8 million, fueled in large part by the aging baby boom generation. Today, someone in the country develops Alzheimer's disease every 66 seconds. By 2050, one new case of Alzheimer's is expected to develop every 33 seconds, resulting in nearly 1 million new cases per year. In 2013, official death certificates recorded 84,767 deaths from Alzheimer's disease, making it the sixth leading cause of death in the United States and the fifth leading cause of death in Americans age ≥ 65 years. Between 2000 and 2013, deaths resulting from stroke, heart disease, and prostate cancer decreased 23%, 14%, and 11%, respectively, whereas deaths from Alzheimer's disease increased 71%. The actual number of deaths to which Alzheimer's disease contributes is likely much larger than the number of deaths from Alzheimer's disease recorded on death certificates. In 2016, an estimated 700,000 Americans age ≥ 65 years will die with Alzheimer's disease, and many of them will die because of the complications caused by Alzheimer's disease. In 2015, more than 15 million family members and other unpaid caregivers provided an estimated 18.1 billion hours of care to people with Alzheimer's and other dementias, a contribution valued at more than $221 billion. Average per-person Medicare payments for services to beneficiaries age ≥ 65 years with Alzheimer's disease and other dementias are more than two and a half times as great as payments for all

  17. New cardiovascular targets to prevent late onset Alzheimer disease.

    Science.gov (United States)

    Claassen, Jurgen A H R

    2015-09-15

    The prevalence of dementia rises to between 20% and 40% with advancing age. The dominant cause of dementia in approximately 70% of these patients is Alzheimer disease. There is no effective disease-modifying pharmaceutical treatment for this neurodegenerative disease. A wide range of Alzheimer drugs that appeared effective in animal models have recently failed to show clinical benefit in patients. However, hopeful news has emerged from recent studies that suggest that therapeutic strategies aimed at reducing cardiovascular disease may also reduce the prevalence of dementia due to Alzheimer disease. This review summarizes the evidence for this link between cardiovascular disease and late onset Alzheimer dementia. Only evidence from human research is considered here. Longitudinal studies show an association between high blood pressure and pathological accumulation of the protein amyloid-beta42, and an even stronger association between vascular stiffness and amyloid accumulation, in elderly subjects. Amyloid-beta42 accumulation is considered to be an early marker of Alzheimer disease, and increases the risk of subsequent cognitive decline and development of dementia. These observations could provide an explanation for recent observations of reduced dementia prevalence associated with improved cardiovascular care.

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

    Science.gov (United States)

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

    2017-03-01

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

  19. Inductive reasoning in Alzheimer's disease.

    Science.gov (United States)

    Smith, E E; Rhee, J; Dennis, K; Grossman, M

    2001-12-01

    We evaluated knowledge of basic level and superordinate semantic relations and the role of cognitive resources during inductive reasoning in probable Alzheimer's disease (AD). Nineteen mildly demented AD patients and 17 healthy control subjects judged the truthfulness of arguments with a premise and a conclusion that contain familiar concepts coupled with "blank" predicates, such as "Spiders contain phosphatidylcholine; therefore all insects contain phosphatidylcholine." Like healthy control subjects, AD patients were relatively insensitive to the typicality of the premise category when judging the strength of arguments with a conclusion containing a basic-level concept, but were relatively sensitive to typicality during judgments of arguments containing a superordinate in the conclusion. Moreover, AD patients resembled control subjects in judging arguments with an immediate superordinate in the conclusion compared to arguments with a distant superordinate. AD patients differed from control subjects because they could not take advantage of two premises in an argument containing basic-level concepts. We conclude that semantic knowledge is sufficiently preserved in AD to support inductive reasoning, but that limited cognitive resources may interfere with AD patients' ability to consider the entire spectrum of information available during semantic challenges.

  20. The burden of Alzheimer's disease.

    Science.gov (United States)

    Burns, Alistair

    2000-07-01

    Alzheimer's disease (AD) imposes a severe burden upon patients and their carers. In particular, family carers of AD patients face extreme hardship and distress that represents a major but often hidden burden on healthcare systems. Carers often experience clinically significant alterations in physical and mental health, particularly depression. A number of individual features of the dementia syndrome that are known to be particularly burdensome to carers include the degree of cognitive impairment, amount of help required with activities of daily living, personality changes and the presence of psychiatric symptoms and behavioural disturbances. The neuropsychiatric features of AD patients can adversely impact the relationship between the patient and caregiver generating feelings of strain, burden and social isolation. Individual characteristics of the caregiver including personality, gender, degree of formal and informal support and physical and mental health, as well as attributional style ('coping style') and expressed emotion (critical or hostile attitudes), also dictate carer burden. As informal caregivers play such a crucial role in the care of AD patients, appropriate management strategies that incorporate interventions which address the specific burdens of the individual caregiver are essential. Reducing the burden of care can be achieved by the combination of a number of individual and general measures, including education, respite and emotion-focused interventions. These measures, accompanied by non-pharmacological strategies, are extremely important in the total care of the AD patient, with the emphasis on maintaining people in the community as long as possible.

  1. Alzheimer's Disease Facts and Figures

    Medline Plus

    Full Text Available ... Almost two-thirds of Americans with Alzheimer's are women. African-Americans are about twice as likely to ... 1 billion. Approximately two-thirds of caregivers are women, and 34 percent are age 65 or older. ...

  2. Alzheimer's Disease Facts and Figures

    Medline Plus

    Full Text Available ... to those with Alzheimer's and other dementias, a contribution to the nation valued at $230.1 billion. ... NIA-AA) 2011 workgroup and the International Work Group (IWG) have proposed guidelines that use detectable measures ...

  3. The pilot European Alzheimer's Disease Neuroimaging Initiative of the European Alzheimer's Disease Consortium

    DEFF Research Database (Denmark)

    Frisoni, G.B.; Henneman, W.J.; Weiner, M.W.

    2008-01-01

    BACKGROUND: In North America, the Alzheimer's Disease Neuroimaging Initiative (ADNI) has established a platform to track the brain changes of Alzheimer's disease. A pilot study has been carried out in Europe to test the feasibility of the adoption of the ADNI platform (pilot E-ADNI). METHODS: Sev...

  4. Oxidative stress and Alzheimer disease.

    Science.gov (United States)

    Christen, Y

    2000-02-01

    Research in the field of molecular biology has helped to provide a better understanding of both the cascade of biochemical events that occurs with Alzheimer disease (AD) and the heterogeneous nature of the disease. One hypothesis that accounts for both the heterogeneous nature of AD and the fact that aging is the most obvious risk factor is that free radicals are involved. The probability of this involvement is supported by the fact that neurons are extremely sensitive to attacks by destructive free radicals. Furthermore, lesions are present in the brains of AD patients that are typically associated with attacks by free radicals (eg, damage to DNA, protein oxidation, lipid peroxidation, and advanced glycosylation end products), and metals (eg, iron, copper, zinc, and aluminum) are present that have catalytic activity that produce free radicals. beta-Amyloid is aggregated and produces more free radicals in the presence of free radicals; beta-amyloid toxicity is eliminated by free radical scavengers. Apolipoprotein E is subject to attacks by free radicals, and apolipoprotein E peroxidation has been correlated with AD. In contrast, apolipoprotein E can act as a free radical scavenger and this behavior is isoform dependent. AD has been linked to mitochondrial anomalies affecting cytochrome-c oxidase, and these anomalies may contribute to the abnormal production of free radicals. Finally, many free radical scavengers (eg, vitamin E, selegeline, and Ginkgo biloba extract EGb 761) have produced promising results in relation to AD, as has desferrioxamine-an iron-chelating agent-and antiinflammatory drugs and estrogens, which also have an antioxidant effect.

  5. Stem cell treatment for Alzheimer's disease.

    Science.gov (United States)

    Li, Ming; Guo, Kequan; Ikehara, Susumu

    2014-10-23

    Alzheimer's disease (AD) is a progressive and neurodegenerative disorder that induces dementia in older people. It was first reported in 1907 by Alois Alzheimer, who characterized the disease as causing memory loss and cognitive impairment. Pathologic characteristics of AD are β-amyloid plaques, neurofibrillary tangles and neurodegeneration. Current therapies only target the relief of symptoms using various drugs, and do not cure the disease. Recently, stem cell therapy has been shown to be a potential approach to various diseases, including neurodegenerative disorders, and in this review, we focus on stem cell therapies for AD.

  6. Assessing neuronal networks: understanding Alzheimer's disease.

    LENUS (Irish Health Repository)

    Bokde, Arun L W

    2012-02-01

    Findings derived from neuroimaging of the structural and functional organization of the human brain have led to the widely supported hypothesis that neuronal networks of temporally coordinated brain activity across different regional brain structures underpin cognitive function. Failure of integration within a network leads to cognitive dysfunction. The current discussion on Alzheimer\\'s disease (AD) argues that it presents in part a disconnection syndrome. Studies using functional magnetic resonance imaging, positron emission tomography and electroencephalography demonstrate that synchronicity of brain activity is altered in AD and correlates with cognitive deficits. Moreover, recent advances in diffusion tensor imaging have made it possible to track axonal projections across the brain, revealing substantial regional impairment in fiber-tract integrity in AD. Accumulating evidence points towards a network breakdown reflecting disconnection at both the structural and functional system level. The exact relationship among these multiple mechanistic variables and their contribution to cognitive alterations and ultimately decline is yet unknown. Focused research efforts aimed at the integration of both function and structure hold great promise not only in improving our understanding of cognition but also of its characteristic progressive metamorphosis in complex chronic neurodegenerative disorders such as AD.

  7. Biomarkers for early detection of Alzheimer disease.

    Science.gov (United States)

    Barber, Robert C

    2010-09-01

    The existence of an effective biomarker for early detection of Alzheimer disease would facilitate improved diagnosis and stimulate therapeutic trials. Multidisciplinary clinical diagnosis of Alzheimer disease is time consuming and expensive and relies on experts who are rarely available outside of specialty clinics. Thus, many patients do not receive proper diagnosis until the disease has progressed beyond stages in which treatments are maximally effective. In the clinical trial setting, rapid, cost-effective screening of patients for Alzheimer disease is of paramount importance for the development of new treatments. Neuroimaging of cortical amyloid burden and volumetric changes in the brain and assessment of protein concentrations (eg, β-amyloid 1-42, total tau, phosphorylated tau) in cerebrospinal fluid are diagnostic tools that are not widely available. Known genetic markers do not provide sufficient discriminatory power between different forms of dementia to be useful in isolation. Recent studies using panels of biomarkers for diagnosis of Alzheimer disease or mild cognitive impairment have been promising, though no such studies have been cross-validated in independent samples of subjects. The ideal biomarker enabling early detection of Alzheimer disease has not yet been identified.

  8. Targeting synaptic dysfunction in Alzheimer's disease therapy.

    Science.gov (United States)

    Nisticò, Robert; Pignatelli, Marco; Piccinin, Sonia; Mercuri, Nicola B; Collingridge, Graham

    2012-12-01

    In the past years, major efforts have been made to understand the genetics and molecular pathogenesis of Alzheimer's disease (AD), which has been translated into extensive experimental approaches aimed at slowing down or halting disease progression. Advances in transgenic (Tg) technologies allowed the engineering of different mouse models of AD recapitulating a range of AD-like features. These Tg models provided excellent opportunities to analyze the bases for the temporal evolution of the disease. Several lines of evidence point to synaptic dysfunction as a cause of AD and that synapse loss is a pathological correlate associated with cognitive decline. Therefore, the phenotypic characterization of these animals has included electrophysiological studies to analyze hippocampal synaptic transmission and long-term potentiation, a widely recognized cellular model for learning and memory. Transgenic mice, along with non-Tg models derived mainly from exogenous application of Aβ, have also been useful experimental tools to test the various therapeutic approaches. As a result, numerous pharmacological interventions have been reported to attenuate synaptic dysfunction and improve behavior in the different AD models. To date, however, very few of these findings have resulted in target validation or successful translation into disease-modifying compounds in humans. Here, we will briefly review the synaptic alterations across the different animal models and we will recapitulate the pharmacological strategies aimed at rescuing hippocampal plasticity phenotypes. Finally, we will highlight intrinsic limitations in the use of experimental systems and related challenges in translating preclinical studies into human clinical trials.

  9. Nicotine binding in human striatum: elevation in schizophrenia and reductions in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease and in relation to neuroleptic medication.

    Science.gov (United States)

    Court, J A; Piggott, M A; Lloyd, S; Cookson, N; Ballard, C G; McKeith, I G; Perry, R H; Perry, E K

    2000-01-01

    Striatal nicotinic acetylcholine receptors with high affinity for nicotinic agonists are involved with the release of a number of neurotransmitters, including dopamine. Previous findings as to whether these receptors are changed in Parkinson's disease and Alzheimer's disease are inconsistent and no previous investigations have focused on these receptors in dementia with Lewy bodies and schizophrenia, which are also associated with disorders of movement. The present autoradiographic study of striatal [3H]nicotine binding in Alzheimer's and Parkinson's diseases, dementia with Lewy bodies and schizophrenia was conducted with particular reference to the potentially confounding variables of tobacco use and neuroleptic medication. [3H]Nicotine binding in both dorsal and ventral caudate and putamen was significantly reduced in Parkinson's disease (43-67%, n=13), Alzheimer's disease (29-37%, n=13) and dementia with Lewy bodies (50-61%, n=20) compared to age-matched controls (n=42). Although tobacco use in the control group was associated with increased [3H]nicotine binding (21-38%), and neuroleptic treatment in dementia with Lewy bodies and Alzheimer's disease was associated with reduced [3H]nicotine binding (up to 29%), differences between neurodegenerative disease groups and controls persisted in subgroups of Alzheimer's disease cases (26-33%, n=6, in the ventral striatum) and dementia with Lewy body cases (30-49%, n=7, in both dorsal and ventral striatum) who had received no neuroleptic medication compared to controls who had not smoked (n=10). In contrast, striatal [3H]nicotine binding in a group of elderly (56-85 years) chronically medicated individuals with schizophrenia (n=6) was elevated compared with the entire control group (48-78%, n=42) and with a subgroup that had smoked (24-49%, n=8). The changes observed in [3H]nicotine binding are likely to reflect the presence of these receptors on multiple sites within the striatum, which may be differentially modulated

  10. Imaging markers for Alzheimer disease

    Science.gov (United States)

    Bocchetta, Martina; Chételat, Gael; Rabinovici, Gil D.; de Leon, Mony J.; Kaye, Jeffrey; Reiman, Eric M.; Scheltens, Philip; Barkhof, Frederik; Black, Sandra E.; Brooks, David J.; Carrillo, Maria C.; Fox, Nick C.; Herholz, Karl; Nordberg, Agneta; Jack, Clifford R.; Jagust, William J.; Johnson, Keith A.; Rowe, Christopher C.; Sperling, Reisa A.; Thies, William; Wahlund, Lars-Olof; Weiner, Michael W.; Pasqualetti, Patrizio; DeCarli, Charles

    2013-01-01

    Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, 18F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured (“metric”: visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR−), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR− between 0.25 and 0.08, whereas prognostic LR+ and LR− were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR− from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR−. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR−. Within markers, the largest proportion of diagnostic LR+ and LR− variability was within 18F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials. PMID:23897875

  11. Immunotherapeutic Strategies for Alzheimer's Disease Treatment

    Directory of Open Access Journals (Sweden)

    Beka Solomon

    2009-01-01

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

  12. Geriatric Dentistry and the Alzheimer Disease

    Directory of Open Access Journals (Sweden)

    Marcelo Coelho GOIATO

    2006-08-01

    Full Text Available Introduction: The world population is getting old, mainly in countries in development like Brazil. So, the number of pathologies, which appears in the elderly, will happen in a higher frequency. Among these diseases, we can point Alzheimer, an irreversible dementia, that has been related to age, cerebral vascular disease, stroke, immunological defects and to genetic factors (Down Syndrome. It is known that with the progression of dementia, patients present difficulties of oral hygiene caused by decrease of motor and cognitive functions of Alzheimer's bearers. These patients demand specific strategies for a dental treatment without bigger difficulties. Objective: the aim of this paper was to review the articles about the relationship of geriatric dentistry and Alzheimer disease focusing and the characteristics of the patients with this kind of dementia and the cares to them. For this purpose, a peer-reviewed literature was completed using Medline database for the period from 1972 to 2006, including alzheimer disease and dentistry, and BBO for the period from 1987 to 2004, with geriatric keyword. Conclusion: The available data indicate that individuals with Alzheimer disease have more oral health problems than individuals without dementia.

  13. Evidence that a synthetic amyloid-ß oligomer-binding peptide (ABP) targets amyloid-ß deposits in transgenic mouse brain and human Alzheimer's disease brain.

    Science.gov (United States)

    Chakravarthy, Balu; Ito, Shingo; Atkinson, Trevor; Gaudet, Chantal; Ménard, Michel; Brown, Leslie; Whitfield, James

    2014-03-14

    The synthetic ~5 kDa ABP (amyloid-ß binding peptide) consists of a region of the 228 kDa human pericentrioloar material-1 (PCM-1) protein that selectively and avidly binds in vitro Aβ1-42 oligomers, believed to be key co-drivers of Alzheimer's disease (AD), but not monomers (Chakravarthy et al., (2013) [3]). ABP also prevents Aß1-42 from triggering the apoptotic death of cultured human SHSY5Y neuroblasts, likely by sequestering Aß oligomers, suggesting that it might be a potential AD therapeutic. Here we support this possibility by showing that ABP also recognizes and binds Aβ1-42 aggregates in sections of cortices and hippocampi from brains of AD transgenic mice and human AD patients. More importantly, ABP targets Aβ1-42 aggregates when microinjected into the hippocampi of the brains of live AD transgenic mice.

  14. Aroma and taste perceptions with Alzheimer disease and stroke.

    Science.gov (United States)

    Aliani, Michel; Udenigwe, Chibuike C; Girgih, Abraham T; Pownall, Trisha L; Bugera, Jacqeline L; Eskin, Michael N A

    2013-01-01

    Chemosensory disorders of smell or taste in humans have been attributed to various physiological and environmental factors including aging and disease conditions. Aroma and taste greatly condition our food preference, selection and, consumption; the decreased appetite in patients with known neurodegenerative diseases may lead to dietary restrictions that could negatively impact nutritional and health status. The decline in olfactory and gustatory systems in patients with Alzheimer disease and various types of stroke are described.

  15. 75 FR 67899 - National Alzheimer's Disease Awareness Month, 2010

    Science.gov (United States)

    2010-11-04

    ... terrible disease. As we continue our fight against Alzheimer's disease, we must seek new ways to prevent... and attention to those facing Alzheimer's disease. Until we find more effective treatments and a cure... Documents#0;#0; ] Proclamation 8591 of October 29, 2010 National Alzheimer's Disease Awareness Month,...

  16. Therapeutic potential of resveratrol in Alzheimer's disease

    OpenAIRE

    Vingtdeux, Valérie; Dreses-Werringloer, Ute; Zhao, Haitian; Davies, Peter; Marambaud, Philippe

    2008-01-01

    Several epidemiological studies indicate that moderate consumption of red wine is associated with a lower incidence of dementia and Alzheimer's disease. Red wine is enriched in antioxidant polyphenols with potential neuroprotective activities. Despite scepticism concerning the bioavailability of these polyphenols, in vivo data have clearly demonstrated the neuroprotective properties of the naturally occurring polyphenol resveratrol in rodent models for stress and diseases. Furthermore, recent...

  17. Neuroinflammation in Alzheimer's disease wanes with age

    NARCIS (Netherlands)

    Hoozemans, J.J.M.; Rozemuller, A.J.M.; van Haastert, E.S.; Eikelenboom, P.; van Gool, W.A.

    2011-01-01

    ABSTRACT: BACKGROUND: Inflammation is a prominent feature in Alzheimer's disease (AD). It has been proposed that aging has an effect on the function of inflammation in the brain, thereby contributing to the development of age-related diseases like AD. However, the age-dependent relationship between

  18. Looking for Signs of Alzheimer's Disease

    Science.gov (United States)

    Hodgson, Lynne Gershenson; Cutler, Stephen J.

    2003-01-01

    This study examined the correlates of symptom-seeking behavior for Alzheimer's disease (AD) among middle-aged persons. Symptom seeking, the tendency to search for signs of disease, is one manifestation of an individual's concern about developing AD. The data were obtained from a survey of two subsamples of 40-60 year old adults: 1) 108 adult…

  19. Llama VHH as immunotherapeutics in Alzheimer's disease

    NARCIS (Netherlands)

    Dorresteijn, B.

    2013-01-01

    Alzheimer's Disease (AD) is the most common form of dementia among elderly in the Western world. AD is a devastating neurodegenerative disease where patients starting with episodic memory problems end up completely bedridden and care dependent. At present there is no real therapy stopping or reversi

  20. Current treatments for patients with Alzheimer disease.

    Science.gov (United States)

    Osborn, Gerald G; Saunders, Amanda Vaughn

    2010-09-01

    There is neither proven effective prevention for Alzheimer disease nor a cure for patients with this disorder. Nevertheless, a spectrum of biopsychosocial therapeutic measures is available for slowing progression of the illness and enhancing quality of life for patients. These measures include a range of educational, psychological, social, and behavioral interventions that remain fundamental to effective care. Also available are a number of pharmacologic treatments, including prescription medications approved by the US Food and Drug Administration for Alzheimer disease, "off-label" uses of medications to manage target symptoms, and controversial complementary therapies. Physicians must make the earliest possible diagnosis to use these treatments most effectively. Physicians' goals should be to educate patients and their caregivers, to plan long-term care options, to maximally manage concurrent illnesses, to slow and ameliorate the most disabling symptoms, and to preserve effective functioning for as long as possible. The authors review the various current treatments for patients with Alzheimer disease.

  1. Is Alzheimer's disease a homogeneous disease entity?

    Science.gov (United States)

    Korczyn, Amos D

    2013-10-01

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

  2. Human beta-secretase and Alzheimer's disease%人β-分泌酶与阿尔茨海默病

    Institute of Scientific and Technical Information of China (English)

    邓青山; 马全红; 徐如祥

    2015-01-01

    Alzheimer's disease (AD) is the most common cause of dementia, neurodegenera-tive diseases, mainly characterized by progressive cognitive dysfunction and behavioral disabilities, its pathological characteristics are nerve cells outside insoluble amyloid beta and intracellular fiber which is formed by a phosphorylated tau tangles. This kind of extracellular oligomeric is mainly composed of Aβ, which is sequentially cleavaged the amyloid precursor protein APP byβ-secretase andγ-secretase. Deposition and excessive tau protein phosphorylation in cells form a nerve fiber tangles (NFTs), so as to cause oxidative stress and chronic inflammation damage, which leads to neuronal loss and synaptic dysfunction. In the past, based on the understanding of AD pathology characteristics, we focused on Aβand NFTs as the main direction of AD treatment, but over decades of research we have not made great progress. In recent years, as the in-depth and developmental understanding of beta amyloid protein precursor protein (APP) processing, people pay more and more attention toβ-site APP-Cleav-ing Enzyme 1, a key enzyme in Alzheimer disease (AD). Therefore, theβ-secretase (BACE1) related features ,functions and the related treatment progress in Alzheimer disease are reviewed in this paper.%阿尔茨海默病(AD)是最常见的引起痴呆的神经退行性疾病,主要表现为进行性的认知功能障碍和行为能力障碍,其病理特征是神经细胞外不溶性淀粉样蛋白Aβ以及胞内由过磷酸化tau形成的纤维缠结。这种胞外聚合物主要由Aβ4两组成,它是由淀粉样前体蛋白APP依次经β分泌酶(β-secretase)和γ分泌酶(γ-secretase)剪切所产生的。沉积和细胞内过量的Tau蛋白磷酸化形成神经纤维缠结(NFTs),从而引起氧化应激和慢性炎症损伤,导致神经元丢失和突触功能障碍。基于对AD病理特征认识,以往将针对Aβ和NFTs的治疗作为AD治疗的主要方向,但是经

  3. Proteins in human brain cortex are modified by oxidation, glycoxidation, and lipoxidation. Effects of Alzheimer disease and identification of lipoxidation targets.

    Science.gov (United States)

    Pamplona, Reinald; Dalfó, Esther; Ayala, Victòria; Bellmunt, Maria Josep; Prat, Joan; Ferrer, Isidre; Portero-Otín, Manuel

    2005-06-03

    Diverse oxidative pathways, such as direct oxidation of amino acids, glycoxidation, and lipoxidation could contribute to Alzheimer disease pathogenesis. A global survey for the amount of structurally characterized probes for these reactions is lacking and could overcome the lack of specificity derived from measurement of 2,4-dinitrophenylhydrazine reactive carbonyls. Consequently we analyzed (i) the presence and concentrations of glutamic and aminoadipic semialdehydes, N(epsilon)-(carboxymethyl)-lysine, N(epsilon)-(carboxyethyl)-lysine, and N(epsilon)-(malondialdehyde)-lysine by means of gas chromatography/mass spectrometry, (ii) the biological response through expression of the receptor for advanced glycation end products, (iii) the fatty acid composition in brain samples from Alzheimer disease patients and age-matched controls, and (iv) the targets of N(epsilon)-(malondialdehyde)-lysine formation in brain cortex by proteomic techniques. Alzheimer disease was associated with significant, although heterogeneous, increases in the concentrations of all evaluated markers. Alzheimer disease samples presented increases in expression of the receptor for advanced glycation end products with high molecular heterogeneity. Samples from Alzheimer disease patients also showed content of docosahexaenoic acid, which increased lipid peroxidizability. In accordance, N(epsilon)-(malondialdehyde)-lysine formation targeted important proteins for both glial and neuronal homeostasis such as neurofilament L, alpha-tubulin, glial fibrillary acidic protein, ubiquinol-cytochrome c reductase complex protein I, and the beta chain of ATP synthase. These data support an important role for lipid peroxidation-derived protein modifications in Alzheimer disease pathogenesis.

  4. 77 FR 66519 - National Alzheimer's Disease Awareness Month, 2012

    Science.gov (United States)

    2012-11-06

    ... Documents#0;#0; ] Proclamation 8897 of November 1, 2012 National Alzheimer's Disease Awareness Month, 2012... country confront the tragic realities of Alzheimer's disease--an irreversible, fatal illness that robs men... Americans grows in the coming years, Alzheimer's disease will continue to pose serious risks to our...

  5. 76 FR 68615 - National Alzheimer's Disease Awareness Month, 2011

    Science.gov (United States)

    2011-11-04

    ... Documents#0;#0; ] Proclamation 8745 of November 1, 2011 National Alzheimer's Disease Awareness Month, 2011... heartbreak of watching a loved one struggle with Alzheimer's disease is a pain they know all too well. Alzheimer's disease burdens an increasing number of our Nation's elders and their families, and it...

  6. 78 FR 66611 - National Alzheimer's Disease Awareness Month, 2013

    Science.gov (United States)

    2013-11-05

    ... Documents#0;#0; ] Proclamation 9050 of October 31, 2013 National Alzheimer's Disease Awareness Month, 2013 By the President of the United States of America A Proclamation Alzheimer's disease is an... younger Americans with early-onset Alzheimer's disease. This month, we stand with everyone confronting...

  7. Animal models for Alzheimer's disease and frontotemporal dementia: a perspective

    Directory of Open Access Journals (Sweden)

    Jürgen Götz

    2009-11-01

    Full Text Available In dementia research, animal models have become indispensable tools. They not only model aspects of the human condition, but also simulate processes that occur in humans and hence provide insight into how disease is initiated and propagated. The present review discusses two prominent human neurodegenerative disorders, Alzheimer's disease and frontotemporal dementia. It discusses what we would like to model in animals and highlights some of the more recent achievements using species as diverse as mice, fish, flies and worms. Advances in imaging and therapy are explored. We also discuss some anticipated new models and developments. These will reveal how key players in the pathogenesis of Alzheimer's disease and frontotemporal dementia, such as the peptide Aβ (amyloid β and the protein tau, cause neuronal dysfunction and eventually, neuronal demise. Understanding these processes fully will lead to early diagnosis and therapy.

  8. Alzheimer's disease drug development: translational neuroscience strategies.

    Science.gov (United States)

    Cummings, Jeffrey L; Banks, Sarah J; Gary, Ronald K; Kinney, Jefferson W; Lombardo, Joseph M; Walsh, Ryan R; Zhong, Kate

    2013-06-01

    Alzheimer's disease (AD) is an urgent public health challenge that is rapidly approaching epidemic proportions. New therapies that defer or prevent the onset, delay the decline, or improve the symptoms are urgently needed. All phase 3 drug development programs for disease-modifying agents have failed thus far. New approaches to drug development are needed. Translational neuroscience focuses on the linkages between basic neuroscience and the development of new diagnostic and therapeutic products that will improve the lives of patients or prevent the occurrence of brain disorders. Translational neuroscience includes new preclinical models that may better predict human efficacy and safety, improved clinical trial designs and outcomes that will accelerate drug development, and the use of biomarkers to more rapidly provide information regarding the effects of drugs on the underlying disease biology. Early translational research is complemented by later stage translational approaches regarding how best to use evidence to impact clinical practice and to assess the influence of new treatments on the public health. Funding of translational research is evolving with an increased emphasis on academic and NIH involvement in drug development. Translational neuroscience provides a framework for advancing development of new therapies for AD patients.

  9. Identification of Genes Involved in the Early Stages of Alzheimer Disease Using a Neural Network Algorithm

    Directory of Open Access Journals (Sweden)

    Barati

    2016-07-01

    Full Text Available Alzheimer disease is one form of dementia in old age. Alzheimer disease, the incurable disease, which is usually in the seventh decade of human life, shows its symptoms. The disease may be present for years without clinical symptoms. The current study identified the genes with altered expression in patients with Alzheimer disease. The important sequence of each gene in Alzheimer disease was found and introduced as a biomarker of this disease. The present study used microarray libraries related to Alzheimer disease. Finally, the data were weighted using 10 data mining methods, including methods such as support vector machine (SVM, deviation, information gain ratio and the Gini coefficient. Sequences with least two algorithm weights above 0.5 were selected as the most important sequences. Then, a neural network algorithm (neural net, auto multilayer perceptron and perceptron was run on 11 data bases from the weighted perceptron algorithm, resulting in a careful 97% best performance.

  10. Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer's disease

    OpenAIRE

    Nicolia, Vincenzina; Lucarelli, Marco; Fuso, Andrea

    2015-01-01

    International audience; Many different environmental factors (nutrients, pollutants, chemicals, physical activity, lifestyle, physical and mental stress) can modulate epigenetic markers in the developing and adult organism. Epigenetics, in turn, can cause and is associated with several neurodegenerative and aging-dependent human diseases. Alzheimer's disease certainly represents one of the most relevant neurodegenerative disorders due to its incidence and its huge socio-economic impact. There...

  11. Normal tension glaucoma and Alzheimer disease

    DEFF Research Database (Denmark)

    Bach-Holm, Daniella; Kessing, Svend Vedel; Mogensen, Ulla

    2012-01-01

    PURPOSE: To investigate whether normal tension glaucoma (NTG) is associated with increased risk of developing dementia/Alzheimer disease (AD). METHODS: A total of 69 patients with NTG were identified in the case note files in the Glaucoma Clinic, University Hospital of Copenhagen (Rigshospitalet...

  12. Progression of Alzheimer Disease in Europe

    DEFF Research Database (Denmark)

    Vellas, B; Hausner, L; Frolich, L

    2012-01-01

    The clinical progression of Alzheimer disease (AD) was studied in European subjects under treatment with AChE inhibitors (AChE-I) in relation to geographical location over a 2-years period. One thousand three hundred and six subjects from 11 European countries were clustered into 3 regions (North...

  13. Early psychosocial intervention in Alzheimer's disease

    DEFF Research Database (Denmark)

    Søgaard, Rikke; Sørensen, Jan; Waldorff, Frans Boch

    2014-01-01

    OBJECTIVE: To assess the cost utility of early psychosocial intervention for patients with Alzheimer's disease and their primary caregivers. DESIGN: Cost utility evaluation alongside a multicentre, randomised controlled trial with 3 years of follow-up. SETTING: Primary care and memory clinics in ...

  14. Structural Neuroimaging in Aging and Alzheimer's Disease

    NARCIS (Netherlands)

    Vernooij, Meike W.; Smits, Marion

    2012-01-01

    The role of structural neuroimaging in the diagnosis of Alzheimer's disease (AD) is becoming increasingly important. As a consequence, a basic understanding of what are normal brain changes in aging is key to be able to recognize what is abnormal. The first part of this article discusses normal vers

  15. Estrogen receptor beta treats Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Zhu Tian; Jia Fan; Yang Zhao; Sheng Bi; Lihui Si; Qun Liu

    2013-01-01

    In vitro studies have shown that estrogen receptor β can attenuate the cytotoxic effect of amyloid β protein on PC12 cells through the Akt pathway without estrogen stimulation. In this study, we aimed to observe the effect of estrogen receptor β in Alzheimer's disease rat models established by intraventricular injection of amyloid β protein. Estrogen receptor β lentiviral particles delivered via intraventricular injection increased Akt content in the hippocampus, decreased interleukin-1β mRNA, tumor necrosis factor α mRNA and amyloid β protein levels in the hippocampus, and improved the learning and memory capacities in Alzheimer's disease rats. Estrogen receptor β short hairpin RNA lentiviral particles delivered via intraventricular injection had none of the above impacts on Alzheimer's disease rats. These experimental findings indicate that estrogen receptor β, independent from estrogen, can reduce inflammatory reactions and amyloid β deposition in the hippocampus of Alzheimer's disease rats, and improve learning and memory capacities. This effect may be mediated through activation of the Akt pathway.

  16. Aripiprazole in the treatment of Alzheimer's disease

    NARCIS (Netherlands)

    De Deyn, P.P.; Drenth, Annemieke F. J.; Kremer, B.P.; Oude Voshaar, R.C.; Van Dam, D.

    2013-01-01

    Introduction: Psychosis is a common and difficult to treat symptom in Alzheimer's disease (AD). It is a cause of diminished quality of life and care-giver distress. Atypical antipsychotics are frequently used for the treatment of dementia-related psychosis, despite FDA warnings because of increased

  17. Aripiprazole in the treatment of Alzheimer's disease

    NARCIS (Netherlands)

    Deyn, P.P. de; Drenth, A.F.; Kremer, B.; Oude Voshaar, R.C.; Dam, D. Van

    2013-01-01

    INTRODUCTION: Psychosis is a common and difficult to treat symptom in Alzheimer's disease (AD). It is a cause of diminished quality of life and caregiver distress. Atypical antipsychotics are frequently used for the treatment of dementia-related psychosis, despite FDA warnings because of increased m

  18. Alzheimer disease : presenilin springs a leak

    NARCIS (Netherlands)

    Gandy, S.; Doeven, M.K.; Poolman, B.

    2006-01-01

    Presenilins are thought to contribute to Alzheimer disease through a protein cleavage reaction that produces neurotoxic amyloid-beta peptides. A new function for presenilins now comes to light - controlling the leakage of calcium out of the endoplasmic reticulum. Is this a serious challenge to the '

  19. Cannabinoids in late-onset Alzheimer's disease

    NARCIS (Netherlands)

    Ahmed, A.; Marck, M.A. van der; Elsen, G. van den; Olde Rikkert, M.G.M.

    2015-01-01

    Given the lack of effective treatments for late-onset Alzheimer's disease (LOAD) and the substantial burden on patients, families, health care systems, and economies, finding an effective therapy is one of the highest medical priorities. The past few years have seen a growing interest in the medicin

  20. Atorvastatin attenuates oxidative stress in Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Cai Zhiyou; Yan Yong; Wang Yonglong

    2008-01-01

    Objective: To investigate serum level of SOD, MDA, ox-LDL, AchE and Ach in AD, to study atorvastatin influence on serum level of SOD, MDA, ox-LDL, AchE and Acb in AD and its neuroprotection mechanisms. Methods Subjects were divided into: normal blood lipid level group with Alzheimer's disease (A), higher blood lipid level group with Alzheimer's disease (AH), normal blood lipid level Alzheimer's disease group with atorvastatin treeatment (AT),higher blood lipid level Alzheimer's disease group with atorvastatin treeatment(AHT). Ox-LDL was measured by enzyme linked immunosorbent assay; SOD, MDA, ox-LDL, AchE, Ach and blood lipid level in AD was measured by biochemistry. Results: The serum level of MDA, AchE in AH group after atorvastatin treatment is lower ;The serum level of SOD, Ach in AH group is more increased than that of in A group; The serum level of ox-LDL in AH, A groups is lower than that of in A group; The dementia degree is lower after atorvastatin treatment. Conclusion: Atorvastatin can decrease serum level of MDA, AchE and ox-LDL, and increase that of SOD, Acb, and attenuate dementia symptom in AD, especially, with hyperlipemia. The hypothesis of atorvastatin neuroprotection is concluded that atorvastatin may restrain free radical reaction and retard oxidation in AD.

  1. New criteria for diagnosing Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Andrei Yuryevich Emelin

    2011-01-01

    Full Text Available Department of Nervous Diseases, S.M. Kirov Military Medical Academy, Saint Petersburg The paper gives an analysis of new diagnostic criteria for different stages of Alzheimer Х s disease (AD, which is proposed by the U.S. National Institute on Aging. It considers possibilities for the early diagnosis of AD, including its preclinical diagnosis using the laboratory and neuroimaging markers beta-amyloid, neuronal damage.

  2. Alzheimer disease: current concepts & future directions.

    Science.gov (United States)

    Musiek, Erik S; Schindler, Suzanne E

    2013-01-01

    Alzheimer disease (AD) is the most common cause of dementia in individuals over age 65, and is expected to cause a major public health crisis as the number of older Americans rapidly expands in the next three decades. Herein, we review current strategies for diagnosis and management of AD, and discuss ongoing clinical research and future therapeutic directions in the battle against this devastating disease.

  3. A disease state fingerprint for evaluation of Alzheimer's disease

    DEFF Research Database (Denmark)

    Mattila, Jussi; Koikkalainen, Juha; Virkki, Arho

    2011-01-01

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

  4. Possible Role of the Transglutaminases in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Antonio Martin

    2011-01-01

    Full Text Available Transglutaminases are ubiquitous enzymes which catalyze posttranslational modifications of proteins. Recently, transglutaminase-catalyzed post-translational modification of proteins has been shown to be involved in the molecular mechanisms responsible for human diseases. Transglutaminase activity has been hypothesized to be involved also in the pathogenetic mechanisms responsible for several human neurodegenerative diseases. Alzheimer's disease and other neurodegenerative diseases, such as Parkinson's disease, supranuclear palsy, Huntington's disease, and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This paper focuses on the possible molecular mechanisms by which transglutaminase activity could be involved in the pathogenesis of Alzheimer's disease and other neurodegenerative diseases, and on the possible therapeutic effects of selective transglutaminase inhibitors for the cure of patients with diseases characterized by aberrant transglutaminase activity.

  5. Genetic variants associated with neurodegenerative Alzheimer disease in natural models.

    Science.gov (United States)

    Salazar, Claudia; Valdivia, Gonzalo; Ardiles, Álvaro O; Ewer, John; Palacios, Adrián G

    2016-02-26

    The use of transgenic models for the study of neurodegenerative diseases has made valuable contributions to the field. However, some important limitations, including protein overexpression and general systemic compensation for the missing genes, has caused researchers to seek natural models that show the main biomarkers of neurodegenerative diseases during aging. Here we review some of these models-most of them rodents, focusing especially on the genetic variations in biomarkers for Alzheimer diseases, in order to explain their relationships with variants associated with the occurrence of the disease in humans.

  6. Alzheimer's Disease Facts and Figures

    Medline Plus

    Full Text Available ... we make the decision that our assumptions and definitions of disease are no longer consistent with the ... this disease. As research advances a biomarker-based method for diagnosis and treatment at the earliest stages ...

  7. Stress, exercise, and Alzheimer's disease: A neurovascular pathway

    OpenAIRE

    Nation, Daniel A.; Hong, Suzi; Jak, Amy J.; Delano-Wood, Lisa; Mills, Paul J.; Bondi, Mark W.; Dimsdale, Joel E.

    2011-01-01

    Genetic factors are known to play a role in Alzheimer's disease (AD) vulnerability, yet less than 1% of incident AD cases are directly linked to genetic causes, suggesting that environmental variables likely play a role in the majority of cases. Several recent human and animal studies have examined the effects of behavioral factors, specifically psychological stress and exercise, on AD vulnerability. Numerous animal studies have found that, while stress exacerbates neuropathological changes a...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1996-12-31

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

  9. Alzheimer's disease: synaptic dysfunction and Abeta

    LENUS (Irish Health Repository)

    Shankar, Ganesh M

    2009-11-23

    Abstract Synapse loss is an early and invariant feature of Alzheimer\\'s disease (AD) and there is a strong correlation between the extent of synapse loss and the severity of dementia. Accordingly, it has been proposed that synapse loss underlies the memory impairment evident in the early phase of AD and that since plasticity is important for neuronal viability, persistent disruption of plasticity may account for the frank cell loss typical of later phases of the disease. Extensive multi-disciplinary research has implicated the amyloid β-protein (Aβ) in the aetiology of AD and here we review the evidence that non-fibrillar soluble forms of Aβ are mediators of synaptic compromise. We also discuss the possible mechanisms of Aβ synaptotoxicity and potential targets for therapeutic intervention.

  10. Does prevention for Alzheimer's disease exist?

    Directory of Open Access Journals (Sweden)

    Sonia Maria Dozzi Brucki

    Full Text Available Abstract The prevention of Alzheimer's disease is a growing public health concern amidst an ageing population. Meanwhile, there is no effective or curative treatment available where prevention could greatly reduce health costs. This review was based on reports of potential preventive factors, including modifiable lifestyle factors, as well as preventive pharmacological strategies. Although the present review was not systematic, the reports selected from PubMed using "Alzheimer's disease" and "prevention" as key-words, allow us to affirm that pursuing a healthy lifestyle; physical, cognitive, leisure activities; good social engagement; a high consumption of fish, low consumption of dietary fat and moderate consumption of wine, and control of vascular risk factors appear to be potential factors for delaying dementia.

  11. [Ethical considerations in the presymptomatic diagnosis of Alzheimer's disease].

    Science.gov (United States)

    Kessel Sardiñas, Humberto

    2011-10-01

    Research into the human genome has undoubtedly opened up a new perspective in medicine. The ability to identify the cause of specific diseases, especially neurodegenerative diseases, will definitively change the concepts of disease and treatment, while advances such as antibiotic therapy and anesthesia will be relegated to history. However, the arrival of genome medicine poses major bioethical challenges, many of which remain to be resolved. We review the applicability, results and consequences of predictions based on genetic tests for presymptomatic Alzheimer's disease, as well as the dilemmas and contradictions that are already arising as a result of the commercialization of predictive tests for public use with little or no medical supervision. Given that there is currently no effective treatment of Alzheimeŕs disease, the greatest challenge and contradiction lies in managing the results of predictive tests. There are no indications for the performance of predictive genetic tests in late or sporadic Alzheimer's disease or for counselling of persons requesting these tests. The PICOGEN program provides a safe, effective, reliable and satisfactory option for persons requesting these tests who meet the inclusion criteria. Currently, caution should be the norm when considering the performance of predictive tests in presymptomatic dementia.

  12. Neurofibrillary pathology and aluminum in Alzheimer's disease

    OpenAIRE

    Shin, R. W.; Lee, V.M.Y.; Trojanowski, J.Q.

    1995-01-01

    Since the first reports of aluminum-induced neurofibrillary degeneration in experimental animals, extensive studies have been performed to clarify the role played by aluminum in the pathogenesis of Alzheimer's disease (AD). Additional evidence implicating aluminum in AD includes elevated levels of aluminum in the AD brain, epidemiological data linking aluminum exposure to AD, and interactions between aluminum and protein components in the pathological lesions o...

  13. [Progress in epigenetic research on Alzheimer disease].

    Science.gov (United States)

    Yang, Nannan; Wei, Yang; Xu, Qian; Tang, Beisha

    2016-04-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder, which features mainly with memory impairment as the initial symptom of progressive loss of cognitive function. Its main pathological changes include senile plaques and neurofibrillary tangles. The pathogenesis of AD is still unclear, though it may be connected with aging, genetic factors and environmental factors. Among these, aging and environmental factors can be modified by epigenetics. In this paper, advances in the study of epigenetic mechanisms related to the pathogenesis of AD are reviewed.

  14. Association of Alzheimer's disease and Chlamydophila pneumoniae.

    Science.gov (United States)

    Stallings, Tiffany L

    2008-06-01

    This paper critically reviews the association of infection by Chlamydophila pneumoniae (C. pneumoniae) and Alzheimer's disease (AD). The aging population has increased interest in finding the cause of AD, but studies have yielded contradictory results that are likely due to varying diagnostic tools and different uses of diagnostic tests. Knowledge of AD's characteristics, risk factors, and hypothesized etiologies has expanded since Alois Alzheimer's initial description of AD. Epidemiologic and projection studies provide incidence estimates of AD through a two-stage method: (1) primary diagnosis of dementia by cognitive testing such as Mini-Mental State Examination (MMSE), and (2) clinical diagnosis of AD through criteria such as National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA). Cross-sectional studies yield prevalence estimates of infection by C. pneumoniae by detecting immunoglobulins through laboratory tests such as microimmunofluorescence (MIF). Studies examining the association of C. pneumoniae and AD are limited, but brain autopsy provides information about presence, proximity to areas associated with AD, and bacterial load. Standardization of diagnostic techniques would allow for better comparability of studies, but uncertainty about the best method of diagnosis of infection by C. pneumoniae and AD may call for revised or novel diagnostic tools.

  15. Alzheimer's Disease: A Pathogenetic Autoimmune Disorder Caused by Herpes Simplex in a Gene-Dependent Manner

    Directory of Open Access Journals (Sweden)

    C. J. Carter

    2010-01-01

    Full Text Available Herpes simplex is implicated in Alzheimer's disease and viral infection produces Alzheimer's disease like pathology in mice. The virus expresses proteins containing short contiguous amino acid stretches (5–9aa “vatches” = viralmatches homologous to APOE4, clusterin, PICALM, and complement receptor 1, and to over 100 other gene products relevant to Alzheimer's disease, which are also homologous to proteins expressed by other pathogens implicated in Alzheimer's disease. Such homology, reiterated at the DNA level, suggests that gene association studies have been tracking infection, as well as identifying key genes, demonstrating a role for pathogens as causative agents. Vatches may interfere with the function of their human counterparts, acting as dummy ligands, decoy receptors, or via interactome interference. They are often immunogenic, and antibodies generated in response to infection may target their human counterparts, producing protein knockdown, or generating autoimmune responses that may kill the neurones in which the human homologue resides, a scenario supported by immune activation in Alzheimer's disease. These data may classify Alzheimer's disease as an autoimmune disorder created by pathogen mimicry of key Alzheimer's disease-related proteins. It may well be prevented by vaccination and regular pathogen detection and elimination, and perhaps stemmed by immunosuppression or antibody adsorption-related therapies.

  16. Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer's disease mouse model through modulation of neuroinflammation.

    Science.gov (United States)

    Lee, Hyun Ju; Lee, Jong Kil; Lee, Hyun; Carter, Janet E; Chang, Jong Wook; Oh, Wonil; Yang, Yoon Sun; Suh, Jun-Gyo; Lee, Byoung-Hee; Jin, Hee Kyung; Bae, Jae-Sung

    2012-03-01

    Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) have a potential therapeutic role in the treatment of neurological disorders, but their current clinical usage and mechanism of action has yet to be ascertained in Alzheimer's disease (AD). Here we report that hUCB-MSC transplantation into amyloid precursor protein (APP) and presenilin1 (PS1) double-transgenic mice significantly improved spatial learning and memory decline. Furthermore, amyloid-β peptide (Aβ) deposition, β-secretase 1 (BACE-1) levels, and tau hyperphosphorylation were dramatically reduced in hUCB-MSC transplanted APP/PS1 mice. Interestingly, these effects were associated with reversal of disease-associated microglial neuroinflammation, as evidenced by decreased microglia-induced proinflammatory cytokines, elevated alternatively activated microglia, and increased anti-inflammatory cytokines. These findings lead us to suggest that hUCB-MSC produced their sustained neuroprotective effect by inducing a feed-forward loop involving alternative activation of microglial neuroinflammation, thereby ameliorating disease pathophysiology and reversing the cognitive decline associated with Aβ deposition in AD mice.

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

    Science.gov (United States)

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

    2015-12-17

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

  18. Inflammaging as a prodrome to Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Rrapo Elona

    2008-11-01

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

  19. Predicting cognitive decline in Alzheimer's disease: an integrated analysis

    DEFF Research Database (Denmark)

    Lopez, Oscar L; Schwam, Elias; Cummings, Jeffrey

    2010-01-01

    Numerous patient- and disease-related factors increase the risk of rapid cognitive decline in patients with Alzheimer's disease (AD). The ability of pharmacological treatment to attenuate this risk remains undefined.......Numerous patient- and disease-related factors increase the risk of rapid cognitive decline in patients with Alzheimer's disease (AD). The ability of pharmacological treatment to attenuate this risk remains undefined....

  20. Alzheimer's Disease Facts and Figures

    Medline Plus

    Full Text Available ... we make the decision that our assumptions and definitions of disease are no longer consistent with the scientific evidence, and no longer serve our health care needs. The arc of scientific progress is ...

  1. REST and stress resistance in ageing and Alzheimer's disease

    Science.gov (United States)

    Lu, Tao; Aron, Liviu; Zullo, Joseph; Pan, Ying; Kim, Haeyoung; Chen, Yiwen; Yang, Tun-Hsiang; Kim, Hyun-Min; Drake, Derek; Liu, X. Shirley; Bennett, David A.; Colaiácovo, Monica P.; Yankner, Bruce A.

    2014-03-01

    Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

  2. To differentiate Alzheimer's disease earlier: introduction of Alzheimer's Disease Neuroimaging Initiative (ADNI

    Directory of Open Access Journals (Sweden)

    Zhi-gang QI

    2014-04-01

    Full Text Available Alzheimer's disease (AD brought about much pressure in modern aging society both economically and psychologically, so it is meaningful to carry out AD research. Being considered as the most successful multi-center, inter-disciplinary and longitudinal research in AD field, Alzheimer's Disease Neuroimaging Initiative (ADNI has obtained outstanding achievements. In this review, we attempt to introduce the research plan of ADNI project for reference. doi: 10.3969/j.issn.1672-6731.2014.04.003

  3. Relationship Between Tau Pathology and Neuroinflammation in Alzheimer's Disease

    OpenAIRE

    Metcalfe, Maria Jose; Figueiredo-Pereira, Maria E.

    2010-01-01

    Alzheimer's disease is a chronic, age-related neurodegenerative disorder. Neurofibrillary tangles are among the pathological hallmarks of Alzheimer's disease. Neurofibrillary tangles consist of abnormal protein fibers known as paired helical filaments. The accumulation of paired helical filaments is one of the most characteristic cellular changes in Alzheimer's disease. Tau protein, a microtubule-associated protein, is the major component of paired helical filaments. Tau in paired helical fil...

  4. GPCR, a rider of Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Xiaosong LIU; Jian ZHAO

    2011-01-01

    Alzheimer's disease (AD) is the most common type of dementia that affects thinking,learning,memory and behavior of older people.Based on the previous studies,three pathogenic pathways are now commonly accepted as the culprits of this disease namely,amyloid-β pathway,tauopathology and cholinergic dysfunction.This review focuses on the current findings on the regulatory roles of G protein-coupled receptors (GPCRs) in the pathological progression of AD and discusses the potential of the GPCRs as novel therapeutic targets for AD.

  5. Visual system manifestations of Alzheimer's disease.

    Science.gov (United States)

    Kusne, Yael; Wolf, Andrew B; Townley, Kate; Conway, Mandi; Peyman, Gholam A

    2016-11-19

    Alzheimer's disease (AD) is an increasingly common disease with massive personal and economic costs. While it has long been known that AD impacts the visual system, there has recently been an increased focus on understanding both pathophysiological mechanisms that may be shared between the eye and brain and how related biomarkers could be useful for AD diagnosis. Here, were review pertinent cellular and molecular mechanisms of AD pathophysiology, the presence of AD pathology in the visual system, associated functional changes, and potential development of diagnostic tools based on the visual system. Additionally, we discuss links between AD and visual disorders, including possible pathophysiological mechanisms and their relevance for improving our understanding of AD.

  6. Synaptic Plasticity, Dementia and Alzheimer Disease.

    Science.gov (United States)

    Skaper, Stephen D; Facci, Laura; Zusso, Morena; Giusti, Pietro

    2017-01-13

    Neuroplasticity is not only shaped by learning and memory but is also a mediator of responses to neuron attrition and injury (compensatory plasticity). As an ongoing process it reacts to neuronal cell activity and injury, death, and genesis, which encompasses the modulation of structural and functional processes of axons, dendrites, and synapses. The range of structural elements that comprise plasticity includes long-term potentiation (a cellular correlate of learning and memory), synaptic efficacy and remodelling, synaptogenesis, axonal sprouting and dendritic remodelling, and neurogenesis and recruitment. Degenerative diseases of the human brain continue to pose one of biomedicine's most intractable problems. Research on human neurodegeneration is now moving from descriptive to mechanistic analyses. At the same time, it is increasing apparent that morphological lesions traditionally used by neuropathologists to confirm post-mortem clinical diagnosis might furnish us with an experimentally tractable handle to understand causative pathways. Consider the aging-dependent neurodegenerative disorder Alzheimer's disease (AD) which is characterised at the neuropathological level by deposits of insoluble amyloid b-peptide (Ab) in extracellular plaques and aggregated tau protein, which is found largely in the intracellular neurofibrillary tangles. We now appreciate that mild cognitive impairment in early AD may be due to synaptic dysfunction caused by accumulation of non-fibrillar, oligomeric Ab, occurring well in advance of evident widespread synaptic loss and neurodegeneration. Soluble Ab oligomers can adversely affect synaptic structure and plasticity at extremely low concentrations, although the molecular substrates by which synaptic memory mechanisms are disrupted remain to be fully elucidated. The dendritic spine constitutes a primary locus of excitatory synaptic transmission in the mammalian central nervous system. These structures protruding from dendritic shafts

  7. Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer's disease.

    Science.gov (United States)

    Nicolia, Vincenzina; Lucarelli, Marco; Fuso, Andrea

    2015-08-01

    Many different environmental factors (nutrients, pollutants, chemicals, physical activity, lifestyle, physical and mental stress) can modulate epigenetic markers in the developing and adult organism. Epigenetics, in turn, can cause and is associated with several neurodegenerative and aging-dependent human diseases. Alzheimer's disease certainly represents one of the most relevant neurodegenerative disorders due to its incidence and its huge socio-economic impact. Therefore, it is easy to understand why recent literature focuses on the epigenetic modifications associated with Alzheimer's disease and other neurodegenerative disorders. One of the most intriguing and, at the same time, worrying evidence is that even "mild" environmental factors (such as behavioral or physical stress) as well as the under-threshold exposure to pollutants and chemicals, can be effective. Finally, even mild nutrients disequilibria can result in long-lasting and functional alterations of many epigenetic markers, although they don't have an immediate acute effect. Therefore, we will probably have to re-define the current risk threshold for many factors, molecules and stresses. Among the many different environmental factors affecting the epigenome, nutrition represents one of the most investigated fields; the reasons are probably that each person interacts with nutrients and that, in turn, nutrients can modulate at molecular level the epigenetic biochemical pathways. The role that nutrition can exert in modulating epigenetic modifications in Alzheimer's disease will be discussed with particular emphasis on the role of B vitamins and DNA methylation.

  8. Olive Oil and its Potential Effects on Alzheimer's Disease

    Science.gov (United States)

    Antony, Shan; Zhang, G. P.

    Alzheimer's disease is a neuro-degenerative brain disease that is responsible for affecting the lives of hundreds of thousands of people every year. There has been no evidence to suggest a cure for the disease and the only existing treatments have very low rates of success in trial patients. This is largely due to the fact that the brain is one of the most undiscovered parts of the human body. Brain chemistry is highly complex and responds to its environment in random and radical ways. My research includes testing the reactionary outcomes of combining compounds of olive oil with the 20 basic amino acids. Regions around the world with olive oil based diets show a direct correlation to lower rates of Alzheimer's. Testing few compounds of olive oil with chemicals already found in the brain may yield to a better understanding as to why that is. I took the compounds tyrosol, hydroxytyrosol, and oleocanthal, and combined them with the 20 basic amino acids and calculated the total energy of the new molecule. The molecules produced with acceptably low energy values will be the center of further research. These molecules could lead to truly understanding olive oil's effect on the brain, and ultimately, the cure or prevention of Alzheimer's disease.

  9. A semi-physiological model of amyloid-β biosynthesis and clearance in human cerebrospinal fluid: a tool for alzheimer's disease research and drug development.

    Science.gov (United States)

    Haug, Karin G; Staab, Alexander; Dansirikul, Chantaratsamon; Lehr, Thorsten

    2013-07-01

    Stable isotope labeling kinetics (SILK) was successfully applied to quantify endogenous amyloid-β (Aβ) metabolism in human cerebrospinal fluid (CSF). A semi-physiological model describing Aβ biosynthesis and degradation in human CSF and the impact of the γ-secretase inhibitor semagacestat should be developed and validated based on digitized data from three published SILK studies. Aβ biosynthesis was adequately characterized by six transit compartments. At each transition step, a first-order degradation process was implemented. A two-compartment model best described semagacestat CSF concentration-time profiles. Semagacestat concentrations were linked to the Aβ production by an inhibitory Emax model. For model validation, three individual Aβ profiles from literature were successfully predicted. Model application demonstrated a 35% decreased Aβ elimination rate constant in Alzheimer's disease (AD) patients. Study design optimization revealed that SILK studies could be conducted with significant less sampling points compared to the standard protocol without losing information about the Aβ metabolism, if analyzed by the presented model. In conclusion, the analysis outlined the advantages and opportunities of integrating all available data and knowledge into a semi-physiological model. The model can serve as valuable tool for researchers and clinicians interested in the pathology of AD as well as in the development of new therapeutics for AD.

  10. 78 FR 9396 - Draft Guidance for Industry on Alzheimer's Disease: Developing Drugs for the Treatment of Early...

    Science.gov (United States)

    2013-02-08

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Alzheimer's Disease: Developing Drugs for the Treatment of Early Stage Disease; Availability AGENCY: Food and Drug Administration... a draft guidance for industry entitled ``Alzheimer's Disease: Developing Drugs for the Treatment...

  11. Alzheimer's disease: new diagnostic and therapeutic tools

    Directory of Open Access Journals (Sweden)

    Caruso Calogero

    2008-08-01

    Full Text Available Abstract On March 19, 2008 a Symposium on Pathophysiology of Ageing and Age-Related diseases was held in Palermo, Italy. Here, the lectures of M. Racchi on History and future perspectives of Alzheimer Biomarkers and of G. Scapagnini on Cellular Stress Response and Brain Ageing are summarized. Alzheimer's disease (AD is a heterogeneous and progressive neurodegenerative disease, which in Western society mainly accounts for clinica dementia. AD prevention is an important goal of ongoing research. Two objectives must be accomplished to make prevention feasible: i individuals at high risk of AD need to be identified before the earliest symptoms become evident, by which time extensive neurodegeneration has already occurred and intervention to prevent the disease is likely to be less successful and ii safe and effective interventions need to be developed that lead to a decrease in expression of this pathology. On the whole, data here reviewed strongly suggest that the measurement of conformationally altered p53 in blood cells has a high ability to discriminate AD cases from normal ageing, Parkinson's disease and other dementias. On the other hand, available data on the involvement of curcumin in restoring cellular homeostasis and rebalancing redox equilibrium, suggest that curcumin might be a useful adjunct in the treatment of neurodegenerative illnesses characterized by inflammation, such as AD.

  12. [Stigmatization in Alzheimer's disease, a review].

    Science.gov (United States)

    Cavayas, Marilèna; Raffard, Stéphane; Gély-Nargeot, Marie-Christine

    2012-09-01

    Stigma against chronic disease or mental illness is a well-known phenomenon and results in devastating consequences for individuals who suffer from these diseases and their families. However, few studies have evaluated the stigma and its various processes associated with Alzheimer's disease (AD). The aim of the present review is to discuss the concepts that underlie stigma and its different forms, and then to explain its causes and consequences. Indeed, if the stigma primarily affects individuals with a diagnosis of AD, recent studies have shown that the caregivers of the patients as well as their relatives are also exposed to stigma by association. Moreover, past and current studies on other chronic diseases highlight the importance of using methods issued from experimental social psychology to assess the explicit representations but also the implicit stigma associated with the disease. Finally, several researches and possible interventions are proposed to reduce the stigma associated with AD and related concepts such as MCI.

  13. New cardiovascular targets to prevent late onset Alzheimer disease

    NARCIS (Netherlands)

    Claassen, J.A.H.R.

    2015-01-01

    The prevalence of dementia rises to between 20% and 40% with advancing age. The dominant cause of dementia in approximately 70% of these patients is Alzheimer disease. There is no effective disease-modifying pharmaceutical treatment for this neurodegenerative disease. A wide range of Alzheimer drugs

  14. Common Alzheimer's Disease Research Ontology: National Institute on Aging and Alzheimer's Association collaborative project.

    Science.gov (United States)

    Refolo, Lorenzo M; Snyder, Heather; Liggins, Charlene; Ryan, Laurie; Silverberg, Nina; Petanceska, Suzana; Carrillo, Maria C

    2012-07-01

    Alzheimer's disease is recognized as a public health crisis worldwide. As public and private funding agencies around the world enhance and expand their support of Alzheimer's disease research, there is an urgent need to coordinate funding strategies and leverage resources to maximize the impact on public health and avoid duplication of effort and inefficiency. Such coordination requires a comprehensive assessment of the current landscape of Alzheimer's disease research in the United States and internationally. To this end, the National Institute on Aging at the National Institutes of Health and the Alzheimer's Association developed the Common Alzheimer's Disease Research Ontology (CADRO) as a dynamic portfolio analysis tool that can be used by funding agencies worldwide for strategic planning and coordination.

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

    Science.gov (United States)

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

    2016-12-01

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

  16. Neuroimaging Measures as Endophenotypes in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Meredith N. Braskie

    2011-01-01

    Full Text Available Late onset Alzheimer's disease (AD is moderately to highly heritable. Apolipoprotein E allele ε4 (APOE4 has been replicated consistently as an AD risk factor over many studies, and recently confirmed variants in other genes such as CLU, CR1, and PICALM each increase the lifetime risk of AD. However, much of the heritability of AD remains unexplained. AD is a complex disease that is diagnosed largely through neuropsychological testing, though neuroimaging measures may be more sensitive for detecting the incipient disease stages. Difficulties in early diagnosis and variable environmental contributions to the disease can obscure genetic relationships in traditional case-control genetic studies. Neuroimaging measures may be used as endophenotypes for AD, offering a reliable, objective tool to search for possible genetic risk factors. Imaging measures might also clarify the specific mechanisms by which proposed risk factors influence the brain.

  17. Immunotherapy against amyloid pathology in Alzheimer's disease.

    Science.gov (United States)

    Galimberti, Daniela; Ghezzi, Laura; Scarpini, Elio

    2013-10-15

    The first drugs developed for Alzheimer's disease (AD), anticholinesterase inhibitors (AchEI), increase acetylcholine levels, previously demonstrated to be reduced in AD. To date, four AchEI are approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine. These treatments are symptomatic, whereas drugs under development are supposed to modify pathological steps leading to AD, thus acting on the evolution of the disease. For this reason they are currently termed "disease modifying" drugs. To block the progression of the disease, they have to interfere with pathogenic steps at the basis of clinical symptoms, including the deposition of extracellular amyloid beta (Aβ) plaques and of intracellular neurofibrillary tangles. The most innovative approach is represented by the vaccination and passive immunization against Aβ peptide. In this article, current knowledge about concluded and ongoing clinical trials with both vaccination with different antigens and passive immunization will be reviewed and discussed.

  18. Development of transgenic rats producing human β-amyloid precursor protein as a model for Alzheimer's disease: Transgene and endogenous APP genes are regulated tissue-specifically

    Directory of Open Access Journals (Sweden)

    Chan Anthony WS

    2008-02-01

    Full Text Available Abstract Background Alzheimer's disease (AD is a devastating neurodegenerative disorder that affects a large and growing number of elderly individuals. In addition to idiopathic disease, AD is also associated with autosomal dominant inheritance, which causes a familial form of AD (FAD. Some instances of FAD have been linked to mutations in the β-amyloid protein precursor (APP. Although there are numerous mouse AD models available, few rat AD models, which have several advantages over mice, have been generated. Results Fischer 344 rats expressing human APP driven by the ubiquitin-C promoter were generated via lentiviral vector infection of Fischer 344 zygotes. We generated two separate APP-transgenic rat lines, APP21 and APP31. Serum levels of human amyloid-beta (Aβ40 were 298 pg/ml for hemizygous and 486 pg/ml for homozygous APP21 animals. Serum Aβ42 levels in APP21 homozygous rats were 135 pg/ml. Immunohistochemistry in brain showed that the human APP transgene was expressed in neurons, but not in glial cells. These findings were consistent with independent examination of enhanced green fluorescent protein (eGFP in the brains of eGFP-transgenic rats. APP21 and APP31 rats expressed 7.5- and 3-times more APP mRNA, respectively, than did wild-type rats. Northern blots showed that the human APP transgene, driven by the ubiquitin-C promoter, is expressed significantly more in brain, kidney and lung compared to heart and liver. A similar expression pattern was also seen for the endogenous rat APP. The unexpected similarity in the tissue-specific expression patterns of endogenous rat APP and transgenic human APP mRNAs suggests regulatory elements within the cDNA sequence of APP. Conclusion This manuscript describes the generation of APP-transgenic inbred Fischer 344 rats. These are the first human AD model rat lines generated by lentiviral infection. The APP21 rat line expresses high levels of human APP and could be a useful model for AD. Tissue

  19. Microglia, Alzheimer's Disease, and Complement

    Directory of Open Access Journals (Sweden)

    Helen Crehan

    2012-01-01

    Full Text Available Microglia, the immune cell of the brain, are implicated in cascades leading to neuronal loss and cognitive decline in Alzheimer’s disease (AD. Recent genome-wide association studies have indicated a number of risk factors for the development of late-onset AD. Two of these risk factors are an altered immune response and polymorphisms in complement receptor 1. In view of these findings, we discuss how complement signalling in the AD brain and microglial responses in AD intersect. Dysregulation of the complement cascade, either by changes in receptor expression, enhanced activation of different complement pathways or imbalances between complement factor production and complement cascade inhibitors may all contribute to the involvement of complement in AD. Altered complement signalling may reduce the ability of microglia to phagocytose apoptotic cells and clear amyloid beta peptides, modulate the expression by microglia of complement components and receptors, promote complement factor production by plaque-associated cytokines derived from activated microglia and astrocytes, and disrupt complement inhibitor production. The evidence presented here indicates that microglia in AD are influenced by complement factors to adopt protective or harmful phenotypes and the challenge ahead lies in understanding how this can be manipulated to therapeutic advantage to treat late onset AD.

  20. Serotonin: A New Hope in Alzheimer's Disease?

    Science.gov (United States)

    Claeysen, Sylvie; Bockaert, Joël; Giannoni, Patrizia

    2015-07-15

    Alzheimer's disease (AD) is the most common form of dementia affecting 35 million individuals worldwide. Current AD treatments provide only brief symptomatic relief. It is therefore urgent to replace this symptomatic approach with a curative one. Increasing serotonin signaling as well as developing molecules that enhance serotonin concentration in the synaptic cleft have been debated as possible therapeutic strategies to slow the progression of AD. In this Viewpoint, we discuss exciting new insights regarding the modulation of serotonin signaling for AD prevention and therapy.

  1. Alzheimer's disease camouflaged by histrionic personality disorder.

    Science.gov (United States)

    Hellwig, Sabine; Dykierek, Petra; Hellwig, Bernhard; Zwernemann, Stefan; Meyer, Philipp T

    2012-02-01

    A common condition in Alzheimer's disease (AD) is unawareness of deficits. Different concepts try to elucidate the nature of this symptom. An essential question relates to the interaction of organic and psychogenic factors. Here we present a patient who displayed her cognitive deficits as attention-seeking behaviour. There was a history of histrionic personality disorder according to ICD-10 criteria. Unexpectedly, the final diagnosis after extensive diagnostic work-up was AD. The unusual coincidence of AD and a histrionic personality disorder hampered the clinical process of diagnosing dementia. We discuss unawareness as a complex concept incorporating neuroanatomical, psychiatric, and psychosocial aspects.

  2. Alzheimer's disease - the ways of prevention.

    Science.gov (United States)

    Kivipelto, M; Solomon, A

    2008-01-01

    Several vascular and lifestyle related factors have been suggested to influence the development of dementia and Alzheimer's disease (AD), creating new prevention opportunities. This paper discusses current epidemiological evidence and new findings from the Finnish population based CAIDE study linking some of these factors to dementia/AD. Such findings provide an optimistic outlook especially for persons with genetic susceptibility; it may be possible to reduce the risk or postpone the onset of dementia by adopting healthy lifestyle options. The interplay of genes and environment in the aetiology of AD needs to be further investigated as well as the role of lifestyle and pharmacological interventions for the prevention of dementia.

  3. Anti-Aβ drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Naoki Yahata

    Full Text Available BACKGROUND: Alzheimer's disease (AD is a neurodegenerative disorder that causes progressive memory and cognitive decline during middle to late adult life. The AD brain is characterized by deposition of amyloid β peptide (Aβ, which is produced from amyloid precursor protein by β- and γ-secretase (presenilin complex-mediated sequential cleavage. Induced pluripotent stem (iPS cells potentially provide an opportunity to generate a human cell-based model of AD that would be crucial for drug discovery as well as for investigating mechanisms of the disease. METHODOLOGY/PRINCIPAL FINDINGS: We differentiated human iPS (hiPS cells into neuronal cells expressing the forebrain marker, Foxg1, and the neocortical markers, Cux1, Satb2, Ctip2, and Tbr1. The iPS cell-derived neuronal cells also expressed amyloid precursor protein, β-secretase, and γ-secretase components, and were capable of secreting Aβ into the conditioned media. Aβ production was inhibited by β-secretase inhibitor, γ-secretase inhibitor (GSI, and an NSAID; however, there were different susceptibilities to all three drugs between early and late differentiation stages. At the early differentiation stage, GSI treatment caused a fast increase at lower dose (Aβ surge and drastic decline of Aβ production. CONCLUSIONS/SIGNIFICANCE: These results indicate that the hiPS cell-derived neuronal cells express functional β- and γ-secretases involved in Aβ production; however, anti-Aβ drug screening using these hiPS cell-derived neuronal cells requires sufficient neuronal differentiation.

  4. [A new definition for Alzheimer's disease].

    Science.gov (United States)

    Dubois, Bruno

    2013-01-01

    In 2007 and 2010, the International Working Group on Research Criteria for Alzheimer's Disease introduced a new conceptual framework that included a diagnostic algorithm covering early prodromal stages. There is a growing consensus that Alzheimer's disease (AD) should be considered as a clinical-biological entity characterized by: i) a well-defined clinical phenotype (an amnestic syndrome of the hippocampal type in typical AD), and ii) biomarkers, especially pathophysiological biomarkers, of the underlying disease process. The IWG criteria created the possibility for AD to be diagnosed prior to the onset of dementia, and also integrated biomarkers into the diagnostic framework. Although these criteria were intended for research purposes, they are increasingly used in expert centers for early diagnosis, for example of young-onset AD and complex cases (posterior cortical atrophy, primary progressive aphasia, etc.), where biomarkers can improve the diagnostic accuracy. In this article we present this new approach, together with the results of ongoing validation studies and data obtained by a French research team.

  5. Human umbilical cord mesenchymal stem cells transplantation improves cognitive function in Alzheimer's disease mice by decreasing oxidative stress and promoting hippocampal neurogenesis.

    Science.gov (United States)

    Cui, YuanBo; Ma, ShanShan; Zhang, ChunYan; Cao, Wei; Liu, Min; Li, DongPeng; Lv, PengJu; Xing, Qu; Qu, RuiNa; Yao, Ning; Yang, Bo; Guan, FangXia

    2017-03-01

    Stem cell transplantation represents a promising therapy for central nervous system injuries, but its application to Alzheimer's disease (AD) is still limited and the potential mechanism for cognition improvement remains to be elucidated. In the present study, we used Tg2576 mice which express AD-like pathological forms of amyloid precursor protein (APP) to investigate the effects of human umbilical cord mesenchymal stem cells (hUC-MSCs) intravenous transplantation on AD mice. Interestingly, hUC-MSCs transplantation significantly ameliorated cognitive function of AD mice without altering Aβ levels in hippocampus. Remarkably, hUC-MSCs transplantation reduced oxidative stress in hippocampus of AD mice by decreasing the level of malondialdehyde (MDA), increasing the level of nitric oxide (NO), enhancing the activity of superoxide dismutase (SOD) and neuronal nitric oxide synthase (nNOS). The mechanisms underlying the improved cognitive function may be linked to hippocampal neurogenesis and an up-regulation of neuronal synaptic plasticity related proteins levels including silent information regulator 1 (Sirt1), brain-derived neurotrophic factor (BDNF) and synaptophysin (SYN). Taken together, our findings suggest that hUC-MSCs can improve cognition of AD mice by decreasing oxidative stress and promoting hippocampal neurogenesis. These results suggest that modulating hUC-MSCs to generate excess neuroprotective factors could provide a viable therapy to treat AD.

  6. β-Amyloid peptide increases levels of iron content and oxidative stress in human cell and Caenorhabditis elegans models of Alzheimer disease.

    Science.gov (United States)

    Wan, Li; Nie, Guangjun; Zhang, Jie; Luo, Yunfeng; Zhang, Peng; Zhang, Zhiyong; Zhao, Baolu

    2011-01-01

    Recent studies indicate that the deposition of β-amyloid peptide (Aβ) is related to the pathogenesis of Alzheimer disease (AD); however, the underlying mechanism is still not clear. The abnormal interactions of Aβ with metal ions such as iron are implicated in the process of Aβ deposition and oxidative stress in AD brains. In this study, we observed that Aβ increased the levels of iron content and oxidative stress in SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw) and in Caenorhabditis elegans Aβ-expressing strain CL2006. Intracellular iron and calcium levels and reactive oxygen species and nitric oxide generation significantly increased in APPsw cells compared to control cells. The activity of superoxide dismutase and the antioxidant levels of APPsw cells were significantly lower than those of control cells. Moreover, iron treatment decreased cell viability and mitochondrial membrane potential and aggravated oxidative stress damage as well as the release of Aβ1-40 from the APPsw cells. The iron homeostasis disruption in APPsw cells is very probably associated with elevated expression of the iron transporter divalent metal transporter 1, but not transferrin receptor. Furthermore, the C. elegans with Aβ-expression had increased iron accumulation. In aggregate, these results demonstrate that Aβ accumulation in neuronal cells correlated with neuronal iron homeostasis disruption and probably contributed to the pathogenesis of AD.

  7. Inhibition of human high-affinity copper importer Ctr1 orthologous in the nervous system of Drosophila ameliorates Aβ42-induced Alzheimer's disease-like symptoms.

    Science.gov (United States)

    Lang, Minglin; Fan, Qiangwang; Wang, Lei; Zheng, Yajun; Xiao, Guiran; Wang, Xiaoxi; Wang, Wei; Zhong, Yi; Zhou, Bing

    2013-11-01

    Disruption of copper homeostasis has been implicated in Alzheimer's disease (AD) during the last 2 decades; however, whether copper is a friend or a foe is controversial. Within a genetically tractable Drosophila AD model, we manipulated the expression of human high-affinity copper importer orthologous in Drosophila to explore the in vivo roles of copper ions in the development of AD. We found that inhibition of Ctr1C expression by RNAi in Aβ-expressing flies significantly reduced copper accumulation in the brains of the flies as well as ameliorating neurodegeneration, enhancing climbing ability, and prolonging lifespan. Interestingly, Ctr1C inhibition led to a significant increase in higher-molecular-weight Aβ42 forms in brain lysates, whereas it was accompanied by a trend of decreased expression of amyloid-β degradation proteases (including NEP1-3 and IDE) with age and reduced Cu-Aβ interaction-induced oxidative stress in Ctr1C RNAi flies. Similar results were obtained from inhibiting another copper importer Ctr1B and overexpressing a copper exporter DmATP7 in the nervous system of AD flies. These results imply that copper may play a causative role in developing AD, as either Aβ oligomers or aggregates were less toxic in a reduced copper environment or one with less copper binding. Early manipulation of brain copper uptake can have a great effect on Aβ pathology.

  8. Excitatory amino acid binding sites in the hippocampal region of Alzheimer's disease and other dementias.

    OpenAIRE

    1990-01-01

    Quantitative receptor autoradiography was used to measure muscarinic cholinergic, benzodiazepine, kainate, phencyclidine (PCP), N-methyl-D-aspartate (NMDA) (measured in Tris acetate), quisqualate-sensitive, non-quisqualate-sensitive and total glutamate (measured in Tris chloride buffer) binding sites in adjacent sections of the hippocampal region of 10 Alzheimer's disease, nine control, and six demented, non-Alzheimer's disease postmortem human brains. The measurements were compared to the nu...

  9. Prevention of Alzheimer disease: The roles of nutrition and primary care.

    Science.gov (United States)

    Bane, Tabitha J; Cole, Connie

    2015-05-15

    Risk factors for developing Alzheimer disease include hypercholesterolemia, hypertension, obesity, and diabetes. Due to lack of effective treatments for Alzheimer disease, nutrition and primary prevention becomes important.

  10. Imbalanced cholesterol metabolism in Alzheimer's disease.

    Science.gov (United States)

    Xue-shan, Zhao; Juan, Peng; Qi, Wu; Zhong, Ren; Li-hong, Pan; Zhi-han, Tang; Zhi-sheng, Jiang; Gui-xue, Wang; Lu-shan, Liu

    2016-05-01

    Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease that is mainly caused by β-amyloid accumulation. A large number of studies have shown that elevated cholesterol levels may perform a function in AD pathology, and several cholesterol-related gene polymorphisms are associated with this disease. Although numerous studies have shown the important function of cholesterol in AD pathogenesis and development, the underlying mechanism remains unclear. To further elucidate cholesterol metabolism disorder and AD, we first, review metabolism and regulation of the cholesterol in the brain. Second, we summarize the literature stating that hypercholesterolemia is one of the risk factors of AD. Third, we discuss the main mechanisms of abnormal cholesterol metabolism that increase the risk of AD. Finally, the relationships between AD and apolipoprotein E, PCSK9, and LRP1 are discussed in this article.

  11. Imaging Alzheimer's disease pathophysiology with PET

    Directory of Open Access Journals (Sweden)

    Lucas Porcello Schilling

    Full Text Available ABSTRACT Alzheimer's disease (AD has been reconceptualised as a dynamic pathophysiological process characterized by preclinical, mild cognitive impairment (MCI, and dementia stages. Positron emission tomography (PET associated with various molecular imaging agents reveals numerous aspects of dementia pathophysiology, such as brain amyloidosis, tau accumulation, neuroreceptor changes, metabolism abnormalities and neuroinflammation in dementia patients. In the context of a growing shift toward presymptomatic early diagnosis and disease-modifying interventions, PET molecular imaging agents provide an unprecedented means of quantifying the AD pathophysiological process, monitoring disease progression, ascertaining whether therapies engage their respective brain molecular targets, as well as quantifying pharmacological responses. In the present study, we highlight the most important contributions of PET in describing brain molecular abnormalities in AD.

  12. Metal ions, Alzheimer's disease and chelation therapy.

    Science.gov (United States)

    Budimir, Ana

    2011-03-01

    In the last few years, various studies have been providing evidence that metal ions are critically involved in the pathogenesis of major neurological diseases (Alzheimer, Parkinson). Metal ion chelators have been suggested as potential therapies for diseases involving metal ion imbalance. Neurodegeneration is an excellent target for exploiting the metal chelator approach to therapeutics. In contrast to the direct chelation approach in metal ion overload disorders, in neurodegeneration the goal seems to be a better and subtle modulation of metal ion homeostasis, aimed at restoring ionic balance. Thus, moderate chelators able to coordinate deleterious metals without disturbing metal homeostasis are needed. To date, several chelating agents have been investigated for their potential to treat neurodegeneration, and a series of 8-hydroxyquinoline analogues showed the greatest potential for the treatment of neurodegenerative diseases.

  13. Human neural stem cells improve cognition and promote synaptic growth in two complementary transgenic models of Alzheimer's disease and neuronal loss.

    Science.gov (United States)

    Ager, Rahasson R; Davis, Joy L; Agazaryan, Andy; Benavente, Francisca; Poon, Wayne W; LaFerla, Frank M; Blurton-Jones, Mathew

    2015-07-01

    Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder, affecting over 35 million people worldwide. Pathologically, AD is characterized by the progressive accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles within the brain. Together, these pathologies lead to marked neuronal and synaptic loss and corresponding impairments in cognition. Current treatments, and recent clinical trials, have failed to modify the clinical course of AD; thus, the development of novel and innovative therapies is urgently needed. Over the last decade, the potential use of stem cells to treat cognitive impairment has received growing attention. Specifically, neural stem cell transplantation as a treatment for AD offers a novel approach with tremendous therapeutic potential. We previously reported that intrahippocampal transplantation of murine neural stem cells (mNSCs) can enhance synaptogenesis and improve cognition in 3xTg-AD mice and the CaM/Tet-DT(A) model of hippocampal neuronal loss. These promising findings prompted us to examine a human neural stem cell population, HuCNS-SC, which has already been clinically tested for other neurodegenerative disorders. In this study, we provide the first evidence that transplantation of research grade HuCNS-SCs can improve cognition in two complementary models of neurodegeneration. We also demonstrate that HuCNS-SC cells can migrate and differentiate into immature neurons and glia and significantly increase synaptic and growth-associated markers in both 3xTg-AD and CaM/Tet-DTA mice. Interestingly, improvements in aged 3xTg-AD mice were not associated with altered Aβ or tau pathology. Rather, our findings suggest that human NSC transplantation improves cognition by enhancing endogenous synaptogenesis. Taken together, our data provide the first preclinical evidence that human NSC transplantation could be a safe and effective therapeutic approach for treating AD.

  14. Distinct Mechanisms of Impairment in Cognitive Ageing and Alzheimer's Disease

    Science.gov (United States)

    Mapstone, Mark; Dickerson, Kathryn; Duffy, Charles J.

    2008-01-01

    Similar manifestations of functional decline in ageing and Alzheimer's disease obscure differences in the underlying cognitive mechanisms of impairment. We sought to examine the contributions of top-down attentional and bottom-up perceptual factors to visual self-movement processing in ageing and Alzheimer's disease. We administered a novel…

  15. The Alzheimer's Disease Knowledge Scale: Development and Psychometric Properties

    Science.gov (United States)

    Carpenter, Brian D.; Balsis, Steve; Otilingam, Poorni G.; Hanson, Priya K.; Gatz, Margaret

    2009-01-01

    Purpose: This study provides preliminary evidence for the acceptability, reliability, and validity of the new Alzheimer's Disease Knowledge Scale (ADKS), a content and psychometric update to the Alzheimer's Disease Knowledge Test. Design and Methods: Traditional scale development methods were used to generate items and evaluate their psychometric…

  16. Software tool for improved prediction of Alzheimer's disease

    DEFF Research Database (Denmark)

    Soininen, Hilkka; Mattila, Jussi; Koikkalainen, Juha

    2012-01-01

    Diagnostic criteria of Alzheimer's disease (AD) emphasize the integration of clinical data and biomarkers. In practice, collection and analysis of patient data vary greatly across different countries and clinics.......Diagnostic criteria of Alzheimer's disease (AD) emphasize the integration of clinical data and biomarkers. In practice, collection and analysis of patient data vary greatly across different countries and clinics....

  17. Are Judgments of Semantic Relatedness Systematically Impaired in Alzheimer's Disease?

    Science.gov (United States)

    Hornberger, M.; Bell, B.; Graham, K. S.; Rogers, T. T.

    2009-01-01

    We employed a triadic comparison task in patients with Alzheimer's disease (AD) and healthy controls to contrast (a) multidimensional scaling (MDS) and accuracy-based assessments of semantic memory, and (b) degraded-store versus degraded-access accounts of semantic impairment in Alzheimer's disease (AD). Similar to other studies using triadic…

  18. Providing Counseling for Individuals with Alzheimer's Disease and Their Caregivers

    Science.gov (United States)

    Granello, Paul F.; Fleming, Matthew S.

    2008-01-01

    Alzheimer's disease is a progressive condition that results in brain wasting and eventual death. With its increasing diagnosis rate, counselors will likely acquire clients with Alzheimer's disease or their caregivers. Important background information and several practical counseling methods are provided that may assist counselors working with this…

  19. HEAD TRAUMA AND THE RISK OF ALZHEIMERS-DISEASE

    NARCIS (Netherlands)

    VANDUIJN, CM; TANJA, TA; HAAXMA, R; SCHULTE, W; SAAN, RJ; LAMERIS, AJ; ANTONIDESHENDRIKS, G; HOFMAN, A

    1992-01-01

    A population-based case-control study of the association between head trauma and Alzheimer's disease was conducted in the Netherlands from 1980 to 1987. The study comprised 198 patients with clinically diagnosed early onset Alzheimer's disease and 198 age- and sex-matched population controls. Adjust

  20. Risk factors for Alzheimer's disease : a genetic-epidemiologic study

    NARCIS (Netherlands)

    C.M. van Duijn (Cock)

    1992-01-01

    textabstractThe work presented in this thesis has been motivated by the Jack of knowledge of risk factors for Alzheimer's disease. It has been long recognised that genetic factors are implicated, in particular in early-onset Alzheimer's disease.4 But to what extent are genetic factors involved? Are

  1. Vascular contribution to Alzheimer disease: predictors of rapid progression.

    Science.gov (United States)

    Diomedi, Marina; Misaggi, Giulia

    2013-06-01

    Different courses of Alzheimer disease are observed in clinical practice. The rapidly progressive form could be associated with the presence of a major microcirculatory involvement and hemodynamic insufficiency. This short review aims to provide an overview of the current knowledge of cerebrovascular contribution to Alzheimer disease presentation and progression, hypothesizing the possible vascular markers of rapidly progressive form.

  2. Head trauma and the risk of Alzheimer's disease

    NARCIS (Netherlands)

    C.M. van Duijn (Cock); T.A. Tanja (Teun); R. Haaxma (Rob); W. Schulte (Wim); R.J. Saan; A.J. Lameris; G. Antonides-Hendriks (Gea); A. Hofman (Albert)

    1992-01-01

    textabstractA population-based case-control study of the association between head trauma and Alzheimer's disease was conducted in the Netherlands from 1980 to 1987. The study comprised 198 patients with clinically diagnosed early onset Alzheimer's disease and 198 age- and sex-matched population cont

  3. Telomere shortening reduces Alzheimer's disease amyloid pathology in mice

    NARCIS (Netherlands)

    Rolyan, Harshvardhan; Scheffold, Annika; Heinrich, Annette; Begus-Nahrmann, Yvonne; Langkopf, Britta Heike; Hoelter, Sabine M.; Vogt-Weisenhorn, Daniela M.; Liss, Birgit; Wurst, Wolfgang; Lie, Dieter Chichung; Thal, Dietmar Rudolf; Biber, Knut; Rudolph, Karl Lenhard

    2011-01-01

    Alzheimer's disease is a neurodegenerative disorder of the elderly and advancing age is the major risk factor for Alzheimer's disease development. Telomere shortening represents one of the molecular causes of ageing that limits the proliferative capacity of cells, including neural stem cells. Studie

  4. Alzheimer's disease under the mask of stroke

    Directory of Open Access Journals (Sweden)

    A. A. Naumenko

    2016-01-01

    Full Text Available Cognitive impairments (CIs are common in poststroke patients. The basis for this condition is frequently a neurodegenerative process and most often Alzheimer's disease (AD. Stroke may promote the manifestation of clinically asymptomatic AD, worsen prestroke cognitive deficit or merely manifest prestroke CIs.The paper discusses the epidemiology, risk factors, and pathogenesis of poststroke CIs, current methods for its diagnosis, as well as symptomatic and pathogenetic treatment. The most informative method for the diagnosis of poststroke CIs is neuropsychological examination that should be made in the early poststroke period (if the patient's consciousness is clear. The most common screening tests include mini-mental state examination (the most sensitive to evaluate cognitive dysfunction in Alzheimer type dementias and the Montreal cognitive assessment. Magnetic resonance imaging of the brain, positron emission tomography, cerebrospinal fluid examination, and genetic testing are used to reveal AD at its preclinical stages. Preventive measures include regular physical activity, a balanced diet, and sufficient mental workload. The prevention of stroke and other cardiovascular diseases are also important.The major groups of drugs used to treat AD and vascular CIs are acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. It is expedient to use glutamatergic and acetylcholinergic therapy earlier in patients with obvious CIs that are unassociated with emotional problems and disturbance of consciousness. Akatinol memantine is a drug that can be regarded not only as a symptomatic but also pathogenetic agent. 

  5. [Non-verbal communication in Alzheimer's disease].

    Science.gov (United States)

    Schiaratura, Loris Tamara

    2008-09-01

    This review underlines the importance of non-verbal communication in Alzheimer's disease. A social psychological perspective of communication is privileged. Non-verbal behaviors such as looks, head nods, hand gestures, body posture or facial expression provide a lot of information about interpersonal attitudes, behavioral intentions, and emotional experiences. Therefore they play an important role in the regulation of interaction between individuals. Non-verbal communication is effective in Alzheimer's disease even in the late stages. Patients still produce non-verbal signals and are responsive to others. Nevertheless, few studies have been devoted to the social factors influencing the non-verbal exchange. Misidentification and misinterpretation of behaviors may have negative consequences for the patients. Thus, improving the comprehension of and the response to non-verbal behavior would increase first the quality of the interaction, then the physical and psychological well-being of patients and that of caregivers. The role of non-verbal behavior in social interactions should be approached from an integrative and functional point of view.

  6. CD40 signaling and Alzheimer's disease pathogenesis.

    Science.gov (United States)

    Town, T; Tan, J; Mullan, M

    2001-01-01

    The interaction between CD40 and its cognate ligand, CD40 ligand, is a primary regulator of the peripheral immune response, including modulation of T lymphocyte activation, B lymphocyte differentiation and antibody secretion, and innate immune cell activation, maturation, and survival. Recently, we and others have identified CD40 expression on a variety of CNS cells, including endothelial cells, smooth muscle cells, astroglia and microglia, and have found that, on many of these cells, CD40 expression is enhanced by pro-inflammatory stimuli. Importantly, the CD40-CD40 ligand interaction on microglia triggers a series of intracellular signaling events that are discussed, beginning with Src-family kinase activation and culminating in microglial activation as evidenced by tumor necrosis factor-alpha secretion. Based on the involvement of microglial activation and brain inflammation in Alzheimer's disease pathogenesis, we have investigated co-stimulation of microglia, smooth muscle, and endothelial cells with CD40 ligand in the presence of low doses of freshly solubilized amyloid-beta peptides. Data reviewed herein show that CD40 ligand and amyloid-beta act synergistically to promote pro-inflammatory responses by these cells, including secretion of interleukin-1 beta by endothelial cells and tumor necrosis factor-alpha by microglia. As these cytokines have been implicated in neuronal injury, a comprehensive model of pro-inflammatory CD40 ligand and amyloid-beta initiated Alzheimer's disease pathogenesis (mediated by multiple CNS cells) is proposed.

  7. When is category specific in Alzheimer's disease?

    Science.gov (United States)

    Laws, Keith R; Gale, Tim M; Leeson, Verity C; Crawford, John R

    2005-08-01

    Mixed findings have emerged concerning whether category-specific disorders occur in Alzheimer's disease. Factors that may contribute to these inconsistencies include: ceiling effects/skewed distributions for control data in some studies; differences in the severity of cognitive deficit in patients; and differences in the type of analysis (in particular, if and how controls are used to analyse single case data). We examined picture naming in Alzheimer's patients and matched elderly healthy normal controls in three experiments. These experiments used stimuli that did and did not produce ceiling effects/skewed data in controls. In Experiment 1, we examined for category effects in individual DAT patients using commonly used analyses for single cases (chi2 and z-scores). The different techniques produced quite different outcomes. In Experiment 2a, we used the same techniques on a different group of patients with similar outcomes. Finally, in Experiment 2b, we examined the same patients but (a) used stimuli that did not produce ceiling effects/skewed distributions in healthy controls, and (b) used statistical methods that did not treat the control sample as a population. We found that ceiling effects in controls may markedly inflate the incidence of dissociations in which living things are differentially impaired and seriously underestimate dissociations in the opposite direction. In addition, methods that treat the control sample as a population led to inflation in the overall number of dissociations detected. These findings have implications for the reliability of category effects previously reported both in Alzheimer patients and in other pathologies. In particular, they suggest that the greater proportion of living than nonliving deficits reported in the literature may be an artifact of the methods used.

  8. Prion Disease Induces Alzheimer Disease-Like Neuropathologic Changes

    Science.gov (United States)

    Tousseyn, Thomas; Bajsarowicz, Krystyna; Sánchez, Henry; Gheyara, Ania; Oehler, Abby; Geschwind, Michael; DeArmond, Bernadette; DeArmond, Stephen J.

    2016-01-01

    We examined the brains of 266 patients with prion diseases (PrionD) and found that 46 (17%) had Alzheimer disease (AD)-like changes. To explore potential mechanistic links between PrionD and AD, we exposed human brain aggregates (Hu BrnAggs) to brain homogenate from a patient with sporadic Creutzfeldt-Jakob disease (CJD) and found that the neurons in the Hu BrnAggs produced many β-amyloid (β42) inclusions, whereas uninfected, control-exposed Hu BrnAggs did not. Western blots of 20-pooled CJD-infected BrnAggs verified higher Aβ42 levels than controls. We next examined the CA1 region of the hippocampus from 14 patients with PrionD and found that 5 patients had low levels of scrapie-associated prion protein (PrPSc), many Aβ42 intraneuronal inclusions, low APOE-4, and no significant nerve cell loss. Seven patients had high levels of PrPSc, low Aβ42, high APOE-4 and 40% nerve cell loss, suggesting that APOE-4 and PrPSc together cause neuron loss in PrionD. There were also increased levels of hyperphosphorylated tau protein (Hτ) and Hτ-positive neuropil threads and neuron bodies in both PrionD and AD groups. The brains of 6 age-matched control patients without dementia did not contain Aβ42 deposits; however, there were rare Hτ-positive threads in 5 controls and 2 controls had a few Hτ-positive nerve cell bodies. We conclude that PrionD may trigger biochemical changes similar to AD and suggest that PrionD are diseases of PrPSc, Aβ42, APOE-4 and abnormal tau. PMID:26226132

  9. The role of inflammasome in Alzheimer's disease.

    Science.gov (United States)

    Liu, Li; Chan, Christina

    2014-05-01

    Alzheimer's disease (AD) is a chronic, progressive and irreversible neurodegenerative disease with clinical characteristics of memory loss, dementia and cognitive impairment. Although the pathophysiologic mechanism is not fully understood, inflammation has been shown to play a critical role in the pathogenesis of AD. Inflammation in the central nervous system (CNS) is characterized by the activation of glial cells and release of proinflammatory cytokines and chemokines. Accumulating evidence demonstrates that inflammasomes, which cleave precursors of interleukin-1β (IL-1β) and IL-18 to generate their active forms, play an important role in the inflammatory response in the CNS and in AD pathogenesis. Therefore, modulating inflammasome complex assembly and activation could be a potential strategy for suppressing inflammation in the CNS. This review aims to provide insight into the role of inflammasomes in the CNS, with respect to the pathogenesis of AD, and may provide possible clues for devising novel therapeutic strategies.

  10. ABC Transporters and the Alzheimer's Disease Enigma.

    Science.gov (United States)

    Wolf, Andrea; Bauer, Björn; Hartz, Anika M S

    2012-01-01

    Alzheimer's disease (AD) is considered the "disease of the twenty-first century." With a 10-fold increase in global incidence over the past 100 years, AD is now reaching epidemic proportions and by all projections, AD patient numbers will continue to rise. Despite intense research efforts, AD remains a mystery and effective therapies are still unavailable. This represents an unmet need resulting in clinical, social, and economic problems. Over the last decade, a new AD research focus has emerged: ATP-binding cassette (ABC) transporters. In this article, we provide an overview of the ABC transporters ABCA1, ABCA2, P-glycoprotein (ABCB1), MRP1 (ABCC1), and BCRP (ABCG2), all of which are expressed in the brain and have been implicated in AD. We summarize recent findings on the role of these five transporters in AD, and discuss their potential to serve as therapeutic targets.

  11. Iron: a pathological mediator of Alzheimer disease?

    Science.gov (United States)

    Bishop, Glenda M; Robinson, Stephen R; Liu, Quan; Perry, George; Atwood, Craig S; Smith, Mark A

    2002-01-01

    Brains from patients with Alzheimer disease (AD) show a disruption in the metabolism of iron, such that there is an accumulation of iron in senile plaques, and an altered distribution of iron transport and storage proteins. One of the earliest events in AD is the generation of oxidative stress, which may be related to the generation of free radicals by the excess iron that is observed in the disease. Iron has also been shown to mediate the in vitro toxicity of amyloid-beta peptide, and the presence of iron in most in vitro systems could underlie the toxicity that is normally attributed to amyloid-beta in these studies. In contrast, several recent studies have suggested that amyloid-beta may decrease oxidative stress and decrease the toxicity of iron. Continued examination of the complex interactions that occur between iron and amyloid-beta may assist in the elucidation of the mechanisms that underlie the neurodegeneration that leads to dementia in AD.

  12. Chemokines in CSF of Alzheimer's disease patients

    Directory of Open Access Journals (Sweden)

    Jôice Dias Corrêa

    2011-06-01

    Full Text Available Some studies have linked the presence of chemokines to the early stages of Alzheimer's disease (AD. Then, the identification of these mediators may contribute to diagnosis. Our objective was to evaluate the levels of beta-amyloid (BA, tau, phospho-tau (p-tau and chemokines (CCL2, CXCL8 and CXCL10 in the cerebrospinal fluid (CSF of patients with AD and healthy controls. The correlation of these markers with clinical parameters was also evaluated. The levels of p-tau were higher in AD compared to controls, while the tau/p-tau ratio was decreased. The expression of CCL2 was increased in AD. A positive correlation was observed between BA levels and all chemokines studied, and between CCL2 and p-tau levels. Our results suggest that levels of CCL2 in CSF are involved in the pathogenesis of AD and it may be an additional useful biomarker for monitoring disease progression.

  13. FDA Facilitates Research on Earlier Stages of Alzheimer's Disease

    Science.gov (United States)

    ... Updates FDA Facilitates Research on Earlier Stages of Alzheimer's Disease Share Tweet Linkedin Pin it More sharing ... disease.” back to top New Paths for New Alzheimer’s Drugs FDA’s draft guidance aims to encourage research ...

  14. Cerebral microvascular pathology in aging and Alzheimer's disease

    NARCIS (Netherlands)

    Farkas, E; Luiten, PGM

    2001-01-01

    The aging of the central nervous system and the development of incapacitating neurological diseases like Alzheimer's disease (AD) are generally associated with a wide range of histological and pathophysiological changes eventually leading to compromised cognitive status. Although the diverse trigger

  15. Is immunotherapy an effective treatment for Alzheimer's disease?

    Directory of Open Access Journals (Sweden)

    Licastro Federico

    2004-11-01

    Full Text Available Abstract Immunotherapy in patients with Alzheimer's disease (AD is rapidly becoming a hot topic of modern geriatric and clinical gerontology. Current views see immunization with Aβ peptide, the amyloidogenic protein found in senile plaque of AD patient's brains, or the infusion of preformed antibody specific for human Aβ, as possible therapeutic approaches to improve the cognitive status in the disease. Animal models of the disease have provided positive results from both approaches. Thus, an initial clinical trial using immunization with human Aβ in AD patients was started, but then shortly halted because of an unusually high incidence (6% of meningoencephalitis. A long and currently ongoing debate in the scientific community about the pro or contra of vaccination or passive immunization with Aβ in AD is thereafter started. Here, the authors would like to stress few points of concern regarding these approaches in clinical practice.

  16. Biological and genetic markers of sporadic Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Engelborghs S

    2001-04-01

    Full Text Available With the development of new treatments, there is an increasing need for early diagnosis of sporadic Alzheimer's disease. Therefore, biological markers allowing positive diagnosis early in the course of the disease are highly desirable. Cerebrospinal fluid levels of protein tau were shown to be significantly increased in patients with Alzheimer's disease. Although sensitivity is high, poor specificity limits the diagnostic value of this marker. The same is true for the 42 amino acid isoform of beta-amyloid protein that is significantly decreased in cerebrospinal fluid of Alzheimer's disease patients. However, combining both markers could improve specificity at least allowing differentiation between Alzheimer's disease, normal ageing and depressive pseudodementia. Other biological markers such as cerebrospinal fluid levels of neurotransmitters, cytokines or superoxide dismutase were shown to have even less diagnostic value. The apolipoprotein epsilon 4 allele is a risk factor for Alzheimer's disease but not a diagnostic marker as many individuals who inherit epsilon 4 do not develop the disease. Till now, a single diagnostic marker allowing discrimination between Alzheimer's disease and other dementias does not exist. Combined cerebrospinal fluid levels of beta-amyloid protein and tau protein might be used as a marker that helps discriminating Alzheimer's disease from normal ageing and depression.

  17. Domain adaptation for Alzheimer's disease diagnostics.

    Science.gov (United States)

    Wachinger, Christian; Reuter, Martin

    2016-10-01

    With the increasing prevalence of Alzheimer's disease, research focuses on the early computer-aided diagnosis of dementia with the goal to understand the disease process, determine risk and preserving factors, and explore preventive therapies. By now, large amounts of data from multi-site studies have been made available for developing, training, and evaluating automated classifiers. Yet, their translation to the clinic remains challenging, in part due to their limited generalizability across different datasets. In this work, we describe a compact classification approach that mitigates overfitting by regularizing the multinomial regression with the mixed ℓ1/ℓ2 norm. We combine volume, thickness, and anatomical shape features from MRI scans to characterize neuroanatomy for the three-class classification of Alzheimer's disease, mild cognitive impairment and healthy controls. We demonstrate high classification accuracy via independent evaluation within the scope of the CADDementia challenge. We, furthermore, demonstrate that variations between source and target datasets can substantially influence classification accuracy. The main contribution of this work addresses this problem by proposing an approach for supervised domain adaptation based on instance weighting. Integration of this method into our classifier allows us to assess different strategies for domain adaptation. Our results demonstrate (i) that training on only the target training set yields better results than the naïve combination (union) of source and target training sets, and (ii) that domain adaptation with instance weighting yields the best classification results, especially if only a small training component of the target dataset is available. These insights imply that successful deployment of systems for computer-aided diagnostics to the clinic depends not only on accurate classifiers that avoid overfitting, but also on a dedicated domain adaptation strategy.

  18. Alzheimer disease and pre-emptive suicide.

    Science.gov (United States)

    Davis, Dena S

    2014-08-01

    There is a flood of papers being published on new ways to diagnose Alzheimer disease (AD) before it is symptomatic, involving a combination of invasive tests (eg, spinal tap), and pen and paper tests. This changes the landscape with respect to genetic tests for risk of AD, making rational suicide a much more feasible option. Before the availability of these presymptomatic tests, even someone with a high risk of developing AD could not know if and when the disease was approaching. One could lose years of good life by committing suicide too soon, or risk waiting until it was too late and dementia had already sapped one of the ability to form and carry out a plan. One can now put together what one knows about one's risk, with continuing surveillance via these clinical tests, and have a good strategy for planning one's suicide before one becomes demented. This has implications for how these genetic and clinical tests are marketed and deployed, and the language one uses to speak about them. The phrase 'there is nothing one can do' is insulting and disrespectful of the planned suicide option, as is the language of the Risk Evaluation and Education for Alzheimer's Disease (REVEAL) studies and others that conclude that it is 'safe' to tell subjects their risk status for AD. Further, the argument put forward by some researchers that presymptomatic testing should remain within research protocols, and the results not shared with subjects until such time as treatments become available, disrespects the autonomy of people at high risk who consider suicide an option.

  19. Hippocampal atrophy rates in Alzheimer disease

    Science.gov (United States)

    Henneman, W J.P.; Sluimer, J D.; Barnes, J; van der Flier, W M.; Sluimer, I C.; Fox, N C.; Scheltens, P; Vrenken, H; Barkhof, F

    2009-01-01

    Objective: To investigate the added value of hippocampal atrophy rates over whole brain volume measurements on MRI in patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and controls. Methods: We included 64 patients with AD (67 ± 9 years; F/M 38/26), 44 patients with MCI (71 ± 6 years; 21/23), and 34 controls (67 ± 9 years; 16/18). Two MR scans were performed (scan interval: 1.8 ± 0.7 years; 1.0 T), using a coronal three-dimensional T1-weighted gradient echo sequence. At follow-up, 3 controls and 23 patients with MCI had progressed to AD. Hippocampi were manually delineated at baseline. Hippocampal atrophy rates were calculated using regional, nonlinear fluid registration. Whole brain baseline volumes and atrophy rates were determined using automated segmentation and registration tools. Results: All MRI measures differed between groups (p < 0.005). For the distinction of MCI from controls, larger effect sizes of hippocampal measures were found compared to whole brain measures. Between MCI and AD, only whole brain atrophy rate differed significantly. Cox proportional hazards models (variables dichotomized by median) showed that within all patients without dementia, hippocampal baseline volume (hazard ratio [HR]: 5.7 [95% confidence interval: 1.5–22.2]), hippocampal atrophy rate (5.2 [1.9–14.3]), and whole brain atrophy rate (2.8 [1.1–7.2]) independently predicted progression to AD; the combination of low hippocampal volume and high atrophy rate yielded a HR of 61.1 (6.1–606.8). Within patients with MCI, only hippocampal baseline volume and atrophy rate predicted progression. Conclusion: Hippocampal measures, especially hippocampal atrophy rate, best discriminate mild cognitive impairment (MCI) from controls. Whole brain atrophy rate discriminates Alzheimer disease (AD) from MCI. Regional measures of hippocampal atrophy are the strongest predictors of progression to AD. GLOSSARY AD = Alzheimer disease; BET = brain

  20. The rat as an animal model of Alzheimer's disease

    DEFF Research Database (Denmark)

    Benedikz, Eirikur; Kloskowska, Ewa; Winblad, Bengt

    2009-01-01

    As a disease model, the laboratory rat has contributed enormously to neuroscience research over the years. It has also been a popular animal model for Alzheimer's disease but its popularity has diminished during the last decade, as techniques for genetic manipulation in rats have lagged behind...... that of mice. In recent years, the rat has been making a comeback as an Alzheimer's disease model and the appearance of increasing numbers of transgenic rats will be a welcome and valuable complement to the existing mouse models. This review summarizes the contributions and current status of the rat...... as an animal model of Alzheimer's disease....

  1. Vaccination against Alzheimer disease: an update on future strategies.

    Science.gov (United States)

    Fettelschoss, Antonia; Zabel, Franziska; Bachmann, Martin F

    2014-01-01

    Alzheimer disease is a devastating chronic disease without adequate therapy. More than 10 years ago, it was demonstrated in transgenic mouse models that vaccination may be a novel, disease-modifying therapy for Alzheimer. Subsequent clinical development has been a roller-coaster with some positive and many negative news. Here, we would like to summarize evidence that next generation vaccines optimized for old people and focusing on patients with mild disease stand a good chance to proof efficacious for the treatment of Alzheimer.

  2. Toward precision medicine in Alzheimer's disease.

    Science.gov (United States)

    Reitz, Christiane

    2016-03-01

    In Western societies, Alzheimer's disease (AD) is the most common form of dementia and the sixth leading cause of death. In recent years, the concept of precision medicine, an approach for disease prevention and treatment that is personalized to an individual's specific pattern of genetic variability, environment and lifestyle factors, has emerged. While for some diseases, in particular select cancers and a few monogenetic disorders such as cystic fibrosis, significant advances in precision medicine have been made over the past years, for most other diseases precision medicine is only in its beginning. To advance the application of precision medicine to a wider spectrum of disorders, governments around the world are starting to launch Precision Medicine Initiatives, major efforts to generate the extensive scientific knowledge needed to integrate the model of precision medicine into every day clinical practice. In this article we summarize the state of precision medicine in AD, review major obstacles in its development, and discuss its benefits in this highly prevalent, clinically and pathologically complex disease.

  3. Various MRS application tools for Alzheimer disease and mild cognitive impairment.

    Science.gov (United States)

    Gao, F; Barker, P B

    2014-06-01

    MR spectroscopy is a noninvasive technique that allows the detection of several naturally occurring compounds (metabolites) from well-defined regions of interest within the human brain. Alzheimer disease, a progressive neurodegenerative disorder, is the most common cause of dementia in the elderly. During the past 20 years, multiple studies have been performed on MR spectroscopy in patients with both mild cognitive impairment and Alzheimer disease. Generally, MR spectroscopy studies have found decreased N-acetylaspartate and increased myo-inositol in both patients with mild cognitive impairment and Alzheimer disease, with greater changes in Alzheimer disease than in mild cognitive impairment. This review summarizes the information content of proton brain MR spectroscopy and its related technical aspects, as well as applications of MR spectroscopy to mild cognitive impairment and Alzheimer disease. While MR spectroscopy may have some value in the differential diagnosis of dementias and assessing prognosis, more likely its role in the near future will be predominantly as a tool for monitoring disease response or progression in treatment trials. More work is needed to evaluate the role of MR spectroscopy as a biomarker in Alzheimer disease and its relationship to other imaging modalities.

  4. Metal dyshomeostasis and oxidative stress in Alzheimer's disease.

    Science.gov (United States)

    Greenough, Mark A; Camakaris, James; Bush, Ashley I

    2013-04-01

    Alzheimer's disease is the leading cause of dementia in the elderly and is defined by two pathological hallmarks; the accumulation of aggregated amyloid beta and excessively phosphorylated Tau proteins. The etiology of Alzheimer's disease progression is still debated, however, increased oxidative stress is an early and sustained event that underlies much of the neurotoxicity and consequent neuronal loss. Amyloid beta is a metal binding protein and copper, zinc and iron promote amyloid beta oligomer formation. Additionally, copper and iron are redox active and can generate reactive oxygen species via Fenton (and Fenton-like chemistry) and the Haber-Weiss reaction. Copper, zinc and iron are naturally abundant in the brain but Alzheimer's disease brain contains elevated concentrations of these metals in areas of amyloid plaque pathology. Amyloid beta can become pro-oxidant and when complexed to copper or iron it can generate hydrogen peroxide. Accumulating evidence suggests that copper, zinc, and iron homeostasis may become perturbed in Alzheimer's disease and could underlie an increased oxidative stress burden. In this review we discuss oxidative/nitrosative stress in Alzheimer's disease with a focus on the role that metals play in this process. Recent studies have started to elucidate molecular links with oxidative/nitrosative stress and Alzheimer's disease. Finally, we discuss metal binding compounds that are designed to cross the blood brain barrier and restore metal homeostasis as potential Alzheimer's disease therapeutics.

  5. Alcohol consumption and mortality in patients with mild Alzheimer's disease

    DEFF Research Database (Denmark)

    Berntsen, Sine; Kragstrup, Jakob; Siersma, Volkert

    2015-01-01

    OBJECTIVE: To investigate the association between alcohol consumption and mortality in patients recently diagnosed with mild Alzheimer's disease (AD). DESIGN: A post hoc analysis study based on a clinical trial population. SETTING: The data reported were collected as part of the Danish Alzheimer...

  6. GDF-15 secreted from human umbilical cord blood mesenchymal stem cells delivered through the cerebrospinal fluid promotes hippocampal neurogenesis and synaptic activity in an Alzheimer's disease model.

    Science.gov (United States)

    Kim, Dong Hyun; Lee, Dahm; Chang, Eun Hyuk; Kim, Ji Hyun; Hwang, Jung Won; Kim, Ju-Yeon; Kyung, Jae Won; Kim, Sung Hyun; Oh, Jeong Su; Shim, Sang Mi; Na, Duk Lyul; Oh, Wonil; Chang, Jong Wook

    2015-10-15

    Our previous studies demonstrated that transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into the hippocampus of a transgenic mouse model of Alzheimer's disease (AD) reduced amyloid-β (Aβ) plaques and enhanced cognitive function through paracrine action. Due to the limited life span of hUCB-MSCs after their transplantation, the extension of hUCB-MSC efficacy was essential for AD treatment. In this study, we show that repeated cisterna magna injections of hUCB-MSCs activated endogenous hippocampal neurogenesis and significantly reduced Aβ42 levels. To identify the paracrine factors released from the hUCB-MSCs that stimulated endogenous hippocampal neurogenesis in the dentate gyrus, we cocultured adult mouse neural stem cells (NSCs) with hUCB-MSCs and analyzed the cocultured media with cytokine arrays. Growth differentiation factor-15 (GDF-15) levels were significantly increased in the media. GDF-15 suppression in hUCB-MSCs with GDF-15 small interfering RNA reduced the proliferation of NSCs in cocultures. Conversely, recombinant GDF-15 treatment in both in vitro and in vivo enhanced hippocampal NSC proliferation and neuronal differentiation. Repeated administration of hUBC-MSCs markedly promoted the expression of synaptic vesicle markers, including synaptophysin, which are downregulated in patients with AD. In addition, in vitro synaptic activity through GDF-15 was promoted. Taken together, these results indicated that repeated cisterna magna administration of hUCB-MSCs enhanced endogenous adult hippocampal neurogenesis and synaptic activity through a paracrine factor of GDF-15, suggesting a possible role of hUCB-MSCs in future treatment strategies for AD.

  7. Expression of tryptophan 2,3-dioxygenase and production of kynurenine pathway metabolites in triple transgenic mice and human Alzheimer's disease brain.

    Directory of Open Access Journals (Sweden)

    Wei Wu

    Full Text Available To assess the role of the kynurenine pathway in the pathology of Alzheimer's disease (AD, the expression and localization of key components of the kynurenine pathway including the key regulatory enzyme tryptophan 2,3 dioxygenase (TDO, and the metabolites tryptophan, kynurenine, kynurenic acid, quinolinic acid and picolinic acid were assessed in different brain regions of triple transgenic AD mice. The expression and cell distribution of TDO and quinolinic acid, and their co-localization with neurofibrillary tangles and senile β amyloid deposition were also determined in hippocampal sections from human AD brains. The expression of TDO mRNA was significantly increased in the cerebellum of AD mouse brain. Immunohistochemistry demonstrated that the density of TDO immuno-positive cells was significantly higher in the AD mice. The production of the excitotoxin quinolinic acid strongly increased in the hippocampus in a progressive and age-dependent manner in AD mice. Significantly higher TDO and indoleamine 2,3 dioxygenase 1 immunoreactivity was observed in the hippocampus of AD patients. Furthermore, TDO co-localizes with quinolinic acid, neurofibrillary tangles-tau and amyloid deposits in the hippocampus of AD. These results show that the kynurenine pathway is over-activated in AD mice. This is the first report demonstrating that TDO is highly expressed in the brains of AD mice and in AD patients, suggesting that TDO-mediated activation of the kynurenine pathway could be involved in neurofibrillary tangles formation and associated with senile plaque. Our study adds to the evidence that the kynurenine pathway may play important roles in the neurodegenerative processes of AD.

  8. New Acetylcholinesterase Inhibitors for Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Mona Mehta

    2012-01-01

    Full Text Available Acetylcholinesterase (AChE remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.

  9. Memory for music in Alzheimer's disease: unforgettable?

    Science.gov (United States)

    Baird, Amee; Samson, Séverine

    2009-03-01

    The notion that memory for music can be preserved in patients with Alzheimer's Disease (AD) has been raised by a number of case studies. In this paper, we review the current research examining musical memory in patients with AD. In keeping with models of memory described in the non-musical domain, we propose that various forms of musical memory exist, and may be differentially impaired in AD, reflecting the pattern of neuropathological changes associated with the condition. Our synthesis of this literature reveals a dissociation between explicit and implicit musical memory functions. Implicit, specifically procedural musical memory, or the ability to play a musical instrument, can be spared in musicians with AD. In contrast, explicit musical memory, or the recognition of familiar or unfamiliar melodies, is typically impaired. Thus, the notion that music is unforgettable in AD is not wholly supported. Rather, it appears that the ability to play a musical instrument may be unforgettable in some musicians with AD.

  10. Nutrition and the Risk of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Nan Hu

    2013-01-01

    Full Text Available Alzheimer's disease (AD is a progressive neurodegenerative disorder that accounts for the major cause of dementia, and the increasing worldwide prevalence of AD is a major public health concern. Increasing epidemiological studies suggest that diet and nutrition might be important modifiable risk factors for AD. Dietary supplementation of antioxidants, B vitamins, polyphenols, and polyunsaturated fatty acids are beneficial to AD, and consumptions of fish, fruits, vegetables, coffee, and light-to-moderate alcohol reduce the risk of AD. However, many of the results from randomized controlled trials are contradictory to that of epidemiological studies. Dietary patterns summarizing an overall diet are gaining momentum in recent years. Adherence to a healthy diet, the Japanese diet, and the Mediterranean diet is associated with a lower risk of AD. This paper will focus on the evidence linking many nutrients, foods, and dietary patterns to AD.

  11. Metaphor comprehension in Alzheimer's disease: novelty matters.

    Science.gov (United States)

    Amanzio, Martina; Geminiani, Giuliano; Leotta, Daniela; Cappa, Stefano

    2008-10-01

    The comprehension of non-literal language was investigated in 20 probable Alzheimer's disease (pAD) patients by comparing their performance to that of 20 matched control subjects. pAD patients were unimpaired in the comprehension of conventional metaphors and idioms. However, their performance was significantly lower in the case of non-conventional (novel) metaphor comprehension. This ability was not related to global cognitive deterioration or to deficits in the cognitive domains of attention, memory and language comprehension. On the other hand, the impairment in verbal reasoning appeared to be relevant for both novel and conventional metaphor comprehension. The relationship between novel metaphor comprehension and performance in the visual-spatial planning task of the Behavioral Assessment of the Dysexecutive Syndrome (BADS) suggests that executive impairment, possibly related to prefrontal dysfunction, may be responsible for the pAD patients' poor performance in novel metaphor comprehension. The present findings suggest a role of the prefrontal cortex in novel metaphor comprehension.

  12. Delaying the onset of Alzheimer disease

    Science.gov (United States)

    Craik, Fergus I.M.; Bialystok, Ellen; Freedman, Morris

    2010-01-01

    Objectives: There is strong epidemiologic evidence to suggest that older adults who maintain an active lifestyle in terms of social, mental, and physical engagement are protected to some degree against the onset of dementia. Such factors are said to contribute to cognitive reserve, which acts to compensate for the accumulation of amyloid and other brain pathologies. We present evidence that lifelong bilingualism is a further factor contributing to cognitive reserve. Methods: Data were collected from 211 consecutive patients diagnosed with probable Alzheimer disease (AD). Patients' age at onset of cognitive impairment was recorded, as was information on occupational history, education, and language history, including fluency in English and any other languages. Following this procedure, 102 patients were classified as bilingual and 109 as monolingual. Results: We found that the bilingual patients had been diagnosed 4.3 years later and had reported the onset of symptoms 5.1 years later than the monolingual patients. The groups were equivalent on measures of cognitive and occupational level, there was no apparent effect of immigration status, and the monolingual patients had received more formal education. There were no gender differences. Conclusions: The present data confirm results from an earlier study, and thus we conclude that lifelong bilingualism confers protection against the onset of AD. The effect does not appear to be attributable to such possible confounding factors as education, occupational status, or immigration. Bilingualism thus appears to contribute to cognitive reserve, which acts to compensate for the effects of accumulated neuropathology. GLOSSARY AD = Alzheimer disease; MMSE = Mini-Mental State Examination. PMID:21060095

  13. Understanding Family Interaction Patterns in Families With Alzheimer's Disease.

    Science.gov (United States)

    Schaber, Patricia; Blair, Kate; Jost, Ellen; Schaffer, Molly; Thurner, Emily

    2016-01-01

    This qualitative study explores the dynamic changes that occur in family interaction patterns when Alzheimer's disease is present. Semi-structured interviews were conducted with 15 participants who have a family member with the disease. Using modified analytic induction, guided by the dimensions of the Family Fundamental Interpersonal Relations Orientation (FIRO) Model, participants shared how Alzheimer's disease affected family structure, control dynamics, and intimacy among family members. Findings demonstrate that (a) families reorganize and restructure based on geographic proximity and shifting roles, act out of filial responsibility, and strive to preserve shared meanings and rituals; (b) decision making increases around care of the person with Alzheimer's disease and shifts to the primary caregiver or other family members based on their abilities; and (c) expressions of intimacy intensify while personality is preserved in the person with the disease. The Family FIRO model can inform practitioners using family-centered care with families with Alzheimer's disease.

  14. Disturbed Copper Bioavailability in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Daniela Kaden

    2011-01-01

    Full Text Available Recent data from in vitro, animal, and human studies have shed new light on the positive roles of copper in many aspects of AD. Copper promotes the non-amyloidogenic processing of APP and thereby lowers the Aβ production in cell culture systems, and it increases lifetime and decreases soluble amyloid production in APP transgenic mice. In a clinical trial with Alzheimer patients, the decline of Aβ levels in CSF, which is a diagnostic marker, is diminished in the verum group (8 mg copper/day, indicating a beneficial effect of the copper treatment. These observations are in line with the benefit of treatment with compounds aimed at normalizing metal levels in the brain, such as PBT2. The data reviewed here demonstrate that there is an apparent disturbance in metal homeostasis in AD. More research is urgently needed to understand how this disturbance can be addressed therapeutically.

  15. Explorative and targeted neuroproteomics in Alzheimer's disease.

    Science.gov (United States)

    Brinkmalm, Ann; Portelius, Erik; Öhrfelt, Annika; Brinkmalm, Gunnar; Andreasson, Ulf; Gobom, Johan; Blennow, Kaj; Zetterberg, Henrik

    2015-07-01

    Alzheimer's disease (AD) is a progressive brain amyloidosis that injures brain regions involved in memory consolidation and other higher brain functions. Neuropathologically, the disease is characterized by accumulation of a 42 amino acid peptide called amyloid β (Aβ42) in extracellular senile plaques, intraneuronal inclusions of hyperphosphorylated tau protein in neurofibrillary tangles, and neuronal and axonal degeneration and loss. Biomarker assays capturing these pathologies have been developed for use on cerebrospinal fluid samples but there are additional molecular pathways that most likely contribute to the neurodegeneration and full clinical expression of AD. One way of learning more about AD pathogenesis is to identify novel biomarkers for these pathways and examine them in longitudinal studies of patients in different stages of the disease. Here, we discuss targeted proteomic approaches to study AD and AD-related pathologies in closer detail and explorative approaches to discover novel pathways that may contribute to the disease. This article is part of a Special Issue entitled: Neuroproteomics: Applications in neuroscience and neurology.

  16. Copernicus revisited: amyloid beta in Alzheimer's disease.

    Science.gov (United States)

    Joseph, J; Shukitt-Hale, B; Denisova, N A; Martin, A; Perry, G; Smith, M A

    2001-01-01

    The beta-amyloid hypothesis of Alzheimer's Disease (AD) has dominated the thinking and research in this area for over a decade and a half. While there has been a great deal of effort in attempting to prove its centrality in this devastating disease, and while an enormous amount has been learned about its properties (e.g., putative toxicity, processing and signaling), Abeta has not proven to be both necessary and sufficient for the development, neurotoxicity, and cognitive deficits associated with this disease. Instead, the few treatments that are available have emerged from aging research and are primarily directed toward modification of acetylcholine levels. Clearly, it is time to rethink this position and to propose instead that future approaches should focus upon altering the age-related sensitivity of the neuronal environment to insults involving such factors as inflammation and oxidative stress. In other words "solve the problems of aging and by extension those of AD will also be reduced." This review is being submitted as a rather Lutherian attempt to "nail an alternative thesis" to the gate of the Church of the Holy Amyloid to open its doors to the idea that aging is the most pervasive element in this disease and Abeta is merely one of the planets.

  17. Assessing impulsivity changes in Alzheimer disease.

    Science.gov (United States)

    Rochat, Lucien; Delbeuck, Xavier; Billieux, Joël; d'Acremont, Mathieu; Van der Linden, Anne-Claude Juillerat; Van der Linden, Martial

    2008-01-01

    Impulsive behaviors are common in brain-damaged patients including those with neurodegenerative diseases such as Alzheimer disease (AD). The objective of this study was to develop and validate a short version of the UPPS Impulsive Behavior Scale assessing changes on 4 different dimensions of impulsivity, namely urgency, (lack of) premeditation, (lack of) perseverance, and sensation seeking, arising in the course of a neurodegenerative disease. To this end, caregivers of 83 probable AD patients completed a short questionnaire adapted from the UPPS Impulsive Behavior Scale. Exploratory and confirmatory factor analyses of the data were performed and revealed that a model with 4 distinct but related latent variables corresponding to 4 different dimensions of impulsivity fit the data best. Furthermore, the results showed that lack of perseverance, followed by lack of premeditation and urgency, increased after the onset of the disease, whereas sensation seeking decreased. Overall, the multifaceted nature of impulsivity was confirmed in a sample of AD patients, whose caregivers reported significant changes regarding each facet of impulsivity. Consequently, the short version of the UPPS Impulsive Behavior Scale opens up interesting prospects for a better comprehension of behavioral symptoms of dementia.

  18. Beclin 1 complex in autophagy and Alzheimer disease.

    Science.gov (United States)

    Jaeger, Philipp A; Wyss-Coray, Tony

    2010-10-01

    Beclin 1 is a protein involved in the regulation of autophagy and has been shown to be reduced in patients with Alzheimer disease. This review summarizes the current research data that link disturbances in autophagy, a cellular degradation and maintenance pathway, to the development of Alzheimer disease and related neurodegenerative diseases. It also provides a brief overview of the existing pharmacological interventions available to modulate autophagy activity in mammalian cells.

  19. The Alzheimer's disease β-secretase enzyme, BACE1

    OpenAIRE

    Vassar Robert; Cole Sarah L

    2007-01-01

    Abstract The pathogenesis of Alzheimer's disease is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE1 enzyme is essential for the generation of β-amyloid. BACE1 knockout m...

  20. Altered Mitochondrial DNA Methylation Pattern in Alzheimer Disease-Related Pathology and in Parkinson Disease.

    Science.gov (United States)

    Blanch, Marta; Mosquera, Jose Luis; Ansoleaga, Belén; Ferrer, Isidre; Barrachina, Marta

    2016-02-01

    Mitochondrial dysfunction is linked with the etiopathogenesis of Alzheimer disease and Parkinson disease. Mitochondria are intracellular organelles essential for cell viability and are characterized by the presence of the mitochondrial (mt)DNA. DNA methylation is a well-known epigenetic mechanism that regulates nuclear gene transcription. However, mtDNA methylation is not the subject of the same research attention. The present study shows the presence of mitochondrial 5-methylcytosine in CpG and non-CpG sites in the entorhinal cortex and substantia nigra of control human postmortem brains, using the 454 GS FLX Titanium pyrosequencer. Moreover, increased mitochondrial 5-methylcytosine levels are found in the D-loop region of mtDNA in the entorhinal cortex in brain samples with Alzheimer disease-related pathology (stages I to II and stages III to IV of Braak and Braak; n = 8) with respect to control cases. Interestingly, this region shows a dynamic pattern in the content of mitochondrial 5-methylcytosine in amyloid precursor protein/presenilin 1 mice along with Alzheimer disease pathology progression (3, 6, and 12 months of age). Finally, a loss of mitochondrial 5-methylcytosine levels in the D-loop region is found in the substantia nigra in Parkinson disease (n = 10) with respect to control cases. In summary, the present findings suggest mtDNA epigenetic modulation in human brain is vulnerable to neurodegenerative disease states.

  1. Estrogen Intake and Copper Depositions: Implications for Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Florian Amtage

    2014-06-01

    Full Text Available We present a patient with chronic postmenopausal estrogen intake with presence of Kayser-Fleischer ring in the cornea and Alzheimer's disease and discuss the pathophysiological mechanisms of estrogen intake and copper accumulation in various tissues, including the central nervous system. Sonography was compatible with copper accumulation in the basal ganglia, but the patient showed no clinical signs of Wilson's disease. Magnetic resonance imaging and positron emission tomography revealed a typical pattern for Alzheimer's disease. We propose increased copper levels as a direct effect of estrogen intake due to an augmented ATP7A-mRNA in the intestine. Moreover, we discuss the impact of elevated free serum copper on accompanying Alzheimer's disease, knowing that copper plays a crucial role in the formation of amyloid plaques and tau aggregation. This might offer a partial explanation for the observation that postmenopausal estrogen therapy is associated with a higher risk of mild cognitive impairment and Alzheimer's disease.

  2. Neuroinflammation in Alzheimer's disease wanes with age

    Directory of Open Access Journals (Sweden)

    Hoozemans Jeroen JM

    2011-12-01

    Full Text Available Abstract Background Inflammation is a prominent feature in Alzheimer's disease (AD. It has been proposed that aging has an effect on the function of inflammation in the brain, thereby contributing to the development of age-related diseases like AD. However, the age-dependent relationship between inflammation and clinical phenotype of AD has never been investigated. Methods In this study we have analysed features of the neuroinflammatory response in clinically and pathologically confirmed AD and control cases in relation to age (range 52-97 years. The mid-temporal cortex of 19 controls and 19 AD cases was assessed for the occurrence of microglia and astrocytes by immunohistochemistry using antibodies directed against CD68 (KP1, HLA class II (CR3/43 and glial fibrillary acidic protein (GFAP. Results By measuring the area density of immunoreactivity we found significantly more microglia and astrocytes in AD cases younger than 80 years compared to older AD patients. In addition, the presence of KP1, CR3/43 and GFAP decreases significantly with increasing age in AD. Conclusion Our data suggest that the association between neuroinflammation and AD is stronger in relatively young patients than in the oldest patients. This age-dependent relationship between inflammation and clinical phenotype of AD has implications for the interpretation of biomarkers and treatment of the disease.

  3. Why musical memory can be preserved in advanced Alzheimer's disease.

    Science.gov (United States)

    Jacobsen, Jörn-Henrik; Stelzer, Johannes; Fritz, Thomas Hans; Chételat, Gael; La Joie, Renaud; Turner, Robert

    2015-08-01

    Musical memory is considered to be partly independent from other memory systems. In Alzheimer's disease and different types of dementia, musical memory is surprisingly robust, and likewise for brain lesions affecting other kinds of memory. However, the mechanisms and neural substrates of musical memory remain poorly understood. In a group of 32 normal young human subjects (16 male and 16 female, mean age of 28.0 ± 2.2 years), we performed a 7 T functional magnetic resonance imaging study of brain responses to music excerpts that were unknown, recently known (heard an hour before scanning), and long-known. We used multivariate pattern classification to identify brain regions that encode long-term musical memory. The results showed a crucial role for the caudal anterior cingulate and the ventral pre-supplementary motor area in the neural encoding of long-known as compared with recently known and unknown music. In the second part of the study, we analysed data of three essential Alzheimer's disease biomarkers in a region of interest derived from our musical memory findings (caudal anterior cingulate cortex and ventral pre-supplementary motor area) in 20 patients with Alzheimer's disease (10 male and 10 female, mean age of 68.9 ± 9.0 years) and 34 healthy control subjects (14 male and 20 female, mean age of 68.1 ± 7.2 years). Interestingly, the regions identified to encode musical memory corresponded to areas that showed substantially minimal cortical atrophy (as measured with magnetic resonance imaging), and minimal disruption of glucose-metabolism (as measured with (18)F-fluorodeoxyglucose positron emission tomography), as compared to the rest of the brain. However, amyloid-β deposition (as measured with (18)F-flobetapir positron emission tomography) within the currently observed regions of interest was not substantially less than in the rest of the brain, which suggests that the regions of interest were still in a very early stage of the expected course of

  4. Investigating interventions in Alzheimer's disease with computer simulation models.

    Directory of Open Access Journals (Sweden)

    Carole J Proctor

    Full Text Available Progress in the development of therapeutic interventions to treat or slow the progression of Alzheimer's disease has been hampered by lack of efficacy and unforeseen side effects in human clinical trials. This setback highlights the need for new approaches for pre-clinical testing of possible interventions. Systems modelling is becoming increasingly recognised as a valuable tool for investigating molecular and cellular mechanisms involved in ageing and age-related diseases. However, there is still a lack of awareness of modelling approaches in many areas of biomedical research. We previously developed a stochastic computer model to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ and the micro-tubular binding protein tau. Here we show how we extended this model to include the main processes involved in passive and active immunisation against Aβ and then demonstrate the effects of this intervention on soluble Aβ, plaques, phosphorylated tau and tangles. The model predicts that immunisation leads to clearance of plaques but only results in small reductions in levels of soluble Aβ, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against Aβ. Since, soluble Aβ, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against Aβ may not be effective unless it is performed very early in the disease process or combined with other therapies.

  5. Alzheimer disease and platelets: how’s that relevant

    Directory of Open Access Journals (Sweden)

    Catricala Silvia

    2012-09-01

    Full Text Available Abstract Alzheimer Disease (AD is the most common neurodegenerative disorder worldwide, and account for 60% to 70% of all cases of progressive cognitive impairment in elderly patients. At the microscopic level distinctive features of AD are neurons and synapses degeneration, together with extensive amounts of senile plaques and neurofibrillars tangles. The degenerative process probably starts 20–30 years before the clinical onset of the disease. Senile plaques are composed of a central core of amyloid β peptide, Aβ, derived from the metabolism of the larger amyloid precursor protein, APP, which is expressed not only in the brain, but even in non neuronal tissues. More than 30 years ago, some studies reported that human platelets express APP and all the enzymatic activities necessary to process this protein through the same pathways described in the brain. Since then a large number of evidence has been accumulated to suggest that platelets may be a good peripheral model to study the metabolism of APP, and the pathophysiology of the onset of AD. In this review, we will summarize the current knowledge on the involvement of platelets in Alzheimer Disease. Although platelets are generally accepted as a suitable model for AD, the current scientific interest on this model is very high, because many concepts still remain debated and controversial. At the same time, however, these still unsolved divergences mirror a difficulty to establish constant parameters to better defined the role of platelets in AD.

  6. Mitochondrial dysfunctions in neurodegenerative diseases: relevance to Alzheimer's disease.

    Science.gov (United States)

    Hroudová, Jana; Singh, Namrata; Fišar, Zdeněk

    2014-01-01

    Mitochondrial dysfunctions are supposed to be responsible for many neurodegenerative diseases dominating in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). A growing body of evidence suggests that defects in mitochondrial metabolism and particularly of electron transport chain may play a role in pathogenesis of AD. Structurally and functionally damaged mitochondria do not produce sufficient ATP and are more prominent in producing proapoptotic factors and reactive oxygen species (ROS), and this can be an early stage of several mitochondrial disorders, including neurodegenerative diseases. Mitochondrial dysfunctions may be caused by both mutations in mitochondrial or nuclear DNA that code mitochondrial components and by environmental causes. In the following review, common aspects of mitochondrial impairment concerned about neurodegenerative diseases are summarized including ROS production, impaired mitochondrial dynamics, and apoptosis. Also, damaged function of electron transport chain complexes and interactions between pathological proteins and mitochondria are described for AD particularly and marginally for PD and HD.

  7. Cognitive disability in alzheimer's disease and its management.

    Science.gov (United States)

    Corsi, M; Di Raimo, T; Di Lorenzo, C; Rapp-Ricciardi, M; Archer, T; Ricci, S; Businaro, R

    2016-01-01

    Cognitive disability linked to neurodegenerative diseases and in particular to Alzheimer's disease, remains an increasing cause for concern through a dramatic prevalence increment and associated socio-economic burdens. Initially Alzheimer's disease develops asymptomatically with primary clinical signs, such as memory impairment, decline of spatial and perceptual abilities, occurring at a later stage. This delay implies the possibility of promoting early interventions during the pre-symptomatic stage of the disease. Different strategies have been applied in order to prevent/delay onset of Alzheimer's disease or at least to improve quality of life and health conditions of Alzheimer's disease patients and their caregivers, especially in the absence of current viable therapies. Multidomain interventions, aimed at affecting several risk factors simultaneously, offer a versatility that may attain improved outcomes in comparison with single-domain prevention trials. These multidomain interventions involve diet, physical exercise, cognitive training and social activities, while music therapy, improving self-consciousness and reducing neurofibrils, may contribute to deceleration/delay onset of Alzheimer's disease progression. Information and Communication Technology (ICT) provides broad applications to improve quality of life and well-being of Alzheimer's disease patients and caregivers, suffering from psychological distress, as well as reducing additional public health costs.

  8. Evidence for a membrane defect in Alzheimer disease brain

    Science.gov (United States)

    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.

  9. Assessment of Alzheimer's disease symptom recognition in Korean Americans and psychometric analysis of Alzheimer's Disease Symptom Recognition Scale (ADSRS).

    Science.gov (United States)

    Lee, Sang E; Casado, Banghwa Lee

    2015-01-01

    This study examined recognition of Alzheimer's disease symptoms among Korean Americans (KAs) and assessed psychometric properties of the Alzheimer's Disease Symptom Recognition Scale (ADSRS). A cross-sectional survey collected data from 209 KAs, using a self-administered questionnaire. Results show that KAs recognized symptoms related to memory and cognitive functioning well, but had very limited recognition of neuropsychiatric symptoms. Psychometric analysis of ADSRS identified 4 factors in their symptom recognition. Findings suggest a need to raise awareness of Alzheimer's symptoms over the course of the disease. Assessment using ADSRS can be incorporated in communication in the practice context and public outreach.

  10. Relationship between ubiquilin-1 and BACE1 in human Alzheimer's disease and APdE9 transgenic mouse brain and cell-based models.

    Science.gov (United States)

    Natunen, Teemu; Takalo, Mari; Kemppainen, Susanna; Leskelä, Stina; Marttinen, Mikael; Kurkinen, Kaisa M A; Pursiheimo, Juha-Pekka; Sarajärvi, Timo; Viswanathan, Jayashree; Gabbouj, Sami; Solje, Eino; Tahvanainen, Eveliina; Pirttimäki, Tiina; Kurki, Mitja; Paananen, Jussi; Rauramaa, Tuomas; Miettinen, Pasi; Mäkinen, Petra; Leinonen, Ville; Soininen, Hilkka; Airenne, Kari; Tanzi, Rudolph E; Tanila, Heikki; Haapasalo, Annakaisa; Hiltunen, Mikko

    2016-01-01

    Accumulation of β-amyloid (Aβ) and phosphorylated tau in the brain are central events underlying Alzheimer's disease (AD) pathogenesis. Aβ is generated from amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase-mediated cleavages. Ubiquilin-1, a ubiquitin-like protein, genetically associates with AD and affects APP trafficking, processing and degradation. Here, we have investigated ubiquilin-1 expression in human brain in relation to AD-related neurofibrillary pathology and the effects of ubiquilin-1 overexpression on BACE1, tau, neuroinflammation, and neuronal viability in vitro in co-cultures of mouse embryonic primary cortical neurons and microglial cells under acute neuroinflammation as well as neuronal cell lines, and in vivo in the brain of APdE9 transgenic mice at the early phase of the development of Aβ pathology. Ubiquilin-1 expression was decreased in human temporal cortex in relation to the early stages of AD-related neurofibrillary pathology (Braak stages 0-II vs. III-IV). There was a trend towards a positive correlation between ubiquilin-1 and BACE1 protein levels. Consistent with this, ubiquilin-1 overexpression in the neuron-microglia co-cultures with or without the induction of neuroinflammation resulted in a significant increase in endogenously expressed BACE1 levels. Sustained ubiquilin-1 overexpression in the brain of APdE9 mice resulted in a moderate, but insignificant increase in endogenous BACE1 levels and activity, coinciding with increased levels of soluble Aβ40 and Aβ42. BACE1 levels were also significantly increased in neuronal cells co-overexpressing ubiquilin-1 and BACE1. Ubiquilin-1 overexpression led to the stabilization of BACE1 protein levels, potentially through a mechanism involving decreased degradation in the lysosomal compartment. Ubiquilin-1 overexpression did not significantly affect the neuroinflammation response, but decreased neuronal viability in the neuron-microglia co

  11. Identification of a novel panel of cerebrospinal fluid biomarkers for Alzheimer's disease

    DEFF Research Database (Denmark)

    Simonsen, A.H.; McGuire, J.; Podust, V.N.

    2008-01-01

    An early and accurate diagnosis of Alzheimer's disease (AD) is required to initiate symptomatic treatment with currently approved drugs and will be of even greater importance if disease modifying compounds in development display a clinical effect. Protein profiles of human cerebrospinal fluid sam...

  12. Melanopsin retinal ganglion cell loss in Alzheimer's disease

    DEFF Research Database (Denmark)

    La Morgia, Chiara; Ross-Cisneros, Fred N; Koronyo, Yosef

    2015-01-01

    OBJECTIVE: Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer's disease (AD). We investigated mRGCs in AD, hypothesizing their contribution to circadian dysfunction. METHODS: We assessed retinal nerve...

  13. Lentivirus-expressed siRNA vectors against Alzheimer disease.

    Science.gov (United States)

    Peng, Kevin A; Masliah, Eliezer

    2010-01-01

    Amyloid precursor protein (APP) has been implicated in the pathogenesis of Alzheimer disease, and the accumulation of APP products ultimately leads to the familiar histopathological and clinical manifestations associated with this most common form of dementia. A protein that has been shown to promote APP accumulation is beta-secretase (beta-site APP cleaving enzyme 1, or BACE1), which is increased in the cerebrospinal fluid in those affected with Alzheimer disease. Through in vivo studies using APP transgenic mice, we demonstrated that decreasing the expression of BACE1 via lentiviral vector delivery of BACE1 siRNA has the potential for significantly reducing the cleavage of APP, accumulation of these products, and consequent neurodegeneration. As such, lentiviral-expressed siRNA against BACE1 is a therapeutic possibility in the treatment of Alzheimer disease. We detail the use of lentivirus-expressed siRNA as a method to ameliorate Alzheimer disease neuropathology in APP transgenic mice.

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

    Science.gov (United States)

    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.

  15. Alzheimer's disease and chronic periodontitis: is there an association?

    Science.gov (United States)

    Gaur, Sumit; Agnihotri, Rupali

    2015-04-01

    Alzheimer's disease, an affliction of old age, is one of the leading causes for dementia worldwide. Various risk factors including family history, genetics and infections have been implicated in its pathogenesis. The cognitive decline in this condition is mainly a result of the formation of amyloid deposits that provoke neuroinflammation, ultimately resulting in cell death. Recently, an association between peripheral inflammation and Alzheimer's disease was hypothesized. It was suggested that chronic systemic inflammation worsened the inflammatory processes in the brain. This was mainly attributed to increased levels of pro-inflammatory mediators, such as interleukin-1, interleukin -6 and tumor necrosis factor-α in the plasma. As chronic periodontitis is a widespread peripheral immunoinflammatory condition, it has been proposed to play a significant role in the aggravation of Alzheimer's disease. With this background, the current review focuses on the relationship between Alzheimer's disease and chronic periodontitis, and its therapeutic implications.

  16. Research Sheds Light on Mechanism of Alzheimer's Disease

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    @@ Scientists from the Shanghai Institute of Materia Medica (SIMM) under the CAS Shanghai Institutes for Biological Sciences have made significant progress in suggesting a possible mechanism for the accumulation of amyloid β-peptides (Aβs), which are believed to cause Alzheimer's disease. Aβs are fragments of a protein that is snipped from another protein called amyloid precursor protein (APP). In a healthy brain, these protein fragments would be broken down and eliminated. In Alzheimer's disease, unfortunately, the fragments accumulate to form hard, insoluble plaques, which are the characteristic lesions found in Alzheimer's patients and could dramatically inhibit several genes critical to memory and learning.

  17. Clinical utility of color-form naming in Alzheimer's disease: preliminary evidence

    DEFF Research Database (Denmark)

    Nielsen, Niels Peter; Wiig, Elisabeth H; Warkentin, Siegbert

    2004-01-01

    Performances on Alzheimer's Quick Test color-form naming and Mini-Mental State Examination were compared for 38 adults with Alzheimer's disease and 38 age- and sex-matched normal controls. Group means differed significantly and indicated longer naming times by adults with Alzheimer's disease...... associated with Alzheimer's disease, are preliminary given the relatively small sample....

  18. Alzheimer's Disease - Multiple Languages: MedlinePlus

    Science.gov (United States)

    ... d'Alzheimer - français (French) Bilingual PDF Health Information Translations Inside the Brain: An Interactive Tour English Exploration Interactive de l'Intérieur du Cerveau - français (French) Alzheimer's Association German (Deutsch) Inside the Brain: An Interactive Tour English Im ...

  19. Aluminum and Alzheimer's disease: a new look.

    Science.gov (United States)

    Miu, Andrei C; Benga, Oana

    2006-11-01

    Despite the circumstantial and sometimes equivocal support, the hypothetic involvement of aluminum (Al) in the etiology and pathogenesis of Alzheimer's disease (AD) has subsisted in neuroscience. There are very few other examples of scientific hypotheses on the pathogenesis of a disease that have been revisited so many times, once a new method that would allow a test of Al's accumulations in the brain of AD patients or a comparison between Al-induced and AD neuropathological signs has become available. Although objects of methodological controversies for scientists and oversimplification for lay spectators, several lines of evidence have strongly supported the involvement of Al as a secondary aggravating factor or risk factor in the pathogenesis of AD. We review evidence on the similarities and dissimilarities between Al-induced neurofibrillary degeneration and paired helical filaments from AD, the accumulation of Al in neurofibrillary tangles and senile plaques from AD, the neuropathological dissociation between AD and dialysis associated encephalopathy, and the epidemiological relations between Al in drinking water and the prevalence of AD. We also critically analyze the prospects of Al-amyloid cascade studies and other evolving lines of evidence that might shed insights into the link between Al and AD. The message between the lines of the following article is that the involvement of Al in the pathogenesis of AD should not be discarded, especially in these times when the amyloid dogma of AD etiology shows its myopia.

  20. PIN1 gene variants in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Siedlecki Janusz

    2009-11-01

    Full Text Available Abstract Background Peptidyl-prolyl isomerase, NIMA-interacting 1 (PIN1 plays a significant role in the brain and is implicated in numerous cellular processes related to Alzheimer's disease (AD and other neurodegenerative conditions. There are confounding results concerning PIN1 activity in AD brains. Also PIN1 genetic variation was inconsistently associated with AD risk. Methods We performed analysis of coding and promoter regions of PIN1 in early- and late-onset AD and frontotemporal dementia (FTD patients in comparison with healthy controls. Results Analysis of eighteen PIN1 common polymorphisms and their haplotypes in EOAD, LOAD and FTD individuals in comparison with the control group did not reveal their contribution to disease risk. In six unrelated familial AD patients four novel PIN1 sequence variants were detected. c.58+64C>T substitution that was identified in three patients, was located in an alternative exon. In silico analysis suggested that this variant highly increases a potential affinity for a splicing factor and introduces two intronic splicing enhancers. In the peripheral leukocytes of one living patient carrying the variant, a 2.82 fold decrease in PIN1 expression was observed. Conclusion Our data does not support the role of PIN1 common polymorphisms as AD risk factor. However, we suggest that the identified rare sequence variants could be directly connected with AD pathology, influencing PIN1 splicing and/or expression.

  1. New Perspectives on Alzheimer's Disease and Nutrition.

    Science.gov (United States)

    Gustafson, Deborah R; Clare Morris, Martha; Scarmeas, Nikolaos; Shah, Raj C; Sijben, John; Yaffe, Kristine; Zhu, Xiongwei

    2015-01-01

    Accumulating evidence shows nutritional factors influence the risk of developing Alzheimer's disease (AD) and its rate of clinical progression. Dietary and lifestyle guidelines to help adults reduce their risk have been developed. However, the clinical dementia picture remains complex, and further evidence is required to demonstrate that modifying nutritional status can protect the brain and prevent, delay, or reduce pathophysiological consequences of AD. Moreover, there is a pressing need for further research because of the global epidemic of overweight and obesity combined with longer life expectancy of the general population and generally observed decreases in body weight with aging and AD. A new research approach is needed, incorporating more sophisticated models to account for complex scenarios influencing the relationship between nutritional status and AD. Systematic research should identify and address evidence gaps. Integrating longitudinal epidemiological data with biomarkers of disease, including brain imaging technology, and randomized controlled interventions may provide greater insights into progressive and subtle neurological changes associated with dietary factors in individuals at risk for or living with AD. In addition, greater understanding of mechanisms involved in nutritional influences on AD risk and progression, such as oxidative stress and loss of neuronal membrane integrity, will better inform possible interventional strategies. There is consensus among the authors that nutritional deficits, and even states of excess, are associated with AD, but more work is needed to determine cause and effect. Appropriately designed diets or nutritional interventions may play a role, but additional research is needed on their clinical-cognitive effectiveness.

  2. The role of adenosine in Alzheimer's disease.

    Science.gov (United States)

    Rahman, Anisur

    2009-09-01

    Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system manifested by cognitive and memory deterioration, a variety of neuropsychiatric symptoms, behavioral disturbances, and progressive impairment of daily life activities. Current pharmacotherapies are restricted to symptomatic interventions but do not prevent progressive neuronal degeneration. Therefore, new therapeutic strategies are needed to intervene with these progressive pathological processes. In the past several years adenosine, a ubiquitously released purine ribonucleoside, has become important for its neuromodulating capability and its emerging positive experimental effects in neurodegenerative diseases. Recent research suggests that adenosine receptors play important roles in the modulation of cognitive function. The present paper attempts to review published reports and data from different studies showing the evidence of a relationship between adenosinergic function and AD-related cognitive deficits. Epidemiological studies have found an association between coffee (a nonselective adenosine receptor antagonist) consumption and improved cognitive function in AD patients and in the elderly. Long-term administration of caffeine in transgenic animal models showed a reduced amyloid burden in brain with better cognitive performance. Antagonists of adenosine A2A receptors mimic these beneficial effects of caffeine on cognitive function. Neuronal cell cultures with amyloid beta in the presence of an A2A receptor antagonist completely prevented amyloid beta-induced neurotoxicity. These findings suggest that the adenosinergic system constitutes a new therapeutic target for AD, and caffeine and A2A receptor antagonists may have promise to manage cognitive dysfunction in AD.

  3. Proxy-rated quality of life in Alzheimer's disease

    DEFF Research Database (Denmark)

    Vogel, Asmus; Bhattacharya, Suvosree; Waldemar, Gunhild

    2012-01-01

    The study investigated the change in proxy rated quality of life (QoL) of a large cohort of home living patients with Alzheimer's disease (AD) over a period of 36 months.......The study investigated the change in proxy rated quality of life (QoL) of a large cohort of home living patients with Alzheimer's disease (AD) over a period of 36 months....

  4. Ethnic differences in acetylcholinesterase inhibitor use for Alzheimer disease

    OpenAIRE

    Mehta, Kala M; Yin, Maggie; Resendez, Cynthia; Yaffe, Kristine

    2005-01-01

    Acetylcholinesterase inhibitors (AChIs) have been demonstrated to improve Alzheimer disease symptoms. Whether the use of AChIs varies by ethnicity is unknown. More than 2500 ethnically diverse patients (6% African American, 14% Latino, and 7% Asian patients) from the Alzheimer's Disease Research Centers in California were studied. Compared with white patients with AD, minority patients had 40% lower odds of AChI use (odds ratio 0.6, 95% confidence interval: 0.5 to 0.7).

  5. Ethnic differences in acetylcholinesterase inhibitor use for Alzheimer disease.

    Science.gov (United States)

    Mehta, Kala M; Yin, Maggie; Resendez, Cynthia; Yaffe, Kristine

    2005-07-12

    Acetylcholinesterase inhibitors (AChIs) have been demonstrated to improve Alzheimer disease symptoms. Whether the use of AChIs varies by ethnicity is unknown. More than 2500 ethnically diverse patients (6% African American, 14% Latino, and 7% Asian patients) from the Alzheimer's Disease Research Centers in California were studied. Compared with white patients with AD, minority patients had 40% lower odds of AChI use (odds ratio 0.6, 95% confidence interval: 0.5 to 0.7).

  6. Alzheimer's disease. To tell or not to tell.

    OpenAIRE

    Gordon, M.; Goldstein, D.

    2001-01-01

    OBJECTIVE: To evaluate reasons for telling or not telling patients about a diagnosis of Alzheimer's disease and to assess the effect of such a decision on patients, families, physicians, and the health care system. QUALITY OF EVIDENCE: MEDLINE was searched from January 1966 to December 1999 using the key words "Alzheimer's disease" or "dementia" and "truth disclosure" or "attitude to health." There were no randomized controlled trials (level I evidence) in the literature. Articles identified ...

  7. Biomarkers in translational research of Alzheimer's disease.

    Science.gov (United States)

    Tarawneh, Rawan; Holtzman, David M

    2010-01-01

    The identification and characterization of amyloid-beta (Abeta) and tau as the main pathological substrates of Alzheimer's disease (AD) have driven many efforts in search for suitable biomarkers for AD. In the last decade, research in this area has focused on developing a better understanding of the principles that govern protein deposition, mechanisms that link aggregation to toxicity and neuronal death, and a better understanding of protein dynamics in brain tissue, interstitial fluid and CSF. While Abeta and tau represent the two key pathological mediators of disease, other aspects of this multifaceted disease (e.g. oxidative stress, calcium-mediated toxicity, and neuroinflammation) are being unraveled, with the hope to develop a more comprehensive approach in exploring disease mechanisms. This has not only expanded possible areas for disease-modifying therapies, but has also allowed the introduction of novel, and potentially useful, fluid and radiological markers for the presence and progression of AD pathology. There is no doubt that the identification of several fluid and imaging biomarkers that can reliably detect the early stages of AD will have great implications in the design of clinical trials, in the selection of homogenous research populations, and in the assessment of disease outcomes. Markers with good diagnostic specificity will aid researchers in differentiating individuals with preclinical and probable AD from individuals who do not have AD pathology or have other dementing disorders. Markers that change with disease progression may offer utility in assessing the rates of disease progression and the efficacy of potential therapeutic agents on AD pathology. For both of these purposes, CSF Abeta42, amyloid imaging, and CSF tau appear to be very good markers of the presence of AD pathology as well as predictive of who will progress from MCI to AD. Volumetric MRI is also good at separating individuals with MCI and AD from controls and is predictive of

  8. [Mental time dysfunction in Parkinson's and Alzheimer's diseases].

    Science.gov (United States)

    Honma, Motoyasu; Kuroda, Takeshi; Futamura, Akinori; Sugimoto, Azusa; Kawamura, Mitsuru

    2015-03-01

    Mental time is altered by a number of factors and the underlying neural processing involved is highly complicated. Recent research suggests that mental time in patients with particular neurological diseases is perceptually shorter than in normal individuals. This review introduces mental time dysfunction and a model for processing of mental time in Parkinson's and Alzheimer's disease. Although the two diseases show the same dysfunction of mental time in behavior, we expect the underlying neural mechanism to vary in each disease. It is possible that the dysfunction of mental time in Parkinson's disease is caused by the abnormal striatum acting as a pacemaker, while that in Alzheimer's disease is caused by abnormal hippocampal memory.

  9. Circulating Biomarker Panels in Alzheimer's Disease.

    Science.gov (United States)

    Zafari, Sachli; Backes, Christina; Meese, Eckart; Keller, Andreas

    2015-01-01

    The early diagnosis of diseases frequently represents an important unmet clinical need supporting in-time treatment of pathologies. This also applies to neurodegenerative diseases such as Alzheimer's disease (AD), the most common form of dementia, estimated to affect millions of individuals worldwide. The respective diagnostic and prognostic markers, especially for the preclinical stages of AD, are expected to improve patients' outcome significantly. In the last decades, many approaches to detecting AD have been developed, including markers to discover changes in amyloid-β levels [from cerebrospinal fluid (CSF) or using positron emission tomography] or other brain imaging technologies such as structural magnetic resonance imaging (MRI), functional-connectivity MRI or task-related functional MRI. A major challenge is the detection of AD using minimally or even noninvasive biomarkers from body fluids such as plasma or serum. Circulating biomarker candidates based on mRNAs or proteins measured from blood cells, plasma or serum have been proposed for various pathologies including AD. As for other diseases, there is a tendency to use marker signatures obtained by high-throughput approaches, which allow the generation of profiles of hundreds to thousands of biomarkers simultaneously [microarrays, mass spectrometry or next-generation sequencing (NGS)]. Beyond mRNAs and proteins, recent approaches have measured small noncoding RNA (so-called microRNA) profiles in AD patients' blood samples using NGS or array-based technologies. Generally, the development of marker panels is in its early stages and requires further, substantial clinical validation. In this review, we provide an overview of different circulating AD biomarkers, starting with a brief summary of CSF markers and focusing on novel biomarker signatures such as small noncoding RNA profiles.

  10. Ethical issues in Alzheimer's disease: an overview.

    Science.gov (United States)

    Leuzy, Antoine; Gauthier, Serge

    2012-05-01

    Alzheimer's disease (AD) accounts for the majority of dementia cases and leaves clinicians, patients, family members, caregivers, and researchers faced with numerous ethical issues that vary and evolve as a function of disease stage and severity. While the disclosure of a diagnosis of AD dementia is difficult enough, advances in the neurobiology of AD--embodied in the recent revisions to the AD diagnostic guidelines--have translated into an increasing shift toward the diagnosis being made in its pre-dementia stages, when patients have full insight into their prognosis. Genetic issues in AD are significant in the case of rare families with an early onset (before age 65) form of the disease, owing to the presence of deterministic mutations. While genetic testing for the apolipoprotein E (APOE) gene--a risk factor for sporadic AD--is widely debated, it may become necessary in the context of novel disease-modifying drugs. The current symptomatic drugs--cholinesterase inhibitors (CIs) and the NMDA receptor antagonist memantine--are relatively simple to use but their access is limited in many countries by economic considerations and therapeutic nihilism. Although their efficacy is modest, they influence the design of protocols for new drugs since placebo treatment in clinical trials involving patients with established dementia is rarely allowed beyond 3 months. Driving privileges are lost in the moderate stages of dementia, with this decision ideally reached using a standardized assessment algorithm. Physical restraints are still overused in moderate-to-severe stages, but the alternative non-pharmacological therapies and caregiver training programs are not yet fully validated using randomized studies. End-of-life care is slowly moving towards a palliative care approach similar to that for end-stage cancer. There will be new drugs in the near future, some of which will delay progression from prodromal stages to dementia, but their use will require careful stopping rules.

  11. Evidence for participation of aluminum in neurofibrillary tangle formation and growth in Alzheimer's disease.

    Science.gov (United States)

    Walton, J R

    2010-01-01

    This study examines hippocampal CA1 cells from brains of aged humans, with and without Alzheimer's disease, for hyperphosphorylated tau and aluminum during early neurofibrillary tangle (NFT) formation and growth. A very small proportion of hippocampal pyramidal cells contain cytoplasmic pools within their soma that either appear homogeneous or contain short filaments (i.e., early NFTs). The cytoplasmic pools are aggregates of an aluminum/hyperphosphorylated tau complex similar to that found in mature NFTs. The photographic evidence presented combines with existing evidence to support a role for aluminum in the formation and growth of NFTs in neurons of humans with Alzheimer's disease.

  12. Analysis of genetics and risk factors of Alzheimer's Disease.

    Science.gov (United States)

    Panpalli Ates, M; Karaman, Y; Guntekin, S; Ergun, M A

    2016-06-14

    Alzheimer's Disease is the leading neurodegenerative cause of dementia. The pathogenesis is not clearly understood yet, is believed to be the complex interaction between genetic and environmental factors. Consequently vascular risk factors and Apolipoprotein E genotyping are increasingly gaining importance. This study aimed at assessing the relationships between Alzheimer's Disease and Apolipoprotein E phenotype and vascular risk factors. Patients diagnosed with "possible Alzheimer's Disease" in the Gazi University, Department of Neurology, were included in the study and age-matched volunteer patients who attended the polyclinic were included as a control group. In this study, the risk factors including low education level, smoking, hyperlipidemia, higher serum total cholesterol levels, and hyperhomocysteinemia were found to be statistically significantly more common in the Alzheimer's Disease group in comparison to the Control Group, while all Apolipoprotein E ε4/ε4 genotypes were found in the Alzheimer's Disease group. The presence of the Apolipoprotein E ε4 allele is believed to increase vascular risk factors as well as to affect Alzheimer's Disease directly. The biological indicators which are used in identifying the patients' genes will be probably used in the treatment plan of the patients in the future.

  13. The Role of Mast Cells in Alzheimer's Disease.

    Science.gov (United States)

    Shaik-Dasthagirisaheb, Yasdani B; Conti, Pio

    2016-01-01

    Immunity and inflammation are deeply involved in Alzheimer's disease. The most important properties of pathological Alzheimer's disease are the extracellular deposits of amyloid â-protein plaque aggregates along with other unknown mutated proteins, which are implicated in immunity and inflammation. Mast cells are found in the brain of all mammalian species and in the periphery, and their biological mediators, including cytokines/chemokines, arachidonic acid products and stored enzymes, play an import role in Alzheimer's disease. Cytokines/chemokines, which are generated mostly by microglia and astrocytes in Alzheimer's disease, contribute to nearly every aspect of neuroinflammation and amyloid â-protein plaque aggregates may induce in mast cells the release of a plethora of mediators, including pro-inflammatory cytokines/chemokines such as interleukin-1, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-alpha, vascular endothelial growth factor, transforming growth factor beta, CXCL8 and CCL2-3-4. These proinflammatory cytokines/chemokines are prominent mediators of neuroinflammation in brain disorders such as Alzheimer's disease, and their inhibition may be associated with improved recovery. In this review, we summarize the current knowledge regarding the roles of mast cell mediators (stored and de novo synthesis) in the pathogenesis of Alzheimer's disease.

  14. Neuronal histamine and cognitive symptoms in Alzheimer's disease.

    Science.gov (United States)

    Zlomuzica, Armin; Dere, Dorothea; Binder, Sonja; De Souza Silva, Maria Angelica; Huston, Joseph P; Dere, Ekrem

    2016-07-01

    Alzheimer's disease is a neurodegenerative disorder characterized by extracellular amyloid plaque deposits, mainly composed of amyloid-beta peptide and intracellular neurofibrillary tangles consisting of aggregated hyperphosphorylated tau protein. Amyloid-beta represents a neurotoxic proteolytic cleavage product of amyloid precursor protein. The progressive cognitive decline that is associated with Alzheimer's disease has been mainly attributed to a deficit in cholinergic neurotransmission due to the continuous degeneration of cholinergic neurons e.g. in the basal forebrain. There is evidence suggesting that other neurotransmitter systems including neuronal histamine also contribute to the development and maintenance of Alzheimer's disease-related cognitive deficits. Pathological changes in the neuronal histaminergic system of such patients are highly predictive of ensuing cognitive deficits. Furthermore, histamine-related drugs, including histamine 3 receptor antagonists, have been demonstrated to alleviate cognitive symptoms in Alzheimer's disease. This review summarizes findings from animal and clinical research on the relationship between the neuronal histaminergic system and cognitive deterioration in Alzheimer's disease. The significance of the neuronal histaminergic system as a promising target for the development of more effective drugs for the treatment of cognitive symptoms is discussed. Furthermore, the option to use histamine-related agents as neurogenesis-stimulating therapy that counteracts progressive brain atrophy in Alzheimer's disease is considered. This article is part of a Special Issue entitled 'Histamine Receptors'.

  15. Mitochondrial haplotypes associated with biomarkers for Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Perry G Ridge

    Full Text Available Various studies have suggested that the mitochondrial genome plays a role in late-onset Alzheimer's disease, although results are mixed. We used an endophenotype-based approach to further characterize mitochondrial genetic variation and its relationship to risk markers for Alzheimer's disease. We analyzed longitudinal data from non-demented, mild cognitive impairment, and late-onset Alzheimer's disease participants in the Alzheimer's Disease Neuroimaging Initiative with genetic, brain imaging, and behavioral data. We assessed the relationship of structural MRI and cognitive biomarkers with mitochondrial genome variation using TreeScanning, a haplotype-based approach that concentrates statistical power by analyzing evolutionarily meaningful groups (or clades of haplotypes together for association with a phenotype. Four clades were associated with three different endophenotypes: whole brain volume, percent change in temporal pole thickness, and left hippocampal atrophy over two years. This is the first study of its kind to identify mitochondrial variation associated with brain imaging endophenotypes of Alzheimer's disease. Our results provide additional evidence that the mitochondrial genome plays a role in risk for Alzheimer's disease.

  16. Neuropeptides in Alzheimer's disease: from pathophysiological mechanisms to therapeutic opportunities.

    Science.gov (United States)

    Van Dam, Debby; Van Dijck, Annemie; Janssen, Leen; De Deyn, Peter Paul

    2013-06-01

    Neuropeptides are found throughout the entire nervous system where they can act as neurotransmitter, neuromodulator or neurohormone. In those functions, they play important roles in the regulation of cognition and behavior. In brain disorders like Alzheimer's disease (AD), where abnormal cognition and behavior are observed, the study of neuropeptides is particularly interesting since altered neuropeptides can function as biomarkers or as targets for new medication. In this article neuropeptides with relevance to AD are listed and their influence on cognitive and behavioral disturbances is discussed. Findings from human cerebrospinal fluid and brain tissue, and AD mouse models are described and related to the pathophysiology and symptomatology of the disease. In the past, clinical trials with neuropeptides have often failed due to insufficient delivery to the brain. Therefore, new strategies to target the brain with peptide drugs are also covered.

  17. Neuroimaging in Alzheimer's disease: preclinical challenges toward clinical efficacy.

    Science.gov (United States)

    Dustin, Derek; Hall, Benjamin M; Annapragada, Ananth; Pautler, Robia G

    2016-09-01

    The scope of this review focuses on recent applications in preclinical and clinical magnetic resonance imaging (MRI) toward accomplishing the goals of early detection and responses to therapy in animal models of Alzheimer's disease (AD). Driven by the outstanding efforts of the Alzheimer's Disease Neuroimaging Initiative (ADNI), a truly invaluable resource, the initial use of MRI in AD imaging has been to assess changes in brain anatomy, specifically assessing brain shrinkage and regional changes in white matter tractography using diffusion tensor imaging. However, advances in MRI have led to multiple efforts toward imaging amyloid beta plaques first without and then with the use of MRI contrast agents. These technological advancements have met with limited success and are not yet appropriate for the clinic. Recent developments in molecular imaging inclusive of high-power liposomal-based MRI contrast agents as well as fluorine 19 ((19)F) MRI and manganese enhanced MRI have begun to propel promising advances toward not only plaque imaging but also using MRI to detect perturbations in subcellular processes occurring within the neuron. This review concludes with a discussion about the necessity for the development of novel preclinical models of AD that better recapitulate human AD for the imaging to truly be meaningful and for substantive progress to be made toward understanding and effectively treating AD. Furthermore, the continued support of outstanding programs such as ADNI as well as the development of novel molecular imaging agents and MRI fast scanning sequences will also be requisite to effectively translate preclinical findings to the clinic.

  18. Deliver us from evil: carer burden in Alzheimer's disease.

    Science.gov (United States)

    Zimmermann, Martina

    2010-12-01

    Alzheimer's disease is the most common neurodegenerative disorder in today's developed world that is also increasingly picked out as a focal theme in fictional literature. In dealing with the subjectivity of human experience, such literature enhances the reader's empathy and is able to teach about moral, emotional and philosophical issues, offering the chance to see situations from a position otherwise possibly never taken by the reader. The understanding and insight so gained may well be unscientific, but the literary approach offers an insight into the whole person's perspective and the particularity and uniqueness of a situation that includes ethical conflicts. A key motif of fictional literature centred around dementia remains the burden the adult-child carer is confronted with, considering the parent's remorseless decline and personality change, the sudden demand for devoted and continuous care, and the constantly changing relationship with the declining parent. In the context of an ever increasing demand for a constructive public discussion regarding end-of-life treatment of demented patients, Christine Devars (Le Piano Désaccordé) and Andrés Barba (Ahora Tocad Música de Baile) illustrate how powerful and burdensome the impact of Alzheimer's disease is on both patient and carer and what extremes may be reached under such truly exceptional circumstances.

  19. Convergent genetic and expression data implicate immunity in Alzheimer's disease

    Science.gov (United States)

    Jones, Lesley; Lambert, Jean-Charles; Wang, Li-San; Choi, Seung-Hoan; Harold, Denise; Vedernikov, Alexey; Escott-Price, Valentina; Stone, Timothy; Richards, Alexander; Bellenguez, Céline; Ibrahim-Verbaas, Carla A; Naj, Adam C; Sims, Rebecca; Gerrish, Amy; Jun, Gyungah; DeStefano, Anita L; Bis, Joshua C; Beecham, Gary W; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A; Jones, Nicola; Smith, Albert V; Chouraki, Vincent; Thomas, Charlene; Ikram, M Arfan; Zelenika, Diana; Vardarajan, Badri N; Kamatani, Yoichiro; Lin, Chiao-Feng; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L; Ruiz, Agustin; Bihoreau, Marie-Thérèse; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Hanon, Olivier; Fitzpatrick, Annette L; Buxbaum, Joseph D; Campion, Dominique; Crane, Paul K; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L; De Jager, Philip L; Deramecourt, Vincent; Johnston, Janet A; Evans, Denis; Lovestone, Simon; Letteneur, Luc; Kornhuber, Johanes; Tárraga, Lluís; Rubinsztein, David C; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M; Fiévet, Nathalie; Huentelman, Matthew J; Gill, Michael; Emilsson, Valur; Brown, Kristelle; Kamboh, M Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B; Myers, Amanda J; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Kehoe, Pat; Rogaeva, Ekaterina; Gallacher, John; George-Hyslop, Peter St; Clarimon, Jordi; Lleὀ, Alberti; Bayer, Anthony; Tsuang, Debby W; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petra; Collinge, John; Sorbi, Sandro; Garcia, Florentino Sanchez; Fox, Nick; Hardy, John; Naranjo, Maria Candida Deniz; Razquin, Cristina; Bosco, Paola; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Mancuso, Michelangelo; Moebus, Susanne; Mecocci, Patrizia; del Zompo, Maria; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Bullido, Maria; Panza, Francesco; Caffarra, Paolo; Nacmias, Benedetta; Gilbert, John R; Mayhaus, Manuel; Jessen, Frank; Dichgans, Martin; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M; Ingelsson, Martin; Beekly, Duane; Alavarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G; Coto, Eliecer; Hamilton-Nelson, Kara L; Mateo, Ignacio; Owen, Michael J; Faber, Kelley M; Jonsson, Palmi V; Combarros, Onofre; O'Donovan, Michael C; Cantwell, Laura B; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H; Bennett, David A; Harris, Tamara B; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee FAG; Passmore, Peter; Montine, Thomas J; Bettens, Karolien; Rotter, Jerome I; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M; Kukull, Walter A; Hannequin, Didier; Powell, John F; Nalls, Michael A; Ritchie, Karen; Lunetta, Kathryn L; Kauwe, John SK; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R; Pastor, Pau; Schmidt, Reinhold; Rujescu, Dan; Dartigues, Jean-François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M; Graff, Caroline; Psaty, Bruce M; Haines, Jonathan L; Lathrop, Mark; Pericak-Vance, Margaret A; Launer, Lenore J; Farrer, Lindsay A; van Duijn, Cornelia M; Van Broekhoven, Christine; Ramirez, Alfredo; Schellenberg, Gerard D; Seshadri, Sudha; Amouyel, Philippe; Holmans, Peter A

    2015-01-01

    Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics. PMID:25533204

  20. Dissecting Alzheimer disease in Down syndrome using mouse models

    Directory of Open Access Journals (Sweden)

    Xun Yu eChoong

    2015-10-01

    Full Text Available Down syndrome (DS is a common genetic condition caused by the presence of three copies of chromosome 21 (trisomy 21. This greatly increases the risk for Alzheimer disease (AD, but although virtually all people with DS have AD neuropathology by 40 years of age, not all develop dementia. To dissect the genetic contribution of trisomy 21 to DS phenotypes including those relevant to AD, a range of DS mouse models has been generated which are trisomic for chromosome segments syntenic to human chromosome 21. Here, we consider key characteristics of human AD in DS (AD-DS, and our current state of knowledge on related phenotypes in AD and DS mouse models. We go on to review important features needed in future models of AD-DS, to understand this type of dementia and so highlight pathogenic mechanisms relevant to all populations at risk of AD.

  1. Mercury exposure and Alzheimer's disease in India - An imminent threat?

    Science.gov (United States)

    Chakraborty, Parthasarathi

    2017-03-02

    India is an industrial giant with one of the fastest growing major economies in the world. Primary energy consumption in India is third after China and the USA. Greater energy production brings the burden of increasing emissions of mercury (Hg). India ranks second for Hg emissions. Rising atmospheric Hg release, high Hg evasion processes, and increasing monomethylmercury (highly neurotoxin) accumulations in marine food products increase the potential for human and ecosystem Hg exposure. Hg has been identified to increase the risk of getting Alzheimer's disease (AD). There are increasing reports of AD and dementia in different age groups in India. The relationship between increasing Hg exposure and increasing neurodegenerative disorder in India is not known. This commentary points to the need for better understanding of the relationship between Hg release and AD in India, and other countries, and how to protect human health and the environment from the adverse effects of Hg.

  2. Iron and copper toxicity in diseases of aging, particularly atherosclerosis and Alzheimer's disease.

    Science.gov (United States)

    Brewer, George J

    2007-02-01

    In this review, we point out that natural selection does not act to lessen human diseases after the reproductive and caregiving period and that normal levels of iron and copper that may be healthy during the reproductive years appear to be contributing to diseases of aging and possibly the aging process itself. It is clear that oxidant damage contributes to many of the diseases of aging, such as atherosclerosis, Alzheimer's disease, Parkinson's diseases, diabetes, diseases of inflammation, diseases of fibrosis, diseases of autoimmunity, and so on. It is equally clear that both iron and copper can contribute to excess production of damaging reactive oxygen species through Fenton chemistry. Here, we examine the evidence that "normal" levels of iron and copper contribute to various diseases of aging.

  3. Biomarkers in Alzheimer's Disease-Recent Update.

    Science.gov (United States)

    Sharma, Sushil; Lipincott, Walter

    2017-02-20

    Alzheimer disease (AD) is an age-related neurodegenerative disorder, characterized by loss of memory and cognitive function. It is the common cause of dementia in elderly and is a global health concern as the population of people aged 85 and older, is growing alarmingly. Although pharmacotherapy for the treatment of AD has improved, lot of work remains to treat this devastating disease. AD pathology begins even before the onset of clinical symptoms. Because therapies could be more effective if implemented early in the disease progression, it is highly prudent to discover reliable biomarkers, to detect its exact pathophysiology during pre-symptomatic stage. Biomarker(s) with high sensitivity and specificity would facilitate AD diagnosis at early stages. Currently, CSF amyloid β 1-42, total tau, and phosphorylated tau181 are used as AD biomarkers. This report describes conventional and potential in-vitro and in-vivo biomarkers of AD. Particularly, in-vitro transcriptomic, proteomic, lipidomic, and metabolomic; body fluid biomarkers (C-reactive proteins, homocysteine, α-sunuclein index, and dehydroepiandrosterone sulphate) from blood, serum, plasma, CSF, and saliva; and neuronal, platelets, and lymphocyte microRNA, mtDNA, and Charnoly body are detected. In-vivo physiological and neurobehavioral biomarkers are evaluated by analyzing computerized EEG, event-related potentials, circadian rhythm, and multimodality fusion imaging including: CT, MRI, SPECT, and PET. More specifically, PET imaging biomarkers representing reduced fronto-temporal 18FdG uptake, increased 11C or 18F-PIB uptake, 11C-PBR28 to measure 18 kDa translocator protein (TSPO), a biomarker for inflammation; and 3-D MRI (ventriculomegaly)/MRS are performed for early and effective clinical management of AD.

  4. The Search for Biomarkers in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Anna Meiliana

    2010-04-01

    Full Text Available BACKGROUND: As population demographic shift and the number of individuals with Alzheimer Disease (AD continue to increase, the challenge is to develop targeted, effective treatments and our ability to recognize early symptoms. In view of this, the need for specific AD biomarker is crucial. CONTENT: In recent years it has become evident that CSF concentrations of some brain-specific proteins are related to underlying disease pathogenesis and may therefore aid clinical investigation. Among several, we have focused on three candidates that have been suggested to fulfil the requirements for biomarkers of AD: β-amyloid 42 (Aβ42, total Tau (T-tau and tau phosphorylated at various epitopes (P-tau. An increasing number of studies suggest that supplementary use of these CSF markers, preferably in combination, adds to the accuracy of an AD diagnosis. More recently visinin-like protein (VLP-1, a marker for neuronal cell injury has been studied. CSF VLP-1 concentrations were 50% higher in AD patients than in the control population. SUMMARY: The number of studies aimed at the identification of new biomarkers for AD is expected to increase rapidly, not only because of the increasing insights into the pathological mechanisms underlying this disease, but also because new therapies have been developed or are under consideration now, which warrant an early and specific diagnosis for effective treatment of the patients. KEYWORDS: dementia, amyloid plaque, neurofibrillary tangels, amyloid β-peptide 42 (Aβ42, total tau (T-tau, phosphorylated tau (P-tau, visinin–like protein 1 (VLP-1.

  5. Weak central coherence in patients with Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Selina M(a)rdh

    2013-01-01

    Central coherence refers to the ability to interpret details of information into a whole. To date, the concept of central coherence is mainly used in research of autism, Asperger's syndrome and recently in the research on eating disorders. The main purpose of the present study was to examine central coherence in patients with Alzheimer's disease. Nine Alzheimer's disease patients and ten age- and gender-matched control subjects, who differed significantly in neurological assessment, were shown a picture of a fire. Compared to control subjects, the Alzheimer's disease patients described the picture in a fragmented way by mentioning details and separate objects without perceiving the context of the fire. In conclusion, patients with Alzheimer's disease are at the weak end of central coherence, and hence suffer from a fragmented view of their surroundings. The findings have important clinical implications for the understanding of patients with Alzheimer's diseaseand also for the possibility of caregivers to meet the Alzheimer's disease individual in an appropriate way in the everyday care.

  6. Digital communication support and Alzheimer's disease.

    Science.gov (United States)

    Ekström, Anna; Ferm, Ulrika; Samuelsson, Christina

    2015-12-06

    Communication is one of the areas where people with dementia and their caregivers experience most challenges. The purpose of this study is to contribute to the understanding of possibilities and pitfalls of using personalized communication applications installed on tablet computers to support communication for people with dementia and their conversational partners. The study is based on video recordings of a woman, 52 years old, with Alzheimer's disease interacting with her husband in their home. The couple was recorded interacting with and without a tablet computer including a personalized communication application. The results from the present study reveal both significant possibilities and potential difficulties in introducing a digital communication device to people with dementia and their conversational partners. For the woman in the present study, the amount of interactive actions and the number of communicative actions seem to increase with the use of the communication application. The results also indicate that problems associated with dementia are foregrounded in interaction where the tablet computer is used.

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

    Science.gov (United States)

    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.

  8. Transcranial Magnetic Stimulation Studies in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Andrea Guerra

    2011-01-01

    Full Text Available Although motor deficits affect patients with Alzheimer's disease (AD only at later stages, recent studies demonstrated that primary motor cortex is precociously affected by neuronal degeneration. It is conceivable that neuronal loss is compensated by reorganization of the neural circuitries, thereby maintaining motor performances in daily living. Effectively several transcranial magnetic stimulation (TMS studies have demonstrated that cortical excitability is enhanced in AD and primary motor cortex presents functional reorganization. Although the best hypothesis for the pathogenesis of AD remains the degeneration of cholinergic neurons in specific regions of the basal forebrain, the application of specific TMS protocols pointed out a role of other neurotransmitters. The present paper provides a perspective of the TMS techniques used to study neurophysiological aspects of AD showing also that, based on different patterns of cortical excitability, TMS may be useful in discriminating between physiological and pathological brain aging at least at the group level. Moreover repetitive TMS might become useful in the rehabilitation of AD patients. Finally integrated approaches utilizing TMS together with others neuro-physiological techniques, such as high-density EEG, and structural and functional imaging as well as biological markers are proposed as promising tool for large-scale, low-cost, and noninvasive evaluation of at-risk populations.

  9. Script representation in patients with Alzheimer's disease.

    Science.gov (United States)

    Allain, Philippe; Le Gall, Didier; Foucher, Céline; Etcharry-Bouyx, Frédérique; Barré, Jean; Dubas, Frédéric; Berrut, Gilles

    2008-03-01

    We examined script representation in 26 patients with Alzheimer's disease (AD) compared to 31 healthy elderly subjects (HE). Participants were asked to sort cards describing actions belonging to eight scripts according to the script to which they belonged and according to their order of execution. Each script included actions which were low in centrality and distinctiveness (non-central actions and non-distinctive actions--NCA & NDA), and which were high in centrality (central actions--CA), distinctiveness (distinctive actions--DA), centrality and distinctiveness (central actions and distinctive action--CA & DA). These actions were presented in three conditions. In the first condition (scripts with headers--SH), the 43 actions belonging to three different scripts were given with each script header written on separate cards. The second condition (scripts without headers--SwH) used 46 actions belonging to three other scripts, but no script header was provided. In the third condition (scripts with distractor header--SDH), the 28 actions belonging to two other scripts were given with each script header and a distractor header written on separate cards. The results showed that performance of subjects with AD was significantly lower in all conditions. Overall, AD patients made significantly more sequencing errors than HE subjects. AD patients also committed significantly more sorting errors than HE subjects for all types of actions (NCA & NDA, CA, DA, CA & DA). These data are consistent with the view that AD produces impairment of both the syntactic and semantic dimensions of script representation.

  10. Sex and the development of Alzheimer's disease.

    Science.gov (United States)

    Pike, Christian J

    2017-01-02

    Men and women exhibit differences in the development and progression of Alzheimer's disease (AD). The factors underlying the sex differences in AD are not well understood. This Review emphasizes the contributions of sex steroid hormones to the relationship between sex and AD. In women, events that decrease lifetime exposure to estrogens are generally associated with increased AD risk, whereas estrogen-based hormone therapy administered near the time of menopause may reduce AD risk. In men, estrogens do not exhibit age-related reduction and are not significantly associated with AD risk. Rather, normal age-related depletions of testosterone in plasma and brain predict enhanced vulnerability to AD. Both estrogens and androgens exert numerous protective actions in the adult brain that increase neural functioning and resilience as well as specifically attenuating multiple aspects of AD-related neuropathology. Aging diminishes the activational effects of sex hormones in sex-specific manners, which is hypothesized to contribute to the relationship between aging and AD. Sex steroid hormones may also drive sex differences in AD through their organizational effects during developmental sexual differentiation of the brain. Specifically, sex hormone actions during early development may confer inherent vulnerability of the female brain to development of AD in advanced age. The combined effects of organizational and activational effects of sex steroids yield distinct sex differences in AD pathogenesis, a significant variable that must be more rigorously considered in future research. © 2016 Wiley Periodicals, Inc.

  11. [Prevention of Alzheimer's Disease and Nutrients].

    Science.gov (United States)

    Otsuka, Mieko

    2016-07-01

    The dietary recommendations for the prevention and management of Alzheimer's disease (AD), are the Mediterranean diet and the Japanese-style diet, both of which contain well-balanced nutrients from fish and vegetables. These diets are rich in vitamin E, carotenes, antioxidant flavonoids, vitamin B12, folate, and n-3PUFA. According to recent review supplementation of folate and vitamin E may protect against elderly people's cognitive decline when the serum folate is <12 nmol/L or the vitamin E intake is <6.1 mg/day. Another nutritional topic with regard to dementia and diet is the association of type-2 diabetes and hyperinsulinemia with AD. Expression array data of the brain tissue of AD patients in the Hisayama study strongly suggests a disturbance in insulin signaling in the AD brain. The dysfunction of insulin signaling could directly lead to disrupted glucose utilization in the AD brain. Instead of improperly utilized glucose, the medium chain triglyceride ketone bodies can be an alternative energy resource for the AD brain. In conclusion, the dietary recommendations for the prevention and management of AD are a high consumption of fish, vegetables, and low glycemic index fruits; a moderate amount of meat and dairy products; and a lower amount of carbohydrates and refined sugar.

  12. Spatial Navigation in Preclinical Alzheimer's Disease

    Science.gov (United States)

    Allison, Samantha L.; Fagan, Anne M.; Morris, John C.; Head, Denise

    2016-01-01

    Although several previous studies have demonstrated navigational deficits in early-stage symptomatic Alzheimer's disease (AD), navigational abilities in preclinical AD have not been examined. The present investigation examined the effects of preclinical AD and early-stage symptomatic AD on spatial navigation performance. Performance on tasks of wayfinding and route learning in a virtual reality environment were examined. Comparisons were made across the following three groups: Clinically normal without preclinical AD (n = 42), clinically normal with preclinical AD (n = 13), and early-stage symptomatic AD (n = 16) groups. Preclinical AD was defined based on cerebrospinal fluid Aβ42 levels below 500 pg/ml. Preclinical AD was associated with deficits in the use of a wayfinding strategy, but not a route learning strategy. Moreover, post-hoc analyses indicated that wayfinding performance had moderate sensitivity and specificity. Results also confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting the earliest cognitive deficits of AD. PMID:26967209

  13. Impairments of auditory scene analysis in Alzheimer's disease.

    Science.gov (United States)

    Goll, Johanna C; Kim, Lois G; Ridgway, Gerard R; Hailstone, Julia C; Lehmann, Manja; Buckley, Aisling H; Crutch, Sebastian J; Warren, Jason D

    2012-01-01

    Parsing of sound sources in the auditory environment or 'auditory scene analysis' is a computationally demanding cognitive operation that is likely to be vulnerable to the neurodegenerative process in Alzheimer's disease. However, little information is available concerning auditory scene analysis in Alzheimer's disease. Here we undertook a detailed neuropsychological and neuroanatomical characterization of auditory scene analysis in a cohort of 21 patients with clinically typical Alzheimer's disease versus age-matched healthy control subjects. We designed a novel auditory dual stream paradigm based on synthetic sound sequences to assess two key generic operations in auditory scene analysis (object segregation and grouping) in relation to simpler auditory perceptual, task and general neuropsychological factors. In order to assess neuroanatomical associations of performance on auditory scene analysis tasks, structural brain magnetic resonance imaging data from the patient cohort were analysed using voxel-based morphometry. Compared with healthy controls, patients with Alzheimer's disease had impairments of auditory scene analysis, and segregation and grouping operations were comparably affected. Auditory scene analysis impairments in Alzheimer's disease were not wholly attributable to simple auditory perceptual or task factors; however, the between-group difference relative to healthy controls was attenuated after accounting for non-verbal (visuospatial) working memory capacity. These findings demonstrate that clinically typical Alzheimer's disease is associated with a generic deficit of auditory scene analysis. Neuroanatomical associations of auditory scene analysis performance were identified in posterior cortical areas including the posterior superior temporal lobes and posterior cingulate. This work suggests a basis for understanding a class of clinical symptoms in Alzheimer's disease and for delineating cognitive mechanisms that mediate auditory scene analysis

  14. Abeta-degrading enzymes in Alzheimer's disease.

    Science.gov (United States)

    Miners, James Scott; Baig, Shabnam; Palmer, Jennifer; Palmer, Laura E; Kehoe, Patrick G; Love, Seth

    2008-04-01

    In Alzheimer's disease (AD) Abeta accumulates because of imbalance between the production of Abeta and its removal from the brain. There is increasing evidence that in most sporadic forms of AD, the accumulation of Abeta is partly, if not in some cases solely, because of defects in its removal--mediated through a combination of diffusion along perivascular extracellular matrix, transport across vessel walls into the blood stream and enzymatic degradation. Multiple enzymes within the central nervous system (CNS) are capable of degrading Abeta. Most are produced by neurons or glia, but some are expressed in the cerebral vasculature, where reduced Abeta-degrading activity may contribute to the development of cerebral amyloid angiopathy (CAA). Neprilysin and insulin-degrading enzyme (IDE), which have been most extensively studied, are expressed both neuronally and within the vasculature. The levels of both of these enzymes are reduced in AD although the correlation with enzyme activity is still not entirely clear. Other enzymes shown capable of degrading Abetain vitro or in animal studies include plasmin; endothelin-converting enzymes ECE-1 and -2; matrix metalloproteinases MMP-2, -3 and -9; and angiotensin-converting enzyme (ACE). The levels of plasmin and plasminogen activators (uPA and tPA) and ECE-2 are reported to be reduced in AD. Reductions in neprilysin, IDE and plasmin in AD have been associated with possession of APOEepsilon4. We found no change in the level or activity of MMP-2, -3 or -9 in AD. The level and activity of ACE are increased, the level being directly related to Abeta plaque load. Up-regulation of some Abeta-degrading enzymes may initially compensate for declining activity of others, but as age, genetic factors and diseases such as hypertension and diabetes diminish the effectiveness of other Abeta-clearance pathways, reductions in the activity of particular Abeta-degrading enzymes may become critical, leading to the development of AD and CAA.

  15. Biomedicine and Informatics Model of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Kang Cheng

    2007-01-01

    Full Text Available In a perspective of biomedicine and informatics, the mechanism of Alzheimer's, senile amnesia, or other aging-associated and cognitive impairment related diseases involve four important informative processing procedures: propagation, consolidation, retrieval and cognition, In this study, we systematically model the four procedures based on published experimental data. When modeling the propagation, we develop an equivalent circuit of biological membrane to describe how the neuron signals are propagated, attenuated, compensated, transferred, oscillated and filtered; and how wrong signals are related to the diseases. Our circuit involves complex admittances, resonance angular frequencies, propagating constants, active pump currents, transfer functions in frequency domain and memory functions in time domain. Our circuit explains recurrent of brain neurons and clinical EEG frequencies as well as represents an encoding of current or electric field intensity (EFI. When modeling the consolidation and the retrieval of long term memory (LTM, we emphasize the EFI consists of a non conservative electric field intensity (NCEFI and a conservative electric field intensity (CEFI. It is mostly a NCEFI of acquired information to evoke an informative flow: from the inherited or mutant DNA to the transcribed RNA, from the transcribed RNA to the translated proteins. Some new synthesized proteins relate to the memory functions. The charges of the proteins and the memory functions mostly store the LTM and play an important role during the LTM retrieval. When modeling the cognition in working memory (WM, our model demonstrates: if a sum of two sets of EFI signals is enhanced positively (or negatively, at a sub-cellular level (especially at the axon hillock, the sum supports a positive (or negative cognition; otherwise, the sum tends to be no cognition. A set of related brain neurons in WM work organically to vote, by EFI signal outputs through their axons, if they

  16. Early behavioural changes in familial Alzheimer's disease in the Dominantly Inherited Alzheimer Network.

    Science.gov (United States)

    Ringman, John M; Liang, Li-Jung; Zhou, Yan; Vangala, Sitaram; Teng, Edmond; Kremen, Sarah; Wharton, David; Goate, Alison; Marcus, Daniel S; Farlow, Martin; Ghetti, Bernardino; McDade, Eric; Masters, Colin L; Mayeux, Richard P; Rossor, Martin; Salloway, Stephen; Schofield, Peter R; Cummings, Jeffrey L; Buckles, Virginia; Bateman, Randall; Morris, John C

    2015-04-01

    Prior studies indicate psychiatric symptoms such as depression, apathy and anxiety are risk factors for or prodromal symptoms of incipient Alzheimer's disease. The study of persons at 50% risk for inheriting autosomal dominant Alzheimer's disease mutations allows characterization of these symptoms before progressive decline in a population destined to develop illness. We sought to characterize early behavioural features in carriers of autosomal dominant Alzheimer's disease mutations. Two hundred and sixty-one persons unaware of their mutation status enrolled in the Dominantly Inherited Alzheimer Network, a study of persons with or at-risk for autosomal dominant Alzheimer's disease, were evaluated with the Neuropsychiatric Inventory-Questionnaire, the 15-item Geriatric Depression Scale and the Clinical Dementia Rating Scale (CDR). Ninety-seven asymptomatic (CDR = 0), 25 mildly symptomatic (CDR = 0.5), and 33 overtly affected (CDR > 0.5) autosomal dominant Alzheimer's disease mutation carriers were compared to 106 non-carriers with regard to frequency of behavioural symptoms on the Neuropsychiatric Inventory-Questionnaire and severity of depressive symptoms on the Geriatric Depression Scale using generalized linear regression models with appropriate distributions and link functions. Results from the adjusted analyses indicated that depressive symptoms on the Neuropsychiatric Inventory-Questionnaire were less common in cognitively asymptomatic mutation carriers than in non-carriers (5% versus 17%, P = 0.014) and the odds of experiencing at least one behavioural sign in cognitively asymptomatic mutation carriers was lower than in non-carriers (odds ratio = 0.50, 95% confidence interval: 0.26-0.98, P = 0.042). Depression (56% versus 17%, P = 0.0003), apathy (40% versus 4%, P Alzheimer's disease, we demonstrated increased rates of depression, apathy, and other behavioural symptoms in the mildly symptomatic, prodromal phase of autosomal dominant Alzheimer's disease that

  17. Palmomental reflex a relevant sign in early Alzheimer's disease diagnosis?

    OpenAIRE

    Gabelle, Audrey; Gutierrez, Laure-Anne; Dartigues, Jean-François; Ritchie, Karen,; Touchon, Jacques; Berr, Claudine

    2016-01-01

    International audience; AbstractBackground: Sophisticated and expensive biomarkers are proposed for the diagnostic of Alzheimer disease (AD). Amyloid process seems to be early in AD and brain amyloid load affects the frontal lobe. Our objective is to determine if certain simple clinical signs especially frontal-related signs could help reach an earlier and better diagnosis. Methods: In the frame of the 3-City cohort, we conducted a nested case-control study comparing incident cases of Alzheim...

  18. Alzheimer's Association

    Science.gov (United States)

    ... will not share your information. * Required. View archives. Alzheimer's impact is growing Alzheimer's disease is the sixth- ... Last Updated: Our vision is a world without Alzheimer's Formed in 1980, the Alzheimer's Association advances research ...

  19. Smoking and Progression of Alzheimers Disease: Connecting Edges

    Directory of Open Access Journals (Sweden)

    Vivek Sharma

    2014-06-01

    Full Text Available Smoking is a practice to burn and inhale the smoke and is primarily a route of administration for recreational drugs. The combustion releases the active substances in drugs such as nicotine and make them available for absorption through the lungs.The most common form of smoking is ciggarate smoking and is associated with life threatening complications like heart diseases, lung cancer, atherosclerosis, rheumatoid arthritis, osteoporosios, immune system dysfunction, hypertension, chronic obstructive pulmonary diseases, miscarriage, premature birth and dysfunctions of reproductive system as well. Smoking affet almost every organ of the body however, compared to the volume of research on the cardiovascular, pulmonary and cancer related health consequences of chronic smoking, lesser attention has been devoted to investigation of its effects on human neurocognition and brain neurobiology. In central nervous system, it leads to deficiencies in auditory verbal learning and/or memory, general intellectual abilities, visual search speeds, processing speed, cognitive flexibility, working memory and executive functions across a wide age range. The present work makes an effort to compile the evidence to challenge the notion/myth that smoking may be neuroprotective in cases of Alzheimers disease. The neuroprotective effects of smoking may be accredited only to nicotinic content of cigarrate smoke that too in part, but smoke is a deadly mixture of thousands of chemicals that must have disastrous effect on central nervous system. The various effets of cigarrate smoke and its ingredients on pathological markers of Alzheimers disease as oxidative stress, senile plaques, tau hyperphosphorylation, neuroinflammation, synapse loss and effects on blood brain barrier are disussed. [Archives Medical Review Journal 2014; 23(3.000: 534-561

  20. Decreased Heme Oxygenase Activity in Patients with Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Berkay Cataloglu

    2013-04-01

    Full Text Available Alzheimer's disease is a neurodegenerative disorder characterized with progressive im-pairment of cognitive functions. Heme oxygenase is an enzyme that degrades the heme molecule resulting in equimolar amounts of the carbon monoxide, ferrous iron, and bili-verdin. Up to now, heme oxygenase activity and its metabolic effects in Alzheimer's dis-ease have been investigated in so many studies; most of them were performed in post-mortem brain tissues of Alzheimer's disease patients or in animal models. Therefore, we aimed to investigate heme oxygenase activity in leukocytes of Alzheimer's disease pa-tients as a peripheral sample. Mean heme oxygenase activity was significantly lower in patients with Alzheimer's disease (0.53 +/- 0.32 nmol/h/mg protein compared to control sucjects (1.19 +/- 0.84 nmol/h/mg protein (p= 0.001. We think that reduction in leukocyte heme oxygenase activity may limit disease progression through preserving peripheral mitochondrial function by reducing the formation of free iron and carbon monoxide. [Dis Mol Med 2013; 1(2.000: 31-34

  1. New drug treatments show neuroprotective effects in Alzheimer's and Parkinson's diseases.

    Science.gov (United States)

    Hölscher, Christian

    2014-11-01

    Type 2 diabetes is a risk factor for Alzheimer's disease and Parkinson's disease. Insulin signaling in the brains of people with Alzheimer's disease or Parkinson's disease is impaired. Preclinical studies of growth factors showed impressive neuroprotective effects. In animal models of Alzheimer's disease and Parkinson's disease, insulin, glia-derived neurotrophic factor, or analogues of the incretin glucagon-like peptide-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality in Alzheimer's disease and Parkinson's disease. On the basis of these promising findings, several clinical trials are ongoing with the first encouraging clinical results published. This gives hope for developing effective treatments for Alzheimer's disease and Parkinson's disease that are currently unavailable.

  2. Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case–control study

    Science.gov (United States)

    Steele, Natasha Z. R.; Geier, Ethan G.; Damotte, Vincent; Boehme, Kevin L.; Mukherjee, Shubhabrata; Crane, Paul K.; Kauwe, John S. K.; Kramer, Joel H.; Miller, Bruce L.; Hollenbach, Jill A.; Huang, Yadong

    2017-01-01

    Background Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations. Methods and findings Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case–control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999–2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer’s Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984–2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005–2007 and longitudinal cognitive data from the Alzheimer’s Disease Neuroimaging Initiative (n = 346, mean follow-up 3.15 ± 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 (p = 9.6 x 10−4, odds ratio [OR] [95% confidence interval] = 1.21 [1.08–1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk

  3. Apolipoprotein E: Risk factor for Alzheimer disease

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, M.S.; Thibodeau, S.N.; Tangalos, E.G.; Petersen, R.C.; Kokmen, E.; Smith, G.E.; Schaid, D.J.; Ivnik, R.J. (Mayo Clinic, Rochester, MN (United States))

    1994-04-01

    The apolipoprotein E gene (APOE) has three common alleles (E2, E3, and E4) that determine six genotypes in the general population. In this study, the authors examined 77 patients with late-onset Alzheimer disease (AD), along with an equal number of age- and sex-matched controls, for an association with the APOE-E4 allele. They show that the frequency of this allele among AD patients was significantly higher than that among the control population (.351 vs. .130, P = .000006). The genotype frequencies also differed between the two groups (P = .0002), with the APOE-E4/E3 genotype being the most common in the AD group and the APOE-E3/E3 being the most common in the control group. In the AD group, homozygosity for E4 was found in nine individuals, whereas none was found in the control group. The odds ratio for AD, when associated with one or two E4 alleles, was 4.6 (95% confidence interval [CI] 1.9-12.3), while the odds ratio for AD, when associated with heterozygosity for APOE-E4, was 3.6 (05% CI 1.5-9.8). Finally, the median age at onset among the AD patients decreased from 83 to 78 to 74 years as the number of APOE-E4 alleles increased from 0 to 1 to 2, respectively (test for trend, P = .001). The data, which are in agreement with recent reports, suggest that the APOE-E4 allele is associated with AD and that this allelic variant may be an important risk factor for susceptibility to AD in the general population. 30 refs., 5 tabs.

  4. New Drugs from Marine Organisms in Alzheimer's Disease.

    Science.gov (United States)

    Russo, Patrizia; Kisialiou, Aliaksei; Lamonaca, Palma; Moroni, Rossana; Prinzi, Giulia; Fini, Massimo

    2015-12-25

    Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Current approved drugs may only ameliorate symptoms in a restricted number of patients and for a restricted period of time. Currently, there is a translational research challenge into identifying the new effective drugs and their respective new therapeutic targets in AD and other neurodegenerative disorders. In this review, selected examples of marine-derived compounds in neurodegeneration, specifically in AD field are reported. The emphasis has been done on compounds and their possible relevant biological activities. The proposed drug development paradigm and current hypotheses should be accurately investigated in the future of AD therapy directions although taking into account successful examples of such approach represented by Cytarabine, Trabectedin, Eribulin and Ziconotide. We review a complexity of the translational research for such a development of new therapies for AD. Bryostatin is a prominent candidate for the therapy of AD and other types of dementia in humans.

  5. Postural balance in Alzheimer's disease patients undergoing sensory pitfalls

    Directory of Open Access Journals (Sweden)

    Brunna Berton

    Full Text Available Abstract Despite consensus regarding the interference of cognitive processes on the human balance, the impact that different sensory stimuli have on the stabilometric measures remains unclear. Here, we investigated changes in the postural balance of individuals with Alzheimer's disease (AD and in healthy controls undergoing different proprioceptive and somesthetic pitfalls. We included 17 subjects submitted to eight sensorimotor dynamics with differences in the support bases, contact surfaces, and visual clues. The measurements used to assess participants balance were as follows: position of the body in space, range of instability, area of the support base, and velocity of postural control. From a total of 56 cross-sectional analyses, 21.42% pointed out differences between groups. Longitudinal analyses showed that tasks with proprioceptive and somesthetic pitfalls similarly impact imbalance in both groups. The current results suggest that AD subjects and healthy controls had different patterns submitted to balance, but suffered similar interference when undergoing proprioceptive and somesthetic challenges.

  6. Astrocytic expression of the Alzheimer's disease beta-secretase (BACE1) is stimulus-dependent

    DEFF Research Database (Denmark)

    Hartlage-Rübsamen, Maike; Zeitschel, Ulrike; Apelt, Jenny

    2003-01-01

    The beta-site APP-cleaving enzyme (BACE1) is a prerequisite for the generation of beta-amyloid peptides, which give rise to cerebrovascular and parenchymal beta-amyloid deposits in the brain of Alzheimer's disease patients. BACE1 is neuronally expressed in the brains of humans and experimental...... paradigms studied. In contrast, BACE1 expression by reactive astrocytes was evident in chronic but not in acute models of gliosis. Additionally, we observed BACE1-immunoreactive astrocytes in proximity to beta-amyloid plaques in the brains of aged Tg2576 mice and Alzheimer's disease patients....

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

    Science.gov (United States)

    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. [Elderly depression and depressive state with Alzheimer's disease].

    Science.gov (United States)

    Hattori, Hideyuki

    2009-04-01

    Depression and dementia, particularly Alzheimer's disease, are frequently observed in the elderly, and their diagnosis and treatment require complex knowledge of gerontology and psychiatry. Gerontologically, these diseases should be considered as geriatric syndrome. For the differentiation between depression and that associated with Alzheimer's disease, radiological examinations such as single photon emission CT and psychological examinations using the Geriatric Depression Scale (GDS) and Vitality Index are useful. Against depressive state with Alzheimer's disease, in addition to donepezil hydrochloride, selective serotonin reuptake inhibitors (SSRI) and serotonin-noradrenaline reuptake inhibitors (SNRI) are effective, and a small dose of sulpiride is also expected to be effective. In the treatment of elderly depression, its stage should be classified as acute or chronic. Treatment in the acute stage is similar to that in other age groups. In the chronic stage, activation treatment focusing on the prevention of functional decreases is necessary. For both depression and dementia, care and support for daily life are indispensable.

  9. [Does acidosis in brain play a role in Alzheimer's disease?].

    Science.gov (United States)

    Pirchl, Michael; Humpel, Christian

    2009-01-01

    Alzheimer's disease is characterized by beta-amyloid plaques, tau pathology, cell death of cholinergic neurons, inflammatory processes and cerebrovascular damage. The reasons for the development of this chronic disease are not known yet. We hypothesize that chronic long lasting mild damage of the cerebrovascular brain capillaries cause hypoperfusion, acidosis and neurodegeneration, and induces a cell death cascade with beta-amyloid dysfunction and tau-pathology and inflammation. Vascular risk factors, such as hyperhomocysteinemia or hypercholesterolemia, may play a role in this process. The accumulation of chronic silent strokes may cause cognitive defects as seen in vascular dementia and Alzheimer's disease. This summary tries to link the different events, which occur in Alzheimer's disease, focusing on the cerebrovascular hypothesis.

  10. Benzodiazepines may have protective effects against Alzheimer disease.

    Science.gov (United States)

    Fastbom, J; Forsell, Y; Winblad, B

    1998-03-01

    In this study, we examined the association between benzodiazepine use and the occurrence of Alzheimer disease and vascular dementia. The study was based on longitudinal data from a case-control study of 668 individuals aged 75 and older. The elderly were examined extensively by physicians, and family interviews were assessed. Dementia diagnosis was made by using DSM-III-R criteria. Individuals with a history of continuous use of benzodiazepines (BDZ+) were compared with nonusers (BDZ-), with respect to the incidence of Alzheimer disease or vascular dementia at follow-up 3 years later. It was found that there was a significantly lower incidence of Alzheimer disease in the BDZ+ group than in the BDZ- group. This negative association remained significant when controlling for age, gender, level of education, use of nonsteriodal antiinflammatory drugs, and estrogens. These results suggest that benzodiazepines may have protective effects against the disease.

  11. Aluminum and Alzheimer's disease, a personal perspective after 25 years.

    Science.gov (United States)

    Perl, Daniel P; Moalem, Sharon

    2006-01-01

    It is now 25 years since the publication of our original paper investigating the association aluminum with Alzheimer's disease. This publication reported on the results of scanning electron microscopy coupled x-ray spectrometry microprobe elemental studies of both neurofibrillary tangle-bearing and tangle-free neurons in the hippocampus of cases of Alzheimer's disease and controls. Peaks related to the presence of aluminum were consistently detected within the tangle-bearing neurons. This paper supported the association of aluminum and Alzheimer's disease on the cellular level of resolution and caused considerable interest and discussion. Subsequent work demonstrated prominent evidence of aluminum accumulation in the tangle-bearing neurons of cases of amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. This latter observation has now been replicated using five different forms of microanalysis. Finally, using laser microprobe mass analysis, we demonstrated that the abnormally high aluminum-related signal which we originally detected was actually located within the neurofibrillary tangle, itself, and was accompanied by excess concentrations of iron. Although it is unlikely that aluminum represents an etiologic cause of Alzheimer's disease, we believe that this highly reactive element, known to cross-link hyperphosphorylated proteins, may play an active role in the pathogenesis of critical neuropathologic lesion in Alzheimer's disease and other related disorders.

  12. Epigenetics in Alzheimer's Disease: Perspective of DNA Methylation.

    Science.gov (United States)

    Qazi, Talal Jamil; Quan, Zhenzhen; Mir, Asif; Qing, Hong

    2017-01-14

    Research over the years has shown that causes of Alzheimer's disease are not well understood, but over the past years, the involvement of epigenetic mechanisms in the developing memory formation either under pathological or physiological conditions has become clear. The term epigenetics represents the heredity of changes in phenotype that are independent of altered DNA sequences. Different studies validated that cytosine methylation of genomic DNA decreases with age in different tissues of mammals, and therefore, the role of epigenetic factors in developing neurological disorders in aging has been under focus. In this review, we summarized and reviewed the involvement of different epigenetic mechanisms especially the DNA methylation in Alzheimer's disease (AD), late-onset Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and autosomal dominant Alzheimer's disease (ADAD). Down to the minutest of details, we tried to discuss the methylation patterns like mitochondrial DNA methylation and ribosomal DNA (rDNA) methylation. Additionally, we mentioned some therapeutic approaches related to epigenetics, which could provide a potential cure for AD. Moreover, we reviewed some recent studies that validate DNA methylation as a potential biomarker and its role in AD. We hope that this review will provide new insights into the understanding of AD pathogenesis from the epigenetic perspective especially from the perspective of DNA methylation.

  13. Alzheimer's disease, apolipoprotein E and hormone replacement therapy.

    Science.gov (United States)

    Depypere, H; Vierin, A; Weyers, S; Sieben, A

    2016-12-01

    Alzheimer's disease is the most frequent cause of dementia in older patients. The prevalence is higher in women than in men. This may be the result of both the higher life expectancy of women and the loss of neuroprotective estrogen after menopause. Earlier age at menopause (spontaneous or surgical) is associated with an enhanced risk of developing Alzheimer's disease. Therefore, it is postulated that estrogen could be protective against it. If so, increasing exposure to estrogen through the use of postmenopausal hormone replacement could also be protective against Alzheimer's disease. The results of the clinical studies that have examined this hypothesis are inconclusive, however. One explanation for this is that estrogen treatment is protective only if it is initiated in the years immediately after menopause. Another possibility is that the neuroprotective effects of estrogen are negated by a particular genotype of apolipoprotein E. This protein plays an important role in cholesterol transport to the neurons. Studies that have examined the link between estrogen replacement therapy, Alzheimer's disease and the E4 allele of ApoE are inconclusive. This article reviews the literature on the influence of hormone replacement therapy on the incidence and progression of Alzheimer's disease.

  14. Brain imaging of mild cognitive impairment and Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Changhao Yin; Siou Li; Weina Zhao; Jiachun Feng

    2013-01-01

    The rapidly increasing prevalence of cognitive impairment and Alzheimer's disease has the potential to create a major worldwide healthcare crisis. Structural MRI studies in patients with Alzheimer's disease and mild cognitive impairment are currently attracting considerable interest. It is extremely important to study early structural and metabolic changes, such as those in the hippocampus, entorhinal cortex, and gray matter structures in the medial temporal lobe, to allow the early detection of mild cognitive impairment and Alzheimer's disease. The microstructural integrity of white matter can be studied with diffusion tensor imaging. Increased mean diffusivity and decreased fractional anisotropy are found in subjects with white matter damage. Functional imaging studies with positron emission tomography tracer compounds enable detection of amyloid plaques in the living brain in patients with Alzheimer's disease. In this review, we will focus on key findings from brain imaging studies in mild cognitive impairment and Alzheimer's disease, including structural brain changes studied with MRI and white matter changes seen with diffusion tensor imaging, and other specific imaging methodologies will also be discussed.

  15. Memantine Attenuates Alzheimer's Disease-Like Pathology and Cognitive Impairment.

    Directory of Open Access Journals (Sweden)

    Xiaochuan Wang

    Full Text Available Deficiency of protein phosphatase-2A is a key event in Alzheimer's disease. An endogenous inhibitor of protein phosphatase-2A, inhibitor-1, I1PP2A, which inhibits the phosphatase activity by interacting with its catalytic subunit protein phosphatase-2Ac, is known to be upregulated in Alzheimer's disease brain. In the present study, we overexpressed I1PP2A by intracerebroventricular injection with adeno-associated virus vector-1-I1PP2A in Wistar rats. The I1PP2A rats showed a decrease in brain protein phosphatase-2A activity, abnormal hyperphosphorylation of tau, neurodegeneration, an increase in the level of activated glycogen synthase kinase-3beta, enhanced expression of intraneuronal amyloid-beta and spatial reference memory deficit; littermates treated identically but with vector only, i.e., adeno-associated virus vector-1-enhanced GFP, served as a control. Treatment with memantine, a noncompetitive NMDA receptor antagonist which is an approved drug for treatment of Alzheimer's disease, rescued protein phosphatase-2A activity by decreasing its demethylation at Leu309 selectively and attenuated Alzheimer's disease-like pathology and cognitive impairment in adeno-associated virus vector-1-I1PP2A rats. These findings provide new clues into the possible mechanism of the beneficial therapeutic effect of memantine in Alzheimer's disease patients.

  16. Alzheimer's Disease in the Danish Malnutrition Period 1999-2007

    DEFF Research Database (Denmark)

    Sparre-Sørensen, Maja; Kristensen, Gustav David Westergaard

    2015-01-01

    BACKGROUND: Several studies published over the last few years have shown that malnutrition is a risk factor for developing and worsening Alzheimer's disease (AD) and that a balanced diet can delay the onset of the disease. During the period from January 1999 to January 2007, a statistically...... from AD associated with the period when the general nutritional state among the elderly in Denmark worsened (from 1999 to 2007). CONCLUSION: The study concludes that the malnutrition period resulted in an excess death rate from Alzheimer's disease. All in all, a total of 345 extra lives were lost...

  17. The S100B/RAGE Axis in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Estelle Leclerc

    2010-01-01

    Full Text Available Increasing evidence suggests that the small EF-hand calcium-binding protein S100B plays an important role in Alzheimer's disease. Among other evidences are the increased levels of both S100B and its receptor, the Receptor for Advanced Glycation Endproducts (RAGEs in the AD diseased brain. The regulation of RAGE signaling by S100B is complex and probably involves other ligands including the amyloid beta peptide (A, the Advanced Glycation Endproducts (AGEs, or transtheyretin. In this paper we discuss the current literature regarding the role of S100B/RAGE activation in Alzheimer's disease.

  18. Time estimation in mild Alzheimer's disease patients

    Directory of Open Access Journals (Sweden)

    Nichelli Paolo

    2009-07-01

    Full Text Available Abstract Background Time information processing relies on memory, which greatly supports the operations of hypothetical internal timekeepers. Scalar Expectancy Theory (SET postulates the existence of a memory component that is functionally separated from an internal clock and other processing stages. SET has devised several experimental procedures to map these cognitive stages onto cerebral regions and neurotransmitter systems. One of these, the time bisection procedure, has provided support for a dissociation between the clock stage, controlled by dopaminergic systems, and the memory stage, mainly supported by cholinergic neuronal networks. This study aimed at linking the specific memory processes predicted by SET to brain mechanisms, by submitting time bisection tasks to patients with probable Alzheimer's disease (AD, that are known to present substantial degeneration of the fronto-temporal regions underpinning memory. Methods Twelve mild AD patients were required to make temporal judgments about intervals either ranging from 100 to 600 ms (short time bisection task or from 1000 to 3000 ms (long time bisection task. Their performance was compared with that of a group of aged-matched control participants and a group of young control subjects. Results Long time bisection scores of AD patients were not significantly different from those of the two control groups. In contrast, AD patients showed increased variability (as indexed by increased WR values in timing millisecond durations and a generalized inconsistency of responses over the same interval in both the short and long bisection tasks. A similar, though milder, decreased millisecond interval sensitivity was found for elderly subjects. Conclusion The present results, that are consistent with those of previous timing studies in AD, are interpreted within the SET framework as not selectively dependent on working or reference memory disruptions but as possibly due to distortions in different

  19. Stem cell therapy for Alzheimer's disease.

    Science.gov (United States)

    Abdel-Salam, Omar M E

    2011-06-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder which impairs the memory and intellectual abilities of the affected individuals. Loss of episodic as well as semantic memory is an early and principal feature. The basal forebrain cholinergic system is the population of neurons most affected by the neurodegenerative process. Extracellular as well as intracellular deposition of beta-amyloid or Abeta (Abeta) protein, intracellular formation of neurofibrillary tangles and neuronal loss are the neuropathological hallmarks of AD. In the last few years, hopes were raised that cell replacement therapy would provide cure by compensating the lost neuronal systems. Stem cells obtained from embryonic as well as adult tissue and grafted into the intact brain of mice or rats were mostly followed by their incorporation into the host parenchyma and differentiation into functional neural lineages. In the lesioned brain, stem cells exhibited targeted migration towards the damaged regions of the brain, where they engrafted, proliferated and matured into functional neurones. Neural precursor cells can be intravenously administered and yet migrate into brain damaged areas and induce functional recovery. Observations in animal models of AD have provided evidence that transplanted stem cells or neural precursor cells (NPCs) survive, migrate, and differentiate into cholinergic neurons, astrocytes, and oligodendrocytes with amelioration of the learning/memory deficits. Besides replacement of lost or damaged cells, stem cells stimulate endogenous neural precursors, enhance structural neuroplasticity, and down regulate proinflammatory cytokines and neuronal apoptotic death. Stem cells could also be genetically modified to express growth factors into the brain. In the last years, evidence indicated that the adult brain of mammals preserves the capacity to generate new neurons from neural stem/progenitor cells. Inefficient adult neurogenesis may contribute to the

  20. Ten Challenges of the Amyloid Hypothesis of Alzheimer's Disease

    DEFF Research Database (Denmark)

    Kepp, Kasper Planeta

    2017-01-01

    The inability to effectively halt or cure Alzheimer's disease (AD), exacerbated by the recent failures of high-profile clinical trials, emphasizes the urgent need to understand the complex biochemistry of this major neurodegenerative disease. In this paper, ten central, current challenges...

  1. Alzheimer's disease and Down's syndrome: treating two paths to dementia

    NARCIS (Netherlands)

    Weksler, M.E.; Szabo, P.; Relkin, N.R.; Reidenberg, M.M.; Weksler, B.B.; Coppus, A.M.W.

    2013-01-01

    Successful therapy of dementia, like any disease, depends upon understanding its pathogenesis. This review contrasts the dominant pathways to dementia which differ in Alzheimer's disease (AD) and in Down's syndrome (DS). Impaired clearance of neurotoxic amyloid beta peptides (Abeta) leads to dementi

  2. Targeting the hematopoietic system for the treatment of Alzheimer's disease.

    Science.gov (United States)

    Lampron, Antoine; Gosselin, David; Rivest, Serge

    2011-06-01

    Alzheimer's disease (AD) is the most prevalent cause of dementia in humans. This disease is characterized by the presence of amyloid beta (Ab) deposits in the parenchyma (also known as amyloid plaques or senile plaques) and in the cerebral vasculature. Though Ab formation and deposits are strongly correlated with cognitive impairment, the mechanisms responsible for the synaptic dysfunctions and loss of neurons in AD remain largely unknown. Many studies have provided evidence that microglial cells are attracted to amyloid deposits both in human samples and in rodent transgenic models that develop this disease. We have recently found that blood-derived microglia and not their resident counterparts have the ability to eliminate amyloid deposits by a cell-specific phagocytic mechanism. These bone marrow-derived microglia have consequently a great therapeutic potential for AD patients. Molecular strategies aiming to improve their recruitment could lead to a new powerful tool for the elimination of toxic Ab and improve cognitive functions. However, numerous limitations have to be taken into consideration before recommending such a cellular therapy and these are discussed in the present review.

  3. Efficacy of psychosocial intervention in patients with mild Alzheimer's disease

    DEFF Research Database (Denmark)

    Waldorff, F B; Buss, D V; Eckermann, A

    2012-01-01

    OBJECTIVE: To assess the efficacy at 12 months of an early psychosocial counselling and support programme for outpatients with mild Alzheimer's disease and their primary care givers. DESIGN: Multicentre, randomised, controlled, rater blinded trial. SETTING: Primary care and memory clinics in five...... Danish districts. PARTICIPANTS: 330 outpatients with mild Alzheimer's disease and their 330 primary care givers. INTERVENTIONS: Participating dyads (patient and primary care giver) were randomised to control support during follow-up or to control support plus DAISY intervention (multifaceted and semi...... for attrition (P = 0.0146 and P = 0.0103 respectively). CONCLUSIONS: The multifaceted, semi-tailored intervention with counselling, education, and support for patients with mild Alzheimer's disease and their care givers did not have any significant effect beyond that with well structured follow-up support at 12...

  4. Aluminum as a risk factor for Alzheimer's disease.

    Science.gov (United States)

    Ferreira, Pricilla Costa; Piai, Kamila de Almeida; Takayanagui, Angela Maria Magosso; Segura-Muñoz, Susana Inés

    2008-01-01

    The purpose of the study was to condense existing scientific evidence about the relation between aluminum (Al) exposure and risk for the development of Alzheimer's Disease (AD), evaluating its long-term effects on the population's health. A systematic literature review was carried out in two databases, MEDLINE and LILACS, between 1990 and 2005, using the uniterms: "Aluminum exposure and Alzheimer Disease" and "Aluminum and risk for Alzheimer Disease". After application of the Relevance Test, 34 studies were selected, among which 68% established a relation between Al and AD, 23.5% were inconclusive and 8.5% did not establish a relation between Al and AD. Results showed that Al is associated to several neurophysiologic processes that are responsible for the characteristic degeneration of AD. In spite of existing polemics all over the world about the role of Al as a risk factor for AD, in recent years, scientific evidence has demonstrated that Al is associated with the development of AD.

  5. Complement Biomarkers as Predictors of Disease Progression in Alzheimer's Disease.

    Science.gov (United States)

    Hakobyan, Svetlana; Harding, Katharine; Aiyaz, Mohammed; Hye, Abdul; Dobson, Richard; Baird, Alison; Liu, Benjamine; Harris, Claire Louise; Lovestone, Simon; Morgan, Bryan Paul

    2016-09-06

    There is a critical unmet need for reliable markers of disease and disease course in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). The growing appreciation of the importance of inflammation in early AD has focused attention on inflammatory biomarkers in cerebrospinal fluid or plasma; however, non-specific inflammation markers have disappointed to date. We have adopted a targeted approach, centered on an inflammatory pathway already implicated in the disease. Complement, a core system in innate immune defense and potent driver of inflammation, has been implicated in pathogenesis of AD based on a confluence of genetic, histochemical, and model data. Numerous studies have suggested that measurement of individual complement proteins or activation products in cerebrospinal fluid or plasma is useful in diagnosis, prediction, or stratification, but few have been replicated. Here we apply a novel multiplex assay to measure five complement proteins and four activation products in plasma from donors with MCI, AD, and controls. Only one complement analyte, clusterin, differed significantly between control and AD plasma (controls, 295 mg/l; AD, 388 mg/l: p converted to dementia one year later compared to non-converters; a model combining these three analytes with informative co-variables was highly predictive of conversion. The data confirm the relevance of complement biomarkers in MCI and AD and build the case for using multi-parameter models for disease prediction and stratification.

  6. New NIA Booklet By and For People With Early-Stage Alzheimer's Disease

    Science.gov (United States)

    ... Booklet By and For People With Early-Stage Alzheimer's Disease Past Issues / Fall 2007 Table of Contents ... you have a family member or friends with Alzheimer's disease? Are you wondering what they're going ...

  7. Mortality from Alzheimer's Disease in the United States: Data for 2000 and 2010

    Science.gov (United States)

    ... the National Technical Information Service NCHS Mortality From Alzheimer's Disease in the United States: Data for 2000 ... dementia, National Vital Statistics System, death rate, aging Alzheimer's disease mortality increased compared with selected major causes ...

  8. Early complement components in Alzheimer's disease brains.

    Science.gov (United States)

    Veerhuis, R; Janssen, I; Hack, C E; Eikelenboom, P

    1996-01-01

    Activation products of the early complement components C1, C4 and C3 can be found colocalized with diffuse and fibrillar beta-amyloid (beta/A4) deposits in Alzheimer's disease (AD) brains. Immunohistochemically, C1-esterase inhibitor (C1-Inh) and the C1 subcomponents C1s and C1r can not, or only occasionally, be detected in plaques or in astrocytes. The present finding that C1q, C1s and C1-Inh mRNA are present in both AD and control brains suggests that the variable immunohistochemical staining results for C1r, C1s and C1-Inh are due to a rapid consumption, and that the inability to detect C1s, C1r or C1-Inh is probably due to the dissociation of C1s-C1-Inh and C1r-C1-Inh complexes from the activator-bound C1q into the fluid phase. Employing monoclonal antibodies specific for different forms of C1-Inh, no complexed C1-Inh could be found, whereas inactivated C1-Inh seems to be present in astrocytes surrounding beta/A4 plaques in AD brains. These findings, together with our finding (using reverse transcriptase-polymerase chain reaction) that C1-Inh is locally produced in the brain, suggest that in the brain complement activation at the C1 level is regulated by C1-Inh. Immunohistochemically, no evidence for the presence of the late complement components C5, C7 and C9, or of the membrane attack complex (MAC), was found in beta/A4 plaques. In contrast to the mRNA encoding the early components, that of the late complement components appears to be hardly detectable (C7) or absent (C9). Thus, without blood-brain-barrier impairment, the late complement components are probably present at too low a concentration to allow the formation of the MAC, which is generally believed to be responsible for at least some of the neurodegenerative effects observed in AD. Therefore, the present findings support the idea that in AD, complement does not function as an inflammatory mediator through MAC formation, but through the action of early component activation products.

  9. Cerebral microbleeds in early Alzheimer's disease.

    Science.gov (United States)

    Poliakova, T; Levin, O; Arablinskiy, A; Vasenina, E; Zerr, I

    2016-10-01

    We hypothesize that cerebral microbleeds (CMB) in patients with different neuropsychological profiles (amnestic or non-amnestic) and MRI features of vascular damage could provide important information on the underlying pathological process in early Alzheimer's disease. The study was performed at two trial sites. We studied 136 outpatients with cognitive decline. MRI was performed using a magnetic field of 1.5 and 3 T. Neuropsychological assessment included Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment scale (MoCA), Addenbrooke's Cognitive Examination (ACE-R), Cambridge Cognitive Examination battery (CAMCOG) (Part 3), Clock Drawing Test, fluency test and the visual memory test (SCT). CSF was examined for standard parameters such as tau, phosphorylated tau, amyloid-β 1-40 and 42 and Qalbumin, in accordance with established protocols and genotype. In 61 patients (45 %), at least 1 CMB was found. Most of the CMBs were described in the amnestic profile (67 %). In 86 % of the cases, multiple CMB were observed. The ratio of Aβ1-40/42 in non-amnestic patients with CMB was significantly lower (mean 0.6) than in patients without CMB (mean 1.2). A notable difference in the albumin ratio as an indicator of the BBB was observed between groups with and without CMB. In the CMP-positive group, the E2 genotype was observed more frequently, and the E4 genotype less frequently, than in the CMB-negative group. Based on the cerebrospinal fluid-serum albumin ratio, we were able to show that patients with CMB present several features of BBB dysfunction. According to logistic regression, the predictive factors for CMB in patients with cognitive decline were age, WMHs score and albumin ratio. We found a significant reduction in the Aβ-amyloid ratio in the non-amnestic profile group with CMB (particularly in the cortical region) in comparison to those without CMB. While this is an interesting finding, its significance needs to be assessed in a prospective follow-up.

  10. Endothelial progenitor cells with Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    KONG Xiao-dong; ZHANG Yun; LIU Li; SUN Ning; ZHANG Ming-yi; ZHANG Jian-ning

    2011-01-01

    Background Endothelial dysfunction is thought to be critical events in the pathogenesis of Alzheimer's disease (AD).Endothelial progenitor cells (EPCs) have provided insight into maintaining and repairing endothelial function. To study the relation between EPCs and AD, we explored the number of circulating EPCs in patients with AD.Methods A total of 104 patients were recruited from both the outpatients and inpatients of the geriatric neurology department at General Hospital, rianjin Medical University. Consecutive patients with newly diagnosed AD (n=30),patients with vascular dementia (VaD, n=34), and healthy elderly control subjects with normal cognition (n=40) were enrolled after matching for age, gender, body mass index, medical history, current medication and Mini Mental State Examination. Middle cerebral artery flow velocity was examined with transcranial Doppler. Endothelial function was evaluated according to the level of EPCs, and peripheral blood EPCs was counted by flow cytometry.Results There were no significant statistical differences of clinical data in AD, VaD and control groups (P >0.05). The patients with AD showed decreased CD34-positive (CD34+) or CD133-positive (CD133+) levels compared to the control subjects, but there were no significant statistical differences in patients with AD. The patients with AD had significantly lower CD34+CD133+ EPCs(CD34 and CD133 double positive endothelial progenitor cells) than the control subjects (P <0.05). In the patients with AD, a lower CD34+CD133+ EPCs count was independently associated with a lower Mini-Mental State Examination score (r=0.514, P=0.004). Patients with VaD also showed a significant decrease in CD34+CD133+ EPCs levels, but this was not evidently associated with the Mini-Mental State Examination score. The changes of middle cerebral artery flow velocity were similar between AD and VaD. Middle cerebral artery flow velocity was decreased in the AD and VaD groups and significantly lower than

  11. Biophysical alterations in lipid rafts from human cerebral cortex associate with increased BACE1/AβPP interaction in early stages of Alzheimer's disease.

    Science.gov (United States)

    Díaz, Mario; Fabelo, Noemí; Martín, Virginia; Ferrer, Isidre; Gómez, Tomás; Marín, Raquel

    2015-01-01

    In the present study, we have assessed the biophysical properties of lipid rafts from different brain areas in subjects exhibiting early neuropathological stages of Alzheimer's disease (AD). By means of steady-state fluorescence polarization analyses using two environment-sensitive fluorescent probes, we demonstrate that lipid rafts from cerebellum, and frontal and entorhinal cortices, exhibit different biophysical behaviors depending on the stage of the disease. Thus, while membrane anisotropies were similar in the cerebellum along stages, lipid rafts from frontal and entorhinal cortices at AD stages I/II and AD III were significantly more liquid-ordered than in control subjects, both at the aqueous interface and hydrophobic core of the raft membrane. Thermotropic analyses demonstrated the presence of Arrhenius breakpoints between 28.3-32.0 °C, which were not influenced by the disease stage. However, analyses of membrane microviscosity (ηapp) demonstrate that frontal and entorhinal lipid rafts are notably more viscous and liquid-ordered all across the membrane from early stages of the disease. These physicochemical alterations in lipid rafts do not correlate with changes in cholesterol or sphingomyelin levels, but to reduced unsaturation index and increased saturate/polyunsaturated ratios in phospholipid acyl chains. Moreover, we demonstrate that β-secretase/AβPP (amyloid-β protein precursor) interaction and lipid raft microviscosity are strongly, and positively, correlated in AD frontal and entorhinal cortices. These observations strengthens the hypothesis that physical properties of these microdomains modulate the convergence of amyloidogenic machinery toward lipid rafts, and also points to a critical role of polyunsaturated fatty acids in amyloidogenic processing of AβPP.

  12. The Category Cued Recall test in very mild Alzheimer's disease

    DEFF Research Database (Denmark)

    Vogel, Asmus; Mortensen, E.L.; Gade, A.

    2007-01-01

    Episodic memory tests that measure cued recall may be particularly effective in the diagnosis of early Alzheimer's disease (AD) because they examine both episodic and semantic memory functions. The Category Cued Recall (CCR) test provides superordinate semantic cues at encoding and retrieval......, and high discriminative validity has been claimed for this test. The aim of this study was to investigate the discriminative validity for this test when compared with the 10-word memory list from Alzheimer's Disease Assessment Scale (ADAS-cog) that measures free recall. The clinical diagnosis of AD...

  13. Corpus callosum atrophy in patients with mild Alzheimer's disease

    DEFF Research Database (Denmark)

    Frederiksen, Kristian Steen; Garde, Ellen; Skimminge, Arnold

    2011-01-01

    Several studies have found atrophy of the corpus callosum (CC) in patients with Alzheimer's disease (AD). However, it remains unclear whether callosal atrophy is already present in the early stages of AD, and to what extent it may be associated with other structural changes in the brain, such as ......Several studies have found atrophy of the corpus callosum (CC) in patients with Alzheimer's disease (AD). However, it remains unclear whether callosal atrophy is already present in the early stages of AD, and to what extent it may be associated with other structural changes in the brain...

  14. Rivastigmine in the treatment of hypersexuality in Alzheimer disease.

    Science.gov (United States)

    Canevelli, Marco; Talarico, Giuseppina; Tosto, Giuseppe; Troili, Fernanda; Lenzi, Gian Luigi; Bruno, Giuseppe

    2013-01-01

    Inappropriate sexual behaviors (ISB) represent uncommon and often misdiagnosed clinical disorders among patients with Alzheimer disease. So far, no randomized clinical trials regarding the treatment of ISB in demented people have been conducted, but available data from case series and isolated case reports suggest the efficacy of selective serotonin reuptake inhibitors (SSRIs), antipsychotics, antiandrogens, and H2-receptor antagonists. Controversial data exist on the therapeutic influence of cholinesterase inhibitors on sexual disorders. In the present article, we describe the case of an Alzheimer disease patient presenting hypersexuality, successfully treated with rivastigmine. Thus, we perform a revision of the existing literature regarding the therapeutical effect of cholinesterase inhibitors in the treatment of ISB.

  15. Effectiveness of exercise on cognitive impairment and Alzheimer's disease.

    Science.gov (United States)

    Balsamo, Sandor; Willardson, Jeffrey M; Frederico, Santos de Santana; Prestes, Jonato; Balsamo, Denise Coscrato; Dahan, da Cunha Nascimento; Dos Santos-Neto, Leopoldo; Nobrega, Otávio T

    2013-01-01

    Physical activity has a protective effect on brain function in older people. Here, we briefly reviewed the studies and results related to the effects of exercise on cognitive impairment and Alzheimer's disease. The main findings from the current body of literature indicate positive evidence for structured physical activity (cardiorespiratory and resistance exercise) as a promising non-pharmacological intervention for preventing cognitive decline. More studies are needed to determine the mechanisms involved in this preventative effect, including on strength, cardiorespiratory, and other types of exercise. Thus, the prevention of Alzheimer's disease may depend on healthy lifestyle habits, such as a structured physical fitness program.

  16. [Alzheimer's disease: a public health problem: yes, but a priority?].

    Science.gov (United States)

    Dartigues, J F; Helmer, C; Dubois, B; Duyckaerts, C; Laurent, B; Pasquier, F; Touchon, J

    2002-03-01

    Alzheimer's Disease is a major Public Health problem for many reasons. First, it is a frequent disease since, in France, the prevalence was estimated at about 400.000 cases, and the annual incidence at 100.000 cases. The frequency of the disease increases, in particular due to the ageing of the population. This disease has major consequences on the life of the patient and his/her caretaker. The cost of the disease is important, estimated at about 50 milliards of French francs. Pharmaceutical treatment and other interventions are possible in particular to delay the nursing home placement. On the other hand, this disease is often ignored, under-diagnosed, underestimated and exposed to inequality in resorting to care. In summary, Alzheimer's Disease (AD) has all the criteria required for a major public health problem. In spite of this observation, AD is not yet considered as a priority for health authorities, although attitudes are changing.

  17. How close is the stem cell cure to the Alzheimer's disease Future and beyond?

    Institute of Scientific and Technical Information of China (English)

    Jun Tang

    2012-01-01

    Alzheimer's disease, a progressive neurodegenerative illness, is the most common form of dementia. So far, there is neither an effective prevention nor a cure for Alzheimer's disease. In recent decades, stem cell therapy has been one of the most promising treatments for Alzheimer's disease patients. This article aims to summarize the current progress in the stem cell treatments for Alzheimer's disease from an experiment to a clinical research.

  18. The Arctic Alzheimer mutation enhances sensitivity to toxic stress in human neuroblastoma cells

    DEFF Research Database (Denmark)

    Sennvik, Kristina; Nilsberth, Camilla; Stenh, Charlotte

    2002-01-01

    The E693G (Arctic) mutation of the amyloid precursor protein was recently found to lead to early-onset Alzheimer's disease in a Swedish family. In the present study, we report that the Arctic mutation decreases cell viability in human neuroblastoma cells. The cell viability, as measured by the MTT...... their secretion of beta-secretase cleaved amyloid precursor protein. The enhanced sensitivity to toxic stress in cells with the Arctic mutation most likely contributes to the pathogenic pathway leading to Alzheimer's disease....

  19. Non-invasive assessment of Alzheimer's disease neurofibrillary pathology using 18F-THK5105 PET.

    Science.gov (United States)

    Okamura, Nobuyuki; Furumoto, Shozo; Fodero-Tavoletti, Michelle T; Mulligan, Rachel S; Harada, Ryuichi; Yates, Paul; Pejoska, Svetlana; Kudo, Yukitsuka; Masters, Colin L; Yanai, Kazuhiko; Rowe, Christopher C; Villemagne, Victor L

    2014-06-01

    Non-invasive imaging of tau pathology in the living brain would be useful for accurately diagnosing Alzheimer's disease, tracking disease progression, and evaluating the treatment efficacy of disease-specific therapeutics. In this study, we evaluated the clinical usefulness of a novel tau-imaging positron emission tomography tracer 18F-THK5105 in 16 human subjects including eight patients with Alzheimer's disease (three male and five females, 66-82 years) and eight healthy elderly controls (three male and five females, 63-76 years). All participants underwent neuropsychological examination and 3D magnetic resonance imaging, as well as both 18F-THK5105 and 11C-Pittsburgh compound B positron emission tomography scans. Standard uptake value ratios at 90-100 min and 40-70 min post-injection were calculated for 18F-THK5105 and 11C-Pittsburgh compound B, respectively, using the cerebellar cortex as the reference region. As a result, significantly higher 18F-THK5105 retention was observed in the temporal, parietal, posterior cingulate, frontal and mesial temporal cortices of patients with Alzheimer's disease compared with healthy control subjects. In patients with Alzheimer's disease, the inferior temporal cortex, which is an area known to contain high densities of neurofibrillary tangles in the Alzheimer's disease brain, showed prominent 18F-THK5105 retention. Compared with high frequency (100%) of 18F-THK5105 retention in the temporal cortex of patients with Alzheimer's disease, frontal 18F-THK5105 retention was less frequent (37.5%) and was only observed in cases with moderate-to-severe Alzheimer's disease. In contrast, 11C-Pittsburgh compound B retention was highest in the posterior cingulate cortex, followed by the ventrolateral prefrontal, anterior cingulate, and superior temporal cortices, and did not correlate with 18F-THK5105 retention in the neocortex. In healthy control subjects, 18F-THK5105 retention was ∼10% higher in the mesial temporal cortex than in the

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

    Science.gov (United States)

    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.

  1. Down syndrome and Alzheimer's disease: Common pathways, common goals.

    Science.gov (United States)

    Hartley, Dean; Blumenthal, Thomas; Carrillo, Maria; DiPaolo, Gilbert; Esralew, Lucille; Gardiner, Katheleen; Granholm, Ann-Charlotte; Iqbal, Khalid; Krams, Michael; Lemere, Cynthia; Lott, Ira; Mobley, William; Ness, Seth; Nixon, Ralph; Potter, Huntington; Reeves, Roger; Sabbagh, Marwan; Silverman, Wayne; Tycko, Benjamin; Whitten, Michelle; Wisniewski, Thomas

    2015-06-01

    In the United States, estimates indicate there are between 250,000 and 400,000 individuals with Down syndrome (DS), and nearly all will develop Alzheimer's disease (AD) pathology starting in their 30s. With the current lifespan being 55 to 60 years, approximately 70% will develop dementia, and if their life expectancy continues to increase, the number of individuals developing AD will concomitantly increase. Pathogenic and mechanistic links between DS and Alzheimer's prompted the Alzheimer's Association to partner with the Linda Crnic Institute for Down Syndrome and the Global Down Syndrome Foundation at a workshop of AD and DS experts to discuss similarities and differences, challenges, and future directions for this field. The workshop articulated a set of research priorities: (1) target identification and drug development, (2) clinical and pathological staging, (3) cognitive assessment and clinical trials, and (4) partnerships and collaborations with the ultimate goal to deliver effective disease-modifying treatments.

  2. Characteristics of familial aggregation in early-onset Alzheimer`s disease: Evidence of subgroups

    Energy Technology Data Exchange (ETDEWEB)

    Campion, D. [INSERM, Paris (France); Martinez, M.; Babron, M.C. [and others

    1995-06-19

    Characteristics of familial aggregation of Alzheimer`s Disease were studied in 92 families ascertained through a clinically diagnosed proband with an onset below age 60 years. In each family data were systematically collected on the sibships of the proband, of his father, and of his mother. A total of 926 relatives were included and 81% of the living relatives (i.e., 251 individuals) were directly examined. The estimated cumulative risk among first degree relatives was equal to 35% by age 89 years (95% confidence interval 22 to 47%). This result does not support the hypothesis that an autosomal dominant gene, fully penetrant by age 90 years, is segregating within all these pedigrees. Despite the fact that all probands were selected for an onset before age 60 years it was shown that two types of families could be delineated with respect to age at onset among affected relatives: all secondary cases with an onset below age 60 years were contributed by a particular group of families (type 1 families), whereas all secondary cases with an onset after age 60 years were contributed by another group of families (type 2 families). Although genetic interpretation of these findings is not straightforward, they support the hypothesis of etiologic heterogeneity in the determinism of early-onset Alzheimer`s disease. 58 refs., 5 figs., 2 tabs.

  3. Hypertension accelerates the progression of Alzheimer-like pathology in a mouse model of the disease.

    Science.gov (United States)

    Cifuentes, Diana; Poittevin, Marine; Dere, Ekrem; Broquères-You, Dong; Bonnin, Philippe; Benessiano, Joëlle; Pocard, Marc; Mariani, Jean; Kubis, Nathalie; Merkulova-Rainon, Tatyana; Lévy, Bernard I

    2015-01-01

    Cerebrovascular impairment is frequent in patients with Alzheimer disease and is believed to influence clinical manifestation and severity of the disease. Cardiovascular risk factors, especially hypertension, have been associated with higher risk of developing Alzheimer disease. To investigate the mechanisms underlying the hypertension, Alzheimer disease cross talk, we established a mouse model of dual pathology by infusing hypertensive doses of angiotensin II into transgenic APPPS1 mice overexpressing mutated human amyloid precursor and presenilin 1 proteins. At 4.5 months, at the early stage of disease progression, only hypertensive APPPS1 mice presented impairment of temporal order memory performance in the episodic-like memory task. This cognitive deficit was associated with an increased number of cortical amyloid deposits (223±5 versus 207±5 plaques/mm(2); PHypertensive APPPS1 mice presented several cerebrovascular alterations, including a 25% reduction in cerebral microvessel density and a 30% to 40% increase in cerebral vascular amyloid deposits, as well as a decrease in vascular endothelial growth factor A expression in the brain, compared with normotensive APPPS1 mice. Moreover, the brain levels of nitric oxide synthase 1 and 3 and the nitrite/nitrate levels were reduced in hypertensive APPPS1 mice (by 49%, 34%, and 33%, respectively, compared with wild-type mice; Phypertension accelerates the development of Alzheimer disease-related structural and functional alterations, partially through cerebral vasculature impairment and reduced nitric oxide production.

  4. Towards non-invasive diagnostic imaging of early-stage Alzheimer's disease

    Science.gov (United States)

    Viola, Kirsten L.; Sbarboro, James; Sureka, Ruchi; de, Mrinmoy; Bicca, Maíra A.; Wang, Jane; Vasavada, Shaleen; Satpathy, Sreyesh; Wu, Summer; Joshi, Hrushikesh; Velasco, Pauline T.; Macrenaris, Keith; Waters, E. Alex; Lu, Chang; Phan, Joseph; Lacor, Pascale; Prasad, Pottumarthi; Dravid, Vinayak P.; Klein, William L.

    2015-01-01

    One way to image the molecular pathology in Alzheimer's disease is by positron emission tomography using probes that target amyloid fibrils. However, these fibrils are not closely linked to the development of the disease. It is now thought that early-stage biomarkers that instigate memory loss are composed of Aβ oligomers. Here, we report a sensitive molecular magnetic resonance imaging contrast probe that is specific for Aβ oligomers. We attach oligomer-specific antibodies onto magnetic nanostructures and show that the complex is stable and binds to Aβ oligomers on cells and brain tissues to give a magnetic resonance imaging signal. When intranasally administered to an Alzheimer's disease mouse model, the probe readily reached hippocampal Aβ oligomers. In isolated samples of human brain tissue, we observed a magnetic resonance imaging signal that distinguished Alzheimer's disease from controls. Such nanostructures that target neurotoxic Aβ oligomers are potentially useful for evaluating the efficacy of new drugs and ultimately for early-stage Alzheimer's disease diagnosis and disease management.

  5. Electromagnetic field treatment protects against and reverses cognitive impairment in Alzheimer's disease mice.

    Science.gov (United States)

    Arendash, Gary W; Sanchez-Ramos, Juan; Mori, Takashi; Mamcarz, Malgorzata; Lin, Xiaoyang; Runfeldt, Melissa; Wang, Li; Zhang, Guixin; Sava, Vasyl; Tan, Jun; Cao, Chuanhai

    2010-01-01

    Despite numerous studies, there is no definitive evidence that high-frequency electromagnetic field (EMF) exposure is a risk to human health. To the contrary, this report presents the first evidence that long-term EMF exposure directly associated with cell phone use (918 MHz; 0.25 w/kg) provides cognitive benefits. Both cognitive-protective and cognitive-enhancing effects of EMF exposure were discovered for both normal mice and transgenic mice destined to develop Alzheimer's-like cognitive impairment. The cognitive interference task utilized in this study was designed from, and measure-for-measure analogous to, a human cognitive interference task. In Alzheimer's disease mice, long-term EMF exposure reduced brain amyloid-beta (Abeta) deposition through Abeta anti-aggregation actions and increased brain temperature during exposure periods. Several inter-related mechanisms of EMF action are proposed, including increased Abeta clearance from the brains of Alzheimer's disease mice, increased neuronal activity, and increased cerebral blood flow. Although caution should be taken in extrapolating these mouse studies to humans, we conclude that EMF exposure may represent a non-invasive, non-pharmacologic therapeutic against Alzheimer's disease and an effective memory-enhancing approach in general.

  6. The immunopathogenic role of reactive oxygen species in Alzheimer disease.

    Science.gov (United States)

    Mohsenzadegan, Monireh; Mirshafiey, Abbas

    2012-09-01

    Reactive oxygen species (ROS) are produced in many normal and abnormal processes in humans, including atheroma, asthma, joint diseases, cancer, and aging. Basal levels of ROS production in cells could be related to several physiological functions including cell proliferation, apoptosis and homeostasis. However, excessive ROS production above basal levels would impair and oxidize DNA, lipids, sugars and proteins and consequently result in dysfunction of these molecules within cells and finally cell death. A leading theory of the cause of aging indicates that free radical damage and oxidative stress play a major role in the pathogenesis of Alzheimer disease (AD). Because the brain utilizes 20% more oxygen than other tissues that also undergo mitochondrial respiration, the potential for ROS exposure increases. In fact, AD has been demonstrated to be highly associated with cellular oxidative stress, including augmentation of protein oxidation, protein nitration, glycoloxidation and lipid peroxidation as well as accumulation of Amyloid β (Aβ). The treatment with anti-oxidant compounds can provide protection against oxidative stress and Aβ toxicity. In this review, our aim was to clarify the role of ROS in pathogenesis of AD and will discuss therapeutic efficacy of some antioxidants studies in recent years in this disease.

  7. Therapeutics for Alzheimer's disease based on the metal hypothesis.

    Science.gov (United States)

    Bush, Ashley I; Tanzi, Rudolph E

    2008-07-01

    Alzheimer's disease is the most common form of dementia in the elderly, and it is characterized by elevated brain iron levels and accumulation of copper and zinc in cerebral beta-amyloid deposits (e.g., senile plaques). Both ionic zinc and copper are able to accelerate the aggregation of Abeta, the principle component of beta-amyloid deposits. Copper (and iron) can also promote the neurotoxic redox activity of Abeta and induce oxidative cross-linking of the peptide into stable oligomers. Recent reports have documented the release of Abeta together with ionic zinc and copper in cortical glutamatergic synapses after excitation. This, in turn, leads to the formation of Abeta oligomers, which, in turn, modulates long-term potentiation by controlling synaptic levels of the NMDA receptor. The excessive accumulation of Abeta oligomers in the synaptic cleft would then be predicted to adversely affect synaptic neurotransmission. Based on these findings, we have proposed the "Metal Hypothesis of Alzheimer's Disease," which stipulates that the neuropathogenic effects of Abeta in Alzheimer's disease are promoted by (and possibly even dependent on) Abeta-metal interactions. Increasingly sophisticated pharmaceutical approaches are now being implemented to attenuate abnormal Abeta-metal interactions without causing systemic disturbance of essential metals. Small molecules targeting Abeta-metal interactions (e.g., PBT2) are currently advancing through clinical trials and show increasing promise as disease-modifying agents for Alzheimer's disease based on the "metal hypothesis."

  8. Alzheimer's disease due to loss of function

    DEFF Research Database (Denmark)

    Kepp, Kasper Planeta

    2016-01-01

    the gain-of-function amyloid hypothesis. In the loss-of-function scenario, the central event of Aβ aggregation is interpreted as a loss of soluble, functional monomer Aβ rather than toxic overload of oligomers. Accordingly, new research models and treatment strategies should focus on remediation....... The amyloid hypothesis has dominated the field with its assumption that buildup of pathogenic β-amyloid (Aβ) peptide causes disease. This paradigm has been criticized, yet most data suggest that Aβ plays a key role in the disease. Here, a new loss-of-function hypothesis is synthesized that accounts......-loss view accounts for recent findings on the structure and chemical features of Aβ variants and their coupling to human patient data. The lost normal function of APP/Aβ is argued to be metal transport across neuronal membranes, a view with no apparent anomalies and substantially more explanatory power than...

  9. Spherons as a drug target in Alzheimer's disease.

    Science.gov (United States)

    Averback, P

    1998-10-01

    Spherons are unique brain entities that are causally linked to the amyloid plaques (SPs [senile plaques]) of Alzheimer's disease (AD). SPs are the quantitatively major tissue abnormality of AD. Spherons increase in size (but not in number) gradually throughout life until they reach a size range where they burst and form SPs. Drugs targeted at attenuating the process of spheron transformation into SPs are a logical approach to AD therapy. There are 20 criteria of validity for an SP causal entity that are satisfied by spherons-and no more than a few of these 20 criteria are satisfied by any other known hypothesis. These criteria of validity are reviewed, in addition to common difficulties in understanding spheron theory and a number of common-sense considerations in AD therapeutic research. Spheron-based drug therapy in AD potentially can retard the process of spheron bursting and subsequent plaque formation by: 1) blocking the formation of SPs; 2) reducing the size of SPs; 3) delaying spheron breakdown; and 4) retarding spheron growth. Isolated spherons from human brain are intact human drug targets and can be used as human in vitro or in vivo screening targets. The paramount importance of spherons as a target for drug therapy in AD is emphasized by considering that regardless of any other type of real or potential therapy, there still already exists in every middle-aged adult a full population of spherons in the brain, filled with more than enough amyloid to bring about full-blown AD.

  10. Melatonin in Alzheimer's disease and other neurodegenerative disorders

    OpenAIRE

    Poeggeler B; Cardinali DP; Pandi-Perumal SR; Srinivasan V; Hardeland R

    2006-01-01

    Abstract Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as...

  11. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre.

    Science.gov (United States)

    Toledo, Jon B; Arnold, Steven E; Raible, Kevin; Brettschneider, Johannes; Xie, Sharon X; Grossman, Murray; Monsell, Sarah E; Kukull, Walter A; Trojanowski, John Q

    2013-09-01

    Cerebrovascular disease and vascular risk factors are associated with Alzheimer's disease, but the evidence for their association with other neurodegenerative disorders is limited. Therefore, we compared the prevalence of cerebrovascular disease, vascular pathology and vascular risk factors in a wide range of neurodegenerative diseases and correlate them with dementia severity. Presence of cerebrovascular disease, vascular pathology and vascular risk factors was studied in 5715 cases of the National Alzheimer's Coordinating Centre database with a single neurodegenerative disease diagnosis (Alzheimer's disease, frontotemporal lobar degeneration due to tau, and TAR DNA-binding protein 43 immunoreactive deposits, α-synucleinopathies, hippocampal sclerosis and prion disease) based on a neuropathological examination with or without cerebrovascular disease, defined neuropathologically. In addition, 210 'unremarkable brain' cases without cognitive impairment, and 280 cases with pure cerebrovascular disease were included for comparison. Cases with cerebrovascular disease were older than those without cerebrovascular disease in all the groups except for those with hippocampal sclerosis. After controlling for age and gender as fixed effects and centre as a random effect, we observed that α-synucleinopathies, frontotemporal lobar degeneration due to tau and TAR DNA-binding protein 43, and prion disease showed a lower prevalence of coincident cerebrovascular disease than patients with Alzheimer's disease, and this was more significant in younger subjects. When cerebrovascular disease was also present, patients with Alzheimer's disease and patients with α-synucleinopathy showed relatively lower burdens of their respective lesions than those without cerebrovascular disease in the context of comparable severity of dementia at time of death. Concurrent cerebrovascular disease is a common neuropathological finding in aged subjects with dementia, is more common in Alzheimer

  12. Intracerebral GM-CSF contributes to transendothelial monocyte migration in APP/PS1 Alzheimer's disease mice.

    Science.gov (United States)

    Shang, De S; Yang, Yi M; Zhang, Hu; Tian, Li; Jiang, Jiu S; Dong, Yan B; Zhang, Ke; Li, Bo; Zhao, Wei D; Fang, Wen G; Chen, Yu H

    2016-11-01

    Although tight junctions between human brain microvascular endothelial cells in the blood-brain barrier prevent molecules or cells in the bloodstream from entering the brain, in Alzheimer's disease, peripheral blood monocytes can "open" these tight junctions and trigger subsequent transendothelial migration. However, the mechanism underlying this migration is unclear. Here, we found that the CSF2RB, but not CSF2RA, subunit of the granulocyte-macrophage colony-stimulating factor receptor was overexpressed on monocytes from Alzheimer's disease patients. CSF2RB contributes to granulocyte-macrophage colony-stimulating factor-induced transendothelial monocyte migration. Granulocyte-macrophage colony-stimulating factor triggers human brain microvascular endothelial cells monolayer tight junction disassembly by downregulating ZO-1 expression via transcription modulation and claudin-5 expression via the ubiquitination pathway. Interestingly, intracerebral granulocyte-macrophage colony-stimulating factor blockade abolished the increased monocyte infiltration in the brains of APP/PS1 Alzheimer's disease model mice. Our results suggest that in Alzheimer's disease patients, high granulocyte-macrophage colony-stimulating factor levels in the brain parenchyma and cerebrospinal fluid induced blood-brain barrier opening, facilitating the infiltration of CSF2RB-expressing peripheral monocytes across blood-brain barrier and into the brain. CSF2RB might be useful as an Alzheimer's disease biomarker. Thus, our findings will help to understand the mechanism of monocyte infiltration in Alzheimer's disease pathogenesis.

  13. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease.

    Science.gov (United States)

    Ossenkoppele, Rik; Schonhaut, Daniel R; Schöll, Michael; Lockhart, Samuel N; Ayakta, Nagehan; Baker, Suzanne L; O'Neil, James P; Janabi, Mustafa; Lazaris, Andreas; Cantwell, Averill; Vogel, Jacob; Santos, Miguel; Miller, Zachary A; Bettcher, Brianne M; Vossel, Keith A; Kramer, Joel H; Gorno-Tempini, Maria L; Miller, Bruce L; Jagust, William J; Rabinovici, Gil D

    2016-05-01

    SEE SARAZIN ET AL DOI101093/BRAIN/AWW041 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The advent of the positron emission tomography tracer (18)F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-β pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-β-negative cognitively normal individuals, who underwent (18)F-AV1451 (tau), (11)C-PiB (amyloid-β) and (18)F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P Alzheimer's disease', n = 7) specifically targeted the clinically affected posterior brain regions, while (11)C-PiB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation (n = 5) showed highest (18)F-AV1451 retention in medial temporal and lateral temporoparietal regions. Patients with logopenic variant primary progressive aphasia ('language variant of Alzheimer's disease', n = 5) demonstrated asymmetric left greater than right hemisphere (18)F-AV1451 uptake in three of five patients. Across 30 FreeSurfer-defined regions of interest in 16 Alzheimer's disease patients with all three positron emission tomography scans available, there was a strong negative association between (18)F-AV1451 and (18)F-FDG uptake (Pearson's r = -0.49 ± 0.07, P right temporoparietal cortex). In conclusion, tau imaging-contrary to amyloid-β imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are

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

    Science.gov (United States)

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

    2015-02-01

    labelling. In addition, valproic acid worked synergistically with Mg132 in elevating ubiquitin load and causing cell death. These findings highlight important pathological relationships linking a compromise in protein turnover with the histone changes observed in Alzheimer's disease post-mortem human brain.

  15. Generic and disease-specific measures of quality of life in patients with mild Alzheimer's disease

    DEFF Research Database (Denmark)

    Bhattacharya, Sumangala; Vogel, A.; Hansen, M.L.;

    2010-01-01

    The aim of the study was to investigate the pattern of association of generic and disease-specific quality of life (QoL) scales with standard clinical outcome variables in Alzheimer's disease (AD).......The aim of the study was to investigate the pattern of association of generic and disease-specific quality of life (QoL) scales with standard clinical outcome variables in Alzheimer's disease (AD)....

  16. Alzheimer's Project

    Medline Plus

    Full Text Available ... disease has on those with Alzheimer's and their families. September 14, 2009 "The Alzheimer's Project" wins two ... way Americans thinks about Alzheimer's disease. Tell your family and friends. Post info on your Web site . ...

  17. Alzheimer's Treatment

    Science.gov (United States)

    ... of this page please turn JavaScript on. Feature: Alzheimer's Disease Alzheimer's Treatment Past Issues / Winter 2015 Table of Contents Currently, there is no cure for Alzheimer's. Because it is a complex disease, scientists believe ...

  18. Neuropeptides in Alzheimer's Disease : From Pathophysiological Mechanisms to Therapeutic Opportunities

    NARCIS (Netherlands)

    Van Dam, Debby; Van Dijck, Annemie; Janssen, Leen; De Deyn, Peter Paul

    2013-01-01

    Neuropeptides are found throughout the entire nervous system where they can act as neurotransmitter, neuromodulator or neurohormone. In those functions, they play important roles in the regulation of cognition and behavior. In brain disorders like Alzheimer's disease (AD), where abnormal cognition a

  19. Exercise, cognition and Alzheimer's disease : More is not necessarily better

    NARCIS (Netherlands)

    Eggermont, L; Swaab, D; Luiten, P; Scherder, E

    2006-01-01

    Regional hypoperfusion, associated with a reduction in cerebral metabolism, is a hallmark of Alzheimer's disease (AD) and contributes to cognitive decline. Cerebral perfusion and hence cognition can be enhanced by exercise. The present review describes first how the effects of exercise on cerebral p

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

    DEFF Research Database (Denmark)

    Nilsson, Tatjana; Bogdanovic, Nenad; Volkman, Inga

    2006-01-01

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

  1. Awareness of deficits in mild cognitive impairment and Alzheimer's disease

    DEFF Research Database (Denmark)

    Vogel, Asmus; Stokholm, Jette; Gade, Anders

    2004-01-01

    In this study we investigated impaired awareness of cognitive deficits in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Very few studies have addressed this topic, and methodological inconsistencies make the comparison of previous studies difficult. From a prospective...

  2. Music Enhances Autobiographical Memory in Mild Alzheimer's Disease

    Science.gov (United States)

    El Haj, Mohamad; Postal, Virginie; Allain, Philippe

    2012-01-01

    Studies have shown that the "Four Seasons" music may enhance the autobiographical performance of Alzheimer's disease (AD) patients. We used a repeated measures design in which autobiographical recall of 12 mild AD patients was assessed using a free narrative method under three conditions: (a) in "Silence," (b) after being exposed to the opus "Four…

  3. Autonomic Dysfunction in Patients with Mild to Moderate Alzheimer's Disease

    DEFF Research Database (Denmark)

    Jensen-Dahm, Christina; Waldemar, Gunhild; Staehelin Jensen, Troels

    2015-01-01

    BACKGROUND: Autonomic function has received little attention in Alzheimer's disease (AD). AD pathology has an impact on brain regions which are important for central autonomic control, but it is unclear if AD is associated with disturbance of autonomic function. OBJECTIVE: To investigate autonomic...

  4. Semantic memory impairment in the earliest phases of Alzheimer's disease

    DEFF Research Database (Denmark)

    Vogel, Asmus; Gade, Anders; Stokholm, Jette

    2005-01-01

    The presence and the nature of semantic memory dysfunction in Alzheimer's disease (AD) have been widely debated. This study aimed to determine the frequency of impaired semantic test performances in mild AD and to study whether incipient semantic impairments could be identified in predementia AD...

  5. Nicotinic Acetylcholine Receptors in the Pathophysiology of Alzheimer's Disease

    DEFF Research Database (Denmark)

    Thomsen, Morten Skøtt; Andreasen T., Jesper; Arvaniti, Maria

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) have been pursued for decades as potential molecular targets to treat cognitive dysfunction in Alzheimer's disease (AD) due to their positioning within regions of the brain critical in learning and memory, such as the prefrontal cortex and hippocampus...

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

    NARCIS (Netherlands)

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

    2013-01-01

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

  7. Neural activities during affective processing in people with Alzheimer's disease

    NARCIS (Netherlands)

    Lee, Tatia M. C.; Sun, Delin; Leung, Mei-Kei; Chu, Leung-Wing; Keysers, Christian

    2013-01-01

    This study examined brain activities in people with Alzheimer's disease when viewing happy, sad, and fearful facial expressions of others. A functional magnetic resonance imaging and a voxel-based morphometry methodology together with a passive viewing of emotional faces paradigm were employed to co

  8. Knowledge of Natural Kinds in Semantic Dementia and Alzheimer's Disease

    Science.gov (United States)

    Cross, Katy; Smith, Edward E.; Grossman, Murray

    2008-01-01

    We examined the semantic impairment for natural kinds in patients with probable Alzheimer's disease (AD) and semantic dementia (SD) using an inductive reasoning paradigm. To learn about the relationships between natural kind exemplars and how these are distinguished from manufactured artifacts, subjects judged the strength of arguments such as…

  9. Taking Control of Alzheimer's Disease: A Training Evaluation

    Science.gov (United States)

    Silverstein, Nina M.; Sherman, Robin

    2010-01-01

    The purpose of the current study was to evaluate a training program for persons with early-stage Alzheimer's disease and their care partners. Care partners were mailed two surveys, one for themselves and one for the person with dementia. Domains covered in the training included an overview of cognitive disorders, treatment of symptoms including…

  10. Financial Conflicts Facing Late-Life Remarried Alzheimer's Disease Caregivers

    Science.gov (United States)

    Sherman, Carey Wexler; Bauer, Jean W.

    2008-01-01

    This qualitative study explores financial conflicts faced by late-life remarried wives providing care for their husbands with Alzheimer's disease. Interviews with 9 women identified intergenerational secrets and tensions regarding financial and inheritance decisions. Participants' remarried spouse status, underlying family boundary ambiguities,…

  11. Relationship between Helicobacter pylori infection and Alzheimer disease.

    Science.gov (United States)

    Kountouras, J; Tsolaki, M; Gavalas, E; Boziki, M; Zavos, C; Karatzoglou, P; Chatzopoulos, D; Venizelos, I

    2006-03-28

    The authors investigated the association between Helicobacter pylori infection (Hp-I) and Alzheimer disease (AD) by using histology for diagnosis of Hp-I. Fifty patients with AD and 30 iron deficiency anemic control participants without AD were included. The histologic prevalence of Hp-I was 88% in patients with AD and 46.7% in controls (p < 0.001).

  12. Advances in the prevention of Alzheimer's disease and dementia

    NARCIS (Netherlands)

    Solomon, A.; Mangialasche, F.; Richard, E.; Andrieu, S.; Bennett, D.A.; Breteler, M.; Fratiglioni, L.; Hooshmand, B.; Khachaturian, A.S.; Schneider, L.S.; Skoog, I.; Kivipelto, M.

    2014-01-01

    BACKGROUND: Definitions and diagnostic criteria for all medical conditions are regularly subjected to reviews and revisions as knowledge advances. In the field of Alzheimer's disease (AD) research, it has taken almost three decades for diagnostic nomenclature to undergo major re-examination. The shi

  13. The impact of Alzheimer's disease on the chinese economy

    DEFF Research Database (Denmark)

    Keogh-Brown, Marcus R; Jensen, Henning Tarp; Arrighi, H Michael;

    2016-01-01

    BACKGROUND: Recent increases in life expectancy may greatly expand future Alzheimer's Disease (AD) burdens. China's demographic profile, aging workforce and predicted increasing burden of AD-related care make its economy vulnerable to AD impacts. Previous economic estimates of AD predominantly...

  14. Are Alzheimer's disease, hypertension, and cerebrocapillary damage related?

    NARCIS (Netherlands)

    Farkas, E; De Vos, RAI; Steur, ENHJ; Luiten, PGM

    2000-01-01

    Alzheimer's disease (AD) patients are often subject to vascular dysfunction besides their specific CNS pathology, which warrants further examination of the interaction between vascular factors and the development of dementia. The association of decreased cerebral blood flow (CBF) or hypertension wit

  15. The Effect of Alzheimer's Disease and Aging on Conceptual Combination

    Science.gov (United States)

    Taler, Vanessa; Chertkow, Howard; Saumier, Daniel

    2005-01-01

    Alzheimer's disease (AD) subjects, healthy elderly, and young adults interpreted a series of novel noun-noun expressions composed of familiar object words. Subjects interpreted each item by selecting one of three possible definitions: a definition in which the referents of each noun were associated together in a particular context (e.g., rabbit…

  16. Cardiovascular risk factors and future risk of Alzheimer's disease

    NARCIS (Netherlands)

    R.F.A.G. de Bruijn (Renée); M.A. Ikram (Arfan)

    2014-01-01

    textabstractAlzheimer's disease (AD) is the most common neurodegenerative disorder in elderly people, but there are still no curative options. Senile plaques and neurofibrillary tangles are considered hallmarks of AD, but cerebrovascular pathology is also common. In this review, we summarize finding

  17. Voice Onset Time Production in Speakers with Alzheimer's Disease

    Science.gov (United States)

    Baker, Julie; Ryalls, Jack; Brice, Alejandro; Whiteside, Janet

    2007-01-01

    In the present study, voice onset time (VOT) measurements were compared between a group of individuals with moderate Alzheimer's disease (AD) and a group of healthy age- and gender-matched peers. Participants read a list of consonant-vowel-consonant (CVC) words, which included the six stop consonants. The VOT measurements were made from…

  18. Semantic Priming for Coordinate Distant Concepts in Alzheimer's Disease Patients

    Science.gov (United States)

    Perri, R.; Zannino, G. D.; Caltagirone, C.; Carlesimo, G. A.

    2011-01-01

    Semantic priming paradigms have been used to investigate semantic knowledge in patients with Alzheimer's disease (AD). While priming effects produced by prime-target pairs with associative relatedness reflect processes at both lexical and semantic levels, priming effects produced by words that are semantically related but not associated should…

  19. Retrograde amnesia for semantic information in Alzheimer's disease

    NARCIS (Netherlands)

    Meeter, M.; Kollen, A.; Scheltens, P.

    2005-01-01

    Patients with mild to moderate Alzheimer's disease and normal controls were tested on a retrograde amnesia test with semantic content (Neologism and Vocabulary Test, or NVT), consisting of neologisms to be defined. Patients showed a decrement as compared to normal controls, pointing to retrograde am

  20. Caffeine and coffee as therapeutics against Alzheimer's disease.

    Science.gov (United States)

    Arendash, Gary W; Cao, Chuanhai

    2010-01-01

    Epidemiologic studies have increasingly suggested that caffeine/coffee could be an effective therapeutic against Alzheimer's disease (AD). We have utilized a transgenic mouse model for AD in well-controlled studies to determine if caffeine and/or coffee have beneficial actions to protect against or reverse AD-like cognitive impairment and AD pathology. AD mice given caffeine in their drinking water from young adulthood into older age showed protection against memory impairment and lower brain levels of the abnormal protein (amyloid-beta; Abeta) thought to be central to AD pathogenesis. Moreover, "aged" cognitively-impaired AD mice exhibited memory restoration and lower brain Abeta levels following only 1-2 months of caffeine treatment. We believe that the cognitive benefits of chronic caffeine administration in AD mice are due to caffeine itself, and not metabolites of caffeine; this, because our long-term administration of theophylline to AD mice provided no cognitive benefits. In acute studies involving AD mice, one oral caffeine treatment quickly reduced both brain and plasma Abeta levels - similarly rapid alterations in plasma Abeta levels were seen in humans following acute caffeine administration. "Caffeinated" coffee provided to AD mice also quickly decreased plasma Abeta levels, but not "decaffeinated" coffee, suggesting that caffeine is critical to decreasing blood Abeta levels. Caffeine appears to provide its disease-modifying effects through multiple mechanisms, including a direct reduction of Abeta production through suppression of both beta- and gamma-secretase levels. These results indicate a surprising ability of moderate caffeine intake (the human equivalent of 500 mg caffeine or 5 cups of coffee per day) to protect against or treat AD in a mouse model for the disease and a therapeutic potential for caffeine against AD in humans.

  1. Feasibility of an early Alzheimer's disease immunosignature diagnostic test.

    Science.gov (United States)

    Restrepo, Lucas; Stafford, Phillip; Johnston, Stephen Albert

    2013-01-15

    A practical diagnostic test is needed for early Alzheimer's disease (AD) detection. Immunosignaturing, a technology that employs antibody binding to a random-sequence peptide microarray, generates profiles that distinguish transgenic mice engineered with familial AD mutations (APPswe/PSEN1-dE9) from non-transgenic littermates. It can also detect an AD-like signature in humans. Here, we assess the changes in the immunosignature at different time points of the disease in mice and humans. We also evaluate the accuracy of the late-stage signature as a test to discriminate between young mice with familial AD mutations from non-transgenic littermates. Plasma samples from AD patients were assayed 3-12 months apart, while APPswe/PSEN1-dE9 and non-transgenic controls supplied plasma at monthly intervals until they reached 15 months of age. Microarrays with 10,000 random-sequence peptides were used to compare antibody binding patterns. These patterns gradually changed over the life-span of mice. Strong, characteristic signatures were observed in transgenic mice at early, mid and late stages, but these profiles had minimal overlap. The signature of young transgenic mice had an error rate of 18% at classifying plasma samples from late-stage transgenic mice. Conversely, the late-stage transgenic mice signature discriminated between young transgenic mice and littermates with an error rate of 21%. Less distinctive profiles were recognizable throughout the transgenic mice lifespan, being detectable as early as 2 months. The human signature had minimal change on short-term follow-up. Our results call for a reappraisal of the way incipient AD is studied, as biomarkers seen in late-stages of the disease may not be relevant in earlier stages.

  2. Biological metals and Alzheimer's disease: implications for therapeutics and diagnostics.

    Science.gov (United States)

    Duce, James A; Bush, Ashley I

    2010-09-01

    The equilibrium of metal ions is critical for many physiological functions, particularly in the central nervous system, where metals are essential for development and maintenance of enzymatic activities, mitochondrial function, myelination, neurotransmission as well as learning and memory. Due to their importance, cells have evolved complex machinery for controlling metal-ion homeostasis. However, disruption of these mechanisms, or absorption of detrimental metals with no known biological function, alter the ionic balance and can result in a disease state, including several neurodegenerative disorders such as Alzheimer's disease. Understanding the complex structural and functional interactions of metal ions with the various intracellular and extracellular components of the central nervous system, under normal conditions and during neurodegeneration, is essential for the development of effective therapies. Accordingly, assisting the balance of metal ions back to homeostatic levels has been proposed as a disease-modifying therapeutic strategy for Alzheimer's disease as well as other neurodegenerative diseases.

  3. Influence of age on androgen deprivation therapy-associated Alzheimer's disease.

    Science.gov (United States)

    Nead, Kevin T; Gaskin, Greg; Chester, Cariad; Swisher-McClure, Samuel; Dudley, Joel T; Leeper, Nicholas J; Shah, Nigam H

    2016-10-18

    We recently found an association between androgen deprivation therapy (ADT) and Alzheimer's disease. As Alzheimer's disease is a disease of advanced age, we hypothesize that older individuals on ADT may be at greatest risk. We conducted a retrospective multi-institutional analysis among 16,888 individuals with prostate cancer using an informatics approach. We tested the effect of ADT on Alzheimer's disease using Kaplan-Meier age stratified analyses in a propensity score matched cohort. We found a lower cumulative probability of remaining Alzheimer's disease-free between non-ADT users age ≥70 versus those age Alzheimer's disease was 2.9%, 1.9% and 0.5% among ADT users ≥70, non-ADT users ≥70 and individuals Alzheimer's disease risk. Future work should investigate the ADT Alzheimer's disease association in advanced age populations given the greater potential clinical impact.

  4. Alteration in nicotine binding sites in Parkinson's disease, Lewy body dementia and Alzheimer's disease: possible index of early neuropathology.

    Science.gov (United States)

    Perry, E K; Morris, C M; Court, J A; Cheng, A; Fairbairn, A F; McKeith, I G; Irving, D; Brown, A; Perry, R H

    1995-01-01

    High-affinity nicotine binding, considered to primarily reflect the presence of CNS alpha 4 beta 2 nicotinic receptor subunits, was examined autoradiographically in brain regions most severely affected by Alzheimer and Parkinson types of pathology. In the midbrain, the high density of binding associated with the pars compacta of the substantia nigra was extensively reduced (65-75%, particularly in the lateral portion) in both Lewy body dementia and Parkinson's disease. Since loss of dopaminergic neurons in Lewy body dementia was only moderate (40%), loss or down-regulation of the nicotinic receptor may precede degeneration of dopaminergic neurons in this region. In the dorsolateral tegmentum, where diffuse cholinergic perikarya are located, nicotine binding was highly significantly decreased in both Lewy body dementia and Parkinson's disease with almost no overlap between the normal and disease groups, indicative of a major pathological involvement in or around the pedunculopontine cholinergic neurons. In the hippocampus, binding was decreased around the granular layer in Lewy body dementia and Alzheimer's disease, although unchanged in the stratum lacunosum moleculare, where binding was relatively higher. Dense bands of receptor binding in the presubiculum and parahippocampal gyrus--areas of highest binding in human cortex--were diminished in Alzheimer's disease but not Lewy body dementia. In temporal neocortex there were reductions in Alzheimer's disease throughout the cortical layers but in Lewy body dementia only in lower layers, in which Lewy bodies are concentrated. Abnormalities of the nicotinic receptor in the diseases examined appear to be closely associated with primary histopathological changes: dopaminergic cell loss in Parkinson's disease and Lewy body dementia, amyloid plaques and tangles in subicular and entorhinal areas in Alzheimer's disease. Loss or down-regulation of the receptor may precede neurodegeneration.

  5. Systematic review of atorvastatin for the treatment of Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Yuan Sun; Genfa Wang; Zhihong Pan; Shuyan Chen

    2012-01-01

    OBJECTIVE: To assess the clinical efficacy and safety of atorvastatin in the treatment of Alz-heimer's disease.DATA SOURCES: Medline (1948/2011-04), Embase (1966/2011-04), Cochrane Library (Issue 3, 2011), Chinese National Knowledge Infrastructure (1989/2011-04), and the Chinese Biomedical Literature Database (1979/2011-04) were searched for randomized clinical trials regardless of lan-guage. Abstracts of conference papers were manually searched. Furthermore, Current Controlled Trials (http://controlled-trials.com), Clinical Trials.gov (http://clinicaltrials.gov), and Chinese Clinical Trial Registry (http://www.chictr.org) were also searched.Key words included Alzheimer disease, dementia, cognition, affection, memory dysfunction, hydroxymethylglutaryl-CoA reductase inhibitors, atorvastatin and statins.DATA SELECTION: Randomized controlled trials of grade A or B according to quality evaluation criteria of the Cochrane Collaboration were selected, in which atorvastatin and placebo were used to evaluate the effects of atorvastatin in the treatment of Alzheimer's disease. Study methodological quality was evaluated based on criteria described in Cochrane Reviewer's Handbook 5.0.1. Revman 5.1 software was used for data analysis.MAIN OUTCOME MEASURES: Clinical efficacy, safety, withdrawal from the studies, and withdrawal due to adverse effects.CONCLUSION: There is insufficient evidence to recommend atorvastatin for the treatment of mild to moderate Alzheimer's disease, because there was no benefit on general function, cognitive function or mental/behavior abnormality outcome measures. Efficacy and safety need to be confirmed by larger and higher quality randomized controlled trials, especially for moderate to severe Alzheimer's disease, because results of this systematic review may be limited by selection bias, implementation bias, as well as measurement bias.

  6. Translocator protein (TSPO) role in aging and Alzheimer's disease.

    Science.gov (United States)

    Repalli, Jayanthi

    2014-01-01

    Cellular damage and deregulated apoptotic cell death lead to functional impairment, and a main consequence of these events is aging. Cellular damage is initiated by different stress/risk factors such as oxidative stress, inflammation, and heavy metals. These stress/risk factors affect the cellular homeostasis by altering methylation status of several aging and Alzheimer's disease associated genes; these effects can be manifested immediately after exposure to stress and at later stages of life. However, when cellular damage exceeds certain threshold levels apoptosis is initiated. This review discusses the stress factors involved in cellular damage and the role and potential of TSPO-mediated cell death in aging as well as in Alzheimer's disease, which is also characterized by extensive cell death. Mitochondrial-mediated apoptotic death through the release of cytochrome c is regulated by TSPO, and increased expression of this protein is observed in both elderly people and in patients with Alzheimer's disease. TSPO forms and mediates opening of the mitochondrial membrane pore, mPTP and oxidizes cardiolipin, and these events lead to the leakage of apoptotic death mediators, such as cytochrome c, resulting in cell death. However, TSPO has many proposed functions and can also increase steroid synthesis, which leads to inhibition of inflammation and inhibition of the release of apoptotic factors, thereby decreasing cell damage and promoting cell survival. Thus, TSPO mediates apoptosis and decreases the cell damage, which in turn dictates the process of aging as well as the functionality of organs such as the brain. TSPO modulation with ligands in the Alzheimer's disease mouse model showed improvement in behavioral symptoms, and studies in Drosophila species showed increased cell survival and prolonged lifespan in flies after TSPO inhibition. These data suggest that since effects/signs of stress can manifest at any time, prevention through change in lifestyle and TSPO

  7. Neuroprotective Effect against Alzheimer's Disease of Porcine Brain Extract

    Directory of Open Access Journals (Sweden)

    Wipawee Thukham-Mee

    2012-01-01

    Full Text Available Problem statement: Despite the increasing importance of Alzheimer’s disease, no effective therapeutic strategy is available. Therefore, neuroprotective strategy is still required. Recent findings show that numerous substances possessing antioxidant can improve neurodegeneration and memory impairment. Based on the antioxidant effect and its reputation to serve as brain tonic in traditional folklore, we hypothesized that porcine brain extract could mitigate neurodegeneration and memory impairment. Therefore, this study was set up to determine the effect of porcine brain extract on memory impairment and neurodegeneration in animal models of Alzheimer’s disease. Approach: Male Wistar rats (180-220 g had been orally given porcine brain extract at doses of 0.5 and 2.5 mg kg-1 BW for a period of 4 weeks before and 1 week after the induction of cognitive deficit condition as those found in early phase of Alzheimer’s disease via the intraventricular injection of AF64A, a cholinotoxin. Rats were assessed the spatial memory using Morris water maze test. Then, they were determined neuron density in hippocampus using histological techniques. Moreover, the assessment of acetylcholinesterase (AChE activity and malondialdehyde (MDA level in hippocampus were also performed. Results: It was found that both doses of porcine brain extract could enhance memory, neuron and cholinergic neuron density in all subregions of hippocampus. In addition, the decreased AChE and MDA were also observed. Therefore, our results suggested that the possible underlying mechanism of the extract might occur partly via the decrease in oxidative stress marker, MDA and AChE. Conclusion: This study clearly demonstrates that porcine brain extract can protect against memory impairment and neurodegeneration in animal model of Alzheimer’s disease. Therefore, it should be serve as the potential food supplement or adjuvant therapy against Alzheimer’s disease and other age-related cognitive

  8. The draft "National Plan" to address Alzheimer's disease - National Alzheimer's Project Act (NAPA).

    Science.gov (United States)

    Khachaturian, Zaven S; Khachaturian, Ara S; Thies, William

    2012-05-01

    This perspective updates the status of the "National Plan to Address Alzheimer's Disease" and the recommendations of the NAPA Advisory Council's Sub-committee on Research. Here, we identify some of the critical issues the future reiterations of the National Plan should consider during implementation phase of the plan. The Journal invites the scientific community to contribute additional ideas and suggestions towards a national research initiative.

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

    Science.gov (United States)

    Murphy, Matthew C; Jones, David T; Jack, Clifford R; Glaser, Kevin J; Senjem, Matthew L; Manduca, Armando; Felmlee, Joel P; Carter, Rickey E; Ehman, Richard L; Huston, John

    2016-01-01

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

  10. The pathological interaction between diabetes and presymptomatic Alzheimer's disease.

    Science.gov (United States)

    Burdo, Joseph R; Chen, Qi; Calcutt, Nigel A; Schubert, David

    2009-12-01

    Since diabetes is a risk factor for Alzheimer's disease (AD), we asked if there is a functional interaction between high glucose and elevated beta amyloid peptide (Abeta) in cultured brain microvascular endothelial cells and presymptomatic AD transgenic mice. When cultured brain microvascular endothelial cells are exposed to both high glucose and low levels of Abeta, there is a synergistic interaction to cause an increased accumulation of advanced glycation products (AGE) and reactive oxygen species (ROS). When presymptomatic mice expressing mutant human amyloid precursor protein and presenilin are made diabetic, they have a decrease in cognitive function relative to control mice. Associated with the cognitive deficit are increases in brain microvascular AGE and iNOS expression, and the loss of the synaptic spine protein drebrin. No amyloid plaques or tangles are observed within the brains of any group. These data show that diabetes causes a synergistic potentiation of some indices of AD in transgenic animals that are presymptomatic for the classical features of the disease.

  11. Ryanodine receptors: physiological function and deregulation in Alzheimer disease.

    Science.gov (United States)

    Del Prete, Dolores; Checler, Frédéric; Chami, Mounia

    2014-06-05

    Perturbed Endoplasmic Reticulum (ER) calcium (Ca2+) homeostasis emerges as a central player in Alzheimer disease (AD). Accordingly, different studies have reported alterations of the expression and the function of Ryanodine Receptors (RyR) in human AD-affected brains, in cells expressing familial AD-linked mutations on the β amyloid precursor protein (βAPP) and presenilins (the catalytic core in γ-secretase complexes cleaving the βAPP, thereby generating amyloid β (Aβ) peptides), as well as in the brain of various transgenic AD mice models. Data converge to suggest that RyR expression and function alteration are associated to AD pathogenesis through the control of: i) βAPP processing and Aβ peptide production, ii) neuronal death; iii) synaptic function; and iv) memory and learning abilities. In this review, we document the network of evidences suggesting that RyR could play a complex dual "compensatory/protective versus pathogenic" role contributing to the setting of histopathological lesions and synaptic deficits that are associated with the disease stages. We also discuss the possible mechanisms underlying RyR expression and function alterations in AD. Finally, we review recent publications showing that drug-targeting blockade of RyR and genetic manipulation of RyR reduces Aβ production, stabilizes synaptic transmission, and prevents learning and memory deficits in various AD mouse models. Chemically-designed RyR "modulators" could therefore be envisioned as new therapeutic compounds able to delay or block the progression of AD.

  12. The link between iron, metabolic syndrome, and Alzheimer's disease.

    Science.gov (United States)

    Grünblatt, Edna; Bartl, Jasmin; Riederer, Peter

    2011-03-01

    Both Alzheimer's disease (AD), the most common form of dementia, and type-2 diabetes mellitus (T2DM), a disease associated with metabolic syndrome (MetS), affect a great number of the world population and both have increased prevalence with age. Recently, many studies demonstrated that pre-diabetes, MetS, and T2DM are risk factors in the development of AD and have many common mechanisms. The main focus of studies is the insulin resistance outcome found both in MetS as well as in brains of AD subjects. However, oxidative stress (OS)-related mechanisms, which are well known to be involved in AD, including mitochondrial dysfunction, elevated iron concentration, reactive oxygen species (ROS), and stress-related enzyme or proteins (e.g. heme oxygenase-1, transferrin, etc.), have not been elucidated in MetS or T2DM brains although OS and iron are involved in the degeneration of the pancreatic islet β cells. Therefore, this review sets to cover the current literature regarding OS and iron in MetS and T2DM and the similarities to mechanisms in AD both in human subjects as well as in animal models.

  13. Neurosteroid biosynthetic pathways changes in prefrontal cortex in Alzheimer's disease.

    Science.gov (United States)

    Luchetti, Sabina; Bossers, Koen; Van de Bilt, Saskia; Agrapart, Vincent; Morales, Rafael Ramirez; Frajese, Giovanni Vanni; Swaab, Dick F

    2011-11-01

    Expression of the genes for enzymes involved in neurosteroid biosynthesis was studied in human prefrontal cortex (PFC) in the course of Alzheimer's disease (AD) (n=49). Quantitative RT-PCR (qPCR) revealed that mRNA levels of diazepam binding inhibitor (DBI), which is involved in the first step of steroidogenesis and in GABAergic transmission, were increased, as were mRNA levels for several neurosteroid biosynthetic enzymes. Aromatase, 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1) and aldo-keto reductase 1C2 (AKR1C2), were all increased in the late stages of AD. Several GABA-A subunits were significantly reduced in AD. Increased expression of aromatase in the PFC was confirmed by immunohistochemistry and was found to be localized predominantly in astrocytes. These data suggest a role for estrogens and allopregnanolone produced by astrocytes in the PFC in AD, possibly as part of a rescue program. The reduced gene expression of some synaptic and extra-synaptic GABA-A subunits may indicate a deficit of modulation of GABA-A receptors by neuroactive steroids, which may contribute to the neuropsychiatric characteristics of this disease.

  14. Can oral infection be a risk factor for Alzheimer's disease?

    Directory of Open Access Journals (Sweden)

    Ingar Olsen

    2015-09-01

    Full Text Available Alzheimer's disease (AD is a scourge of longevity that will drain enormous resources from public health budgets in the future. Currently, there is no diagnostic biomarker and/or treatment for this most common form of dementia in humans. AD can be of early familial-onset or sporadic with a late-onset. Apart from the two main hallmarks, amyloid-beta and neurofibrillary tangles, inflammation is a characteristic feature of AD neuropathology. Inflammation may be caused by a local central nervous system insult and/or by peripheral infections. Numerous microorganisms are suspected in AD brains ranging from bacteria (mainly oral and non-oral Treponema species, viruses (herpes simplex type I, and yeasts (Candida species. A causal relationship between periodontal pathogens and non-oral Treponema species of bacteria has been proposed via the amyloid-beta and inflammatory links. Periodontitis constitutes a peripheral oral infection that can provide the brain with intact bacteria and virulence factors and inflammatory mediators due to daily, transient bacteremias. If and when genetic risk factors meet environmental risk factors in the brain, disease is expressed, in which neurocognition may be impacted, leading to the development of dementia. To achieve the goal of finding a diagnostic biomarker and possible prophylactic treatment for AD, there is an initial need to solve the etiological puzzle contributing to its pathogenesis. This review therefore addresses oral infection as the plausible etiology of late-onset AD (LOAD.

  15. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders.

    Science.gov (United States)

    Jucker, Mathias; Walker, Lary C

    2011-10-01

    The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism-corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prionlike induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson/Lewy body disease, Huntington disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations

  16. Botanics: a potential source of new therapies for Alzheimer's disease?

    Directory of Open Access Journals (Sweden)

    Syad AN

    2014-04-01

    Full Text Available Arif Nisha Syad, Kasi Pandima Devi Department of Biotechnology, Alagappa University, Karaikudi, Tamil Nadu, India Abstract: Alzheimer's disease is an age-related, complex neurodegenerative disorder characterized by loss of memory and impairment of multiple cognitive functions. Several factors contribute to the progression and development of the disease including amyloid beta accumulation, neurofibrillary tangle formation, cholinergic deficit, oxidative stress, neuroinflammation, and apoptosis. Numerous traditional and herbal medicinal plants have been used to treat several cognitive disorders including Alzheimer's disease. They act as excellent antioxidants, anti-inflammatory mediators, and cholinesterase and β-secretase inhibitors. In addition, these natural compounds also prevent the accumulation of amyloid beta and its fibril formation. Besides acting as core-molecules, these natural compounds act as a template for the production and synthesis of several drug leads with improved pharmacokinetic potentials and greater efficacies. Hence, herbal medicines that have interesting pharmacological effects with noticeable anti-Alzheimer's potential deserve increased attention for further development to drug entities. The present article reviews the botanical pharmacology with special reference to anti-Alzheimer activity of plants and plant-derived compounds. Keywords: neurodegeneration, medicinal plants, antioxidants, Aβ peptide, neuroprotective, clinical trials

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

    Directory of Open Access Journals (Sweden)

    Jin Wu

    2010-01-01

    Full Text Available 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.

  18. A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Qi Chen

    Full Text Available Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD, the focus is the amyloid beta peptide (Aß that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.

  19. Non-invasive therapy to reduce the body burden of aluminium in Alzheimer's disease.

    Science.gov (United States)

    Exley, Christopher; Korchazhkina, Olga; Job, Deborah; Strekopytov, Stanislav; Polwart, Anthony; Crome, Peter

    2006-09-01

    There are unexplained links between human exposure to aluminium and the incidence, progression and aetiology of Alzheimer's disease. The null hypothesis which underlies any link is that there would be no Alzheimer's disease in the effective absence of a body burden of aluminium. To test this the latter would have to be reduced to and retained at a level that was commensurate with an Alzheimer's disease-free population. In the absence of recent human interference in the biogeochemical cycle of aluminium the reaction of silicic acid with aluminium has acted as a geochemical control of the biological availability of aluminium. This same mechanism might now be applied to both the removal of aluminium from the body and the reduced entry of aluminium into the body while ensuring that essential metals, such as iron, are unaffected. Based upon the premise that urinary aluminium is the best non-invasive estimate of body burden of aluminium patients with Alzheimer's disease were asked to drink 1.5 L of a silicic acid-rich mineral water each day for five days and, by comparison of their urinary excretion of aluminium pre-and post this simple procedure, the influence upon their body burden of aluminium was determined. Drinking the mineral water increased significantly (Paluminium (86.0 +/- 24.3 to 62.2 +/- 23.2 nmol/mmol creatinine). The latter was achieved without any significant (P>0.05) influence upon the urinary excretion of iron (20.7 +/- 9.5 to 21.7 +/- 13.8 nmol/mmol creatinine). The reduction in urinary aluminium supported the future longer-term use of silicic acid as non-invasive therapy for reducing the body burden of aluminium in Alzheimer's disease.

  20. Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease.

    Science.gov (United States)

    Pistollato, Francesca; Sumalla Cano, Sandra; Elio, Iñaki; Masias Vergara, Manuel; Giampieri, Francesca; Battino, Maurizio

    2016-10-01

    It has been hypothesized that alterations in the composition of the gut microbiota might be associated with the onset of certain human pathologies, such as Alzheimer disease, a neurodegenerative syndrome associated with cerebral accumulation of amyloid-β fibrils. It has been shown that bacteria populating the gut microbiota can release significant amounts of amyloids and lipopolysaccharides, which might play a role in the modulation of signaling pathways and the production of proinflammatory cytokines related to the pathogenesis of Alzheimer disease. Additionally, nutrients have been shown to affect the composition of the gut microbiota as well as the formation and aggregation of cerebral amyloid-β. This suggests that modulating the gut microbiome and amyloidogenesis through specific nutritional interventions might prove to be an effective strategy to prevent or reduce the risk of Alzheimer disease. This review examines the possible role of the gut in the dissemination of amyloids, the role of the gut microbiota in the regulation of the gut-brain axis, the potential amyloidogenic properties of gut bacteria, and the possible impact of nutrients on modulation of microbiota composition and amyloid formation in relation to the pathogenesis of Alzheimer disease.

  1. Frontal variant of Alzheimer's disease and typical Alzheimer's disease: a comparative study

    Directory of Open Access Journals (Sweden)

    Bernardino Fernández-Calvo

    2013-01-01

    Full Text Available Clinical heterogeneity is one of the characteristics of Alzheimer's disease (AD. Hence, the atypical frontal or dysexecutive presentation is becoming increasingly well-known, although the underlying factors are still unknown. In this study, the neuropsychological performance of two groups of patients with AD (frontal variant--ADfv--and typical--TAD were compared. The ADfv group (n = 13 was selected due to the existence of frontal hypoperfusion on a simple photon emission computer tomography (SPECT. The results revealed that the ADfv group displayed a severe dysexecutive disorder, more severe neuropsychiatric symptomatology (disinhibition and apathy, more functional impairment, and it generated a higher caregiver overload than the TAD group without frontal impairment (n = 47. Despite the facts that the ADfv group's performance was poorer in all the neuropsychological tests, significant group differences were only found in the processing speed and visuoconstruction tasks. Logistic regression analysis revealed that the processing speed and mental flexibility scores significantly predicted a diagnosis of ADfv. The existence of the grasp reflex, anosognosia, and the absence of apolipoprotein E epsilon 4 allele (APOE e4 were also more prevalent in the ADfv group. This group had a predominance of males and it was more likely to have a positive family history of AD. To conclude, the study suggests that ADfv represents a subtype of AD that seems to have different clinical, neuropsychological, and genetic characteristics from TAD.

  2. Vascular and Alzheimer's disease markers independently predict brain atrophy rate in Alzheimer's Disease Neuroimaging Initiative controls.

    Science.gov (United States)

    Barnes, Josephine; Carmichael, Owen T; Leung, Kelvin K; Schwarz, Christopher; Ridgway, Gerard R; Bartlett, Jonathan W; Malone, Ian B; Schott, Jonathan M; Rossor, Martin N; Biessels, Geert Jan; DeCarli, Charlie; Fox, Nick C

    2013-08-01

    This study assessed relationships among white matter hyperintensities (WMH), cerebrospinal fluid (CSF), Alzheimer's disease (AD) pathology markers, and brain volume loss. Subjects included 197 controls, 331 individuals with mild cognitive impairment (MCI), and 146 individuals with AD with serial volumetric 1.5-T MRI. CSF Aβ1-42 (n = 351) and tau (n = 346) were measured. Brain volume change was quantified using the boundary shift integral (BSI). We assessed the association between baseline WMH volume and annualized BSI, adjusting for intracranial volume. We also performed multiple regression analyses in the CSF subset, assessing the relationships of WMH and Aβ1-42 and/or tau with BSI. WMH burden was positively associated with BSI in controls (p = 0.02) but not MCI or AD. In multivariable models, WMH (p = 0.003) and Aβ1-42 (p = 0.001) were independently associated with BSI in controls; in MCI Aβ1-42 (p brain atrophy in the context of AD pathology in pre-dementia stages.

  3. Research progress on animal models of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Wen DONG

    2015-08-01

    Full Text Available Alzheimer's disease (AD is a degenerative disease of the central nervous system, and its pathogenesis is complex. Animal models play an important role in study on pathogenesis and treatment of AD. This paper summarized methods of building models, observation on animal models and evaluation index in recent years, so as to provide related evidence for basic and clinical research in future. DOI: 10.3969/j.issn.1672-6731.2015.08.003

  4. Evaluation of medication treatment for Alzheimer's disease on clinical evidence

    Directory of Open Access Journals (Sweden)

    Meng-qiu LI

    2014-03-01

    Full Text Available Objective To formulate the best treatment plan for Alzheimer's disease patients by evaluating the therapeutic efficacy and side effect of various evidence-based programs. Methods Alzheimer's disease, donepezil, rivastigmine, galantamine, memantine, rosiglitazone, etc. were defined as retrieval words. PubMed, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure (CNKI databases were used with applying of manual searching. Systematic reviews, randomized controlled trials (RCT, controlled clinical trials and case-observation studies were collected and evaluated by Jadad Scale. Results After screening, 33 selected resources included 14 systematic reviews, 14 randomized controlled trials, 4 controlled clinical trials and 1 case-observation study. According to Jadad Scale, total 28 articles were evaluated to be high quality (12 with score 4, 10 score 5, 6 score 7, and 5 were low quality with score 3. It was summarized as follows: 1 Alzheimer's disease is a progressive neurodegenerative disease for which no cure exists. To date, only symptomatic treatments with cholinesterase inhibitors (donepezil, rivastigmine, galantamine and an N-methyl-D-aspartate (NMDA receptor noncompetitive antagonist (memantine, are effective and well tolerated to counterbalance the neurotransmitter disturbance, but cannot limit or impact on disease progression. 2 Disease modifying drug is an potential agent, with persistent effect on slowing the progression of structural damage, and can be detected even after withdrawing the treatment. Many types of disease modifying drugs are undergoing clinical trials. Conclusions Using evidence-based medicine methods can provide best clinical evidence on Alzheimer's disease treatment. doi: 10.3969/j.issn.1672-6731.2014.03.009

  5. Gene Therapy Strategies for Alzheimer's Disease: An Overview.

    Science.gov (United States)

    Alves, Sandro; Fol, Romain; Cartier, Nathalie

    2016-02-01

    Key neuropathological hallmarks of Alzheimer's disease (AD) are extracellular amyloid plaques and intracellular accumulation of hyperphosphorylated Tau protein. The mechanisms underlying these neuropathological changes remain unclear. So far, research on AD therapy has had limited success in terms of symptomatic treatments although it has also had several failures for disease-modifying drugs. Gene transfer strategies to the brain have contributed to evaluate in animal models many interesting tracks, some of which should deserve clinical applications in AD patients in the future.

  6. Pleiotropic Protective Effects of Phytochemicals in Alzheimer's Disease

    OpenAIRE

    2012-01-01

    Alzheimer's disease (AD) is a severe chronic neurodegenerative disorder of the brain characterised by progressive impairment in memory and cognition. In the past years an intense research has aimed at dissecting the molecular events of AD. However, there is not an exhaustive knowledge about AD pathogenesis and a limited number of therapeutic options are available to treat this neurodegenerative disease. Consequently, considering the heterogeneity of AD, therapeutic agents acting on multiple l...

  7. A Survey of TCM Treatment for Alzheimer's Disease

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    @@ Alzheimer's disease (AD) is a disorder in the aged people, characterized by irreversible and progressive degeneration of the intelligence, memory, ability of orientation, judgment, speech and thinking. It is often accompanied with character changes. Statistical data show that 5%-15% of the old people suffer from mild to severe symptoms of dementia, which becomes a burden to their families and the society. The following is a survey of TCM treatment for the disease.

  8. Would decreased aluminum ingestion reduce the incidence of Alzheimer's disease?

    OpenAIRE

    McLachlan, D R; Kruck, T P; Lukiw, W.J.; Krishnan, S S

    1991-01-01

    Although the cause of Alzheimer's disease (AD) remains unknown there is mounting evidence that implicates aluminum as a toxic environmental factor of considerable importance. Four independent lines of evidence--laboratory studies of the effects of intracerebral aluminum on the cognitive and memory performance of animals, biochemical studies, epidemiologic studies and the slowing of the progress of the disease with the use of an agent that removes aluminum from the body--now support the concep...

  9. Impaired awareness of deficits and neuropsychiatric symptoms in early Alzheimer's disease: the Danish Alzheimer Intervention Study (DAISY)

    DEFF Research Database (Denmark)

    Vogel, Asmus; Waldorff, Frans Boch; Waldemar, Gunhild

    2010-01-01

    Impaired awareness may be associated with increased neuropsychiatric symptoms in moderate to severe Alzheimer's disease, but relatively little is known about the association in early Alzheimer's disease. The aim of this study was to investigate if impaired awareness was associated with a higher...... frequency of neuropsychiatric symptoms in early Alzheimer's disease. In a Danish multicenter study, 321 patients with MMSE score > or =20 were evaluated. Patients with poor insight had significantly more neuropsychiatric symptoms than patients with full insight. When patients had increasing neuropsychiatric...

  10. Eyeblink classical conditioning differentiates normal aging from Alzheimer's disease.

    Science.gov (United States)

    Woodruff-Pak, D S

    2001-01-01

    Eyeblink classical conditioning is a useful paradigm for the study of the neurobiology of learning, memory, and aging, which also has application in the differential diagnosis of neurodegenerative diseases expressed in advancing age. Converging evidence from studies of eyeblink conditioning in neurological patients and brain imaging in normal adults document parallels in the neural substrates of this form of associative learning in humans and non-human mammals. Age differences in the short-delay procedure (400 ms CS-US interval) appear in middle age in humans and may be caused at least in part by cerebellar cortical changes such as loss of Purkinje cells. Whereas the hippocampus is not essential for conditioning in the delay procedure, disruption of hippocampal cholinergic neurotransmission impairs acquisition and slows the rate of learning. Alzheimer's disease (AD) profoundly disrupts the hippocampaL cholinergic system, and patients with AD consistently perform poorly in eyeblink conditioning. We hypothesize that disruption of hippocampal cholinergic pathways in AD in addition to age-associated Purkinje cell loss results in severely impaired eyeblink conditioning. The earliest pathology in AD occurs in entorhinal cortical input to hippocampus, and eyeblink conditioning may detect this early disruption before declarative learning and memory circuits become impaired. A case study is presented in which eyeblink conditioning detected impending dementia six years before changes on other screening tests indicated impairment. Because eyeblink conditioning is simple, non-threatening, and non-invasive, it may become a useful addition to test batteries designed to differentiate normal aging from mild cognitive impairment that progresses to AD and AD from other types of dementia.

  11. Mortality from Alzheimer's disease in Brazil, 2000-2009

    Directory of Open Access Journals (Sweden)

    Jane Blanco Teixeira

    2015-04-01

    Full Text Available Alzheimer's disease is the most prevalent type of dementia in the elderly worldwide. To evaluate the mortality trend from Alzheimer's disease in Brazil, a descriptive study was conducted with the Mortality Information System of the Brazilian Ministry of Health (2000-2009. Age and sex-standardized mortality rates were calculated in Brazil's state capitals, showing the percentage variation by exponential regression adjustment. The state capitals as a whole showed an annual growth in mortality rates in the 60 to 79 year age bracket of 8.4% in women and 7.7% in men. In the 80 and older age group, the increase was 15.5% in women and 14% in men. Meanwhile, the all-cause mortality rate declined in both elderly men and women. The increase in mortality from Alzheimer's disease occurred in the context of chronic diseases as a proxy for increasing prevalence of the disease in the population. The authors suggest healthcare strategies for individuals with chronic non-communicable diseases

  12. Insight into the Molecular Imaging of Alzheimer's Disease

    Science.gov (United States)

    Bhagat, Neeta

    2016-01-01

    Alzheimer's disease is a complex neurodegenerative disease affecting millions of individuals worldwide. Earlier it was diagnosed only via clinical assessments and confirmed by postmortem brain histopathology. The development of validated biomarkers for Alzheimer's disease has given impetus to improve diagnostics and accelerate the development of new therapies. Functional imaging like positron emission tomography (PET), single photon emission computed tomography (SPECT), functional magnetic resonance imaging (fMRI), and proton magnetic resonance spectroscopy provides a means of detecting and characterising the regional changes in brain blood flow, metabolism, and receptor binding sites that are associated with Alzheimer's disease. Multimodal neuroimaging techniques have indicated changes in brain structure and metabolic activity, and an array of neurochemical variations that are associated with neurodegenerative diseases. Radiotracer-based PET and SPECT potentially provide sensitive, accurate methods for the early detection of disease. This paper presents a review of neuroimaging modalities like PET, SPECT, and selected imaging biomarkers/tracers used for the early diagnosis of AD. Neuroimaging with such biomarkers and tracers could achieve a much higher diagnostic accuracy for AD and related disorders in the future. PMID:26880871

  13. Perspectives for multimodal neurochemical and imaging biomarkers in Alzheimer's disease.

    Science.gov (United States)

    Teipel, Stefan J; Sabri, Osama; Grothe, Michel; Barthel, Henryk; Prvulovic, David; Buerger, Katharina; Bokde, Arun L W; Ewers, Michael; Hoffmann, Wolfgang; Hampel, Harald

    2013-01-01

    The diagnosis of Alzheimer's disease (AD) is presently going through a paradigm shift from disease categories to dimensions and toward the implementation of biomarkers to support identification of predementia and even preclinical asymptomatic stages of the disease. We outline the methodological basis of presently available biomarkers and technological methodologies in AD, including exploratory and hypothesis-based plasma and blood candidates, cerebrospinal fluid markers of amyloid load and axonal destruction, and imaging markers of amyloid deposition, synaptic dysfunction, cortical functional and structural disconnection, and regional atrophy. We integrate biomarker findings into a comprehensive model of AD pathogenesis from healthy aging to cognitive decline, the resilience to cerebral amyloid load (RECAL) matrix. The RECAL framework integrates factors of risk and resilience to cerebral amyloid load for individual risk prediction. We show the clinical consequences when the RECAL matrix is operationalized into a diagnostic algorithm both for individual counseling of subjects and for the identification of at risk samples for primary and secondary preventive trials. We discuss the implication of biomarkers for the identification of prodromal AD for the primary care system that seems presently not even prepared to cope with the increasing number of subjects afflicted with late stage AD dementia, let alone future cohorts of subjects searching counseling or treatment of predementia and asymptomatic stages of AD. The paradigm shift in AD diagnosis and its operationalization into a diagnostic framework will have major implications for our understanding of disease pathogenesis. Now, for the first time, we have access to in vivo markers of key events in AD pathogenesis integrated into a heuristic framework that makes strong predictions on pattern of multimodal biomarkers in different stages of AD. Critical testing of these predictions will help us to modify or even falsify

  14. The Alzheimer's disease β-secretase enzyme, BACE1

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    Vassar Robert

    2007-11-01

    Full Text Available Abstract The pathogenesis of Alzheimer's disease is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE1 enzyme is essential for the generation of β-amyloid. BACE1 knockout mice do not produce β-amyloid and are free from Alzheimer's associated pathologies including neuronal loss and certain memory deficits. The fact that BACE1 initiates the formation of β-amyloid, and the observation that BACE1 levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE1 inhibition thus reducing β-amyloid and its associated toxicities. However, new data indicates that complete abolishment of BACE1 may be associated with specific behavioral and physiological alterations. Recently a number of non-APP BACE1 substrates have been identified. It is plausible that failure to process certain BACE1 substrates may underlie some of the reported abnormalities in the BACE1-deficient mice. Here we review BACE1 biology, covering aspects ranging from the initial identification and characterization of this enzyme to recent data detailing the apparent dysregulation of BACE1 in Alzheimer's disease. We pay special attention to the putative function of BACE1 during healthy conditions and discuss in detail the relationship that exists between key risk factors for AD, such as vascular disease (and downstream cellular consequences, and the pathogenic alterations in BACE1 that are observed in the diseased state.

  15. A family living with Alzheimer's disease: The communicative challenges.

    Science.gov (United States)

    Jones, Danielle

    2015-09-01

    Alzheimer's disease irrevocably challenges a person's capacity to communicate with others. Earlier research on these challenges focused on the language disorders associated with the condition and situated language deficit solely in the limitations of a person's cognitive and semantic impairments. This research falls short of gaining insight into the actual interactional experiences of a person with Alzheimer's and their family. Drawing on a UK data set of 70 telephone calls recorded over a two-and-a-half year period (2006-2008) between one elderly woman with Alzheimer's disease, and her daughter and son-in-law, this paper explores the role which communication (and its degeneration) plays in family relationships. Investigating these interactions, using a conversation analytic approach, reveals that there are clearly communicative difficulties, but closer inspection suggests that they arise due to the contingencies that are generated by the other's contributions in the interaction. That being so, this paper marks a departure from the traditional focus on language level analysis and the assumption that deficits are intrinsic to the individual with Alzheimer's, and instead focuses on the collaborative communicative challenges that arise in the interaction itself and which have a profound impact on people's lives and relationships.

  16. Alzheimer's disease risk alleles in TREM2 illuminate innate immunity in Alzheimer's disease.

    Science.gov (United States)

    Golde, Todd E; Streit, Wolfgang J; Chakrabarty, Paramita

    2013-01-01

    Genetic studies have provided the best evidence for cause and effect relationships in Alzheimer's disease (AD). Indeed, the identification of deterministic mutations in the APP, PSEN1 and PSEN2 genes and subsequent preclinical studies linking these mutations to alterations in Aβ production and aggregation have provided pivotal support for the amyloid cascade hypothesis. In addition, genetic, pathologic and biological studies of APOE have also indicated that the genetic risk for AD associated with APOE4 can be attributed, at least in part, to its pro-amyloidogenic effect on Aβ. In recent years a number of SNPs that show unequivocal genome-wide association with AD risk have implicated novel genetic loci as modifiers of AD risk. However, the functional implications of these genetic associations are largely unknown. For almost all of these associations, the functional variants have not been identified. Very recently, two large consortiums demonstrated that rare variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene confer significant risk for AD. TREM2 is a type 1 membrane receptor protein primarily expressed on microglia in the central nervous system that has been shown to regulate phagocytosis and activation of monocytes. Previously it had been shown that homozygous loss of function mutations in TREM2 cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL, Nasu Hakola disease) and also a pure form of early-onset dementia. The association of TREM2 variants with AD brings innate immune signaling into the light, affirming innate immunity's role as a significant factor in AD pathogenesis.

  17. Magnetoencephalography as a Putative Biomarker for Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Edward Zamrini

    2011-01-01

    Full Text Available Alzheimer's Disease (AD is the most common dementia in the elderly and is estimated to affect tens of millions of people worldwide. AD is believed to have a prodromal stage lasting ten or more years. While amyloid deposits, tau filaments, and loss of brain cells are characteristics of the disease, the loss of dendritic spines and of synapses predate such changes. Popular preclinical detection strategies mainly involve cerebrospinal fluid biomarkers, magnetic resonance imaging, metabolic PET scans, and amyloid imaging. One strategy missing from this list involves neurophysiological measures, which might be more sensitive to detect alterations in brain function. The Magnetoencephalography International Consortium of Alzheimer's Disease arose out of the need to advance the use of Magnetoencephalography (MEG, as a tool in AD and pre-AD research. This paper presents a framework for using MEG in dementia research, and for short-term research priorities.

  18. DNA-repair in mild cognitive impairment and Alzheimer's disease.

    Science.gov (United States)

    Bucholtz, Nina; Demuth, Ilja

    2013-10-01

    While the pathogenesis of the sporadic form of Alzheimer disease (late onset Alzheimer disease, LOAD) is not fully understood, it seems to be clear that a combination of genetic and environmental factors are involved and influence the course of the disease. Among these factors, elevated levels of oxidative stress have been recognized and individual differences in the capacity to deal with DNA damage caused by its effects have been the subject of numerous studies. This review summarizes the research on DNA repair proteins and genes in the context of LOAD pathogenesis and its possible prodromal stage, mild cognitive impairment (MCI). The current status of the research in this field is discussed with respect to methodological issues which might have compromised the outcome of some studies and future directions of investigation on this subject are depicted.

  19. Extensive nuclear sphere generation in the human Alzheimer's brain.

    Science.gov (United States)

    Kolbe, Katharina; Bukhari, Hassan; Loosse, Christina; Leonhardt, Gregor; Glotzbach, Annika; Pawlas, Magdalena; Hess, Katharina; Theiss, Carsten; Müller, Thorsten

    2016-12-01

    Nuclear spheres are protein aggregates consisting of FE65, TIP60, BLM, and other yet unknown proteins. Generation of these structures in the cellular nucleus is putatively modulated by the amyloid precursor protein (APP), either by its cleavage or its phosphorylation. Nuclear spheres were preferentially studied in cell culture models and their existence in the human brain had not been known. Existence of nuclear spheres in the human brain was studied using immunohistochemistry. Cell culture experiments were used to study regulative mechanisms of nuclear sphere generation. The comparison of human frontal cortex brain samples from Alzheimer's disease (AD) patients to age-matched controls revealed a dramatically and highly significant enrichment of nuclear spheres in the AD brain. Costaining demonstrated that neurons are distinctly affected by nuclear spheres, but astrocytes never are. Nuclear spheres were predominantly found in neurons that were negative for threonine 668 residue in APP phosphorylation. Cell culture experiments revealed that JNK3-mediated APP phosphorylation reduces the amount of sphere-positive cells. The study suggests that nuclear spheres are a new APP-derived central hallmark of AD, which might be of crucial relevance for the molecular mechanisms in neurodegeneration.

  20. Connected speech as a marker of disease progression in autopsy-proven Alzheimer's disease.

    Science.gov (United States)

    Ahmed, Samrah; Haigh, Anne-Marie F; de Jager, Celeste A; Garrard, Peter

    2013-12-01

    Although an insidious history of episodic memory difficulty is a typical presenting symptom of Alzheimer's disease, detailed neuropsychological profiling frequently demonstrates deficits in other cognitive domains, including language. Previous studies from our group have shown that language changes may be reflected in connected speech production in the earliest stages of typical Alzheimer's disease. The aim of the present study was to identify features of connected speech that could be used to examine longitudinal profiles of impairment in Alzheimer's disease. Samples of connected speech were obtained from 15 former participants in a longitudinal cohort study of ageing and dementia, in whom Alzheimer's disease was diagnosed during life and confirmed at post-mortem. All patients met clinical and neuropsychological criteria for mild cognitive impairment between 6 and 18 months before converting to a status of probable Alzheimer's disease. In a subset of these patients neuropsychological data were available, both at the point of conversion to Alzheimer's disease, and after disease severity had progressed from the mild to moderate stage. Connected speech samples from these patients were examined at later disease stages. Spoken language samples were obtained using the Cookie Theft picture description task. Samples were analysed using measures of syntactic complexity, lexical content, speech production, fluency and semantic content. Individual case analysis revealed that subtle changes in language were evident during the prodromal stages of Alzheimer's disease, with two-thirds of patients with mild cognitive impairment showing significant but heterogeneous changes in connected speech. However, impairments at the mild cognitive impairment stage did not necessarily entail deficits at mild or moderate stages of disease, suggesting non-language influences on some aspects of performance. Subsequent examination of these measures revealed significant linear trends over the

  1. Dual task and postural control in Alzheimer's and Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Larissa Pires de Andrade

    2014-03-01

    Full Text Available Patients with neurodegenerative diseases are required to use cognitive resources while maintaining postural control. The aim of this study was to investigate the effects of a frontal cognitive task on postural control in patients with Alzheimer, Parkinson and controls. Thirty-eight participants were instructed to stand upright on a force platform in two experimental conditions: single and dual task. Participants with Parkinson's disease presented an increase in the coefficient of variation greater than 100% in the dual task as compared to the single task for center of pressure (COP area and COP path. In addition, patients with Parkinson's and Alzheimer's disease had a higher number of errors during the execution of the cognitive task when compared to the group of elderly without neurodegenerative diseases. The motor cortex, which is engaged in postural control, does not seem to compete with frontal brain regions in the performance of the cognitive task. However, patients with Parkinson's and Alzheimer's disease presented worsened performance in cognitive task.

  2. Studying infrared light therapy for treating Alzheimer's disease

    Science.gov (United States)

    Han, Mengmeng; Wang, Qiyan; Zeng, Yuhui; Meng, Qingqiang; Zhang, Jun; Wei, Xunbin

    2016-03-01

    Alzheimer's disease (AD) is an extensive neurodegenerative disease. It is generally believed that there are some connections between AD and amyloid protein plaques in the brain. AD is a chronic disease that usually starts slowly and gets worse over time. The typical symptoms are memory loss, language disorders, mood swings and behavioral issues. Gradual losses of somatic functions eventually lead patients to death. Currently, the main therapeutic method is pharmacotherapy, which may temporarily reduce symptoms, but has many side effects. No current treatment can reverse AD's deterioration. Infrared (IR) light therapy has been studied in a range of single and multiple irradiation protocols in previous studies and was found beneficial for neuropathology. In our research, we have verified the effect of infrared light on AD through Alzheimer's disease mouse model. This transgenic mouse model is made by co-injecting two vectors encoding mutant amyloid precursor protein (APP) and mutant presenilin-1 (PSEN1). We designed an experimental apparatus for treating mice, which primarily includes a therapeutic box and a LED array, which emits infrared light. After the treatment, we assessed the effects of infrared light by testing cognitive performance of the mice in Morris water maze. Our results show that infra-red therapy is able to improve cognitive performance in the mouse model. It might provide a novel and safe way to treat Alzheimer's disease.

  3. Neurobiology of apathy in Alzheimer's disease Neurobiologia da apatia na doença de Alzheimer

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    Henrique Cerqueira Guimarães

    2008-06-01

    Full Text Available Apathy is considered the most frequent neuropsychiatric disturbance in dementia and its outcome is generally deleterious. Apathy can be related to a dysfunction of the anatomical-system that supports the generation of voluntary actions, namely the prefrontal cortex and/or the prefrontal-subcortical circuits. In Alzheimer's disease, pathological and neuroimaging data indicate that apathy is likely due to a dysfunction of the medial prefrontal cortex. Accordingly, in this review article, we propose a pathophysiological model to explain apathetic behavior in Alzheimer's disease, combining data from neuroimaging, neuropathology and experimental research on the role of orbito-frontal cortex, anterior cingulate cortex, basal ganglia and dopamine in decision-making neurobiology.Apatia é considerada a alteração neuropsiquiátrica mais freqüente nas demências e suas conseqüências são habitualmente deletérias. Apatia pode ser relacionada à disfunção do sistema anatômico responsável pela geração de ações voluntárias, conhecido com córtex pré-frontal e/ou circuitos pré-frontais-subcorticais. Na doença de Alzheimer, evidências neuropatológicas e de neuroimagem funcional indicam que a apatia é provavelmente decorrente da disfunção do córtex pré-frontal medial. Assim, neste artigo de revisão, apresentamos uma proposta de um modelo fisiopatológico para explicar o comportamento apático na doença de Alzheimer, combinando dados de neuropatologia, neuroimagem e experimentação animal sobre o papel do córtex órbito-frontal, cíngulo anterior, núcleos da base e dopamina na neurobiologia da tomada de decisão.

  4. Apatia na doença de Alzheimer Apathy in Alzheimer's disease

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    Antônio Lúcio Teixeira-Jr

    2006-09-01

    Full Text Available Apatia é a mais comum síndrome neuropsiquiátrica na doença de Alzheimer, afetando entre 30 e 60% dos pacientes. Pode ser definida como perda de motivação e se manifesta com alterações afetivas, cognitivas e comportamentais, determinando, respectivamente, redução da resposta emocional, perda de autocrítica e retração social. Nesse artigo, são apresentadas as características clínicas da síndrome apática e suas perspectivas terapêuticas. Conclui-se que há uma superposição considerável entre apatia e depressão na doença de Alzheimer, mas ambas as condições são consideradas síndromes independentes. Intervenções farmacológicas para apatia incluem psicoestimulantes, como o metilfenidato, agentes dopaminérgicos e inibidores de colinesterase; mas os resultados são controversos e não há tratamento estabelecido.Apathy is the most common neuropsychiatry syndrome in Alzheimer's disease affecting 30-60% of patients. It can be defined as a loss of motivation and manifests in affect, cognition and behavioral changes, determining blunted emotional response, lack of insight and social retraction, respectively. In this paper, the clinical features and the therapeutic perspectives of apathy are presented. There is considerable overlap between apathy and depression in Alzheimer's disease, but both are considered discrete syndromes. Pharmacological interventions for apathy include psychostimulants, such as methylphenidate, dopaminergic agents and cholinesterase inhibitors, but the results are controversial and there is no established treatment.

  5. Homeostatic capabilities of the choroid plexus epithelium in Alzheimer's disease

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    Duncan John

    2004-12-01

    Full Text Available Abstract As the secretory source of vitamins, peptides and hormones for neurons, the choroid plexus (CP epithelium critically provides substances for brain homeostasis. This distributive process of cerebrospinal fluid (CSF volume transmission reaches many cellular targets in the CNS. In ageing and ageing-related dementias, the CP-CSF system is less able to regulate brain interstitial fluid. CP primarily generates CSF bulk flow, and so its malfunctioning exacerbates Alzheimers disease (AD. Considerable attention has been devoted to the blood-brain barrier in AD, but more insight is needed on regulatory systems at the human blood-CSF barrier in order to improve epithelial function in severe disease. Using autopsied CP specimens from AD patients, we immunocytochemically examined expression of heat shock proteins (HSP90 and GRP94, fibroblast growth factor receptors (FGFr and a fluid-regulatory protein (NaK2Cl cotransporter isoform 1 or NKCC1. CP upregulated HSP90, FGFr and NKCC1, even in end-stage AD. These CP adjustments involve growth factors and neuropeptides that help to buffer perturbations in CNS water balance and metabolism. They shed light on CP-CSF system responses to ventriculomegaly and the altered intracranial pressure that occurs in AD and normal pressure hydrocephalus. The ability of injured CP to express key regulatory proteins even at Braak stage V/VI, points to plasticity and function that may be boosted by drug treatment to expedite CSF dynamics. The enhanced expression of human CP 'homeostatic proteins' in AD dementia is discussed in relation to brain deficits and pharmacology.

  6. CSF clearance in Alzheimer Disease measured with dynamic PET.

    Science.gov (United States)

    de Leon, Mony J; Li, Yi; Okamura, Nobuyuki; Tsui, Wai H; Saint Louis, Les A; Glodzik, Lidia; Osorio, Ricardo S; Fortea, Juan; Butler, Tracy; Pirraglia, Elizabeth; Fossati, Silvia; Kim, Hee-Jin; Carare, Roxana O; Nedergaard, Maiken; Benveniste, Helene; Rusinek, Henry

    2017-03-16

    Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer's disease (AD) comes from primarily from rodent models. However, unlike rodents where predominant extra-cranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Using dynamic Positron Emission Tomography (PET) with (18)F-THK5117 a tracer for tau pathology, the ventricular CSF time activity was used as a biomarker for CSF clearance. We tested three hypotheses: 1. Extra-cranial CSF is detected at the superior turbinates; 2. CSF clearance is reduced in AD; and 3. CSF clearance is inversely associated with amyloid deposition. Methods: 15 subjects, 8 with AD and 7 normal control volunteers were examined with (18)F-THK5117. 10 subjects additionally received (11)C-PiB PET scans and 8 were PiB positive. Ventricular time activity curves (TAC) of (18)F-THK5117 were used to identify highly correlated TAC from extra-cranial voxels. Results: For all subjects, the greatest density of CSF positive extra-cranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition. Conclusion: The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinates CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases.

  7. Mitochondrial alterations, oxidative stress and neuroinflammation in Alzheimer's disease.

    Science.gov (United States)

    Verri, M; Pastoris, O; Dossena, M; Aquilani, R; Guerriero, F; Cuzzoni, G; Venturini, L; Ricevuti, G; Bongiorno, A I

    2012-01-01

    Alzheimer's disease (AD) is a multifactorial disorder characterized by the progressive deterioration of neuronal networks. The primary cause and sequence of its progression are only partially understood but abnormalities in folding and accumulation of insoluble proteins such as beta-amyloid and Tau-protein are both associated with the pathogenesis of AD. Mitochondria play a crucial role in cell survival and death, and changes in mitochondrial structure and/or function are related to many human diseases. Increasing evidence suggests that compromised mitochondrial function contributes to the aging process and thus may increase the risk of AD. Dysfunctional mitochondria contribute to reactive oxygen species which can lead to extensive macromolecule oxidative damage and the progression of amyloid pathology. Oxidative stress and amyloid toxicity leave neurons chemically vulnerable. The mitochondrial toxicity induced by beta-amyloid is still not clear but may include numerous mechanisms, such as the increased permeability of mitochondrial membranes, the disruption of calcium homeostasis, the alteration of oxidative phosphorylation with a consequent overproduction of reactive oxygen species. Other mechanisms have been associated with the pathophysiology of AD. Inflammatory changes are observed in AD brain overall, particularly at the amyloid deposits, which are rich in activated microglia. Once stimulated, the microglia release a wide variety of pro-inflammatory mediators including cytokines, complement components and free radicals, all of which potentially contribute to further neuronal dysfunction and eventually death. Clinically, novel approaches to visualize early neuroinflammation in the human brain are needed to improve the monitoring and control of therapeutic strategies that target inflammatory and other pathological mechanisms. Similarly, there is growing interest in developing agents that modulate mitochondrial function.

  8. Aluminum involvement in the progression of Alzheimer's disease.

    Science.gov (United States)

    Walton, J R

    2013-01-01

    The neuroanatomic specificity with which Alzheimer's disease (AD) progresses could provide clues to AD etiopathology. Magnetic resonance imaging studies of AD clinical progression have confirmed general conclusions from earlier studies of AD neuropathological progression wherein neurofibrillary tangle pathology was observed to spread along a well-defined sequence of corticocortical and corticosubcortical connections, preferentially affecting certain cell types, while sparing others. Identical and non-identical twin studies have consistently shown AD has mixed (environmental and genetic) etiopathogenesis. The decades-long prodromal phase over which AD develops suggests slow but progressive accumulation of a toxic or infective agent over time. Major environmental candidates are reviewed to assess which best fits the profile of an agent that slowly accrues in susceptible cell types of AD-vulnerable brain regions to toxic levels by old age, giving rise to AD neuropathology without rapid neuronal lysis. Chronic aluminum neurotoxicity best matches this profile. Many humans routinely ingest aluminum salts as additives contained in processed foods and alum-treated drinking water. The physical properties of aluminum and ferric iron ions are similar, allowing aluminum to use mechanisms evolved for iron to enter vulnerable neurons involved in AD progression, accumulate in those neurons, and cause neurofibrillary damage. The genetic component of AD etiopathogenesis apparently involves a susceptibility gene, yet to be identified, that increases aluminum absorption because AD and Down syndrome patients have higher than normal plasma, and brain, aluminum levels. This review describes evidence for aluminum involvement in AD neuropathology and the clinical progression of sporadic AD.

  9. Prostaglandin signaling suppresses beneficial microglial function in Alzheimer's disease models.

    Science.gov (United States)

    Johansson, Jenny U; Woodling, Nathaniel S; Wang, Qian; Panchal, Maharshi; Liang, Xibin; Trueba-Saiz, Angel; Brown, Holden D; Mhatre, Siddhita D; Loui, Taylor; Andreasson, Katrin I

    2015-01-01

    Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer's disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE2) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE2 receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE2/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.

  10. Weight loss and Alzheimer's disease: temporal and aetiologic connections.

    Science.gov (United States)

    Sergi, Giuseppe; De Rui, Marina; Coin, Alessandra; Inelmen, Emine Meral; Manzato, Enzo

    2013-02-01

    The intermediate and advanced stages of Alzheimer's disease (AD) are frequently associated with weight loss (WL), but WL may even precede the onset of cognitive symptoms. This review focuses on the possible aetiologic and temporal relationships between AD and WL. When WL occurs some years before any signs of cognitive impairment, it may be a risk factor for dementia due to deficiency of several micronutrients, such as vitamins and essential fatty acids, and consequent oxidative tissue damage. The leptin reduction associated with WL may also facilitate cognitive decline. The mechanisms potentially inducing WL in AD include lower energy intake, higher resting energy expenditure, exaggerated physical activity, or combinations of these factors. A hypermetabolic state has been observed in animals with AD, but has not been confirmed in human subjects. This latter mechanism could involve amyloid assemblies that apparently increase the circulating cytokine levels and proton leakage in mitochondria. WL may be caused by patients' increased physical activity as they develop abnormal motor behaviour (restlessness and agitation) and waste energy while trying to perform daily activities. During the course of AD, patients usually find it increasingly difficult to eat, so they ingest less food. AD-related neurodegeneration also affects brain regions involved in regulating appetite. The caregiver has an important role in ensuring an adequate food intake and controlling behavioural disturbances. In conclusion, WL is closely linked to AD, making periodic nutritional assessments and appropriate dietary measures important aspects of an AD patient's treatment.

  11. BACE1 inhibitor drugs in clinical trials for Alzheimer's disease.

    Science.gov (United States)

    Vassar, Robert

    2014-01-01

    β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the β-secretase enzyme required for the production of the neurotoxic β-amyloid (Aβ) peptide that is widely considered to have a crucial early role in the etiology of Alzheimer's disease (AD). As a result, BACE1 has emerged as a prime drug target for reducing the levels of Aβ in the AD brain, and the development of BACE1 inhibitors as therapeutic agents is being vigorously pursued. It has proven difficult for the pharmaceutical industry to design BACE1 inhibitor drugs that pass the blood-brain barrier, however this challenge has recently been met and BACE1 inhibitors are now in human clinical trials to test for safety and efficacy in AD patients and individuals with pre-symptomatic AD. Initial results suggest that some of these BACE1 inhibitor drugs are well tolerated, although others have dropped out because of toxicity and it is still too early to know whether any will be effective for the prevention or treatment of AD. Additionally, based on newly identified BACE1 substrates and phenotypes of mice that lack BACE1, concerns have emerged about potential mechanism-based side effects of BACE1 inhibitor drugs with chronic administration. It is hoped that a therapeutic window can be achieved that balances safety and efficacy. This review summarizes the current state of progress in the development of BACE1 inhibitor drugs and the evaluation of their therapeutic potential for AD.

  12. Human cerebrospinal fluid fatty acid levels differ between supernatant fluid and brain-derived nanoparticle fractions, and are altered in Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Alfred N Fonteh

    Full Text Available Although saturated (SAFA, monounsaturated (MUFA, and polyunsaturated (PUFA fatty acids are important structural components of neuronal membranes and precursors of signaling molecules, knowledge of their metabolism in Alzheimer's disease (AD is limited. Based on recent discovery that lipids in cerebrospinal fluid (CSF are distributed in both brain-derived nanoparticles (NP and supernatant fluid (SF, we hypothesized that fatty acid (FA abundance and distribution into these compartments is altered in early AD pathology.We assayed the FA composition and abundance in CSF fractions from cognitively healthy (CH, mild cognitive impairment (MCI, and AD study participants using gas chromatography-mass spectrometry. In the SF fraction, concentration of docosahexaenoic acid [DHA, (C22:6n-3] was less in AD compared with CH, while alpha linolenic acid [α-LNA, (C18:3n-3] was lower in MCI compared with CH. In the NP fraction, levels of SAFAs (C15:0, C16:0 and a MUFA (C15:1 differentiated CH from MCI, while two MUFAs (C15:1, C19:1 and four PUFAs (C20:2n-6, C20:3n-3, C22:4n-6, C22:5n-3 were higher in AD compared with CH. Levels of even-chain free SAFA and total free FA levels were higher in AD, levels of odd-chain free SAFAs, MUFAs, n-3 PUFAs, and total PUFA, were lower in AD compared with CH. Free n-6 PUFA levels were similar in all three groups.FA metabolism is compartmentalized differently in NP versus SF fractions of CSF, and altered FA levels reflect the importance of abnormal metabolism and oxidative pathways in AD. Depleted DHA in CSF fractions in AD is consistent with the importance of n-3 PUFAs in cognitive function, and suggests that disturbed PUFA metabolism contributes to AD pathology. This study of FA levels in CSF fractions from different cognitive stages shows potential AD biomarkers, and provides further insight into cell membrane dysfunctions, including mechanisms leading to amyloid production.

  13. Discrepancy between self- and proxy-rated pain in Alzheimer's disease: results from the danish Alzheimer intervention study

    DEFF Research Database (Denmark)

    Jensen-Dahm, C.; Vogel, A.; Waldorff, F.B.

    2012-01-01

    OBJECTIVES: To investigate the prevalence of self- and proxy-reported pain in a cohort with Alzheimer's disease (AD) and to identify characteristics of individuals with AD reporting pain. DESIGN: Data were collected at the baseline visit of the Danish Alzheimer Intervention Study. SETTING......: Community. PARTICIPANTS: Three hundred twenty-one community-living individuals with AD (MMSE >/= 20) and their primary caregivers. MEASUREMENTS: Pain was assessed as part of the EuroQol EQ-5D (caregiver- and self-rated). The Cornell Scale for Depression in Dementia, Quality of Life in Alzheimer's Disease...

  14. Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease.

    Science.gov (United States)

    Benzinger, Tammie L S; Blazey, Tyler; Jack, Clifford R; Koeppe, Robert A; Su, Yi; Xiong, Chengjie; Raichle, Marcus E; Snyder, Abraham Z; Ances, Beau M; Bateman, Randall J; Cairns, Nigel J; Fagan, Anne M; Goate, Alison; Marcus, Daniel S; Aisen, Paul S; Christensen, Jon J; Ercole, Lindsay; Hornbeck, Russ C; Farrar, Angela M; Aldea, Patricia; Jasielec, Mateusz S; Owen, Christopher J; Xie, Xianyun; Mayeux, Richard; Brickman, Adam; McDade, Eric; Klunk, William; Mathis, Chester A; Ringman, John; Thompson, Paul M; Ghetti, Bernardino; Saykin, Andrew J; Sperling, Reisa A; Johnson, Keith A; Salloway, Stephen; Correia, Stephen; Schofield, Peter R; Masters, Colin L; Rowe, Christopher; Villemagne, Victor L; Martins, Ralph; Ourselin, Sebastien; Rossor, Martin N; Fox, Nick C; Cash, David M; Weiner, Michael W; Holtzman, David M; Buckles, Virginia D; Moulder, Krista; Morris, John C

    2013-11-19

    Major imaging biomarkers of Alzheimer's disease include amyloid deposition [imaged with [(11)C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [(18)F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer's disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.

  15. Gram-negative bacterial molecules associate with Alzheimer disease pathology

    Science.gov (United States)

    Stamova, Boryana; Jin, Lee-Way; DeCarli, Charles; Phinney, Brett; Sharp, Frank R.

    2016-01-01

    Objective: We determined whether Gram-negative bacterial molecules are associated with Alzheimer disease (AD) neuropathology given that previous studies demonstrate Gram-negative Escherichia coli bacteria can form extracellular amyloid and Gram-negative bacteria have been reported as the predominant bacteria found in normal human brains. Methods: Brain samples from gray and white matter were studied from patients with AD (n = 24) and age-matched controls (n = 18). Lipopolysaccharide (LPS) and E coli K99 pili protein were evaluated by Western blots and immunocytochemistry. Human brain samples were assessed for E coli DNA followed by DNA sequencing. Results: LPS and E coli K99 were detected immunocytochemically in brain parenchyma and vessels in all AD and control brains. K99 levels measured using Western blots were greater in AD compared to control brains (p < 0.01) and K99 was localized to neuron-like cells in AD but not control brains. LPS levels were also greater in AD compared to control brain. LPS colocalized with Aβ1-40/42 in amyloid plaques and with Aβ1-40/42 around vessels in AD brains. DNA sequencing confirmed E coli DNA in human control and AD brains. Conclusions: E coli K99 and LPS levels were greater in AD compared to control brains. LPS colocalized with Aβ1-40/42 in amyloid plaques and around vessels in AD brain. The data show that Gram-negative bacterial molecules are associated with AD neuropathology. They are consistent with our LPS-ischemia-hypoxia rat model that produces myelin aggregates that colocalize with Aβ and resemble amyloid-like plaques. PMID:27784770

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

    Science.gov (United States)

    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

  17. Validation of Alzheimer's disease CSF and plasma biological markers: the multicentre reliability study of the pilot European Alzheimer's Disease Neuroimaging Initiative (E-ADNI)

    DEFF Research Database (Denmark)

    Buerger, Katharina; Frisoni, Giovanni; Uspenskaya, Olga

    2009-01-01

    BACKGROUND: Alzheimer's Disease Neuroimaging Initiatives ("ADNI") aim to validate neuroimaging and biochemical markers of Alzheimer's disease (AD). Data of the pilot European-ADNI (E-ADNI) biological marker programme of cerebrospinal fluid (CSF) and plasma candidate biomarkers are reported. METHODS...

  18. Protein phosphatase 2A, a key player in Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Rong LIU; Qing TIAN

    2009-01-01

    Protein phosphatase 2A (PP2A) is the pre-dominant serine/threonine phosphatase in eukaryotic cells. In the brains of patients with Alzheimer's disease (AD), decreased PP2A activities were observed, which is suggested to be involved in neurofibrillary tangle (NFT) formation, disturbed amyloid precursor protein (APP) secretion and neurodegeneration in AD brain. Based on our research and other previous findings, decreased PP2Ac level, decreased PP2A holoenzyme composition, increased level of PP2A inhibitors, increased PP2Ac Leu309 demethylation and Tyr307 phosphorylation underlie PP2A inactivation in AD. β-amyloid (Aβ) over-production, estrogen deficiency and impaired homocys-teine metabolism are the possible up-stream factors that inactivate PP2A in AD neurons. Further studies are required to disclose the role of PP2A in Alzheimer's disease.

  19. Differentiating Alzheimer disease-associated aggregates with small molecules.

    Science.gov (United States)

    Honson, Nicolette S; Johnson, Ronald L; Huang, Wenwei; Inglese, James; Austin, Christopher P; Kuret, Jeff

    2007-12-01

    Alzheimer disease is diagnosed postmortem by the density and spatial distribution of beta-amyloid plaques and tau-bearing neurofibrillary tangles. The major protein component of each lesion adopts cross-beta-sheet conformation capable of binding small molecules with submicromolar affinity. In many cases, however, Alzheimer pathology overlaps with Lewy body disease, characterized by the accumulation of a third cross-beta-sheet forming protein, alpha-synuclein. To determine the feasibility of distinguishing tau aggregates from beta-amyloid and alpha-synuclein aggregates with small molecule probes, a library containing 72,455 small molecules was screened for antagonists of tau-aggregate-mediated changes in Thioflavin S fluorescence, followed by secondary screens to distinguish the relative affinity for each substrate protein. Results showed that >10-fold binding selectivity among substrates could be achieved, with molecules selective for tau aggregates containing at least three aromatic or rigid moieties connected by two rotatable bonds.

  20. In vivo quantitative susceptibility mapping (QSM in Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Julio Acosta-Cabronero

    Full Text Available BACKGROUND: This study explores the magnetostatic properties of the Alzheimer's disease brain using a recently proposed, magnetic resonance imaging, postprocessed contrast mechanism. Quantitative susceptibility mapping (QSM has the potential to monitor in vivo iron levels by reconstructing magnetic susceptibility sources from field perturbations. However, with phase data acquired at a single head orientation, the technique relies on several theoretical approximations and requires fast-evolving regularisation strategies. METHODS: In this context, the present study describes a complete methodological framework for magnetic susceptibility measurements with a review of its theoretical foundations. FINDINGS AND SIGNIFICANCE: The regional and whole-brain cross-sectional comparisons between Alzheimer's disease subjects and matched controls indicate that there may be significant magnetic susceptibility differences for deep brain nuclei--particularly the putamen--as well as for posterior grey and white matter regions. The methodology and findings described suggest that the QSM method is ready for larger-scale clinical studies.

  1. Oxidative stress mechanisms and potential therapeutics in Alzheimer disease.

    Science.gov (United States)

    Moreira, P I; Siedlak, S L; Aliev, G; Zhu, X; Cash, A D; Smith, M A; Perry, G

    2005-07-01

    Oxidative damage of biological macromolecules is a hallmark of most neurodegenerative disorders such as Alzheimer, Parkinson and diffuse Lewy body diseases. Another important phenomenon involved in these disorders is the alteration of iron and copper homeostasis. Data from the literature support the involvement of metal homeostasis in mitochondrial dysfunction, protein alterations and nucleic acid damage which are relevant in brain function and consequently, in the development of neurodegenerative disorders. Although alterations in transition metal homeostasis, redox activity, and localization are well documented, it must be determined how alterations of specific copper- and iron-containing metalloenzymes are also involved in Alzheimer disease. The clarification of these phenomena can open a new window for understanding the mechanisms underlying neurodegeneration and, consequently, for the development of new therapeutic strategies such as gene therapy and new pharmaceutical formulations with antioxidant and chelating properties.

  2. Regulation of cerebral cholesterol metabolism in Alzheimer disease.

    Science.gov (United States)

    Reiss, Allison B; Voloshyna, Iryna

    2012-03-01

    Alzheimer disease (AD) is an age-related neurodegenerative disorder that manifests as a progressive loss of memory and deterioration of higher cognitive functions. Alzheimer disease is characterized by accumulation in the brain of the β-amyloid peptide generated by β- and γ-secretase processing of amyloid precursor protein. Epidemiological studies have linked elevated plasma cholesterol and lipoprotein levels in midlife with AD development. Cholesterol-fed animal models exhibit neuropathologic features of AD including accumulation of β-amyloid peptide. Specific isoforms of the cholesterol transporter apolipoprotein E are associated with susceptibility to AD. Although multiple lines of evidence indicate a role for cholesterol in AD, the exact impact and mechanisms involved remain largely unknown. This review summarizes the current state of our knowledge of the influence of cholesterol and lipid pathways in AD pathogenesis in vitro and in vivo.

  3. Alzheimer's Disease: Mechanism and Approach to Cell Therapy.

    Science.gov (United States)

    Amemori, Takashi; Jendelova, Pavla; Ruzicka, Jiri; Urdzikova, Lucia Machova; Sykova, Eva

    2015-11-04

    Alzheimer's disease (AD) is the most common form of dementia. The risk of AD increases with age. Although two of the main pathological features of AD, amyloid plaques and neurofibrillary tangles, were already recognized by Alois Alzheimer at the beginning of the 20th century, the pathogenesis of the disease remains unsettled. Therapeutic approaches targeting plaques or tangles have not yet resulted in satisfactory improvements in AD treatment. This may, in part, be due to early-onset and late-onset AD pathogenesis being underpinned by different mechanisms. Most animal models of AD are generated from gene mutations involved in early onset familial AD, accounting for only 1% of all cases, which may consequently complicate our understanding of AD mechanisms. In this article, the authors discuss the pathogenesis of AD according to the two main neuropathologies, including senescence-related mechanisms and possible treatments using stem cells, namely mesenchymal and neural stem cells.

  4. Why nutraceuticals do not prevent or treat Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Naughton Declan P

    2005-04-01

    Full Text Available Abstract A great deal of research has pointed to deleterious roles of metal ions in the development of Alzheimer's disease. These include: i the precipitation and aggregation of amyloid β (Aβ peptides to form senile plaques and neurofibrillary tangles, and/or ii the augmentation of oxidative stress by metal ion mediated production and activation of hydrogen peroxide. The growing trend in nutraceutical intake is in part a result of the belief that they postpone the development of dementias such as Alzheimer's disease. However, pathogenic events centred on metal ions are expected to be aggravated by frequent nutraceutical intake. Novel therapeutic approaches centred on chelators with specificity for copper and iron ions should be fully explored.

  5. Redesigning Systems of Care for Older Adults with Alzheimer' Disease

    Science.gov (United States)

    Callahan, Christopher M.; Sachs, Greg A.; LaMantia, Michael A.; Unroe, Kathleen T.; Arling, Greg A.; Boustani, Malaz A.

    2017-01-01

    The basic principle of care for patients with Alzheimer's disease is support for a patient-caregiver dyad. Any model of care seeking to improve the quality, efficiency, or cost of care for persons with Alzheimer's disease must attend to this principle. Models of care seeking to support this dyad began with strategies focusing mainly on the family caregiver. These models have grown in complexity to encompass team-based care that seeks to coordinate care across settings and providers of care for a defined population of patients. Most Americans in most communities, however, do not have access to these best practices models. While the effectiveness of new models of care is evidence-based, there are multiple barriers to widespread adoption including workforce limitations and the cost of practice redesign. We review the origins and content of current models and describe early efforts to improve their implementation on a broader scale. PMID:24711324

  6. Activin A secreted by human mesenchymal stem cells induces neuronal development and neurite outgrowth in an in vitro model of Alzheimer's disease: neurogenesis induced by MSCs via activin A.

    Science.gov (United States)

    Park, Sang Eon; Lee, Jeongmin; Chang, Eun Hyuk; Kim, Jong Hwa; Sung, Ji-Hee; Na, Duk L; Chang, Jong Wook

    2016-08-01

    Alzheimer's disease (AD) is characterized by progressive loss of memory in addition to cortical atrophy. Cortical atrophy in AD brains begins in the parietal and temporal lobes, which are near the subventricular zone (SVZ). The aim of this study was to activate the neurogenesis in the SVZ of AD brains by human mesenchymal stem cells (hMSCs). Neural stem cells (NSCs) were isolated from SVZ of 4-month-old 5XFAD mice. Co-culture of hMSCs with SVZ-derived NSCs from 5XFAD mice induced neuronal development and neurite outgrowth. To examine the inducing factor of neurogenesis, human cytokine array was performed with co-cultured media, and revealed elevated release of activin A from hMSCs. Also, we confirmed that the mRNA levels of activin A and activin receptor in the SVZ of 5XFAD mice were significantly lower than normal mice. Treatment of human recombinant activin A in SVZ-derived NSCs from 5XFAD mice induced neuronal development and neurite outgrowth. These data suggest that use of hMSCs and activin A to recover neurogenesis in future studies of cortical regeneration to treat AD.

  7. Multi-Channel neurodegenerative pattern analysis and its application in Alzheimer's disease characterization.

    Science.gov (United States)

    Liu, Sidong; Cai, Weidong; Wen, Lingfeng; Feng, David Dagan; Pujol, Sonia; Kikinis, Ron; Fulham, Michael J; Eberl, Stefan

    2014-09-01

    Neuroimaging has played an important role in non-invasive diagnosis and differentiation of neurodegenerative disorders, such as Alzheimer's disease and Mild Cognitive Impairment. Various features have been extracted from the neuroimaging data to characterize the disorders, and these features can be roughly divided into global and local features. Recent studies show a tendency of using local features in disease characterization, since they are capable of identifying the subtle disease-specific patterns associated with the effects of the disease on human brain. However, problems arise if the neuroimaging database involved multiple disorders or progressive disorders, as disorders of different types or at different progressive stages might exhibit different degenerative patterns. It is difficult for the researchers to reach consensus on what brain regions could effectively distinguish multiple disorders or multiple progression stages. In this study we proposed a Multi-Channel pattern analysis approach to identify the most discriminative local brain metabolism features for neurodegenerative disorder characterization. We compared our method to global methods and other pattern analysis methods based on clinical expertise or statistics tests. The preliminary results suggested that the proposed Multi-Channel pattern analysis method outperformed other approaches in Alzheimer's disease characterization, and meanwhile provided important insights into the underlying pathology of Alzheimer's disease and Mild Cognitive Impairment.

  8. Alzheimer Disease: Failure to Tune Out Irrelevant Input?

    OpenAIRE

    Alexander Drzezga; Timo Grimmer; Martin Peller; Marc Wermke; Hartwig Siebner; Rauschecker, Josef P.; Markus Schwaiger; Alexander Kurz

    2005-01-01

    BACKGROUND: Successful cognitive performance depends not only on the activation of specific neuronal networks but also on selective suppression of task-irrelevant modalities, i.e., deactivation of non-required cerebral regions. This ability to suppress the activation of specific brain regions has, to our knowledge, never been systematically evaluated in patients with Alzheimer disease (AD). The aim of the current study was to evaluate both cerebral activation and deactivation in (1) healthy v...

  9. The "Alzheimer's disease signature": potential perspectives for novel biomarkers

    OpenAIRE

    Zella Davide; Di Costanzo Alfonso; Russo Claudio; Intrieri Mariano; Davinelli Sergio; Bosco Paolo; Scapagnini Giovanni

    2011-01-01

    Abstract Alzheimer's disease is a progressive and neurodegenerative disorder which involves multiple molecular mechanisms. Intense research during the last years has accumulated a large body of data and the search for sensitive and specific biomarkers has undergone a rapid evolution. However, the diagnosis remains problematic and the current tests do not accurately detect the process leading to neurodegeneration. Biomarkers discovery and validation are considered the key aspects to support cl...

  10. “Is dopamine involved in Alzheimer's disease?”

    OpenAIRE

    Martorana, Alessandro; Koch, Giacomo

    2014-01-01

    Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and dementia. Recent advances indicate that AD pathogenesis appears more complex than its mere neuropathology. Changes in synaptic plasticity, neuronal disarray and cell death are pathways commonly recognized as pathogenic mechanisms of AD. It is thought that the altered metabolism of certain membrane proteins may lead to the production of amyloid (Aβ) oligomers that are characterized by an...

  11. Cohort profile: the Finnish Medication and Alzheimer's disease (MEDALZ) study

    Science.gov (United States)

    Tolppanen, Anna-Maija; Taipale, Heidi; Koponen, Marjaana; Lavikainen, Piia; Tanskanen, Antti; Tiihonen, Jari; Hartikainen, Sirpa

    2016-01-01

    Purpose The aim of the Medicine use and Alzheimer's disease (MEDALZ) study is to investigate the changes in medication and healthcare service use among persons with Alzheimer's disease (AD) and to evaluate the safety and effectiveness of medications in this group. This is important, because the number of persons with AD is rapidly growing and even though they are a particularly vulnerable patient group, the number of representative, large-scale studies with adequate follow-up time is limited. Participants MEDALZ contains all residents of Finland who received a clinically verified diagnosis of AD between 2005 and 2011 and were community-dwelling at the time of diagnosis (N=70 719). The diagnosis is based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCS-ADRDA) and Diagnostic and Statistical Manual Fourth Edition (DSM-IV) criteria for Alzheimer's disease. The cohort contains socioeconomic data (education, occupational status and taxable income, 1972–2012) and causes of death (2005–2012), data from the prescription register (1995–2012), the special reimbursement register (1972–2012) and the hospital discharge register (1972–2012). Future updates are planned. The average age was 80.1 years (range 34.5–104.6 years). The majority of cohort (65.2%) was women. Currently, the average length of follow-up after AD diagnosis is 3.1 years and altogether 26 045 (36.8%) persons have died during the follow-up. Findings Altogether 53% of the cohort had used psychotropic drugs within 1 year after AD diagnoses. The initiation rate of for example, benzodiazepines and related drugs and antidepressants began to increase already before AD diagnosis. Future plans We are currently assessing if these, and other commonly used medications are related to adverse events such as death, hip fractures, head injuries and pneumonia. PMID:27412109

  12. Mechanisms linking brain insulin resistance to Alzheimer's disease

    OpenAIRE

    Maria Niures P.S. Matioli; Ricardo Nitrini

    2015-01-01

    Several studies have indicated that Diabetes Mellitus (DM) can increase the risk of developing Alzheimer's disease (AD). This review briefly describes current concepts in mechanisms linking DM and insulin resistance/deficiency to AD. Insulin/insulin-like growth factor (IGF) resistance can contribute to neurodegeneration by several mechanisms which involve: energy and metabolism deficits, impairment of Glucose transporter-4 function, oxidative and endoplasmic reticulum stress, mitochondrial dy...

  13. Nicotinic receptor abnormalities in Alzheimer's and Parkinson's diseases.

    OpenAIRE

    1987-01-01

    The status of cholinergic receptors in dementia is related to the question of potential cholinergic therapy. Whilst muscarinic receptor binding is generally reported to be normal or near normal, findings are reported which indicate substantial reductions of hippocampal nicotinic (high affinity nicotine) binding (occurring in conjunction with decreased choline acetyltransferase) in both Alzheimer's and Parkinson's but not Huntington's disease. A further indication that nicotinic receptor funct...

  14. Interneurons, tau and amyloid-β in the piriform cortex in Alzheimer's disease.

    Science.gov (United States)

    Saiz-Sanchez, Daniel; De la Rosa-Prieto, Carlos; Ubeda-Banon, Isabel; Martinez-Marcos, Alino

    2015-07-01

    Impaired olfaction has been described as an early symptom of Alzheimer's disease. Neuroanatomical changes underlying this deficit in the olfactory system are largely unknown. Interestingly, neuropathology begins in the transentorhinal cortex and extends to the neighboring limbic system and basal telencephalic structures that mediate olfactory processing, including the anterior olfactory nucleus and olfactory bulb. The human piriform cortex has been described as a crucial area in odor quality coding; disruption of this region mediates early olfactory deficits in Alzheimer's disease. Most neuropathological investigations have focused on the entorhinal cortex and hippocampus, whereas the piriform cortex has largely been neglected. This work aims to characterize the expression of the neuropathological amyloid-β peptide, tau protein and interneuron population markers (calretinin, parvalbumin and somatostatin) in the piriform cortex of ten Alzheimer-diagnosed (80.4 ± 8.3 years old) and five control (69.6 ± 11.1) cases. Here, we examined the distribution of different interneuronal markers as well as co-localization of interneurons and pathological markers. Results indicated preferential vulnerability of somatostatin- (p = 0.0001 < α = 0.05) and calretinin-positive (p = 0.013 < α = 0.05) cells that colocalized with amyloid-β peptide, while the prevalence of parvalbumin-positive cells was increased (p = 0.045 < α = 0.05) in the Alzheimer's cases. These data may help to reveal the neural basis of olfactory deficits linked to Alzheimer's disease as well as to characterize neuronal populations preferentially vulnerable to neuropathology in regions critically involved in early stages of the disease.

  15. Inflammation and NF-kappa B in Alzheimer's Disease and Diabetes

    OpenAIRE

    Granic, Ivica; Dolga, Amalia; Ingrid M. Nijholt; van Dijk, Gertjan; Eisel, Ulrich L.M.

    2009-01-01

    Inflammatory processes are a hallmark of many chronic diseases including Alzheimer's disease and diabetes mellitus. Fairly recent statistical evidence indicating that type 2 diabetes increases the risk of developing Alzheimer's disease has led to investigations of the potential common processes that could explain this relation. Here, we review the literature on how inflammation and the inducible nuclear factor NF-kappa B might be involved in both diabetes mellitus and Alzheimer's disease and ...

  16. Disturbed calcium signaling in spinocerebellar ataxias and Alzheimer's disease.

    Science.gov (United States)

    Egorova, Polina; Popugaeva, Elena; Bezprozvanny, Ilya

    2015-04-01

    Neurodegenerative disorders, such as spinocerebellar ataxias (SCAs) and Alzheimer's disease (AD) represent a huge scientific and medical question, but the molecular mechanisms of these diseases are still not clear. There is increasing evidence that neuronal calcium signaling is abnormal in many neurodegenerative disorders. Abnormal neuronal calcium release from the endoplasmic reticulum may result in disturbances of cell homeostasis, synaptic dysfunction, and eventual cell death. Neuronal loss is observed in most cases of neurodegenerative diseases. Recent experimental evidence supporting the role of neuronal calcium signaling in the pathogenesis of SCAs and AD is discussed in this review.

  17. [Cognitive plasticity in Alzheimer's disease patients receiving cognitive stimulation programs].

    Science.gov (United States)

    Zamarrón Cassinello, Ma Dolores; Tárraga Mestre, Luis; Fernández-Ballesteros, Rocío

    2008-08-01

    The main purpose of this article is to examine whether cognitive plasticity increases after cognitive training in Alzheimer's disease patients. Twenty six patients participated in this study, all of them diagnosed with mild Alzheimer's disease, 17 of them received a cognitive training program during 6 months, and the other 9 were assigned to the control group. Participants were assigned to experimental or control conditions for clinical reasons. In order to assess cognitive plasticity, all patients were assessed before and after treatment with three subtests from the "Bateria de Evaluación de Potencial de Aprendizaje en Demencias" [Assessment Battery of Learning Potential in Dementia] (BEPAD). After treatment, Alzheimer's disease patients improved their performance in all the tasks assessing cognitive plasticity: viso-spatial memory, audio-verbal memory and verbal fluency. However, the cognitive plasticity scores of the patients in the control group decreased. In conclusion, this study showed that cognitive stimulation programs can improve cognitive functioning in mildly demented patients, and patients who do not receive any cognitive interventions may reduce their cognitive functioning.

  18. Everyday technologies for Alzheimer's disease care: Research findings, directions, and challenges.

    Science.gov (United States)

    Carrillo, Maria C; Dishman, Eric; Plowman, Tim

    2009-11-01

    The Everyday Technologies for Alzheimer's Care initiative was launched by the Alzheimer's Association and Intel Corporation in 2003 to identify and fund promising research in the use of technology-especially information and communication technologies-for monitoring, diagnosing, and treating Alzheimer's disease. At the last two progress meetings, scientific leaders of the two partners, together with aging health technology academic scientists, met to review the most recent research and discuss how current and developing technologies can address growing needs in Alzheimer care.

  19. Alzheimer's Disease: Genes, pathogenesis and risk prediction

    NARCIS (Netherlands)

    K. Sleegers (Kristel); C.M. van Duijn (Cock)

    2001-01-01

    textabstractWith the aging of western society the contribution to morbidity of diseases of the elderly, such as dementia, will increase exponentially. Thorough preventative and curative strategies are needed to constrain the increasing prevalence of these disabling diseases. Better understanding of

  20. Liposomes for Targeted Delivery of Active Agents against Neurodegenerative Diseases (Alzheimer's Disease and Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Carlos Spuch

    2011-01-01

    Full Text Available Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease represent a huge unmet medical need. The prevalence of both diseases is increasing, but the efficacy of treatment is still very limited due to various factors including the blood brain barrier (BBB. Drug delivery to the brain remains the major challenge for the treatment of all neurodegenerative diseases because of the numerous protective barriers surrounding the central nervous system. New therapeutic drugs that cross the BBB are critically needed for treatment of many brain diseases. One of the significant factors on neurotherapeutics is the constraint of the blood brain barrier and the drug release kinetics that cause peripheral serious side effects. Contrary to common belief, neurodegenerative and neurological diseases may be multisystemic in nature, and this presents numerous difficulties for their potential treatment. Overall, the aim of this paper is to summarize the last findings and news related to liposome technology in the treatment of neurodegenerative diseases and demonstrate the potential of this technology for the development of novel therapeutics and the possible applications of liposomes in the two most widespread neurodegenerative diseases, Alzheimer's disease and Parkinson's disease.

  1. The role of iron as a mediator of oxidative stress in Alzheimer disease.

    Science.gov (United States)

    Castellani, Rudy J; Moreira, Paula I; Perry, George; Zhu, Xiongwei

    2012-01-01

    Iron is both essential for maintaining a spectrum of metabolic processes in the central nervous system and elsewhere, and potent source of reactive oxygen species. Redox balance with respect to iron, therefore, may be critical to human neurodegenerative disease but is also in need of better understanding. Alzheimer disease (AD) in particular is associated with accumulation of numerous markers of oxidative stress; moreover, oxidative stress has been shown to precede hallmark neuropathological lesions early in the disease process, and such lesions, once present, further accumulate iron, among other markers of oxidative stress. In this review, we discuss the role of iron in the progression of AD.

  2. Mitochondrial DNA sequence analysis of four Alzheimer`s and Parkinson`s disease patients

    Energy Technology Data Exchange (ETDEWEB)

    Brown, M.D.; Shoffner, J.M.; Wallace, D.C. [Emory Univ. School of Medicine, Atlanta, GA (United States)] [and others

    1996-01-22

    The mitochondrial DNA (mtDNA) sequence was determined on 3 patients with Alzheimer`s disease (AD) exhibiting AD plus Parkinson`s disease (PD) neuropathologic changes and one patient with PD. Patient mtDNA sequences were compared to the standard Cambridge sequence to identify base changes. In the first AD + PD patient, 2 of the 15 nucleotide substitutions may contribute to the neuropathology, a nucleotide pair (np) 4336 transition in the tRNA{sup Gln} gene found 7.4 times more frequently in patients than in controls, and a unique np 721 transition in the 12S rRNA gene which was not found in 70 other patients or 905 controls. In the second AD + PD patient, 27 nucleotide substitutions were detected, including an np 3397 transition in the ND1 gene which converts a conserved methionine to a valine. In the third AD + PD patient, 2 polymorphic base substitutions frequently found at increased frequency in Leber`s hereditary optic neuropathy patients were observed, an np 4216 transition in ND1 and an np 13708 transition in the ND5 gene. For the PD patient, 2 novel variants were observed among 25 base substitutions, an np 1709 substitution in the 16S rRNA gene and an np 15851 missense mutation in the cytb gene. Further studies will be required to demonstrate a casual role for these base substitutions in neurodegenerative disease. 68 refs., 2 tabs.

  3. Single photon emission computed tomography in the diagnosis of Alzheimer`s disease

    Energy Technology Data Exchange (ETDEWEB)

    Hanyu, Haruo; Asano, Tetsuichi; Abe, Shin`e; Arai, Hisayuki; Iwamoto, Toshihiko; Takasaki, Masaru; Shindo, Hiroaki; Abe, Kimihiko [Tokyo Medical Coll. (Japan)

    1997-06-01

    Studies with single photon emission computed tomography (SPECT) have shown temporoparietal (TP) hypoperfusion in patients with Alzheimer`s disease (AD). We evaluated the utility of this findings in the diagnosis of AD. SPECT images with {sup 123}I-iodoamphetamine were analyzed qualitatively by a rater without knowledge of the subject`s clinical status. Sixty-seven of 302 consecutive patients were judged as having TP hypoperfusion by SPECT imaging. This perfusion pattern was observed in 44 of 51 patients with AD, in 5 with mixed dementia, 8 with cerebrovascular disease (including 5 with dementia), 4 with Parkinson`s disease (including 2 with dementia), 1 with normal pressure hydrocephalus, 1 with slowly progressive aphasia, 1 with progressive autonomic failure, 2 with age-associated memory impairment, and 1 with unclassified dementia. The sensitivity for AD was 86.3% (44 of 51 AD), and the specificity was 91.2% (229 of 251 non-AD). Next, we looked for differences in perfusion images between patients with AD and without AD. Some patients without AD had additional hypoperfusion beyond TP areas: deep gray matter hypoperfusion and diffuse frontal hypoperfusion, which could be used to differentiate them from the patients with AD. Others could not be distinguished from patients with AD by their perfusion pattern. Although patients with other cerebral disorders occasionally have TP hypoperfusion, this finding makes the diagnosis of AD very likely. (author)

  4. Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology.

    Science.gov (United States)

    Perez-Nievas, Beatriz G; Stein, Thor D; Tai, Hwan-Ching; Dols-Icardo, Oriol; Scotton, Thomas C; Barroeta-Espar, Isabel; Fernandez-Carballo, Leticia; de Munain, Estibaliz Lopez; Perez, Jesus; Marquie, Marta; Serrano-Pozo, Alberto; Frosch, Mathew P; Lowe, Val; Parisi, Joseph E; Petersen, Ronald C; Ikonomovic, Milos D; López, Oscar L; Klunk, William; Hyman, Bradley T; Gómez-Isla, Teresa

    2013-08-01

    Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer's pathology in their brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer's pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer's pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer's changes ('mismatches'), and demented Alzheimer's cases. Quantification of amyloid-β plaque burden, stereologically-based counts of neurofibrillary tangles, neurons and reactive glia, and morphological analyses of axons were performed in the multimodal association cortex lining the superior temporal sulcus. Levels of synaptic integrity markers, and soluble monomeric and multimeric amyloid-β and tau species were measured. Our results indicate that some individuals can accumulate equivalent loads of amyloid-β plaques and tangles to those found in demented Alzheimer's cases without experiencing dementia. Analyses revealed four main phenotypic differences among these two groups: (i) mismatches had striking preservation of neuron numbers, synaptic markers and axonal geometry compared to demented cases; (ii) demented cases had significantly higher burdens of fibrillar thioflavin-S-positive plaques and of oligomeric amyloid-β deposits reactive to conformer-specific antibody NAB61 than mismatches; (iii) strong and selective accumulation of hyperphosphorylated soluble tau multimers into the synaptic compartment was noted in demented cases compared with controls but not in mismatches; and (iv) the robust glial activation accompanying amyloid-β and tau pathologies in

  5. Association between Periodontitis and Alzheimer's Disease

    OpenAIRE

    Keshava Abbayya; Puthanakar, Nagraj Y; Sanjay Naduwinmani; Chidambar, Y.S.

    2015-01-01

    Alzheimer′s disease (AD) is a neurodegenerative disease which significantly increases with age. Its onset can be either early or late. AD is characterized by the salient inflammatory features, microglial activation, and increased levels of proinflammatory cytokines which contribute to the inflammatory status of the central nervous system (CNS). Whereas, periodontitis is a common oral infection associated with the gram negative anaerobic bacteria. Periodontitis can be marked as a "low-grade sy...

  6. Long noncoding RNAs and Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Luo Q

    2016-06-01

    Full Text Available Qiong Luo,1,2 Yinghui Chen1,2 1Department of Neurology, Jinshan Hospital, 2Department of Neurology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China Abstract: Long noncoding RNAs (lncRNAs are typically defined as transcripts longer than 200 nucleotides. lncRNAs can regulate gene expression at epigenetic, transcriptional, and posttranscriptional levels. Recent studies have shown that lncRNAs are involved in many neurological diseases such as epilepsy, neurodegenerative conditions, and genetic disorders. Alzheimer’s disease is a neurodegenerative disease, which accounts for >80% of dementia in elderly subjects. In this review, we will highlight recent studies investigating the role of lncRNAs in Alzheimer’s disease and focus on some specific lncRNAs that may underlie Alzheimer’s disease pathophysiology and therefore could be potential therapeutic targets. Keywords: lncRNA, Alzheimer’s disease, ncRNAs, amyloid β peptide, BACE1, BC200, BACE1-AS

  7. Beneficial effects of melatonin in experimental models of Alzheimer disease

    Institute of Scientific and Technical Information of China (English)

    Yong CHENG; Zheng FENG; Qing-zhu ZHANG; Jun-tian ZHANG

    2006-01-01

    Alzheimer's disease (AD), a progressive degenerative disorder, is characterized by the presence of amyloid deposits, neurofibrillary tangles and neuron loss.Emerging evidence indicates that antioxidants could be useful either for the prevention or treatment of AD. It has been shown that melatonin is a potent antioxidant and free radical scavenger. Additionally, melatonin stimulates several antioxidative enzymes and improves mitochondrial energy metabolism. These findings led us to study amyloid precursor protein transgenic mice, ovariectomized rats, and pheochromocytoma and astroglioma cell lines, to observe whether melatonin had any effect on Alzheimer's symptoms or pathological changes. We found that melatonin had many beneficial effects in experimental models of AD, including improvement of cognitive function, anti-oxidative injury, anti-apoptosis, inhibition of β-amyloid (Aβ) deposition and Aβ fiber formation. Several groups have shown that melatonin has an inhibitory effect on tau protein hyperphosphorylation.These actions may potentially slow down or stop the progression of dementia.

  8. Preclinical diagnosis of Alzheimer's disease: Prevention or prediction?

    Directory of Open Access Journals (Sweden)

    Ricardo Nitrini

    Full Text Available Abstract The diagnosis of Alzheimer's disease (AD for cases with dementia may be too late to allow effective treatment. Criteria for diagnosis of preclinical AD suggested by the Alzheimer's Association include the use of molecular and structural biomarkers. Preclinical diagnosis will enable testing of new drugs and forms of treatment toward achieving successful preventive treatment. But what are the advantages for the individual? To know that someone who is cognitively normal is probably going to develop AD's dementia when there is no effective preventive treatment is definitely not good news. A research method whereby volunteers are assigned to receive treatment or placebo without knowing whether they are in the control or at-risk arm of a trial would overcome this potential problem. If these new criteria are used wisely they may represent a relevant milestone in the search for a definitive treatment for AD.

  9. Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect

    KAUST Repository

    Demetrius, Lloyd A.

    2015-01-14

    Epidemiological and biochemical studies show that the sporadic forms of Alzheimer\\'s disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events—mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model.

  10. The animal models of dementia and Alzheimer's disease for pre-clinical testing and clinical translation.

    Science.gov (United States)

    Anand, Akshay; Banik, Avijit; Thakur, Keshav; Masters, Colin L

    2012-11-01

    Dementia is a clinical syndrome with abnormal degree of memory loss and impaired ability to recall events from the past often characterized by Alzheimer's disease. The various strategies to treat dementia need validation of novel compounds in suitable animal models for testing their safety and efficacy. These may include novel anti-amnesic drugs derived from synthetic chemistry or those derived from traditional herbal sources. Multiple approaches have been adopted to create reliable animal models ranging from rodents to non-human primates, where the animals are exposed to a predetermined injury or causing genetic ablation across specific regions of brain suspected to affect learning functions. In this review various animal models for Alzheimer's disease and treatment strategies in development of anti dementia drugs are discussed and an attempt has been made to provide a comprehensive report of the latest developments in the field.

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

    Science.gov (United States)

    Leskovjan, Andreana C; Kretlow, Ariane; Lanzirotti, Antonio; Barrea, Raul; Vogt, Stefan; Miller, Lisa M

    2011-03-01

    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.

  12. Metabolic dysfunction in Alzheimer's disease and related neurodegenerative disorders.

    Science.gov (United States)

    Cai, Huan; Cong, Wei-na; Ji, Sunggoan; Rothman, Sarah; Maudsley, Stuart; Martin, Bronwen

    2012-01-01

    Alzheimer's disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer's disease, Huntington's disease, and Parkinson's disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and 'eumetabolic' activities may possess superior efficacies compared to less pluripotent remedies.

  13. Heterogeneous multimodal biomarkers analysis for Alzheimer's disease via Bayesian network.

    Science.gov (United States)

    Jin, Yan; Su, Yi; Zhou, Xiao-Hua; Huang, Shuai

    2016-12-01

    By 2050, it is estimated that the number of worldwide Alzheimer's disease (AD) patients will quadruple from the current number of 36 million, while no proven disease-modifying treatments are available. At present, the underlying disease mechanisms remain under investigation, and recent studies suggest that the disease involves multiple etiological pathways. To better understand the disease and develop treatment strategies, a number of ongoing studies including the Alzheimer's Disease Neuroimaging Initiative (ADNI) enroll many study participants and acquire a large number of biomarkers from various modalities including demographic, genotyping, fluid biomarkers, neuroimaging, neuropsychometric test, and clinical assessments. However, a systematic approach that can integrate all the collected data is lacking. The overarching goal of our study is to use machine learning techniques to understand the relationships among different biomarkers and to establish a system-level model that can better describe the interactions among biomarkers and provide superior diagnostic and prognostic information. In this pilot study, we use Bayesian network (BN) to analyze multimodal data from ADNI, including demographics, volumetric MRI, PET, genotypes, and neuropsychometric measurements and demonstrate our approach to have superior prediction accuracy.

  14. Topological Measurements of DWI Tractography for Alzheimer's Disease Detection

    Science.gov (United States)

    Monaco, Alfonso; Neuroimaging Initiative, Alzheimer's Disease

    2017-01-01

    Neurodegenerative diseases affect brain morphology and connectivity, making complex networks a suitable tool to investigate and model their effects. Because of its stereotyped pattern Alzheimer's disease (AD) is a natural benchmark for the study of novel methodologies. Several studies have investigated the network centrality and segregation changes induced by AD, especially with a single subject approach. In this work, a holistic perspective based on the application of multiplex network concepts is introduced. We define and assess a diagnostic score to characterize the brain topology and measure the disease effects on a mixed cohort of 52 normal controls (NC) and 47 AD patients, from Alzheimer's Disease Neuroimaging Initiative (ADNI). The proposed topological score allows an accurate NC-AD classification: the average area under the curve (AUC) is 95% and the 95% confidence interval is 92%–99%. Besides, the combination of topological information and structural measures, such as the hippocampal volumes, was also investigated. Topology is able to capture the disease signature of AD and, as the methodology is general, it can find interesting applications to enhance our insight into disease with more heterogeneous patterns. PMID:28352290

  15. A composite multivariate polygenic and neuroimaging score for prediction of conversion to Alzheimer's disease

    OpenAIRE

    Filipovych, Roman; Gaonkar, Bilwaj; Davatzikos, Christos

    2012-01-01

    Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) are characterized by widespread pathological changes in the brain. At the same time, Alzheimer's disease is heritable with complex genetic underpinnings that may influence the timing of the related pathological changes in the brain and can affect the progression from MCI to AD. In this paper, we present a multivariate imaging genetics approach for prediction of conversion to Alzheimer's disease in patients with mild cognitive impair...

  16. Posterior cortical atrophy: an atypical variant of Alzheimer disease.

    Science.gov (United States)

    Suárez-González, Aida; Henley, Susie M; Walton, Jill; Crutch, Sebastian J

    2015-06-01

    Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by striking progressive visual impairment and a pattern of atrophy mainly involving posterior cortices. PCA is the most frequent atypical presentation of Alzheimer disease. The purpose of this article is to provide a summary of PCA's neuropsychiatric manifestations. Emotional and psychotic symptoms are discussed in the context of signal characteristic features of the PCA syndrome (the early onset, focal loss of visual perception, focal posterior brain atrophy) and the underlying cause of the disease. The authors' experience with psychotherapeutic intervention and PCA support groups is shared in detail.

  17. Alzheimer's disease care management plan: maximizing patient care.

    Science.gov (United States)

    Treinkman, Anna

    2005-03-01

    Nurse practitioners have the potential to significantly impact the care of patients with dementia. Healthcare providers can now offer patients medications that will control symptoms and prolong functioning. As a result of ongoing contact with patients, NPs play an important role in assessing and screening patients for AD and educating the patients, families, and caregivers about the disease. Alzheimer's disease is a chronic, progressive illness that requires long-term management. Nurse practitioners should be familiar with available medications and appreciate the need to individualize therapy to maximize efficacy and minimize potential adverse drug reactions.

  18. Estado nutricional na doença de Alzheimer Nutritional status in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Jacqueline Machado

    2009-01-01

    Full Text Available OBJETIVO: Descrever aspectos nutricionais de idosos com doença de Alzheimer leve a moderada em ambulatório. MÉTODOS: A amostra contou com a participação de 40 idosos de ambos os sexos, diagnosticados com doença da Alzheimer (NINCDS-ADRDA por seleção consecutiva. Foram realizadas avaliações socioeconômicas de atividades de vida diária, antropométrica, clínica e dietética. RESULTADOS: Do total, 65% eram do sexo feminino. Ao se verificar a capacidade funcional, constatou-se que mais de 70% dos idosos mostraram-se independentes para a realização de suas atividades de vida diária. Com base na avaliação do estado nutricional e na gravidade da doença, os idosos encontraram-se eutróficos, com diferença estatisticamente significativa na circunferência do braço entre os graus de demência. Quanto à presença de enfermidades secundárias à doença, 52% dos idosos apresentaram hipertensão arterial sistêmica, seguido de alterações do tipo artrose (17%. O consumo médio de energia e de macronutrientes dos idosos classificados no estágio leve foi de 1645 kcal, distribuídos em 53,7% para carboidratos, 17,5% para proteínas e 28,8% para lipídeos, enquanto que aqueles no estágio moderado foi de 1482 kcal, distribuídos em 59,3% para carboidratos, 16,1% para proteínas e 24,6% para lipídeos. CONCLUSÃO: Neste estudo descritivo de uma amostra ambulatorial de idosos com DA leve e moderada a maior parte deles apresentou estado nutricional de eutrofia, com consumo dietético adequado de carboidratos, proteínas, lipídeos e vitamina C, embora com baixo consumo alimentar de vitamina E.OBJECTIVE: To describe the nutritional status of elderly subjects with mild to moderate Alzheimer's disease. METHODS: Subjects of both genders (n=40 diagnosed with mild to moderate Alzheimer's disease according to NINCDS-ADRDA criteria, participated in the study. Socioeconomic status, activities of daily life, anthropometric, clinical and dietary

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

    Science.gov (United States)

    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. Clinical symptoms and symptom signatures of Alzheimer's disease subgroups.

    Science.gov (United States)

    Iqbal, Khalid; Flory, Michael; Soininen, Hilkka

    2013-01-01

    Alzheimer's disease (AD) is a multifactorial disorder that involves several different mechanisms. Over 99% of AD patients suffer from the sporadic form of the disease. Based on cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)(1-42), total tau, and ubiquitin--the markers associated with the histopathological hallmarks of the disease (Aβ plaques and abnormally hyperphosphorylated neurofibrillary tangles)--previous studies identified five subgroups of AD. Here we report the potential diagnostic predictive value of hallucination, hypokinesia, paranoia, rigidity, and tremors in aged individuals for AD and differences in the prevalence of these symptoms in the CSF marker-based subgroups of the disease. Analysis of 196 clinically diagnosed AD or Alzheimer with Lewy body, and 75 non-AD neurological and non-neurological control cases, all from a single center, showed that the presence of hallucination, hypokinesia, paranoia, rigidity, or tremors individually, or the presence of any of these, could diagnose AD with sensitivities and specificities of 14% and 99%; 30% and 99%; 15% and 99%; 16% and 100%; 16% and 96%; and 47% and 92%, respectively. The pattern of the prevalence of the above symptoms varied from AD subgroup to subgroup. Presence of any of these symptoms, as well as presence of each individual symptom except tremors, significantly differentiated AD subgroups from the predominantly control cluster. These findings encourage the exploration of hallucination, hypokinesia, paranoia, rigidity, and tremors in identifying various subgroups of AD for stratification of patients for clinical trials to develop therapeutic drugs. This study is for the special issue of the Journal of Alzheimer's Disease honoring Inge Grundke-Iqbal who made several seminal contributions in AD research.