Science.gov

Sample records for alzheimers disease centers

  1. Alzheimer's Disease Research Centers

    MedlinePlus

    ... Street Phoenix, AZ 85006 Website: www.azalz.org Social media: Information Line: 602-239-6500 Director's e-mail: ... CA 95817-4540 Website: http://alzheimer.ucdavis.edu Social media: Information Line: 916-734-5496 Director's e-mail: ...

  2. Alzheimer's Disease Medications

    MedlinePlus

    ... Referral Center Alzheimer's Disease Education and Referral Center Alzheimer's Disease Education and Referral Center Home About Alzheimer’s ... Plan National Alzheimer's Project Act (NAPA) About ADEAR Alzheimer's Disease Medications Fact Sheet Treatment for Mild to ...

  3. Understanding Alzheimer's Disease

    MedlinePlus

    ... Referral Center Alzheimer's Disease Education and Referral Center Alzheimer's Disease Education and Referral Center Home About Alzheimer’s ... National Alzheimer's Project Act (NAPA) About ADEAR Understanding Alzheimer's Disease: What You Need to Know Introduction Many ...

  4. Genetics Home Reference: Alzheimer disease

    MedlinePlus

    ... and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center MalaCards: alzheimer disease MalaCards: alzheimer disease risk factor Merck Manual Consumer Version: Alzheimer Disease Quick Facts ...

  5. About Alzheimer's Disease: Alzheimer's Basics

    MedlinePlus

    ... National Alzheimer's Project Act (NAPA) About ADEAR About Alzheimer's Disease: Alzheimer's Basics What is Alzheimer's disease? What happens to ... with Alzheimer's disease? What is dementia? What is Alzheimer's disease? Alzheimer’s disease is an irreversible, progressive brain ...

  6. Alzheimer disease

    MedlinePlus

    Senile dementia - Alzheimer type (SDAT); SDAT; Dementia - Alzheimer ... The exact cause of Alzheimer disease (AD) is not known. Research shows that certain changes in the brain lead to AD. You are more likely ...

  7. The National Alzheimer's Coordinating Center (NACC) Database: an Alzheimer disease database.

    PubMed

    Beekly, Duane L; Ramos, Erin M; van Belle, Gerald; Deitrich, Woodrow; Clark, Amber D; Jacka, Mary E; Kukull, Walter A

    2004-01-01

    The National Alzheimer's Coordinating Center (NACC) is responsible for developing and maintaining a database of patient information collected from the 29 Alzheimer disease centers (ADCs) funded by the National Institute on Aging. Each of the centers collects center-determined data elements on patients enrolled into its center and transmits a minimum dataset to NACC. Data are managed differently at each center depending on that center's research needs. The centers' data systems vary from a single personal computer running spreadsheet software to a network of servers running an advanced data management system such as Oracle. The challenge for NACC is to expand and adjust previously collected data elements into an integrated database that could be used for administrative as well as research purposes. In addition, NACC sought to allow the centers to have the flexibility they needed for data submission. To accomplish this task, NACC designed a database that contained separate specific datasets each with individual data elements. NACC also designed a data management system to easily collect and manage these data. The NACC web site (www.alz.washington.edu) was created to allow access to the data. PMID:15592144

  8. Home Safety for People with Alzheimer's Disease

    MedlinePlus

    ... Referral Center Alzheimer's Disease Education and Referral Center Alzheimer's Disease Education and Referral Center Home About Alzheimer’s ... NAPA) About ADEAR Home Safety for People with Alzheimer's Disease Introduction Caring for a person with Alzheimer's ...

  9. Alzheimer disease

    MedlinePlus

    ... of brain function that occurs with certain diseases. Alzheimer disease (AD) is one form of dementia. It affects ... The exact cause of Alzheimer disease (AD) is not known. Research shows that certain changes in the brain lead to AD. You are more likely to ...

  10. Tau: The Center of a Signaling Nexus in Alzheimer's Disease

    PubMed Central

    Khan, Shahzad S.; Bloom, George S.

    2016-01-01

    Tau is a microtubule-associated protein whose misfolding, hyper-phosphorylation, loss of normal function and toxic gain of function are linked to several neurodegenerative disorders, including Alzheimer's disease (AD). This review discusses the role of tau in amyloid-β (Aβ) induced toxicity in AD. The consequences of tau dysfunction, starting from the axon and concluding at somadendritic compartments, will be highlighted. PMID:26903798

  11. Alzheimer's Disease

    MedlinePlus

    Alzheimer's disease (AD) is the most common form of dementia among older people. Dementia is a brain disorder that ... higher if a family member has had the disease. No treatment can stop the disease. However, some ...

  12. Preventing Alzheimer's Disease: What Do We Know?

    MedlinePlus

    ... Referral Center Alzheimer's Disease Education and Referral Center Alzheimer's Disease Education and Referral Center Home About Alzheimer’s ... National Alzheimer's Project Act (NAPA) About ADEAR Preventing Alzheimer’s Disease: What Do We Know? Introduction The news ...

  13. Center for Nuclear Medicine Research in Alzheimer`s Disease Health Sciences Center, West Virginia University. Environmental Assessment

    SciTech Connect

    Not Available

    1994-04-01

    The Environmental Assessment (EA) of the Center for Nuclear Medicine Research in Alzheimer`s Disease (CNMR) at the Health Sciences Center, at West Virginia University in Morgantown, West Virginia for the construction and operation was prepared by DOE. The EA documents analysis of the environmental and socioeconomic impacts that might occur as a result of these actions, and characterizes potential impacts on the environment. In the EA, DOE presents its evaluation of potential impacts of construction and operation of the CNMR on health and safety of both workers and the public, as well as on the external environment. Construction impacts include the effects of erosion, waste disposal, air emissions, noise, and construction traffic and parking. Operational impacts include the effects of waste generation (domestic, sanitary, hazardous, medical/biological, radioactive and mixed wastes), radiation exposures, air emissions (radioactive, criteria, and air toxics), noise, and new workers. No sensitive resources (wetlands, special sources of groundwater, protected species) exist in the area of project effect.

  14. Alzheimer's disease.

    PubMed

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

    2016-07-30

    Although the prevalence of dementia continues to increase worldwide, incidence in the western world might have decreased as a result of better vascular care and improved brain health. Alzheimer's disease, the most prevalent cause of dementia, is still defined by the combined presence of amyloid and tau, but researchers are gradually moving away from the simple assumption of linear causality as proposed in the original amyloid hypothesis. Age-related, protective, and disease-promoting factors probably interact with the core mechanisms of the disease. Amyloid β42, and tau proteins are established core cerebrospinal biomarkers; novel candidate biomarkers include amyloid β oligomers and synaptic markers. MRI and fluorodeoxyglucose PET are established imaging techniques for diagnosis of Alzheimer's disease. Amyloid PET is gaining traction in the clinical arena, but validity and cost-effectiveness remain to be established. Tau PET might offer new insights and be of great help in differential diagnosis and selection of patients for trials. In the search for understanding the disease mechanism and keys to treatment, research is moving increasingly into the earliest phase of disease. Preclinical Alzheimer's disease is defined as biomarker evidence of Alzheimer's pathological changes in cognitively healthy individuals. Patients with subjective cognitive decline have been identified as a useful population in whom to look for preclinical Alzheimer's disease. Moderately positive results for interventions targeting several lifestyle factors in non-demented elderly patients and moderately positive interim results for lowering amyloid in pre-dementia Alzheimer's disease suggest that, ultimately, there will be a future in which specific anti-Alzheimer's therapy will be combined with lifestyle interventions targeting general brain health to jointly combat the disease. In this Seminar, we discuss the main developments in Alzheimer's research. PMID:26921134

  15. Home Safety for People with Alzheimer's Disease: General Safety Concerns

    MedlinePlus

    ... Referral Center Alzheimer's Disease Education and Referral Center Alzheimer's Disease Education and Referral Center Home About Alzheimer’s ... NAPA) About ADEAR Home Safety for People with Alzheimer's Disease General Safety Concerns People with Alzheimer's disease ...

  16. Alzheimer disease: modeling an Aβ-centered biological network.

    PubMed

    Campion, D; Pottier, C; Nicolas, G; Le Guennec, K; Rovelet-Lecrux, A

    2016-07-01

    In genetically complex diseases, the search for missing heritability is focusing on rare variants with large effect. Thanks to next generation sequencing technologies, genome-wide characterization of these variants is now feasible in every individual. However, a lesson from current studies is that collapsing rare variants at the gene level is often insufficient to obtain a statistically significant signal in case-control studies, and that network-based analyses are an attractive complement to classical approaches. In Alzheimer disease (AD), according to the prevalent amyloid cascade hypothesis, the pathology is driven by the amyloid beta (Aβ) peptide. In past years, based on experimental studies, several hundreds of proteins have been shown to interfere with Aβ production, clearance, aggregation or toxicity. Thanks to a manual curation of the literature, we identified 335 genes/proteins involved in this biological network and classified them according to their cellular function. The complete list of genes, or its subcomponents, will be of interest in ongoing AD genetic studies. PMID:27021818

  17. Treatments for Alzheimer's Disease

    MedlinePlus

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

  18. Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database.

    PubMed

    Ringman, John M; Monsell, Sarah; Ng, Denise W; Zhou, Yan; Nguyen, Andy; Coppola, Giovanni; Van Berlo, Victoria; Mendez, Mario F; Tung, Spencer; Weintraub, Sandra; Mesulam, Marek-Marsel; Bigio, Eileen H; Gitelman, Darren R; Fisher-Hubbard, Amanda O; Albin, Roger L; Vinters, Harry V

    2016-03-01

    Alzheimer disease (AD) represents a genetically heterogeneous entity. To elucidate neuropathologic features of autosomal dominant AD ([ADAD] due to PSEN1, APP, or PSEN2 mutations), we compared hallmark AD pathologic findings in 60 cases of ADAD and 120 cases of sporadic AD matched for sex, race, ethnicity, and disease duration. Greater degrees of neuritic plaque and neurofibrillary tangle formation and cerebral amyloid angiopathy (CAA) were found in ADAD (p values < 0.01). Moderate to severe CAA was more prevalent in ADAD (63.3% vs. 39.2%, p = 0.003), and persons with PSEN1 mutations beyond codon 200 had higher average Braak scores and severity and prevalence of CAA than those with mutations before codon 200. Lewy body pathology was less extensive in ADAD but was present in 27.1% of cases. We also describe a novel pathogenic PSEN1 mutation (P267A). The finding of more severe neurofibrillary pathology and CAA in ADAD, particularly in carriers of PSEN1 mutations beyond codon 200, warrants consideration when designing trials to treat or prevent ADAD. The finding of Lewy body pathology in a substantial minority of ADAD cases supports the assertion that development of Lewy bodies may be in part driven by abnormal β-amyloid protein precursor processing. PMID:26888304

  19. Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database

    PubMed Central

    Ringman, John M.; Monsell, Sarah; Ng, Denise W.; Zhou, Yan; Nguyen, Andy; Coppola, Giovanni; Van Berlo, Victoria; Mendez, Mario F.; Tung, Spencer; Weintraub, Sandra; Mesulam, Marek-Marsel; Bigio, Eileen H.; Gitelman, Darren R.; Fisher-Hubbard, Amanda O.; Albin, Roger L.; Vinters, Harry V.

    2016-01-01

    Alzheimer disease (AD) represents a genetically heterogeneous entity. To elucidate neuropathologic features of autosomal dominant AD ([ADAD] due to PSEN1, APP, or PSEN2 mutations), we compared hallmark AD pathologic findings in 60 cases of ADAD and 120 cases of sporadic AD matched for sex, race, ethnicity, and disease duration. Greater degrees of neuritic plaque and neurofibrillary tangle formation and cerebral amyloid angiopathy (CAA) were found in ADAD (p values < 0.01). Moderate to severe CAA was more prevalent in ADAD (63.3% vs. 39.2%, p = 0.003), and persons with PSEN1 mutations beyond codon 200 had higher average Braak scores and severity and prevalence of CAA than those with mutations before codon 200. Lewy body pathology was less extensive in ADAD but was present in 27.1% of cases. We also describe a novel pathogenic PSEN1 mutation (P267A). The finding of more severe neurofibrillary pathology and CAA in ADAD, particularly in carriers of PSEN1 mutations beyond codon 200, warrants consideration when designing trials to treat or prevent ADAD. The finding of Lewy body pathology in a substantial minority of ADAD cases supports the assertion that development of Lewy bodies may be in part driven by abnormal β-amyloid protein precursor processing. PMID:26888304

  20. Home Safety for People with Alzheimer's Disease: Natural Disaster Safety

    MedlinePlus

    ... Referral Center Alzheimer's Disease Education and Referral Center Alzheimer's Disease Education and Referral Center Home About Alzheimer’s ... NAPA) About ADEAR Home Safety for People with Alzheimer's Disease Natural Disaster Safety Natural disasters come in ...

  1. About Alzheimer's Disease: Caregiving

    MedlinePlus

    ... National Alzheimer's Project Act (NAPA) About ADEAR About Alzheimer's Disease: Caregiving On this page: Caregiving Tip Sheets and ... Care Caregiving News Caring for a person with Alzheimer’s disease can have high physical, emotional, and financial costs. ...

  2. Home Safety for People with Alzheimer's Disease: Impairment of the Senses

    MedlinePlus

    ... Referral Center Alzheimer's Disease Education and Referral Center Alzheimer's Disease Education and Referral Center Home About Alzheimer’s ... NAPA) About ADEAR Home Safety for People with Alzheimer's Disease Impairment of the Senses Alzheimer’s disease can ...

  3. Alzheimer's Disease

    MedlinePlus

    ... risk of urinary tract and other serious infections. Malnutrition or dehydration: People who have Alzheimer’s disease may ... swallow. It’s important to watch for signs of malnutrition. If you think that a loved one might ...

  4. The growth and impact of Alzheimer's Disease Centers as measured by social network analysis

    PubMed Central

    Hughes, Michael E.; Peeler, John; Hogenesch, John B.; Trojanowski, John Q.

    2014-01-01

    Importance Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective therapies. In 1984, the National Institute on Aging created the first five AD Centers (ADCs) in an effort to coordinate research efforts into the pathology and treatment of AD. Since that time, the ADC program has expanded to include 27 centers in major medical schools throughout the United States. A major aim of ADCs is to develop shared resources – such as tissue samples and patient populations – and thereby promote large-scale, high-impact studies that go beyond the capabilities of any single investigator or institution working in isolation. Objective and Design To quantitatively evaluate the performance of this program over the past quarter century, we systematically harvested every paper published by ADC investigators and used social network analysis to analyze co-publication networks. Results We found that the frequency of collaborations has increased dramatically during this time, even after the expansion of ADCs and the recruitment of new investigators plateaued. Moreover, the collaborations established within the context of the ADC program are increasingly inter-institutional, consistent with the overall goal of the program to catalyze multi-center research teams. Most importantly, we determined that collaborative, multi-center ADC research articles are consistently of higher-impact than AD papers as a whole. Conclusions We conclude that the ADC program has successfully fostered high-impact, multi-university collaborations, and suggest that its structural and administrative features could be replicated in other fields of patient oriented research. PMID:24514750

  5. 7 Warning Signs of Alzheimer's | Alzheimer's disease | NIH MedlinePlus the Magazine

    MedlinePlus

    ... 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 ...

  6. Who Would Take Care of the Person with Alzheimer's Disease If Something Happened to You?

    MedlinePlus

    ... Referral Center Alzheimer's Disease Education and Referral Center Alzheimer's Disease Education and Referral Center Home About Alzheimer’s ... NAPA) About ADEAR Home Safety for People with Alzheimer's Disease Who Would Take Care of the Person ...

  7. Neuropathologic assessment of participants in two multi-center longitudinal observational studies: the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN).

    PubMed

    Cairns, Nigel J; Perrin, Richard J; Franklin, Erin E; Carter, Deborah; Vincent, Benjamin; Xie, Mingqiang; Bateman, Randall J; Benzinger, Tammie; Friedrichsen, Karl; Brooks, William S; Halliday, Glenda M; McLean, Catriona; Ghetti, Bernardino; Morris, John C

    2015-08-01

    It has been hypothesized that the relatively rare autosomal dominant Alzheimer disease (ADAD) may be a useful model of the more frequent, sporadic, late-onset AD (LOAD). Individuals with ADAD have a predictable age at onset and the biomarker profile of ADAD participants in the preclinical stage may be used to predict disease progression and clinical onset. However, the extent to which the pathogenesis and neuropathology of ADAD overlaps with that of LOAD is equivocal. To address this uncertainty, two multicenter longitudinal observational studies, the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN), leveraged the expertise and resources of the existing Knight Alzheimer Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, Missouri, USA, to establish a Neuropathology Core (NPC). The ADNI/DIAN-NPC is systematically examining the brains of all participants who come to autopsy at the 59 ADNI sites in the USA and Canada and the 14 DIAN sites in the USA (eight), Australia (three), UK (one) and Germany (two). By 2014, 41 ADNI and 24 DIAN autopsies (involving nine participants and 15 family members) had been performed. The autopsy rate in the ADNI cohort in the most recent year was 93% (total since NPC inception: 70%). In summary, the ADNI/DIAN NPC has implemented a standard protocol for all sites to solicit permission for brain autopsy and to send brain tissue to the NPC for a standardized, uniform and state-of-the-art neuropathologic assessment. The benefit to ADNI and DIAN of the implementation of the NPC is very clear. The NPC provides final "gold standard" neuropathological diagnoses and data against which the antecedent observations and measurements of ADNI and DIAN can be compared. PMID:25964057

  8. Neuropathologic assessment of participants in two multi-center longitudinal observational studies: the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN)

    PubMed Central

    Cairns, Nigel J.; Perrin, Richard J.; Franklin, Erin E.; Carter, Deborah; Vincent, Benjamin; Xie, Mingqiang; Bateman, Randall J.; Benzinger, Tammie; Friedrichsen, Karl; Brooks, William S; Halliday, Glenda M.; McLean, Catriona; Ghetti, Bernardino; Morris, John C.

    2015-01-01

    It has been hypothesized that the relatively rare autosomal dominant Alzheimer disease (ADAD) may be a useful model of the more frequent, sporadic, late-onset AD (LOAD). Individuals with ADAD have a predictable age at onset and the biomarker profile of ADAD participants in the preclinical stage may be used to predict disease progression and clinical onset. However, the extent to which the pathogenesis and neuropathology of ADAD overlaps with that of LOAD is equivocal. To address this uncertainty, two multicenter longitudinal observational studies, the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN), leveraged the expertise and resources of the existing Knight Alzheimer Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, Missouri, USA, to establish a Neuropathology Core (NPC). The ADNI/DIAN-NPC is systematically examining the brains of all participants who come to autopsy at the 59 ADNI sites in the USA and Canada and the 14 DIAN sites in the USA (8), Australia (3), UK (1), and Germany (2). By 2014, 41 ADNI and 24 DIAN autopsies (involving 9 participants and 15 family members) had been performed. The autopsy rate in the ADNI cohort in the most recent year was 93% (total since NPC inception: 70%). In summary, the ADNI/DIAN NPC has implemented a standard protocol for all sites to solicit permission for brain autopsy and to send brain tissue to the NPC for a standardized, uniform, and state-of-the-art neuropathologic assessment. The benefit to ADNI and DIAN of the implementation of the NPC is very clear. The NPC provides final ‘gold standard’ neuropathological diagnoses and data against which the antecedent observations and measurements of ADNI and DIAN can be compared. PMID:25964057

  9. Vaccination against Alzheimer disease

    PubMed Central

    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. PMID:24535580

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

    PubMed

    Zhagn, Lili; Li, Zhiping

    2014-09-01

    Alzheimer was born in Germany in 1864. In 1887, Alzheimer graduated with a medical doctor degree at the University of Würzburg. In 1888, Alzheimer began to work in the Community Hospital for Mental and Epileptic Patients in Frankfurt am Main for 14 years. During this time, Alzheimer published the six-volume Histologic and Histopathologic Studies of the Cerebral Cortex, with co-author Franz Nissl. In 1903, Alzheimer came to work in the Royal Psychiatric Clinic of the University of Munich. One year later, he published his postdoctoral paper of Histological Studies about the Differential Diagnosis of Progressive Paralysis in 1904. In 1912, Alzheimer was provided the chair of psychiatry at the University of Breslau. On the way to Breslau, Alzheimer got sick, and eventually died in 1915. In 1906, Alzheimer found numerous amyloid plaques and neurofibrillary tangles in the brain of a patient called Auguste under the microscope. In November of the same year, Alzheimer gave a lecture about Auguste's case at the 37(th) Conference of South-West German Psychiatrists in Tübingen, which received little attention. In 1910, Kraepelin mentioned "Alzheimer's disease" for the first time to name the disease of what Auguste got in the 8th edition of Handbook of Psychiatry. Therefore, Alzheimer achieved worldwide recognition. PMID:25579215

  11. Alzheimer - resources

    MedlinePlus

    Resources - Alzheimer ... The following organizations are good resources for information on Alzheimer disease : Alzheimer's Association -- www.alz.org Alzheimer's Disease Education and Referral Center -- www.nia.nih.gov/alzheimers ...

  12. Antioxidants for Alzheimer Disease

    PubMed Central

    Galasko, Douglas R.; Peskind, Elaine; Clark, Christopher M.; Quinn, Joseph F.; Ringman, John M.; Jicha, Gregory A.; Cotman, Carl; Cottrell, Barbara; Montine, Thomas J.; Thomas, Ronald G.; Aisen, Paul

    2013-01-01

    Objective To evaluate whether antioxidant supplements presumed to target specific cellular compartments affected cerebrospinal fluid (CSF) biomarkers. Design Double-blind, placebo-controlled clinical trial. Setting Academic medical centers. Participants Subjects with mild to moderate Alzheimer disease. Intervention Random assignment to treatment for 16 weeks with 800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d of α-lipoic acid (E/C/ALA); 400 mg of coenzyme Q 3 times/d; or placebo. Main Outcome Measures Changes from baseline to 16 weeks in CSF biomarkers related to Alzheimer disease and oxidative stress, cognition (Mini-Mental State Examination), and function (Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale). Results Seventy-eight subjects were randomized; 66 provided serial CSF specimens adequate for biochemical analyses. Study drugs were well tolerated, but accelerated decline in Mini-Mental State Examination scores occurred in the E/C/ALA group, a potential safety concern. Changes in CSF Aβ42, tau, and P-tau181 levels did not differ between the 3 groups. Cerebrospinal fluid F2-isoprostane levels, an oxidative stress biomarker, decreased on average by 19% from baseline to week 16 in the E/C/ALA group but were unchanged in the other groups. Conclusions Antioxidants did not influence CSF biomarkers related to amyloid or tau pathology. Lowering of CSF F2-isoprostane levels in the E/C/ALA group suggests reduction of oxidative stress in the brain. However, this treatment raised the caution of faster cognitive decline, which would need careful assessment if longer-term clinical trials are conducted. Trial Registration clinicaltrials.gov Identifier: NCT00117403 PMID:22431837

  13. Dementia: Depression and Alzheimer's Disease

    MedlinePlus

    MENU Return to Web version Dementia | Depression and Alzheimer’s Disease What is depression? When doctors talk about ... time Thoughts about death or suicide What is Alzheimer's disease? Alzheimer's disease is the most common type ...

  14. Neuropathology of Alzheimer's Disease

    PubMed Central

    Perl, Daniel P.

    2010-01-01

    Alois Alzheimer first pointed out that the disease which would later bear his name has a distinct and recognizable neuropathological substrate. Since then, much has been added to our understanding of the pathological lesions associated with the condition. The 2 primary cardinal lesions associated with Alzheimer's disease are the neurofibrillary tangle and the senile plaque. The neurofibrillary tangle consists of abnormal accumulations of abnormally phosphorylated tau within the perikaryal cytoplasm of certain neurons. The senile plaque consists of a central core of beta-amyloid, a 4-kD peptide, surrounded by abnormally configured neuronal processes or neurites. Other neuropathological lesions are encountered in cases of Alzheimer's disease, but the disease is defined and recognized by these 2 cardinal lesions. Other lesions include poorly understood changes such as granulovacuolar degeneration and eosinophilic rod-like bodies (Hirano bodies). The loss of synaptic components is a change that clearly has a significant impact on cognitive function and represents another important morphological alteration. It is important to recognize that distinguishing between Alzheimer's disease, especially in its early stages, and normal aging may be very difficult, particularly if one is examining the brains of patients who died at an advanced old age. It is also noted that instances of pure forms of Alzheimer's disease, in the absence of other coexistent brain disease processes, such as infarctions or Parkinson's disease–related lesions, are relatively uncommon, and this must be taken into account by researchers who employ postmortem brain tissues for research. PMID:20101720

  15. Treatment of Alzheimer disease.

    PubMed

    Winslow, Bradford T; Onysko, Mary K; Stob, Christian M; Hazlewood, Kathleen A

    2011-06-15

    Alzheimer disease is the most common form of dementia, affecting nearly one-half [corrected] of Americans older than 85 years. It is characterized by progressive memory loss and cognitive decline. Amyloid plaque accumulation, neurofibrillary tau tangles, and depletion of acetylcholine are among the pathologic manifestations of Alzheimer disease. Although there are no proven modalities for preventing Alzheimer disease, hypertension treatment, omega-3 fatty acid supplementation, physical activity, and cognitive engagement demonstrate modest potential. Acetylcholinesterase inhibitors are first-line medications for the treatment of Alzheimer disease, and are associated with mild improvements in cognitive function, behavior, and activities of daily living; however, the clinical relevance of these effects is unclear. The most common adverse effects of acetylcholinesterase inhibitors are nausea, vomiting, diarrhea, dizziness, confusion, and cardiac arrhythmias. Short-term use of the N-methyl-D-aspartate receptor antagonist memantine can modestly improve measures of cognition, behavior, and activities of daily living in patients with moderate to severe Alzheimer disease. Memantine can also be used in combination with acetylcholinesterase inhibitors. Memantine is generally well tolerated, but whether its benefits produce clinically meaningful improvement is controversial. Although N-methyl-D-aspartate receptor antagonists and acetylcholinesterase inhibitors can slow the progression of Alzheimer disease, no pharmacologic agents can reverse the progression. Atypical antipsychotics can improve some behavioral symptoms, but have been associated with increased mortality rates in older patients with dementia. There is conflicting evidence about the benefit of selegiline, testosterone, and ginkgo for the treatment of Alzheimer disease. There is no evidence supporting the beneficial effects of vitamin E, estrogen, or nonsteroidal anti-inflammatory drug therapy. PMID:21671540

  16. Neuroinflammation in Alzheimer's disease.

    PubMed

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

    2015-04-01

    Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease. PMID:25792098

  17. Prediabetes and Alzheimer's Disease

    PubMed Central

    Bitra, V. R.; Rapaka, Deepthi; Akula, Annapurna

    2015-01-01

    Aging patients with diabetes are at higher risk of developing Alzheimer's disease. Emerging evidences demonstrate the role of brain insulin resistance, which is a key mediator in prediabetes and diabetes mellitus that may lead to Alzheimer's disease. Insulin and insulin-like growth factors regulate many biological processes such as axonal growth, protein synthesis, cell growth, gene expression, proliferation, differentiation, and development. Among these, the energy metabolism and synaptic plasticity are the major transduction processes regulated by insulin, which are the core objectives for learning and memory. It was also proposed that hyper insulinemia induced insulin resistance results in injury to the central nervous system by the activation of glycogen synthase kinase 3β which is the key ailment in the cognitive decline. Hence, the endogenous brain specific insulin impairments and signaling account for the majority of Alzheimer's abnormalities. PMID:26798163

  18. Sleep continuity scale in Alzheimer's disease (SCADS): application in daily clinical practice in an Italian center for dementia.

    PubMed

    Manni, R; Sinforiani, E; Terzaghi, M; Rezzani, C; Zucchella, C

    2015-03-01

    Sleep disorders can occur in many neurodegenerative disorders; in a previous paper we constructed a scale investigating sleep discontinuity/fragmentation with the aim to obtain a rapidly and easily administered tool suitable for early identification and longitudinal monitoring of sleep disturbances in Alzheimer's disease (AD). We introduced this instrument in the daily clinical practice in a center for dementia; here we present the results of our experience. Two hundred and sixteen AD outpatients referred to the Alzheimer's Disease Assessment Unit at the IRCCS C. Mondino National Neurological Institute, Pavia, Italy, in the period October 2012 to March 2014 were administered the scale. The questionnaire global score was correlated with measures of cognitive, functional and behavioral impairment; a significant association was found with Mini-Mental State (p = 0.005), Activities of Daily Living (p = 0.01), Neuropsychiatric Inventory (p = 0.01) and Clinical Dementia Rating (p = 0.0005). The present data indicate that the previously validated questionnaire proves to be a suitable, rapid and easy to use tool in investigating sleep quality in AD in daily clinical practice. An early identification and longitudinal monitoring of sleep disturbances in AD may improve pharmacological and non-pharmacological interventions. PMID:25294429

  19. Prevalence of dementia and Alzheimer's disease in elders of nursing homes and a senior center of Durango City, Mexico

    PubMed Central

    Alvarado-Esquivel, Cosme; Hernández-Alvarado, Ana Berthina; Tapia-Rodríguez, Rosa Oralia; Guerrero-Iturbe, Ángel; Rodríguez-Corral, Karina; Martínez, Sergio Estrada

    2004-01-01

    Background Epidemiological reports about dementia and Alzheimer's disease (AD) in elderly people from developing countries are scarce. Therefore, we sought to determine the prevalences of dementia and AD in a population of nursing home residents and senior center attendees of Durango City, Mexico, and to determine whether any socio-demographic characteristics from the subjects associated with dementia or AD exist. Methods One hundred and fifty-five residents of two nursing homes and 125 attendees of a senior center were examined for dementia and Alzheimer's disease. All subjects were tested by the mini-mental state examination, and those who scored twenty-four or less underwent psychiatric and neurological evaluations. Diagnosis of dementia, AD and vascular dementia (VaD) was based on the DSM-IV criteria. Socio-demographic characteristics from each participant were also obtained. Results Residents of nursing homes found to suffer from dementia were 25 out of 155 (16.1%). Eighteen of them (11.6%) had AD, and seven (4.5%) had VaD. None of the attendees of the senior center suffered from dementia. Dementia (pooled AD and VaD cases) correlated with white ethnicity (OR = 3.2; 95%CI = 1.28–8.31), and a history of unemployment (OR = 6.46; 95%CI = 1.42–25.97), while AD correlated with journeymen occupations (OR = 4.55; 95%CI = 1.00–19.29). Conclusion Prevalence of dementia in residents of nursing homes found in this study is much lower than reported from more industrialized countries. AD was more frequent than VaD. Ethnicity and occupation showed effects on the prevalence figures. The prevalence of dementia found has implications for the optimum kind of health care that nursing homes should provide to their residents. PMID:15070420

  20. [Alzheimer's disease and depression].

    PubMed

    Gallarda, T

    1999-11-01

    Alzheimer's disease is the most frequent cause of dementia (60% of all dementias) and affects nearly 300,000 people in France. Alzheimer's disease is a disease of the elderly which generally begins after 60 years and whose prevalence increases markedly after age 75 years. The elderly population is increasing in all Western countries. Alzheimer's disease thus constitutes a veritable emergent public health problem. The rapid inflation of the epidemiological and etiopathogenetic data have contributed to enhanced nosographic definition and finer semiological characterization of the disease. Thus, the classic concept of senile dementia has been totally abandoned. In contrast, the concept of depressive pseudodementia as defined by Kiloh (1961) remains present in the "psychiatric culture". The concept refers to rare clinical situations in which the controversial concept of "test therapy" with antidepressants retains, in the author's opinion, some utility. Depressive or psychobehavioral signs and symptoms frequently inaugurate Alzheimer's disease giving rise to first-line psychiatric management. The use of multidimensional evaluation instruments such as the neuropsychiatric inventory (NPI) has enabled demonstration of the signs and symptoms and their quantification through the course of the disease. In the dementia stage, the psychobehavioral symptoms are related to the patient's awareness of the degradation in his intellectual functions and the loss of independence and to specific neuropathological lesions responsible for "frontal deafferentation". Certain clinical forms of depression of late onset are also characterized by symptoms reflecting hypofrontal signs (blunted affect, apathy, defective initiative, etc.) and severe cognitive disorders. Those depressions are associated with risk factors shared with Alzheimer's disease (sex, age, vascular function, APOE 4) and constitute a risk factor for progression to dementia, requiring regular clinical and neuropsychological

  1. Clearance of amyloid-beta in Alzheimer's disease: shifting the action site from center to periphery.

    PubMed

    Liu, Yu-Hui; Wang, Ye-Ran; Xiang, Yang; Zhou, Hua-Dong; Giunta, Brian; Mañucat-Tan, Noralyn B; Tan, Jun; Zhou, Xin-Fu; Wang, Yan-Jiang

    2015-02-01

    Amyloid-beta (Aβ) is suggested to play a causal role in the pathogenesis of Alzheimer's disease (AD). Immunotherapies are among the most promising Aβ-targeting therapeutic strategies for AD. But, to date, all clinical trials of this modality have not been successful including Aβ vaccination (AN1792), anti-Aβ antibodies (bapineuzumab, solanezumab and ponezumab), and intravenous immunoglobulin (IVIG). We propose that one reason for the failures of these clinical trials may be the adverse effects of targeting the central clearance of amyloid plaques. The potential adverse effects include enhanced neurotoxicity related to Aβ oligomerization from plaques, neuroinflammation related to opsonized Aβ phagocytosis, autoimmunity related to cross-binding of antibodies to amyloid precursor protein (APP) on the neuron membrane, and antibody-mediated vascular and neuroskeletal damage. Overall, the majority of the adverse effects seen in clinical trials were associated with the entry of antibodies into the brain. Finally, we propose that peripheral Aβ clearance would be effective and safe for future Aβ-targeting therapies. PMID:24733588

  2. Down Syndrome and Alzheimer's Disease

    MedlinePlus

    ... 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 ...

  3. Persons with Mild or Moderate Alzheimer's Disease Use a Basic Orientation Technology to Travel to Different Rooms within a Day Center

    ERIC Educational Resources Information Center

    Lancioni, Giulio E.; Perilli, Viviana; Singh, Nirbhay N.; O'Reilly, Mark F.; Sigafoos, Jeff; Bosco, Andrea; De Caro, Maria Fara; Cassano, Germana; Pinto, Katia; Minervini, Mauro

    2011-01-01

    This study assessed whether three patients with Alzheimer's disease could learn to use a basic orientation technology to reach different rooms within a day center. At each travel instance, the technology provided verbal messages (cues) from the room to reach. For the first two patients, the messages were presented at intervals of about 15 s. For…

  4. Etanercept in Alzheimer disease

    PubMed Central

    Butchart, Joseph; Brook, Laura; Hopkins, Vivienne; Teeling, Jessica; Püntener, Ursula; Culliford, David; Sharples, Richard; Sharif, Saif; McFarlane, Brady; Raybould, Rachel; Thomas, Rhodri; Passmore, Peter; Perry, V. Hugh

    2015-01-01

    Objectives: To determine whether the tumor necrosis factor α inhibitor etanercept is well tolerated and obtain preliminary data on its safety in Alzheimer disease dementia. Methods: In a double-blind study, patients with mild to moderate Alzheimer disease dementia were randomized (1:1) to subcutaneous etanercept (50 mg) once weekly or identical placebo over a 24-week period. Tolerability and safety of this medication was recorded including secondary outcomes of cognition, global function, behavior, and systemic cytokine levels at baseline, 12 weeks, 24 weeks, and following a 4-week washout period. This trial is registered with EudraCT (2009-013400-31) and ClinicalTrials.gov (NCT01068353). Results: Forty-one participants (mean age 72.4 years; 61% men) were randomized to etanercept (n = 20) or placebo (n = 21). Etanercept was well tolerated; 90% of participants (18/20) completed the study compared with 71% (15/21) in the placebo group. Although infections were more common in the etanercept group, there were no serious adverse events or new safety concerns. While there were some interesting trends that favored etanercept, there were no statistically significant changes in cognition, behavior, or global function. Conclusions: This study showed that subcutaneous etanercept (50 mg/wk) was well tolerated in this small group of patients with Alzheimer disease dementia, but a larger more heterogeneous group needs to be tested before recommending its use for broader groups of patients. Classification of evidence: This study shows Class I evidence that weekly subcutaneous etanercept is well tolerated in Alzheimer disease dementia. PMID:25934853

  5. [Immunotherapy for Alzheimer's disease].

    PubMed

    Falkentoft, Alexander Christian; Hasselbalch, Steen Gregers

    2016-01-18

    Passive anti-beta-amyloid (Aß) immunotherapy has been shown to clear brain Aß deposits. Results from phase III clinical trials in mild-to-moderate Alzheimer's disease (AD) patients with two monoclonal antibodies bapineuzumab and solanezumab and intravenous immunoglobulin have been disappointing. Subsequent analysis of pooled data from both phase III trials with solanezumab showed a reduction in cognitive decline in patients with mild AD. Solanezumab and new monoclonal antibodies are being tested in patients with prodromal and preclinical AD in search for a disease-modifying treatment. PMID:26815584

  6. New York can be our nation's center for Alzheimer's research.

    PubMed

    Vann, Allan S

    2014-09-01

    More than 5 million people in this country have Alzheimer's disease, and more than 300,000 of those with Alzheimer's live in New York. By 2025, it is estimated that there will be 350,000 residents living with Alzheimer's in New York. Congressman Steve Israel and New York Assemblyman Charles Lavine issued a joint proposal in June, 2013 suggesting that New York become this country's center for Alzheimer's research. Obviously, they would both like to see increased federal funding, but they also know that we cannot count on that happening. So Israel and Lavine have proposed a $3 billion state bonding initiative to secure sufficient funding to tackle this disease. It would be similar to the bonding initiatives that have made California and Texas this nation's centers for stem cell and cancer research. The bond would provide a dedicated funding stream to support research to find effective means to treat, cure, and eventually prevent Alzheimer's, and fund programs to help people currently dealing with Alzheimer's and their caregivers. New York already has some of the major "ingredients" to make an Alzheimer's bond initiative a success, including 3 of our nation's 29 Alzheimer's Disease Research Centers and some of the finest research facilities in the nation for genetic and neuroscience research. One can only imagine the synergy of having these world class institutions working on cooperative grants and projects with sufficient funding to attract even more world class researchers and scientists to New York to find ways to prevent, treat, and cure Alzheimer's. PMID:24550544

  7. Exosomes in Alzheimer's disease.

    PubMed

    Malm, Tarja; Loppi, Sanna; Kanninen, Katja M

    2016-07-01

    Exosomes, nano-sized extracellular vesicles secreted by most cell types, are found everywhere in the body. The role of exosomes in cellular functions has in the past years developed from being considered little more than cellular trashcans, to being proven important intercellular messengers and notable contributors to both health and in disease. A vast number of studies have revealed the multiple, and somewhat controversial role of exosomes in Alzheimer's disease, the most common neurodegenerative disease. Exosomes have been shown to spread toxic amyloid-beta and hyperphosphorylated tau between cells, and they have been suspected of inducing apoptosis and thereby contributing to neuronal loss. On the other hand, exosomes seem to possess the ability to reduce brain amyloid-beta through microglial uptake, and they are known to transfer neuroprotective substances between cells. These features, among many others, make exosomes extremely interesting from the point of view of developing novel therapeutic approaches. The fact that exosomes derived from the central nervous system can be found in bodily fluids also makes them an appealing target for biomarker development, which is not limited only to Alzheimer's disease. PMID:27131734

  8. Antioxidant Therapies for Alzheimer's Disease

    PubMed Central

    Feng, Ye; Wang, Xiaochuan

    2012-01-01

    Alzheimer's disease (AD) is the most common neurodegenerative disease featuring progressive impairments in memory, cognition, and behavior and ultimately leads to death. The histopathological changes of Alzheimer's disease include neuronal and synaptic loss, formation of extracellular senile plaques and intracellular neurofibrillary tangles in brain. Multiple lines of evidence indicate that oxidative stress not only strongly participates in an early stage of Alzheimer's disease prior to cytopathology, but plays an important role in inducing and activating multiple cell signaling pathways that contribute to the lesion formations of toxic substances and then promotes the development of Alzheimer's disease. Many years of studies show that antioxidant therapies have enjoyed general success in preclinical studies. Therefore, this paper mainly focuses on the recent developments of common used antioxidant therapies for Alzheimer's disease and thus provides indications for future potential antioxidant therapeutic strategies of neurodegenerative diseases. PMID:22888398

  9. Causes of Alzheimer's disease

    PubMed Central

    Munoz, D G; Feldman, H

    2000-01-01

    It is now understood that genetic factors play a crucial role in the risk of developing Alzheimer's disease (AD). Rare mutations in at least 3 genes are responsible for early-onset familial AD. A common polymorphism in the apolipoprotein E gene is the major determinant of risk in families with late-onset AD, as well as in the general population. Advanced age, however, remains the major established risk factor for AD, although environmental variables may also have some role in disease expression. Some pathogenic factors directly associated with aging include oxidative damage and mutations in messenger RNA. Other factors unrelated to the aging process may, in the future, be amenable to therapeutic intervention by way of estrogen replacement therapy for postmenopausal women, anti-inflammatory drug therapy and reducing vascular risk factors. Older theories, such as aluminum playing a role in the pathogenesis of AD, have been mostly discarded as our understanding of pathogenic mechanisms of AD has advanced. PMID:11216203

  10. Helping Kids Understand Alzheimer's Disease

    MedlinePlus

    Alzheimer ’s Caregiving Tips Helping Kids Understand Alzheimer’s Disease When a family member has Alzheimer’s disease, it affects everyone in the family, including children and grandchildren. It’s important to talk to ...

  11. Micronutrients and Alzheimer's disease.

    PubMed

    Staehelin, Hannes B

    2005-11-01

    The current high life expectancy is overshadowed by neurodegenerative illnesses that lead to dementia and dependence. Alzheimer's disease (AD) is the most common of these conditions, and is considered to be a proteinopathy, with amyloid-beta42 as a key factor, leading via a cascade of events to neurodegeneration. Major factors involved are oxidative stress, perturbed Ca homeostasis and impaired energy metabolism. Protection against oxidative stress by micronutrients (including secondary bioactive substances) has been shown in transgenic Alzheimer model systems to delay AD. Epidemiological evidence is less conclusive, but the vast majority of the evidence supports a protective effect on cognitive functions in old age and AD. Thus, a diet rich in fruits and vegetables but also containing meat and fish is the most suitable to provide adequate micronutrients. The strong link between cardiovascular risk and AD may be explained by common pathogenetic mechanisms mediated, for example, by homocysteine and thus dependant on B-vitamins (folate and vitamins B(12) and B(6)). However, micronutrients may also be harmful. The high affinity of amyloid for metals (Fe, Al and Zn) favours the generation of reactive oxygen species and triggers an inflammatory response. Micronutrients in a balanced diet have a long-lasting, albeit low, protective impact on brain aging, hence prevention should be life long. PMID:16313699

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

    ERIC Educational Resources Information Center

    Cohen, Gene D.

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

  13. Advancing frontiers in Alzheimer's disease research

    SciTech Connect

    Glenner, G.G.; Wurtman, R.J.

    1987-01-01

    This book contain 16 chapters. Some of the titles are: Transmitter Alterations in Alzheimer's Disease: Relation to Cortical Dysfunction as Suggested by Positron Emission Tomography; Single-Photon Emission Computed Tomography in the Clinical Evaluation of Dementia; Clinical Diagnosis of Alzheimer's Disease; Down's Syndrome and Alzheimer's Disease: What is the Relationship; and Beta Protein: A Possible Marker for Alzheimer's Disease.

  14. Early Alzheimer's disease genetics.

    PubMed

    Schellenberg, Gerard D

    2006-01-01

    The genetics community working on Alzheimer's disease and related dementias has made remarkable progress in the past 20 years. The cumulative efforts by multiple groups have lead to the identification of three autosomal dominant genes for early onset AD. These are the amyloid-beta protein precursor gene (APP), and the genes encoding presenilin1 and 2. The knowledge derived from this work has firmly established Abeta as a critical disease molecule and lead to candidate drugs currently in treatment trials. Work on a related disease, frontotemporal dementia with parkinsonism - chromosome 17 type has also added to our understanding of pathogenesis by revealing that tau, the protein component of neurofibrillary tangles, is also a critical molecule in neurodegeneration. Lessons learned that still influence work on human genetics include the need to recognize and deal with genetic heterogeneity, a feature common to many genetic disorders. Genetic heterogeneity, if recognized, can be source of information. Another critical lesson is that clinical, molecular, and statistical scientists need to work closely on disease projects to succeed in solving the complex problems of common genetic disorders. PMID:16914874

  15. Facilitating Alzheimer disease research recruitment.

    PubMed

    Grill, Joshua D; Galvin, James E

    2014-01-01

    Alzheimer disease (AD) research faces challenges to successful enrollment, especially to clinical trials and biomarker studies. Failure to recruit the planned number of participants in a timely manner threatens the internal validity and success of clinical research, raising concerns about external validity and generalizability of results, and possibly leading to disparities in disease treatment. Methods to improve recruitment exist, but require varying levels of staff effort and financial resources, and evidence of effectiveness is often lacking or inconsistent. In this review, we summarize some of the available methods to improve AD research recruitment, the available literature to support or refute these strategies, and some of the experiences at the authors' AD Research Centers. We discuss the use of community-based participatory research principles and participant registries as a means to enhance research enrollment and increase diversity of research samples. PMID:24322484

  16. Seizures in Alzheimer's disease.

    PubMed

    Born, H A

    2015-02-12

    Alzheimer's disease (AD) increases the risk for late-onset seizures and neuronal network abnormalities. An elevated co-occurrence of AD and seizures has been established in the more prevalent sporadic form of AD. Recent evidence suggests that nonconvulsive network abnormalities, including seizures and other electroencephalographic abnormalities, may be more commonly found in patients than previously thought. Patients with familial AD are at an even greater risk for seizures, which have been found in patients with mutations in PSEN1, PSEN2, or APP, as well as with APP duplication. This review also provides an overview of seizure and electroencephalography studies in AD mouse models. The amyloid-β (Aβ) peptide has been identified as a possible link between AD and seizures, and while Aβ is known to affect neuronal activity, the full-length amyloid precursor protein (APP) and other APP cleavage products may be important for the development and maintenance of cortical network hyperexcitability. Nonconvulsive epileptiform activity, such as seizures or network abnormalities that are shorter in duration but may occur with higher frequency, may contribute to cognitive impairments characteristic of AD, such as amnestic wandering. Finally, the review discusses recent studies using antiepileptic drugs to rescue cognitive deficits in AD mouse models and human patients. Understanding the mechanistic link between epileptiform activity and AD is a research area of growing interest. Further understanding of the connection between neuronal hyperexcitability and Alzheimer's as well as the potential role of epileptiform activity in the progression of AD will be beneficial for improving treatment strategies. PMID:25484360

  17. [Vitamin E and Alzheimer's Disease].

    PubMed

    Shinohara, Moeko; Yamada, Masahito

    2015-12-01

    It has been suggested that oxidative stress may contribute to the pathogenesis of Alzheimer's disease. Vitamin E is a potent antioxidant, and the results of some epidemiological studies have suggested that high intake of vitamin E through food is inversely associated with the incidence of Alzheimer's disease. Randomized controlled studies have shown that treatment with vitamin E could delay functional decline in patients with mild to moderate Alzheimer's disease. However, vitamin E had no cognitive benefits in patients with mild cognitive impairment or in generally healthy older women. Well-designed clinical trials or preventive interventions with vitamin E are necessary to establish its efficacy as therapeutic or preventive agents for Alzheimer's disease. PMID:26618765

  18. Words to Know (Alzheimer's Disease)

    MedlinePlus

    ... the National Institute on Aging Words to Know Aggression (uh-GRESH-un). When a person lashes out ... AD feel. Agitation may cause pacing, sleeplessness, or aggression. Alzheimer's disease (AD) (ALlz-high-merz duh-ZEEZ). ...

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

    PubMed

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

    2013-01-01

    Procedural learning can acquire or develop skills through performance and repetition of a task unconsciously or unintentionally. Procedural skills are considered as the cornerstone in the neuropsychological rehabilitation to promote the autonomy of patients with brain damage, as those with Alzheimer's disease. This review presents data about procedural skills in Alzheimer's disease. Over the past three decades, we have found 40 articles studying various procedural skills in the Alzheimer's disease: motor, perceptual-motor, cognitive, perceptual-cognitive and those developed through serial reaction-time paradigm. We analyzed every study evaluating a procedural skill, indicating the used task and preservation or no preservation of procedural learning. Overall, most of the papers published describe conservation of learning procedures or relatively conserved in Alzheimer's disease, which could be used to promote patient autonomy. PMID:24021069

  20. Neuronutrition and Alzheimer's Disease

    PubMed Central

    Ramesh, Balenahalli N.; Rao, T.S. Sathyanarayana; Prakasam, Annamalai; Sambamurti, Kumar; Rao, K.S. Jagannatha

    2010-01-01

    Alzheimer's disease (AD) is a complex neurological disorder with several unequivocally identified genetic risk factors. Among the several environmental factors proposed for AD, dietary protective and risk factors have been most compelling. In particular, diets rich in saturated fatty acids and alcohol, and deficient in antioxidants and vitamins appear to promote the onset of the disease, while diets rich in unsaturated fatty acids, vitamins, antioxidants, and wine likely suppress its onset. Evidence suggests that diets rich in polyphenols and some spices suppress the onset of AD by scavenging free radicals and preventing oxidative damage. Metal ions are known to catalyze the production of free radicals and induce mental retardation or dementia. Several studies have also identified metals such as Pb, Fe, Al, Cu and Zn in AD pathogenesis. While specific chelators have been tested for therapy, they have not been very successful probably due to late administration after brain damage has been triggered. Since several dietary polyphenols are known to chelate metals, their routine use may also be protective against the onset of AD. PMID:20308778

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

    MedlinePlus

    ... 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 ...

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

    MedlinePlus

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

  3. Mitochondrial Drugs for Alzheimer Disease

    PubMed Central

    Bonda, David J.; Wang, Xinglong; Gustaw-Rothenberg, Katarzyna A.; Perry, George; Smith, Mark A.; Zhu, Xiongwei

    2009-01-01

    Therapeutic strategies for Alzheimer disease (AD) have yet to offer a disease-modifying effect to stop the debilitating progression of neurodegeneration and cognitive decline. Rather, treatments thus far are limited to agents that slow disease progression without halting it, and although much work towards a cure is underway, a greater understanding of disease etiology is certainly necessary for any such achievement. Mitochondria, as the centers of cellular metabolic activity and the primary generators of reactive oxidative species in the cell, received particular attention especially given that mitochondrial defects are known to contribute to cellular damage. Furthermore, as oxidative stress has come to the forefront of AD as a causal theory, and as mitochondrial damage is known to precede much of the hallmark pathologies of AD, it seems increasingly apparent that this metabolic organelle is ultimately responsible for much, if not all of disease pathogenesis. In this review, we review the role of neuronal mitochondria in the pathogenesis of AD and critically assess treatment strategies that utilize this upstream access point as a method for disease prevention. We suspect that, with a revived focus on mitochondrial repair and protection, an effective and realistic therapeutic agent can be successfully developed. PMID:20657666

  4. Mitochondrial Drugs for Alzheimer Disease.

    PubMed

    Bonda, David J; Wang, Xinglong; Gustaw-Rothenberg, Katarzyna A; Perry, George; Smith, Mark A; Zhu, Xiongwei

    2009-12-23

    Therapeutic strategies for Alzheimer disease (AD) have yet to offer a disease-modifying effect to stop the debilitating progression of neurodegeneration and cognitive decline. Rather, treatments thus far are limited to agents that slow disease progression without halting it, and although much work towards a cure is underway, a greater understanding of disease etiology is certainly necessary for any such achievement. Mitochondria, as the centers of cellular metabolic activity and the primary generators of reactive oxidative species in the cell, received particular attention especially given that mitochondrial defects are known to contribute to cellular damage. Furthermore, as oxidative stress has come to the forefront of AD as a causal theory, and as mitochondrial damage is known to precede much of the hallmark pathologies of AD, it seems increasingly apparent that this metabolic organelle is ultimately responsible for much, if not all of disease pathogenesis. In this review, we review the role of neuronal mitochondria in the pathogenesis of AD and critically assess treatment strategies that utilize this upstream access point as a method for disease prevention. We suspect that, with a revived focus on mitochondrial repair and protection, an effective and realistic therapeutic agent can be successfully developed. PMID:20657666

  5. Leptin in Alzheimer's disease.

    PubMed

    Magalhães, C A; Carvalho, M G; Sousa, L P; Caramelli, P; Gomes, K B

    2015-10-23

    Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly population. AD is histologically characterized by accumulation of amyloid-β protein (Aβ) on extracellular plaques and deposition of hyperphosphorylated tau protein in intracellular neurofibrillary tangles. Several studies have shown that obesity may precede dementia and that lifestyle factors play a critical role in the onset of AD. Furthermore, accumulating evidence indicates that obesity is an independent risk factor for developing AD. In this scenario, the understanding of the role of adipose tissue in brain health is essential to clarify the establishment of demential processes. The objective of this work was to review studies regarding leptin, an anorexigenic peptide hormone synthesized in adipocytes, in the context of dementia. Some authors proposed that leptin evaluation might be a better predictor of dementia than traditional anthropometric measures. Leptin, once established as a biomarker, could enhance the understanding of late-onset AD risk over the life course, as well as the clinical progression of prodromal state to manifested AD. Other studies have proposed that leptin presents neuroprotective activities, which could be explained by inhibiting the amyloidogenic process, reducing the levels of tau protein phosphorylation and improving the cognitive function. PMID:26279362

  6. The biological substrates of Alzheimer's disease

    SciTech Connect

    Scheibel, A.B.; Wechsler, A.F.; Brazier, M.A.B.

    1986-01-01

    This book contains 21 selections. Some of the titles are: Dementia of the Alzheimer Type: Genetic Aspects; Determination of Cerebral Metabolic Patterns in Dementia Using Positron Emission Tomography; Pathology of the Basal Forebrain in Alzheimer's Disease and Other Dementias; Characterization of Neurofibrillary Tangles with Monoclonal Antibodies Raised Against Alzheimer Neurofibrillary Tangles; and HLA Associations in Alzheimer's Disease.

  7. Neurobiology of Alzheimer's disease.

    PubMed

    Mohandas, E; Rajmohan, V; Raghunath, B

    2009-01-01

    Alzheimer's disease (AD) is a devastating neurodegenerative disease, the most common among the dementing illnesses. The neuropathological hallmarks of AD include extracellular beta-amyloid (amyloid precursor protein (APP) deposits, intracellular neurofibrillary tangles (NFT)), dystrophic neuritis and amyloid angiopathy. The mismetabolism of APP and the defective clearance of beta amyloid generate a cascade of events including hyperphosphorylated tau (tau) mediated breakdown of microtubular assembly and resultant synaptic failure which results in AD. The exact aetiopathogenesis of AD is still obscure. The preeminent hypotheses of AD include amyloid cascade hypothesis and tau hyperphosphorylation. The amyloid hypothesis states that extracellular amyloid plaques formed by aggregates of Abeta peptide generated by the proteolytic cleavages of APP are central to AD pathology. Intracellular assembly states of the oligomeric and protofibrillar species may facilitate tau hyperphosphorylation, disruption of proteasome and mitochondria function, dysregulation of calcium homeostasis, synaptic failure, and cognitive dysfunction. The tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical filament) and NFTs. Vascular hypothesis is also proposed for AD and it concludes that advancing age and the presence of vascular risk factors create a Critically Attained Threshold of Cerebral Hypoperfusion (CATCH) which leads to cellular and subcellular pathology involving protein synthesis, development of plaques, inflammatory response, and synaptic damage leading to the manifestations of AD. Multiple other aetiological and pathogenetic hypotheses have been put forward including genetics, oxidative stress, dysfunctional calcium homeostasis, hormonal, inflammatory-immunologic, and cell cycle dysregulation with the resultant neurotransmitter dysfunctions and cognitive decline. The available

  8. [Music therapy and Alzheimer disease].

    PubMed

    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. PMID:24908841

  9. Fisher Center for Alzheimer's Research Foundation

    MedlinePlus

    ... Donate for the Cure W e consistently receive top awards and ratings for our accountability: Guidestar Exchange ... Medical Research Charities of America Web Health Awards Top Links Understanding Alzheimer’s Disease Alzheimer's Diagnosis Dementia vs. ...

  10. Alzheimer's Disease | NIH MedlinePlus the Magazine

    MedlinePlus

    ... 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 ...

  11. [Language Symptoms of Alzheimer's Disease].

    PubMed

    Shinagawa, Shunichiro

    2016-05-01

    Alzheimer's disease (AD) is a neurodegenerative disorder mainly characterized by progressive memory disturbance. Language symptoms are considered to be less disease specific and therefore did not attract many researchers, interest until recently. Typical patients with AD present amnesic aphasia in the early disease stage followed by transcortical sensory aphasia; however, their language symptoms are varied. Recently, the concept of logopenic variant of primary progressive aphasia (PPA) has been developed, which is reported to have Alzheimer's neuropathology. Clinicians should verify patients' language abilities, as language can be the key to reveal their true cognitive functions. PMID:27156508

  12. Pharmacogenomics in Alzheimer's disease.

    PubMed

    Cacabelos, Ramón

    2002-02-01

    Alzheimer's disease (AD) is a complex disorder associated with multiple genetic defects either mutational or of susceptibility. Information available on AD genetics does not explain in full the etiopathogenesis of AD, suggesting that environmental factors and/or epigenetic phenomena may also contribute to AD pathology and phenotypic expression of dementia. The genomics of AD is still in its infancy, but is helping to understand novel aspects of the disease including genetic epidemiology, multifactorial risk factors, pathogenic mechanisms associated with genetic networks and genetically-regulated metabolic cascades. AD genomics is also helping to develop new strategies in pharmacogenomic research and prevention. Functional genomics, proteomics, pharmacogenomics, high-throughput methods, combinatorial chemistry and modern bioinformatics will greatly contribute to accelerate drug development for AD and other complex disorders. Main genes involved in AD include mutational loci (APP, PS1, PS2, TAU) and multiple susceptibility loci (APOE, A2M, AACT, LRP1, IL1A, TNF, ACE, BACE, BCHE, CST3, MTHFR, GSK3B, NOS) distributed across the human genome. Genomic associations integrate bigenic, trigenic, tetragenic or polygenic matrix models to investigate the genomic organization of AD in comparison to the control population. Similar genetic models are used in pharmacogenomics to elucidate genotype-specific responses of AD patients to a particular drug or combination of drugs. Using APOE-related monogenic models it has been demonstrated that the therapeutic response to drugs in AD is genotype-specific. A multifactorial therapy combining 3 different drugs yielded positive results during the 6-12 months in approximately 60% of the patients. With this therapeutic strategy, APOE-4/4 carriers were the worst responders, and patients with the APOE-3/4 genotype were the best responders. In bigenic and trigenic models it was possible to differentiate the influencial effect of PS1 and PS2

  13. [Drug treatment of Alzheimer's disease].

    PubMed

    González González, J A

    2001-01-01

    The Alzheimer's disease is caused by a today unknown plurietiopathology that does not allow to establish an effective treatment. In the last years, important advances about neuronal physiology and its molecular bases of functioning has been attempt. At the same time, the research and finding of medicaments which used individually or together allow us to advance from a symptomatic treatment to influence and be effective etiopathologically in the Alzheimer's disease. A few are trying to maintain the structure and function of the neurons (synapsis). Others are concentrated on prevent their death or substitute the damaged cells by embryonic mother cells. Nowadays, there are important projects in an experimental stage of research with the hope that "they will be useful for everything" or unless to slow down or stop the Alzheimer's disease. We are going to talk about these medicaments in this article. PMID:11783035

  14. [Alzheimer's disease, supporting carers].

    PubMed

    Lottin, Arlette; Botter, René

    2016-03-01

    The association France Alzheimer provides carers with resources. It runs training programmes and organises "Memory Cafes". These initiatives give carers the opportunity to talk about their daily struggles, close to home, and to obtain advice on how to better manage their situation. PMID:26975685

  15. About Alzheimer's Disease: Risk Factors and Prevention

    MedlinePlus

    ... About ADEAR About Alzheimer's Disease: Risk Factors and Prevention We can’t control some risk factors for ... as well. NIA Information on Risk Factors and Prevention 2014-2015 Alzheimer's Disease Progress Report: Advancing Research ...

  16. Coping & Caring: Living with Alzheimer's Disease.

    ERIC Educational Resources Information Center

    Leroux, Charles

    This guide on Alzheimer's disease is for those who care for Alzheimer's patients, as well as those who want to learn more about the disease. It answers these questions: (1) what is Alzheimer's? (2) how does the disease progress and how long does it last? (3) how do families cope? and (4) who can provide assistance and information? The guide also…

  17. Caregiver Response to Alzheimer's Disease.

    ERIC Educational Resources Information Center

    Novak, Mark; Guest, Carol

    1989-01-01

    Examined correlates of caregiver burden among 30 caregivers of Alzheimer's disease patients. Results revealed no significant correlation between length of time a caregiver had given care to a particular patient and the caregiver's subjective feelings of caregiver burden. Found significant, moderate correlation between caregiver burden and patient…

  18. Posture Recognition in Alzheimer's Disease

    ERIC Educational Resources Information Center

    Mozaz, Maria; Garaigordobil, Maite; Rothi, Leslie J. Gonzalez; Anderson, Jeffrey; Crucian, Gregory P.; Heilman, Kenneth M.

    2006-01-01

    Background: Apraxia is neurologically induced deficit in the ability perform purposeful skilled movements. One of the most common forms is ideomotor apraxia (IMA) where spatial and temporal production errors are most prevalent. IMA can be associated Alzheimer's disease (AD), even early in its course, but is often not identified possibly because…

  19. Genetic heterogeneity and Alzheimer`s disease

    SciTech Connect

    Schellenberg, G.D.; Wijsman, E.M.; Bird, T.D.

    1994-09-01

    In some early-onset Alzheimer`s disease (AD) families, inheritance is autosomal dominant. (Early-onset AD is arbitarily defined as onset at {le} 60 years.) Two loci have been identified which are causative for early-onset familial AD (FAD). One is the amyloid precursor protein gene in which specific mutation have been identified. The second is a locus at 14q24.3 (AD3) which has been localized by linkage analysis; the gene and specific mutations have not been identified. Linkage studies place this locus between D14S61 and D14S63. These 2 loci, however, do not account for all early-onset FAD. The Volga German (VG) kindreds are descendants of families which emigrated from Germany to the Volga river region of Russia and subsequently to the US; AD in these families is hypothesized to be the result of a common genetic founder. The average age-at-onset in these families is 57 years. Linkage analysis for this group has been negative for the APP gene and for chromosome 14 markers. Thus, there is at least 1 other early-onset FAD locus. Recently, the {epsilon}4 allele of apolipoprotein E (ApoE) was identified as a risk-factor for late-onset AD. In a series of 53 late-onset kindreds, a strong genetic association was observed between the ApoE {epsilon}4 allele and AD. However, when linkage analysis was performed using a highly polymorphic locus at the ApoCII gene, which is within 30 kb of ApoE, significant evidence for co-segregation was not observed. This and other data suggests that while ApoE is an age-at-onset modifying locus, another gene(s), located elsewhere, contribute(s) to late-onset AD. Thus, there is probably at least 1 other late-onset locus. Once the VG locus is identified, it will be possible to determine whether an allelic variant of this locus is responsible for late-onset FAD.

  20. Alzheimer's disease and euthanasia.

    PubMed

    Alvargonzález, David

    2012-12-01

    Employing the tenets of philosophical materialism, this paper discusses the ethical debate surrounding assisted suicide for persons suffering end-stage Alzheimer's. It first presents a classification of the dissociative situations between "human individual" and "human person". It then moves on to discuss challenges to diagnosed persons and their caregivers in relation to the cardinal virtues of Spinozistic ethics--strength of character (fortitudo), firmness (animositas) and generosity (generositas). Finally, a number of ideas attached to the debate--"right of choice", "death with dignity", "quality of life" and "compassion in dying"--are discussed in order to clarify their foundations. PMID:22939533

  1. Immunotherapeutic Approaches to Alzheimer's Disease

    NASA Astrophysics Data System (ADS)

    Monsonego, Alon; Weiner, Howard L.

    2003-10-01

    Although neurodegenerative diseases such as Alzheimer's disease are not classically considered mediated by inflammation or the immune system, in some instances the immune system may play an important role in the degenerative process. Furthermore, it has become clear that the immune system itself may have beneficial effects in nervous system diseases considered neurodegenerative. Immunotherapeutic approaches designed to induce a humoral immune response have recently been developed for the treatment of Alzheimer's disease. These studies have led to human trials that resulted in both beneficial and adverse effects. In animal models, it has also been shown that immunotherapy designed to induce a cellular immune response may be of benefit in central nervous system injury, although T cells may have either a beneficial or detrimental effect depending on the type of T cell response induced. These areas provide a new avenue for exploring immune system-based therapy of neurodegenerative diseases and will be discussed here with a primary focus on Alzheimer's disease. We will also discuss how these approaches affect microglia activation, which plays a key role in therapy of such diseases.

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

    PubMed

    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. PMID:26946341

  3. Endocannabinoid signalling in Alzheimer's disease.

    PubMed

    Maroof, Nazia; Pardon, Marie Christine; Kendall, David A

    2013-12-01

    The ECs (endocannabinoids) AEA (anandamide) and 2-AG (2-arachidonoylglycerol) and their lipid congeners OEA (N-oleoylethanolamide) and PEA (N-palmitoylethanolamide) are multifunctional lipophilic signalling molecules. The ECs, OEA and PEA have multiple physiological roles including involvement in learning and memory, neuroinflammation, oxidative stress, neuroprotection and neurogenesis. They have also been implicated in the pathology of, or perhaps protective responses to, neurodegenerative diseases. This is particularly the case with Alzheimer's disease, the most common age-related dementia associated with impairments in learning and memory accompanied by neuroinflammation, oxidative stress and neurodegeneration. The present mini-review examines the evidence supporting the roles that ECs appear to play in Alzheimer's disease and the potential for beneficial therapeutic manipulation of the EC signalling system. PMID:24256258

  4. Thiamin and Alzheimer's disease.

    PubMed

    Blass, J P; Sheu, K F; Cooper, A J; Jung, E H; Gibson, G E

    1992-01-01

    Because of clinical and neuropathological overlap between the characteristics of dementia of the Alzheimer type (DAT) and of a human thiamin deficiency syndrome (Wernicke-Korsakoff syndrome), thiamin pyrophosphate (TPP) dependent processes have been studied in DAT brain and other tissues. The activities of 3 TPP-dependent enzymes are reduced in DAT brain: transketolase (TK), the pyruvate dehydrogenase complex (PDHC), and the alpha-ketoglutarate dehydrogenase complex (KGDHC). Quantitatively, the most marked reductions are in KGDHC (to less than 20% of normal). In cultured skin fibroblasts, KGDHC activity is reduced to 50-60% of normal, TK activity to 80-90% of normal, and PDHC is normal. Structural and molecular studies of the DAT and non-DAT enzymes are in process. A lesion of KGDHC may be related to the pathogenesis of DAT. Treatment with large doses of thiamin has not been beneficial, but the data are not totally negative. Further studies of thiamin-dependent mechanisms in DAT seem justified. PMID:1297775

  5. Worldwide Alzheimer's disease neuroimaging initiative.

    PubMed

    Carrillo, Maria C; Bain, Lisa J; Frisoni, Giovanni B; Weiner, Michael W

    2012-07-01

    The Alzheimer's Disease Neuroimaging Initiative (ADNI) was launched in 2003 to speed drug development by validating imaging and blood/cerebrospinal fluid biomarkers for Alzheimer's disease clinical treatment trials. ADNI is a naturalistic (nontreatment) multisite longitudinal study. A true public-private partnership, the first phase of ADNI (ADNI 1) set a new standard for data sharing without embargo. In addition, it has been extended to 2017 by additional funding (North American-ADNI Grand Opportunities and ADNI 2) as well as multiple projects around the world, collectively known as Worldwide ADNI (WW-ADNI). The goal of WW-ADNI is to harmonize projects and results across different geographical sites and to encourage and harmonize data management and availability to investigators around the world. WW-ADNI projects are currently underway in North America, Europe, Japan, Australia, Korea, Taiwan, and Argentina, with a nascent program in China and a possible future program in Brazil. PMID:22748939

  6. Recognizing apathy in Alzheimer's disease.

    PubMed

    Lerner, Alan J; Strauss, Milton; Sami, Susie A

    2007-11-01

    Apathy has been increasingly recognized as a neuropsychiatric symptom in many neurologic disorders. In this paper, we review the clinical features of apathy in Alzheimer's disease. We also review screening, the differential diagnosis including depression, medical illnesses, and mild cognitive impairment, and treating modalities and issues. It must also be recognized that apathy per se almost never occurs as an isolated syndrome, so it must be viewed in the context of an individual's entire behavioral and cognitive status. PMID:17999565

  7. Cellular basis of Alzheimer's disease.

    PubMed

    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. PMID:21369424

  8. Progress Report on Alzheimer Disease: Volume III.

    ERIC Educational Resources Information Center

    National Inst. on Aging (DHHS/PHS), Bethesda, MD.

    This report summarizes advances in the understanding of Alzheimer's disease, the major cause of mental disability among older Americans. The demography of the disease is discussed, noting that approximately 2.5 million American adults are afflicted with the disease and that the large increase in the number of Alzheimer's disease patients is due to…

  9. Alzheimer's Disease Facts and Figures

    MedlinePlus

    ... prevented, cured or even slowed. Invest in a world without Alzheimer's. Donate Caregivers In 2015, 15.9 ... Association ® . All rights reserved. Our vision is a world without Alzheimer's Formed in 1980, the Alzheimer's Association ...

  10. Amyloid beta peptide immunotherapy in Alzheimer disease.

    PubMed

    Delrieu, J; Ousset, P J; Voisin, T; Vellas, B

    2014-12-01

    Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation. PMID:25459121

  11. Association studies in late onset sporadic Alzheimer`s disease

    SciTech Connect

    Goate, A.M.; Lendon, C.; Talbot, C.

    1994-09-01

    Alzheimer`s disease (AD) is characterized by an adult onset progressive dementia and the presence of numerous plaques and tangles within the brain at autopsy. The senile plaques are composed of a proteinaceous core surrounded by dystrophic neurites. The major protein component of the core is {beta}-amyloid but antibodies to many other proteins bind to senile plaques, e.g., antibodies to apolioprotein E (ApoE) and to {alpha}1-antichymotrypsin (AACT). Genetic studies have implicated mutations within the {beta}-amyloid precursor protein gene as the cause of AD in a small number of early onset AD families. More recently, assocition studies in late onset AD have demonstrated a positive association between ApoE-{epsilon}4 and AD. We report evidence for a negative association between ApoE-{epsilon}2 and AD in a large sample of sporadic late onset AD cases and matched controls supporting the role of ApoE in the etiology of AD. Ninety-three patients with sporadic AD (average age = 75 years, s.d. 8 yrs.) and 67 normal controls from the same ethnic background (age = 77 yrs., s.d. 10 yrs.) were recruited through the patient registry of the Washington University Alzheimer`s Disease Research Center. We found a statistically significant increase in ApoE-{epsilon}4 allele frequency in patients compared with controls ({chi}{sup 2}=7.75, 1 d.f., one tailed p=0.0027) and a significant decrease in {epsilon}2 allele frequency (Fisher`s exact test, one tailed p=0.0048), whereas the decreased frequency of {epsilon}3 in the patient groups was not statistically significant. Allele {epsilon}2 conferred a strong protective effect in our sample, with the odds ratio for AD for subjects possessing this allele being 0.08 (85% confidence interval 0.01-0.69). Similar studies using a polymorphism within the AACT gene showed no association with alleles at this locus in the entire AD sample or in AD cases homozygous for ApoE-{epsilon}3.

  12. Drug treatments in Alzheimer's disease.

    PubMed

    Briggs, Robert; Kennelly, Sean P; O'Neill, Desmond

    2016-06-01

    Despite the significant public health issue that it poses, only five medical treatments have been approved for Alzheimer's disease (AD) and these act to control symptoms rather than alter the course of the disease. Studies of potential disease-modifying therapy have generally been undertaken in patients with clinically detectable disease, yet evidence suggests that the pathological changes associated with AD begin several years before this. It is possible that pharmacological therapy may be beneficial in this pre-clinical stage before the neurodegenerative process is established. Techniques providing earlier diagnosis, such as cerebrospinal fluid biomarkers and amyloid positron emission tomography neuroimaging, are key to testing this theory in clinical trials. Recent results from trials of agents such as aducanumab are encouraging but must also be interpreted with caution. Such medicines could potentially delay the onset of dementia and would therefore markedly reduce its prevalence. However, we currently remain a good distance away from clinically available disease-modifying therapy. PMID:27251914

  13. Pharmacotherapeutic targets in Alzheimer's disease

    PubMed Central

    Biran, Yif'at; Masters, Colin L; Barnham, Kevin J; Bush, Ashley I; Adlard, Paul A

    2009-01-01

    Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder which is characterized by an increasing impairment in normal memory and cognitive processes that significantly diminishes a person's daily functioning. Despite decades of research and advances in our understanding of disease aetiology and pathogenesis, there are still no effective disease-modifying drugs available for the treatment of AD. However, numerous compounds are currently undergoing pre-clinical and clinical evaluations. These candidate pharma-cotherapeutics are aimed at various aspects of the disease, such as the microtubule-associated τ-protein, the amyloid-β (Aβ) peptide and metal ion dyshomeostasis – all of which are involved in the development and progression of AD. We will review the way these pharmacological strategies target the biochemical and clinical features of the disease and the investigational drugs for each category. PMID:19040415

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

    MedlinePlus

    ... 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 ...

  15. Choosing Alzheimer's disease prevention clinical trial populations.

    PubMed

    Grill, Joshua D; Monsell, Sarah E

    2014-03-01

    To assist investigators in making design choices, we modeled Alzheimer's disease prevention clinical trials. We used longitudinal Clinical Dementia Rating Scale Sum of Boxes data, retention rates, and the proportions of trial-eligible cognitively normal participants age 65 and older in the National Alzheimer's Coordinating Center Uniform Data Set to model trial sample sizes, the numbers needed to enroll to account for drop out, and the numbers needed to screen to successfully complete enrollment. We examined how enrichment strategies affected each component of the model. Relative to trials enrolling 65-year-old individuals, trials enriching for older (minimum 70 or 75) age required reduced sample sizes, numbers needed to enroll, and numbers needed to screen. Enriching for subjective memory complaints reduced sample sizes and numbers needed to enroll more than age enrichment, but increased the number needed to screen. We conclude that Alzheimer's disease prevention trials can enroll elderly participants with minimal effect on trial retention and that enriching for older individuals with memory complaints might afford efficient trial designs. PMID:24119546

  16. Olfactory dysfunction in Alzheimer's disease.

    PubMed

    Zou, Yong-Ming; Lu, Da; Liu, Li-Ping; Zhang, Hui-Hong; Zhou, Yu-Ying

    2016-01-01

    Alzheimer's disease (AD) is a common neurodegenerative disorder with the earliest clinical symptom of olfactory dysfunction, which is a potential clinical marker for AD severity and progression. However, many questions remain unanswered. This article reviews relevant research on olfactory dysfunction in AD and evaluates the predictive value of olfactory dysfunction for the epidemiological, pathophysiological, and clinical features of AD, as well as for the conversion of cognitive impairment to AD. We summarize problems of existing studies and provide a useful reference for further studies in AD olfactory dysfunction and for clinical applications of olfactory testing. PMID:27143888

  17. [Antibody therapy for Alzheimer's disease].

    PubMed

    Tabira, Takeshi; Matsumoto, Shin-Ei; Jin, Haifeng

    2011-11-01

    In order to avoid Abeta-induced autoimmune encephalitis, several monoclonal and polyclonal antibodies are in clinical trials. These are bapineuzumab, solanezumab, ponezumab, gantenerumab, BAN2401, gammaguard and octagam. Since each antibody has a different antigen epitope of Abeta, anti-amyloid activities are different. It is unknown which antibody is effective for Alzheimer disease, and we must wait for the result of clinical trials. Some patients who developed tissue amyloid plaque immuno-reactive (TAPIR) antibody showed slower decline after AN-1792 vaccination. We developed TAPIR-like monoclonal antibody, which was found to react with Abeta oligomers preferentially. PMID:22277519

  18. Golgi fragmentation in Alzheimer's disease

    PubMed Central

    Joshi, Gunjan; Bekier, Michael E.; Wang, Yanzhuang

    2015-01-01

    The Golgi apparatus is an essential cellular organelle for post-translational modifications, sorting, and trafficking of membrane and secretory proteins. Proper functionality of the Golgi requires the formation of its unique cisternal-stacking morphology. The Golgi structure is disrupted in a variety of neurodegenerative diseases, suggesting a common mechanism and contribution of Golgi defects in neurodegenerative disorders. A recent study on Alzheimer's disease (AD) revealed that phosphorylation of the Golgi stacking protein GRASP65 disrupts its function in Golgi structure formation, resulting in Golgi fragmentation. Inhibiting GRASP65 phosphorylation restores the Golgi morphology from Aβ-induced fragmentation and reduces Aβ production. Perturbing Golgi structure and function in neurons may directly impact trafficking, processing, and sorting of a variety of proteins essential for synaptic and dendritic integrity. Therefore, Golgi defects may ultimately promote the development of AD. In the current review, we focus on the cellular impact of impaired Golgi morphology and its potential relationship to AD disease development. PMID:26441511

  19. Alzheimer's disease: molecular concepts and therapeutic targets

    NASA Astrophysics Data System (ADS)

    Fassbender, K.; Masters, C.; Beyreuther, K.

    2001-06-01

    The beta amyloid peptide is the major component of the neuritic plaques, the characteristic lesions in Alzheimer's disease. Mutations in three genes (APP, PS-1, and PS-2) cause familial Alzheimer's disease by alteration of the rate of generation of amyloid peptide or the length of this peptide. However, in the 90% non-familial cases, other factors play a major pathogenetic role. These include the apolipoprotein E genotype, the "plaque-associated" proteins promoting the formation of toxic fibrillar aggregates or the chronic inflammatory responses. The aim of this review is to explain the steps in the complex cascade leading to Alzheimer's disease and, based on this, to report the current efforts to intervene in these different pathophysiological events in order to prevent progression of Alzheimer's disease. Whereas acetylcholine substitution is currently used in clinical practice, future therapeutical strategies to combat Alzheimer's disease may include anti-inflammatory treatments, vaccination against beta amyloid peptide, or treatment with cholesterol-lowering drugs.

  20. Alzheimer's Disease | NIH MedlinePlus the Magazine

    MedlinePlus

    ... 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 ...

  1. Alzheimer's Disease | NIH MedlinePlus the Magazine

    MedlinePlus

    ... of this page please turn JavaScript on. Feature: Alzheimer's Disease Alzheimer's Treatment Past Issues / Winter 2015 Table of ... Administration (FDA) has approved four drugs to treat Alzheimer's disease: for mild to moderate symptoms, rivastigmine, galantamine, and ...

  2. Diabetes and Alzheimer's disease crosstalk.

    PubMed

    Baglietto-Vargas, David; Shi, Jessica; Yaeger, Devin M; Ager, Rahasson; LaFerla, Frank M

    2016-05-01

    Despite intensive research efforts over the past few decades, the mechanisms underlying the etiology of sporadic Alzheimer's disease (AD) remain unknown. This fact is of major concern because the number of patients affected by this medical condition is increasing exponentially and the existing treatments are only palliative in nature and offer no disease modifying affects. Interestingly, recent epidemiological studies indicate that diabetes significantly increases the risk of developing AD, suggesting that diabetes may play a causative role in the development of AD pathogenesis. Therefore, elucidating the molecular interactions between diabetes and AD is of critical significance because it might offer a novel approach to identifying mechanisms that may modulate the onset and progression of sporadic AD cases. This review highlights the involvement of several novels pathological molecular mechanisms induced by diabetes that increase AD pathogenesis. Furthermore, we discuss novel findings in animal model and clinical studies involving the use of anti-diabetic compounds as promising therapeutics for AD. PMID:26969101

  3. Oxidative stress in Alzheimer disease

    PubMed Central

    Durany, Nuria

    2009-01-01

    Alzheimer disease (AD) is a progressive dementia affecting a large proportion of the aging population. The histopathological changes in AD include neuronal cell death, formation of amyloid plaques and neurofibrillary tangles. There is also evidence that brain tissue in patients with AD is exposed to oxidative stress (e.g., protein oxidation, lipid oxidation, DNA oxidation and glycoxidation) during the course of the disease. Advanced glycation endproducts (AGEs) are present in amyloid plaques in AD, and its extracellular accumulation may be caused by an accelerated oxidation of glycated proteins. AGEs participate in neuronal death causing direct (chemical) and indirect (cellular) free radical production and consequently increase oxidative stress. The development of drugs for the treatment of AD that breaks the vicious cycles of oxidative stress and neurodegeneration offer new opportunities. These approaches include AGE-inhibitors, antioxidants and anti-inflammatory substances, which prevent free radical production. PMID:19372765

  4. [Vaccination therapy for Alzheimer's disease].

    PubMed

    Tabira, Takeshi

    2009-11-01

    Since AN-1792 vaccine induced autoimmune encephalitis, several pharmaceutical companies are now concentrated in developing antibody therapy in Alzheimer's disease (AD). Each antibody has own characteristics. Thus, it is unpredictable at present which antibody is the most beneficial until we see the result of clinical trials. If disease modifying antibodies were found, they will be widely used for treatment of AD in near future. As a candidate of such antibodies, we have developed TAPIR-like antibody with much higher affinity to Abeta42 than Abeta40, and it effectively deleted senile plaque amyloid and Abeta oligomers without increasing microhemorrhages. Although passive immunization can avoid autoimmune encephalitis, it is expensive and it is not suitable for prevention. Thus, safe vaccines by active immunization would be better. Vaccines that induce Th2 type immune responses such as oral vaccine or per-nasal vaccine would be promising. PMID:20030228

  5. Neuropathological Alterations in Alzheimer Disease

    PubMed Central

    Serrano-Pozo, Alberto; Frosch, Matthew P.; Masliah, Eliezer; Hyman, Bradley T.

    2011-01-01

    The neuropathological hallmarks of Alzheimer disease (AD) include “positive” lesions such as amyloid plaques and cerebral amyloid angiopathy, neurofibrillary tangles, and glial responses, and “negative” lesions such as neuronal and synaptic loss. Despite their inherently cross-sectional nature, postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and, consequently, the development of diagnostic criteria that are now used worldwide. In addition, clinicopathological correlation studies have been crucial to generate hypotheses about the pathophysiology of the disease, by establishing that there is a continuum between “normal” aging and AD dementia, and that the amyloid plaque build-up occurs primarily before the onset of cognitive deficits, while neurofibrillary tangles, neuron loss, and particularly synaptic loss, parallel the progression of cognitive decline. Importantly, these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloid PET and volumetric MRI. PMID:22229116

  6. Inflammation, Microglia and Alzheimer's Disease

    PubMed Central

    Cameron, Brent; Landreth, Gary E.

    2009-01-01

    Microglia are the brain's tissue macrophage and representative of the innate immune system. These cells normally provide tissue maintenance and immune surveillance of the brain. In the Alzheimer's disease brain amyloid deposition provokes the phenotypic activation of microglia and their elaboration of proinflammatory molecules. Recent work has implicated Toll-like receptors in microglial recognition and response to amyloid fibrils. It is now evident that these cells exhibit more complex and heterogeneous phenotypes than previously appreciated that reflect both the plasticity of cells in this lineage and their ability to transition between activation states. The phenotypic diversity is associated with inactivation of the inflammatory response and tissue repair. We discuss recent evidence that the brain can be infiltrated by circulating monocytes in the diseased brain and that these cells may comprise a unique subpopulation of myeloid cells that may be functionally distinct from the endogenous microglia. PMID:19833208

  7. Clinicopathologic Correlations in a Large Alzheimer Disease Center Autopsy Cohort: Neuritic Plaques and Neurofibrillary Tangles “Do Count” When Staging Disease Severity

    PubMed Central

    Nelson, Peter T.; Jicha, Gregory A.; Schmitt, Frederick A.; Liu, Huaichen; Davis, Daron G.; Mendiondo, Marta S.; Abner, Erin L.; Markesbery, William R.

    2011-01-01

    There is uncertainty regarding the association of cognitive decline in Alzheimer disease (AD) with classic histopathologic features—neurofibrillary tangles (NFTs) and “neuritic” amyloid plaques (NPs). This uncertainty fuels doubts about the diagnostic importance of NFTs and NPs and leads to confusion regarding hypotheses of AD pathogenesis. Three hundred ninety subjects who underwent longitudinal premortem clinical workup and postmortem quantitative neuropathologic assessment served as the group to address this issue. Subjects with concomitant brain disease(s) were analyzed independently to more accurately assess the contribution of distinct pathologies to cognitive decline. More than 60% of patients of all age groups had important non-AD brain pathologies. However, subjects without superimposed brain diseases showed strong correlations between AD-type pathology counts (NFTs > NPs) and premortem Mini-Mental State Examination scores. The observed correlation was stronger in isocortex than in allocortex and was maintained across age groups including patients older than 90 years. A theoretical model is proposed in which our results are interpreted to support the “amyloid cascade hypothesis” of AD pathogenesis. Our data show that there are many important contributory causes to cognitive decline in older persons. However, NFTs and NPs should not be dismissed as irrelevant in AD based on clinicopathologic correlation. PMID:18090922

  8. 2014-2015 Alzheimer's Disease Progress Report

    MedlinePlus

    ... Advocate for strategies to empower patients and engage citizens Alzheimer’s Disease and Related Dementias Dr. Alois Alzheimer ... complex disease day by day. NIH, with the participation of all who search for answers, has set ...

  9. The age factor in Alzheimer's disease.

    PubMed

    Guerreiro, Rita; Bras, Jose

    2015-01-01

    Alzheimer's disease is the most common type of dementia, and it is characterized by a decline in memory or other thinking skills. The greatest risk factor for Alzheimer's disease is advanced age. A recent genome-wide study identified a locus on chromosome 17 associated with the age at onset, and a specific variant in CCL11 is probably responsible for the association. The association of a protective haplotype with a 10-year delay in the onset of Alzheimer's disease and the identification of a CCL11 variant with possible functional roles in this association might allow the future development of immunomodulators with the potential to halve disease incidence. PMID:26482651

  10. Alzheimer's disease therapy - an update.

    PubMed

    Nikolov, R

    1998-05-01

    The 5th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy focused on new therapeutic approaches for the treatment of Alzheimer 's disease (AD) based on the latest basic science data. The two major pharmacological principles of cholinergic therapy are 1) reduction of acetylcholine hydrolysis by means of acetylcholinesterase (AChE) inhibitors; and 2) direct stimulation of nicotinic or muscarinic receptors with selective agonists. Currently used AChE inhibitors are tacrine, donepezil hydrochloride, rivastigmine and metrifonate. In the area of muscarinic and nicotinic receptor modulation, studies were presented on AF-102B and AF-150(S), BIBN-99, CI-1017, RJR-2403, ABT-418, ABT-089, GTS-21 and SIB-1553A. Based on evidence of inflammatory mechanisms in the pathogenesis of AD, selective COX-2 inhibitors for the prevention and treatment of AD are a target of several pharmaceutical companies. Concerning known antiinflammatory drugs, results from controlled trials are expected soon. Estrogen replacement has been reported to produce cognitive and affective improvement in women with AD, and results from a number of studies were presented. Age-associated increases in oxidative stress may play a role in AD and thus antioxidants may also have a place in the therapy of this disease. The antioxidants vitamin E and selegiline are being investigated. Other drugs under investigation are propentofylline, Cerebrolysin, citicoline sodium, CDP-choline, memantine, Egb-761, calagualine and AIT-082. Iododoxorubicin may represent a new class of compounds able to interfere with the beta-amyloid cascade in AD and other brain amyloid diseases. Future preventive strategies in AD include genotype analysis and screening, presymptomatic diagnosis and avoidance of environmental risk factors. PMID:15616667

  11. Alzheimer's Disease and Stem Cell Therapy

    PubMed Central

    Choi, Sung S.; Lee, Sang-Rae; Kim, Seung U.

    2014-01-01

    The loss of neuronal cells in the central nervous system may occur in many neurodegenerative diseases. Alzheimer's disease is a common senile disease in people over 65 years, and it causes impairment characterized by the decline of mental function, including memory loss and cognitive impairment, and affects the quality of life of patients. However, the current therapeutic strategies against AD are only to relieve symptoms, but not to cure it. Because there are only a few therapeutic strategies against Alzheimer's disease, we need to understand the pathogenesis of this disease. Cell therapy may be a powerful tool for the treatment of Alzheimer's disease. This review will discuss the characteristics of Alzheimer's disease and various available therapeutic strategies. PMID:24737939

  12. Alzheimer's disease & metals: therapeutic opportunities

    PubMed Central

    Kenche, Vijaya B; Barnham, Kevin J

    2011-01-01

    Alzheimer's disease (AD) is the most common age related neurodegenerative disease. Currently, there are no disease modifying drugs, existing therapies only offer short-term symptomatic relief. Two of the pathognomonic indicators of AD are the presence of extracellular protein aggregates consisting primarily of the Aβ peptide and oxidative stress. Both of these phenomena can potentially be explained by the interactions of Aβ with metal ions. In addition, metal ions play a pivotal role in synaptic function and their homeostasis is tightly regulated. A breakdown in this metal homeostasis and the generation of toxic Aβ oligomers are likely to be responsible for the synaptic dysfunction associated with AD. Therefore, approaches that are designed to prevent Aβ metal interactions, inhibiting the formation of toxic Aβ species as well as restoring metal homeostasis may have potential as disease modifying strategies for treating AD. This review summarizes the physiological and pathological interactions that metal ions play in synaptic function with particular emphasis placed on interactions with Aβ. A variety of therapeutic strategies designed to address these pathological processes are also described. The most advanced of these strategies is the so-called ‘metal protein attenuating compound’ approach, with the lead molecule PBT2 having successfully completed early phase clinical trials. The success of these various strategies suggests that manipulating metal ion interactions offers multiple opportunities to develop disease modifying therapies for AD. PMID:21232050

  13. Role of Methylglyoxal in Alzheimer's Disease

    PubMed Central

    Zambonin, Laura; Hrelia, Silvana

    2014-01-01

    Alzheimer's disease is the most common and lethal neurodegenerative disorder. The major hallmarks of Alzheimer's disease are extracellular aggregation of amyloid β peptides and, the presence of intracellular neurofibrillary tangles formed by precipitation/aggregation of hyperphosphorylated tau protein. The etiology of Alzheimer's disease is multifactorial and a full understanding of its pathogenesis remains elusive. Some years ago, it has been suggested that glycation may contribute to both extensive protein cross-linking and oxidative stress in Alzheimer's disease. Glycation is an endogenous process that leads to the production of a class of compounds known as advanced glycation end products (AGEs). Interestingly, increased levels of AGEs have been observed in brains of Alzheimer's disease patients. Methylglyoxal, a reactive intermediate of cellular metabolism, is the most potent precursor of AGEs and is strictly correlated with an increase of oxidative stress in Alzheimer's disease. Many studies are showing that methylglyoxal and methylglyoxal-derived AGEs play a key role in the etiopathogenesis of Alzheimer's disease. PMID:24734229

  14. 2008 Alzheimer's disease facts and figures.

    PubMed

    2008-03-01

    Alzheimer's disease is the seventh leading cause of all deaths in the United States and the fifth leading cause of death in Americans older than the age of 65 years. More than 5 million Americans are estimated to have Alzheimer's disease. Every 71 seconds someone in America develops Alzheimer's disease; by 2050 it is expected to occur every 33 seconds. During the coming decades, baby boomers are projected to add 10 million people to these numbers. By 2050, the incidence of Alzheimer's disease is expected to approach nearly a million people per year, with a total estimated prevalence of 11 to 16 million persons. Significant cost implications related to Alzheimer's disease and other dementias include an estimated $148 billion annually in direct (Medicare/Medicaid) and indirect (eg, caregiver lost wages and out-of-pocket expenses, decreased business productivity) costs. Not included in these figures are the estimated 10 million caregivers who annually provide $89 billion in unpaid services to individuals with Alzheimer's disease. This report provides information to increase understanding of the public health impact of Alzheimer's disease, including incidence and prevalence, mortality, lifetime risks, costs, and impact on family caregivers. PMID:18631956

  15. Neddylation dysfunction in Alzheimer's disease.

    PubMed

    Chen, Yuzhi; Neve, Rachael L; Liu, Helena

    2012-11-01

    Ubiquitin-dependent proteolysis is a major mechanism that downregulates misfolded proteins or those that have finished a programmed task. In the last two decades, neddylation has emerged as a major regulatory pathway for ubiquitination. Central to the neddylation pathway is the amyloid precursor protein (APP)-binding protein APP-BP1, which together with Uba3, plays an analogous role to the ubiquitin-activating enzyme E1 in nedd8 activation. Activated nedd8 covalently modifies and activates a major class of ubiquitin ligases called Cullin-RING ligases (CRLs). New evidence suggests that neddylation also modifies Type-1 transmembrane receptors such as APP. Here we review the functions of neddylation and summarize evidence suggesting that dysfunction of neddylation is involved in Alzheimer's disease. PMID:22805479

  16. Biomarker Modeling of Alzheimer's Disease

    PubMed Central

    Jack, Clifford R; Holtzman, David M

    2014-01-01

    Alzheimer's disease (AD) is a slowly progressing disorder in which pathophysiological abnormalities, detectable in vivo by biomarkers, precede overt clinical symptoms by many years to decades. Five AD biomarkers are sufficiently validated to have been incorporated into clinical diagnostic criteria and commonly used in therapeutic trials. Current AD biomarkers fall into 2 categories: biomarkers of amyloid-β plaques and of tau-related neurodegeneration. Three of the 5 are imaging measures and two are cerebrospinal fluid analytes. AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping manner. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) vs. time. In this review we discuss several time-dependent models of AD which take into consideration varying age of onset (early vs. late) and the influence of aging and co-occurring brain pathologies that commonly arise in the elderly. PMID:24360540

  17. [Alzheimer's disease: the infectious hypothesis].

    PubMed

    Roubaud Baudron, Claire; Varon, Christine; Mégraud, Francis; Salles, Nathalie

    2015-12-01

    Several hypotheses are proposed for understanding the Alzheimer's disease (AD) pathological mechanisms, mainly the amyloid theory, but the process inducing Aß peptide deposit, tau protein degeneration, and ultimately neuronal loss, is still to be elucidated. Alteration of the blood-brain barrier and activation of neuroinflammation seem to play an important role in AD neurodegeneration, especially in the decrease of Aß peptide clearance, therefore suggesting a role of infectious agents. Epidemiological and experimental studies on cellular or murine models related to herpes simplex virus (HSV), spirochetes, Chlamydia pneumoniae or Borrelia, and systemic inflammation are reviewed. Aß peptide or tau protein could also behave like a prion protein. Infectious agents could thus have an impact on AD by direct interaction with neurotropism or systemic inflammation. Although the results of these studies are not conclusive, they may contribute to the understanding of AD pathology. PMID:26707559

  18. Noradrenergic dysfunction in Alzheimer's disease

    PubMed Central

    Gannon, Mary; Che, Pulin; Chen, Yunjia; Jiao, Kai; Roberson, Erik D.; Wang, Qin

    2015-01-01

    The brain noradrenergic system supplies the neurotransmitter norepinephrine throughout the brain via widespread efferent projections, and plays a pivotal role in modulating cognitive activities in the cortex. Profound noradrenergic degeneration in Alzheimer's disease (AD) patients has been observed for decades, with recent research suggesting that the locus coeruleus (where noradrenergic neurons are mainly located) is a predominant site where AD-related pathology begins. Mounting evidence indicates that the loss of noradrenergic innervation greatly exacerbates AD pathogenesis and progression, although the precise roles of noradrenergic components in AD pathogenesis remain unclear. The aim of this review is to summarize current findings on noradrenergic dysfunction in AD, as well as to point out deficiencies in our knowledge where more research is needed. PMID:26136654

  19. 77 FR 11116 - Draft National Plan To Address Alzheimer's Disease

    Federal Register 2010, 2011, 2012, 2013, 2014

    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... Alzheimer's disease. Coordinate Alzheimer's disease research and services across all federal...

  20. Interrelations of Down Syndrome and Alzheimer Disease. ARC Facts.

    ERIC Educational Resources Information Center

    Schweber, Miriam

    This fact sheet summarizes the interrelations of Down syndrome and Alzheimer disease in a question and answer format. The following questions are addressed: What is Alzheimer disease? Why is a relationship suggested between Down syndrome and Alzheimer disease? Is there a genetic link between Alzheimer disease and Down syndrome? Why is a…

  1. Quantitative evaluation of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Duchesne, S.; Frisoni, G. B.

    2009-02-01

    We propose a single, quantitative metric called the disease evaluation factor (DEF) and assess its efficiency at estimating disease burden in normal, control subjects (CTRL) and probable Alzheimer's disease (AD) patients. The study group consisted in 75 patients with a diagnosis of probable AD and 75 age-matched normal CTRL without neurological or neuropsychological deficit. We calculated a reference eigenspace of MRI appearance from reference data, in which our CTRL and probable AD subjects were projected. We then calculated the multi-dimensional hyperplane separating the CTRL and probable AD groups. The DEF was estimated via a multidimensional weighted distance of eigencoordinates for a given subject and the CTRL group mean, along salient principal components forming the separating hyperplane. We used quantile plots, Kolmogorov-Smirnov and χ2 tests to compare the DEF values and test that their distribution was normal. We used a linear discriminant test to separate CTRL from probable AD based on the DEF factor, and reached an accuracy of 87%. A quantitative biomarker in AD would act as an important surrogate marker of disease status and progression.

  2. Genetic risk factors in Alzheimer's disease.

    PubMed Central

    Tilley, L; Morgan, K; Kalsheker, N

    1998-01-01

    Following a brief introduction and discussion of the pathological features of Alzheimer's disease, the main emphasis of this review article will be the genetic factors that have been implicated in this disease. These can be divided into two main categories. First, the three genes in which mutations are known to result in early onset autosomal dominant familial Alzheimer's disease will be discussed. These are well characterised but account for only a small proportion of Alzheimer's disease cases. Late onset, sporadic Alzheimer's disease is more common and evidence suggests that there is a genetic component to this type of disease. A number of genetic risk factors have been implicated that might increase the risk of developing sporadic disease. Many of these are controversial and studies have shown conflicting results, which are discussed in this section. Finally, a brief discussion of some of the mechanisms suggested to play a role in the pathogenesis of Alzheimer's disease is included. It is hoped that this will show why particular genes have been implicated in Alzheimer's disease and how they might be able to influence the development of the disease. PMID:10193509

  3. Insulin Resistance in Alzheimer's Disease

    PubMed Central

    Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

    2014-01-01

    Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037

  4. Alzheimer's disease and epigenetic diet.

    PubMed

    Sezgin, Zeynep; Dincer, Yildiz

    2014-12-01

    Alzheimer's disease (AD) is the most common neurodegenerative disease. Many efforts have been directed to prevent AD due to its rising prevalence and the lack of an effective curative treatment. Various epigenetic mechanisms are linked to pathogenesis of AD. Epigenetic alterations may occur through external factors and are known for their reversibility. Dietary factors can influence epigenetic mechanisms. Several neuroprotective nutrients have been shown to enhance cognition, memory and other impaired functions seen in AD. Within recent years neuroprotective nutrients have gained more attention in the field of epigenetic. A growing body of evidence suggest that epigenetic changes triggered by dietary nutrients have an important role in health and in prevention of some diseases, especially neurodegenerative disorders. Several studies have shown that folic acid, vitamin B12, choline, zinc, selenium, dietary polyphenols are capable of interacting with epigenetic mechanisms and ultimately gene expression. Epigenetic mechanisms resulting in neuronal dysfunction may be modified by diet. Therefore manipulation of epigenetic mechanisms via dietary nutrients may affect influence the vulnerability of neurons to degeneration which is seen in AD. The aim of this article is to provide a brief overview about the recent findings related to epigenetic alterations that are linked to AD pathogenesis, and to discuss the bioactive nutrients which can affect these epigenetic mechanisms. PMID:25290336

  5. Can Infections Cause Alzheimer's Disease?

    PubMed Central

    Mawanda, Francis; Wallace, Robert

    2013-01-01

    Late-onset Alzheimer's disease (AD) is the most prevalent cause of dementia among older adults, yet more than a century of research has not determined why this disease develops. One prevailing hypothesis is that late-onset AD is caused by infectious pathogens, an idea widely studied in both humans and experimental animal models. This review examines the infectious AD etiology hypothesis and summarizes existing evidence associating infectious agents with AD in humans. The various mechanisms through which different clinical and subclinical infections could cause or promote the progression of AD are considered, as is the concordance between putative infectious agents and the epidemiology of AD. We searched the PubMed, Web of Science, and EBSCO databases for research articles pertaining to infections and AD and systematically reviewed the evidence linking specific infectious pathogens to AD. The evidence compiled from the literature linking AD to an infectious cause is inconclusive, but the amount of evidence suggestive of an association is too substantial to ignore. Epidemiologic, clinical, and basic science studies that could improve on current understanding of the associations between AD and infections and possibly uncover ways to control this highly prevalent and debilitating disease are suggested. PMID:23349428

  6. Alzheimer's disease: early diagnosis and treatment.

    PubMed

    Chu, L W

    2012-06-01

    With ageing of populations, the worldwide population of persons with dementia will reach over 81 million by 2040, of which the most common cause is Alzheimer's disease. In recent years, there have been major advances in the understanding of its pathogenesis, methods to diagnose it, and treatment. Magnetic resonance brain imaging, cerebrospinal fluid biomarkers, and Pittsburgh compound B and fluorodeoxyglucose positron emission tomography of the brain can facilitate an accurate diagnosis of Alzheimer's disease in its early stage, and diagnose the mild cognitive impairment stage of Alzheimer's disease. At present, only symptomatic but not disease-modifying drug treatments are available. Donepezil, rivastigmine and galantamine are the currently approved cholinesterase inhibitors for the treatment of mild, moderate, and severe Alzheimer's disease. Overall, cholinesterase inhibitors show beneficial effects on cognition, activity of daily living, behaviour, and overall clinical rating. Memantine is another symptomatic treatment for moderate-to-severe Alzheimer's disease patients. It has a small beneficial effect on cognition, activity of daily living, behaviour, and overall clinical rating. Vitamin E has antioxidant properties, and may be used in some Alzheimer's disease patients without vascular risk factors. Concurrent non-pharmacological and psychosocial management of patients and their caregivers have a very important role. Disease-modifying therapies are still under development, whilst immunotherapy may be a viable option in the near future. PMID:22665688

  7. Dementia (Including Alzheimer Disease) (Beyond the Basics)

    MedlinePlus

    ... problems are caused by early Alzheimer disease. Normal age-related changes usually cause minor difficulties in short term memory and a slowed ability to learn and process information. These changes are usually mild and do not ...

  8. Perspectives on the etiology of Alzheimer's disease

    SciTech Connect

    Mozar, H.N.; Bal, D.G.; Howard, J.T.

    1987-03-20

    There is a lack of consensus among investigators concerning the etiology of Alzheimer's disease. Clues are lacking, however, and the authors have assessed them in a broad biologic context. This inquiry has led us to regard Alzheimer's disease as a multifactorial disorder in which a putative infective agent is an essential element. Despite seeming competition among current hypotheses, there is overall unity. The concept that Down's syndrome is a congenital form of Alzheimer's disease and that both conditions are the result of a ubiquitous infective pathogen that affects genetically susceptible individuals offers the broadest unification. In both conditions slow infections develops against the background of aging. Indirect evidence involving immunologic and other biologic phenomena supports the postulated infectious origin. Overlapping pathologic and clinical features of Alzheimer's disease and the known transmissible encephalopathies suggest a similar pathogenesis.

  9. Alzheimer's Disease - Multiple Languages: MedlinePlus

    MedlinePlus

    ... Supplements Videos & Tools You Are Here: Home → Multiple Languages → All Health Topics → Alzheimer's Disease URL of this page: https://medlineplus.gov/languages/alzheimersdisease.html Other topics A-Z A B ...

  10. Alzheimer's Disease - Multiple Languages: MedlinePlus

    MedlinePlus

    ... Supplements Videos & Tools You Are Here: Home → Multiple Languages → All Health Topics → Alzheimer's Disease URL of this page: https://www.nlm.nih.gov/medlineplus/languages/alzheimersdisease.html Other topics A-Z A B ...

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

    PubMed

    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. PMID:26963387

  12. Epigenetic Alterations in Alzheimer's Disease.

    PubMed

    Sanchez-Mut, Jose V; Gräff, Johannes

    2015-01-01

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

  13. Medical foods for Alzheimer's disease.

    PubMed

    Shah, Raj C

    2011-06-01

    Alzheimer's disease (AD) is a neurodegenerative condition associated with cognitive loss, behavioural changes, functional ability decline and caregiver burden. Given the worldwide public health impact of AD, novel interventions to reduce suffering experienced by AD patients need to be developed. Foods may offer a mechanism for intervention complementary to drugs, devices, biologicals and vaccines. Apart from foods with health claims (including dietary supplements), medical foods are also being explored as an intervention option. The purpose of this article is to describe how medical foods may complement other interventions for AD patients by: (i) defining what a medical food is; (ii) discussing whether AD is a condition amenable to medical food intervention; (iii) reviewing current clinical trial data on medical foods used in participants with AD; and (iv) highlighting steps needed to establish a more comprehensive framework for developing medical foods for AD. While medical foods may be defined differently in other countries, the US Orphan Drug Act of 1998 defined a medical food as a food formulated for enteral intake, taken under physician supervision, and intended to meet the distinctive nutritional requirements identified for a disease or condition. For AD to be amenable to medical food intervention, it must: (i) result in limited or impaired capacity to ingest, digest, absorb or metabolize ordinary foodstuff or certain nutrients; or (ii) have unique, medically determined nutrient requirements; and (iii) require dietary management that cannot be achieved by modification of the normal diet alone. While these criteria are most likely met in advanced AD, identifying unique nutritional requirements in early AD that cannot be met by normal diet modification requires a better understanding of AD pathophysiology. A PubMed search using the terms 'medical food' and 'Alzheimer', limited to clinical trials published in English with human participants with AD aged >65

  14. 2016 Alzheimer's disease facts and figures.

    PubMed

    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

  15. [Aβ immunotherapy for Alzheimer's disease].

    PubMed

    Sakai, Kenji; Yamada, Masahito

    2013-04-01

    Alzheimer's disease (AD) is one of the neurodegenerative diseases characterized by the deposition of amyloid-β-protein (Aβ) as senile plaques in the brain parenchyma and phosphorylated-tau accumulation as neurofibrillary tangles in the neurons. Although details of the disease pathomechanisms remain unclear, Aβ likely acts as a key protein for AD initiation and progression, followed by abnormal tau phosphorylation and neuronal death (amyloid-cascade hypothesis). According to this hypothesis, Aβ immunization therapies are created to eliminate Aβ from the brain, and to prevent the neurons from damage by these pathogenic proteins. There are two methods for Aβ immunotherapies: active and passive immunization. Previous studies have shown Aβ removal and improved cognitive function in animal models of AD. Clinical trials on various drugs, including AN1792, bapineuzumab, and solanezumab, have been carried out; however, all trials have failed to demonstrate apparent clinical benefits. On the contrary, side effects emerged, such as meningoencephalitis, vasogenic edema, which are currently called amyloid related imaging abnormalities (ARIA)-E and microhemorrhage (ARIA-H). In neuropathological studies of immunized cases, Aβ was removed from the brain parenchyma and phosphorylated-tau was reduced in the neuronal processes. Moreover, deterioration of the cerebral amyloid angiopathy (CAA) and an increase of microhemorrhages and microinfarcts were described. Aβ is cleared from the brain mainly via the lymphatic drainage pathway. ARIA could stem from severe CAA due to dysfunction of the drainage pathway after immunotherapy. Aβ immunization has a potential of cure for AD patients, although the above-described problems must be overcome before applying this therapy in clinical treatment. PMID:23568994

  16. Cognitive reserve and Alzheimer's disease.

    PubMed

    Xu, Wei; Yu, Jin-Tai; Tan, Meng-Shan; Tan, Lan

    2015-02-01

    Alzheimer's disease (AD), as a neurodegenerative process caused by widespread senile plaques and neurofibrillary tangles, is faced with an increasingly higher incidence as the global aging develops. Cognitive reserve (CR) hypothesis is proposed to elucidate the disjunction between cognitive performance and the pathological level of AD, positing that some life span experiences will lend protection from AD pathological insults. We provide an overview on recent studies involved in validation of the hypothesis as well as the association between AD and CR proxies, such as educational attainment and quality, occupational activity, leisure activity, general intelligence, and enriched environment. We further discuss some potential mechanisms by which CR proxy acts against AD pathological insults including neuroplasticity, neurogenesis, and locus coeruleus-noradrenergic (LC/NA) system. Finally, we review the applications of CR theory for AD prevention and therapy, particularly through physical activity and cognitive training strategy. We believe that a better knowledge of the relationship between AD and CR, accompanied by a successful transition of research accomplishments into practice, will impart much relief to individuals suffering from AD. PMID:24794146

  17. Cognitive debt and Alzheimer's disease.

    PubMed

    Marchant, Natalie L; Howard, Robert J

    2015-01-01

    We propose the concept of Cognitive Debt to characterize thoughts and behaviors that increase vulnerability to symptomatic Alzheimer's disease (AD). Evidence indicates that depression, anxiety, sleep disorder, neuroticism, life stress, and post-traumatic stress disorder increase risk for AD, and we suggest they do so by increasing Cognitive Debt. Repetitive negative thinking (RNT), a behaviorally measurable process common to these factors, may drive Cognitive Debt acquisition. RNT transcends disorder-specific definition, encompasses rumination and worry, and is defined by perseverative, negative thought tendencies. Evidence of dysregulated stress responses supports the concept of Cognitive Debt, of RNT as its causal mechanism, and of an interaction with the APOE-ε4 genotype to increase vulnerability to clinical AD, independent from traditional AD pathology. Defining a more specific behavioral profile of risk would enable interventions to be targeted earlier and more precisely at individuals most vulnerable to developing AD. Additionally, modulating RNT could potentially reduce risk of clinical AD. Interventions to reduce RNT are discussed, as are suggestions for future research. For these reasons we submit that the Cognitive Debt model may aid understanding of the psychological mechanisms that potentially increase predisposition to AD. PMID:25362035

  18. Anatomical heterogeneity of Alzheimer disease

    PubMed Central

    Noh, Young; Jeon, Seun; Seo, Sang Won; Kim, Geon Ha; Cho, Hanna; Ye, Byoung Seok; Yoon, Cindy W.; Kim, Hee Jin; Chin, Juhee; Park, Kee Hyung; Heilman, Kenneth M.

    2014-01-01

    Objective: Because the signs associated with dementia due to Alzheimer disease (AD) can be heterogeneous, the goal of this study was to use 3-dimensional MRI to examine the various patterns of cortical atrophy that can be associated with dementia of AD type, and to investigate whether AD dementia can be categorized into anatomical subtypes. Methods: High-resolution T1-weighted volumetric MRIs were taken of 152 patients in their earlier stages of AD dementia. The images were processed to measure cortical thickness, and hierarchical agglomerative cluster analysis was performed using Ward's clustering linkage. The identified clusters of patients were compared with an age- and sex-matched control group using a general linear model. Results: There were several distinct patterns of cortical atrophy and the number of patterns varied according to the level of cluster analyses. At the 3-cluster level, patients were divided into (1) bilateral medial temporal–dominant atrophy subtype (n = 52, ∼34.2%), (2) parietal-dominant subtype (n = 28, ∼18.4%) in which the bilateral parietal lobes, the precuneus, along with bilateral dorsolateral frontal lobes, were atrophic, and (3) diffuse atrophy subtype (n = 72, ∼47.4%) in which nearly all association cortices revealed atrophy. These 3 subtypes also differed in their demographic and clinical features. Conclusions: This cluster analysis of cortical thickness of the entire brain showed that AD dementia in the earlier stages can be categorized into various anatomical subtypes, with distinct clinical features. PMID:25344382

  19. Calcium signalling and Alzheimer's disease.

    PubMed

    Berridge, Michael J

    2011-07-01

    New insights into how Ca(2+) regulates learning and memory have begun to provide clues as to how the amyloid-dependent remodelling of neuronal Ca(2+) signalling pathways can disrupt the mechanisms of learning and memory in Alzheimer's disease (AD). The calcium hypothesis of AD proposes that activation of the amyloidogenic pathway remodels the neuronal Ca(2+) signalling pathways responsible for cognition by enhancing the entry of Ca(2+) and/or the release of internal Ca(2+) by ryanodine receptors or InsP(3) receptors. The specific proposal is that Ca(2+) signalling remodelling results in a persistent elevation in the level of Ca(2+) that constantly erases newly acquired memories by enhancing the mechanism of long-term depression (LTD). Neurons can still form memories through the process of LTP, but this stored information is rapidly removed by the persistent activation of LTD. Further dysregulation in Ca(2+) signalling will then go on to induce the neurodegeneration that characterizes the later stages of dementia. PMID:21184278

  20. Prescribing patterns for Alzheimer disease

    PubMed Central

    Hillmer, Melinda; Krahn, Murray; Hillmer, Michael; Pariser, Pauline; Naglie, Gary

    2006-01-01

    OBJECTIVE To describe Canadian family physicians’ prescribing practices with regard to Alzheimer disease (AD). DESIGN Cross-sectional survey administered by facsimile. SETTING Four regions in Canada (British Columbia, the Prairie Provinces, Ontario, and the Atlantic Provinces). PARTICIPANTS A stratified random sample of 1000 Canadian family physicians (250 per region) chosen from the Canadian Medical Directory; 81 of whom were excluded as ineligible. MAIN OUTCOME MEASURES Prescribing practices regarding cholinesterase inhibitors (ChIs) for patients with AD. RESULTS Response rate was 36.3%. About 27% of respondents reported that ChIs were prescribed for less than 10% of their AD patients, while 12.5% reported that ChIs were prescribed for more than 90% of their AD patients. More physicians prescribed ChIs in the two regions with provincial formulary coverage (Prairie Provinces and Ontario) than in the two regions without coverage (British Columbia and Atlantic Provinces). Factors that significantly predicted lower prescribing rates included female sex, perception of ChIs’ effectiveness, and self-reported knowledge of ChIs. CONCLUSION Canadian physicians’ prescribing patterns for ChIs vary; the optimal prescribing rate is unclear. Provincial coverage of these drugs along with physicians’ sex, knowledge of ChIs, and perception of the effectiveness of ChIs appear to influence prescribing rates. PMID:16926965

  1. An anemia of Alzheimer's disease.

    PubMed

    Faux, N G; Rembach, A; Wiley, J; Ellis, K A; Ames, D; Fowler, C J; Martins, R N; Pertile, K K; Rumble, R L; Trounson, B; Masters, C L; Bush, A I

    2014-11-01

    Lower hemoglobin is associated with cognitive impairment and Alzheimer's disease (AD). Since brain iron homeostasis is perturbed in AD, we investigated whether this is peripherally reflected in the hematological and related blood chemistry values from the Australian Imaging Biomarker and Lifestyle (AIBL) study (a community-based, cross-sectional cohort comprising 768 healthy controls (HC), 133 participants with mild cognitive impairment (MCI) and 211 participants with AD). We found that individuals with AD had significantly lower hemoglobin, mean cell hemoglobin concentrations, packed cell volume and higher erythrocyte sedimentation rates (adjusted for age, gender, APOE-ɛ4 and site). In AD, plasma iron, transferrin, transferrin saturation and red cell folate levels exhibited a significant distortion of their customary relationship to hemoglobin levels. There was a strong association between anemia and AD (adjusted odds ratio (OR)=2.43, confidence interval (CI) (1.31, 4.54)). Moreover, AD emerged as a strong risk factor for anemia on step-down regression, even when controlling for all other available explanations for anemia (adjusted OR=3.41, 95% CI (1.68, 6.92)). These data indicated that AD is complicated by anemia, which may itself contribute to cognitive decline. PMID:24419041

  2. Alzheimer's Disease: An Exacerbation of Senile Phenoptosis.

    PubMed

    Isaev, N K; Stelmashook, E V; Genrikhs, E E; Oborina, M V; Kapkaeva, M R; Skulachev, V P

    2015-12-01

    Alzheimer's disease is characterized by progressive memory loss and cognitive decline accompanied by degeneration of neuronal synapses, massive loss of neurons in the brain, eventually resulting in complete degradation of personality and death. Currently, the cause of the disease is not fully understood, but it is believed that the person's age is the major risk factor for development of Alzheimer's disease. People who have survived after cerebral stroke or traumatic brain injury have substantially increased risk of developing Alzheimer's disease. Social exclusion, low social activity, physical inactivity, poor mental performance, and low level of education are among risk factors for development of this neurodegenerative disease, which is consistent with the concept of phenoptosis (Skulachev, V. P., et al. (1999) Biochemistry (Moscow), 64, 1418-1426; Skulachev, M. V., and Skulachev, V. P. (2014) Biochemistry (Moscow), 79, 977-993) stating that rate of aging is related to psychological and social aspects in human behavior. Here we assumed that Alzheimer's disease might be considered as an exacerbation of senile phenoptosis. If so, then development of this disease could be slowed using mitochondria-targeted antioxidants due to the accumulated data demonstrating a link between mitochondrial dysfunction and oxidative stress both with normal aging and Alzheimer's disease. PMID:26638682

  3. Alzheimer's Disease. Report of the Secretary's Task Force on Alzheimer's Disease.

    ERIC Educational Resources Information Center

    National Inst. of Mental Health (DHHS), Rockville, MD.

    This report of the Health and Human Services Department Task Force on Alzheimer's Disease addresses nine main areas in a problem-oriented approach aimed at better defining research needs and options as well as training, service, and policy issues relevant to Alzheimer's disease. Individual chapters deal with research in the areas of epidemiology,…

  4. Focused and divided attention in Alzheimer's disease.

    PubMed

    Nebes, R D; Brady, C B

    1989-06-01

    Visual search tasks were used to examine two aspects of selective attention (focused and divided attention) in normal young and older persons and in Alzheimer patients. Normal and demented subjects were equally efficient in using a color cue to selectively search only the relevant items in an array. Thus, focused attention abilities appear to be relatively unimpaired by Alzheimer's disease. By contrast, in comparison to normals, the search time of demented patients rose disproportionately as the number of items over which they had to distribute their attention was increased. This suggests that Alzheimer patients are less efficient than normals in dividing their attention. PMID:2758855

  5. Dissecting risk haplotypes in sporadic Alzheimer's disease.

    PubMed

    Soldner, Frank; Jaenisch, Rudolf

    2015-04-01

    Understanding how genetic risk variants contribute to complex diseases is crucial for predicting disease susceptibility and developing patient-tailored therapies. In this issue of Cell Stem Cell, Young et al. (2015) dissect the function of common non-coding risk haplotypes in the SORL1 locus in the pathogenesis of sporadic Alzheimer's disease using patient-derived induced pluripotent stem cells. PMID:25842969

  6. Cerebrovascular disease in ageing and Alzheimer's disease.

    PubMed

    Love, Seth; Miners, J Scott

    2016-05-01

    Cerebrovascular disease (CVD) and Alzheimer's disease (AD) have more in common than their association with ageing. They share risk factors and overlap neuropathologically. Most patients with AD have Aβ amyloid angiopathy and degenerative changes affecting capillaries, and many have ischaemic parenchymal abnormalities. Structural vascular disease contributes to the ischaemic abnormalities in some patients with AD. However, the stereotyped progression of hypoperfusion in this disease, affecting first the precuneus and cingulate gyrus, then the frontal and temporal cortex and lastly the occipital cortex, suggests that other factors are more important, particularly in early disease. Whilst demand for oxygen and glucose falls in late disease, functional MRI, near infrared spectroscopy to measure the saturation of haemoglobin by oxygen, and biochemical analysis of myelin proteins with differential susceptibility to reduced oxygenation have all shown that the reduction in blood flow in AD is primarily a problem of inadequate blood supply, not reduced metabolic demand. Increasing evidence points to non-structural vascular dysfunction rather than structural abnormalities of vessel walls as the main cause of cerebral hypoperfusion in AD. Several mediators are probably responsible. One that is emerging as a major contributor is the vasoconstrictor endothelin-1 (EDN1). Whilst there is clearly an additive component to the clinical and pathological effects of hypoperfusion and AD, experimental and clinical observations suggest that the disease processes also interact mechanistically at a cellular level in a manner that exacerbates both. The elucidation of some of the mechanisms responsible for hypoperfusion in AD and for the interactions between CVD and AD has led to the identification of several novel therapeutic approaches that have the potential to ameliorate ischaemic damage and slow the progression of neurodegenerative disease. PMID:26711459

  7. Alzheimer's Disease therapeutics: current and future therapies.

    PubMed

    Gao, Lin B; Yu, Xiao F; Chen, Qin; Zhou, Dong

    2016-04-01

    Pathologically, Alzheimer's Disease is characterized by amyloidal protein plaques that lead to dementia in the elderly population. While advances have been made in therapeutics over the course of the last 20 years, the drugs generally target the symptoms rather than the underlying pathology. Unfortunately, despite the advances, the mechanisms behind Alzheimer's Disease have still not been clearly identified. Some of these current treatments include acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor agonists. Recently, the pathophysiology behind this disease is becoming more clearly understood and this has led to some novel therapeutic targets that may be able to break the barrier and target the underlying disease. In this review, we will discuss Alzheimer's Disease pathology and the pharmacological therapy that has been in use for a long time as well as novel therapies. PMID:26933835

  8. Disease-modifying drugs in Alzheimer's disease.

    PubMed

    Ghezzi, Laura; Scarpini, Elio; Galimberti, Daniela

    2013-01-01

    Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and the most common cause of dementia. The early stages of AD are characterized by short-term memory loss. Once the disease progresses, patients experience difficulties in sense of direction, oral communication, calculation, ability to learn, and cognitive thinking. The median duration of the disease is 10 years. The pathology is characterized by deposition of amyloid beta peptide (so-called senile plaques) and tau protein in the form of neurofibrillary tangles. Currently, two classes of drugs are licensed by the European Medicines Agency for the treatment of AD, ie, acetylcholinesterase inhibitors for mild to moderate AD, and memantine, an N-methyl-D-aspartate receptor antagonist, for moderate and severe AD. Treatment with acetylcholinesterase inhibitors or memantine aims at slowing progression and controlling symptoms, whereas drugs under development are intended to modify the pathologic steps leading to AD. Herein, we review the clinical features, pharmacologic properties, and cost-effectiveness of the available acetylcholinesterase inhibitors and memantine, and focus on disease-modifying drugs aiming to interfere with the amyloid beta peptide, including vaccination, passive immunization, and tau deposition. PMID:24353405

  9. Alzheimer's disease research in the context of the national plan to address Alzheimer's disease.

    PubMed

    Snyder, Heather M; Hendrix, James; Bain, Lisa J; Carrillo, Maria C

    2015-01-01

    In 2012, the first National Plan to Address Alzheimer's Disease in the United States (U.S.) was released, a component of the National Alzheimer's Project Act legislation. Since that time, there have been incremental increases in U.S. federal funding for Alzheimer's disease and related dementia research, particularly in the areas of biomarker discovery, genetic link and related biological underpinnings, and prevention studies for Alzheimer's. A central theme in each of these areas has been the emphasis of cross-sector collaboration and private-public partnerships between government, non-profit organizations and for-profit organizations. This paper will highlight multiple private-public partnerships supporting the advancement of Alzheimer's research in the context of the National Plan to Address Alzheimer's. PMID:26096321

  10. Molecular genetics of Alzheimer's disease and aging.

    PubMed

    Cacabelos, Ramon; Fernandez-Novoa, Lucia; Lombardi, Valter; Kubota, Yasuhiko; Takeda, Masatoshi

    2005-07-01

    Alzheimer's disease is a genetically complex disorder associated with multiple genetic defects, either mutational or of susceptibility. Although potentially associated with an accelerated stochastically driven aging process, Alzheimer's disease is an independent clinical entity in which the aging process exerts a deleterious effect on brain activity in conjunction with polymodal genetic factors and other pathological conditions (i.e., age-related cerebrovascular deterioration) and environmental factors (i.e., nutrition). Alzheimer's disease genetics does not explain in full the etiopathogenesis of this disease. Therefore, it is likely that environmental factors and/or epigenetic phenomena also contribute to Alzheimer's disease pathology and phenotypic expression of dementia. The genomics of Alzheimer's disease is still in its infancy, but this field is aiding the understanding of novel aspects of this disease, including genetic epidemiology, multifactorial risk factors, pathogenic mechanisms associated with genetic networks and genetically regulated metabolic cascades. Alzheimer's disease genomics is also helping to develop new strategies in pharmacogenomic research and prevention. Functional genomics, proteomics, pharmacogenomics, high-throughput methods, combinatorial chemistry and modern bioinformatics will greatly contribute to accelerate drug development for Alzheimer's disease and other complex disorders. The multifactorial genetic dysfunction in dementia includes mutational loci (APP, PS1, PS2, TAU) and diverse susceptibility loci (APOE, alpha2M, alphaACT, LRP1, IL1 alpha, TNF, ACE, BACE, BCHE, CST3, MTHFR, GSK3 beta, NOS3 and many other genes) distributed across the human genome, probably converging in a common pathogenic mechanism that leads to premature neuronal death, in which mitochondrial DNA mutations may contribute to increased genetic variability and heterogeneity. In Alzheimer's disease, multiple pathogenic events, including genetic factors

  11. Raman spectroscopy of Alzheimer's diseased tissue

    NASA Astrophysics Data System (ADS)

    Sudworth, Caroline D.; Krasner, Neville

    2004-07-01

    Alzheimer's disease is one of the most common forms of dementia, and causes steady memory loss and mental regression. It is also accompanied by severe atrophy of the brain. However, the pathological biomarkers of the disease can only be confirmed and examined upon the death of the patient. A commercial (Renishaw PLC, UK) Raman system with an 830 nm NIR diode laser was used to analyse brain samples, which were flash frozen at post-mortem. Ethical approval was sought for these samples. The Alzheimer's diseased samples contained a number of biomarkers, including neuritic plaques and tangles. The Raman spectra were examined by order to differentiate between normal and Alzheimer's diseased brain tissues. Preliminary results indicate that Alzheimer's diseased tissues can be differentiated from control tissues using Raman spectroscopy. The Raman spectra differ in terms of peak intensity, and the presence of a stronger amide I band in the 1667 cm-1 region which occurs more prominently in the Alzheimer's diseased tissue. These preliminary results indicate that the beta-amyloid protein originating from neuritic plaques can be identified with Raman spectroscopy.

  12. Imaging markers for Alzheimer disease

    PubMed Central

    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

  13. Use of acetylcholinesterase inhibitors in Alzheimer's disease.

    PubMed

    Moghul, S; Wilkinson, D

    2001-09-01

    Alzheimer's disease is a growing problem in an aging Western world, estimated to have cost the US economy USD 1.75 trillion. Until recently, the management of Alzheimer's disease largely comprised support for the family, nursing care and the use of unlicensed medication to control behavioral disturbances. The three new acetylcholinesterase inhibitors licensed to treat Alzheimer's disease (donepezil, rivastigmine and galantamine) have provided clinicians with a major impetus to their desire to diagnose and treat this lethal disease. Their effects on cognition are proven. More recent work on the effects of acetylcholinesterase inhibitors on behavioral symptoms, activities of daily living and caregiver burden have also been encouraging. Emerging work indicates their likely efficacy in other dementias (e.g., vascular dementia, dementia with Lewy bodies). This review summarizes the evidence concerning the impact of acetylcholinesterase inhibitors in dementia both currently and over the next 5 years. PMID:19811047

  14. Apraxia and Alzheimer's disease: review and perspectives.

    PubMed

    Lesourd, Mathieu; Le Gall, Didier; Baumard, Josselin; Croisile, Bernard; Jarry, Christophe; Osiurak, François

    2013-09-01

    Apraxia is one of the cognitive deficits that characterizes Alzheimer's disease. Despite its prevalence and relevance to diagnosing Alzheimer's disease, this topic has received little attention and is without comprehensive review. The review herein is aimed to fill this gap by first presenting an overview of the impairment caused in different clinical situations: pantomime of tool use, single tool use, real tool use, mechanical problem solving, function and manipulation knowledge tasks, and symbolic/meaningless gestures. On the basis of these results, we then propose alternative interpretations regarding the nature of the underlying mechanisms impaired by the disease. Also presented are principal methodological issues precluding firm conclusions from being drawn. PMID:23904110

  15. Looking for Signs of Alzheimer's Disease

    ERIC Educational Resources Information Center

    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…

  16. Progress Report on Alzheimer's Disease: Volume II.

    ERIC Educational Resources Information Center

    National Inst. on Aging (DHHS/PHS), Bethesda, MD.

    This document provides an overview of the state of scientific study of Alzheimer's disease, a disease of catastrophic proportions whose symptoms include serious forgetfulness; changes in personality; confused, restless, and irritable behavior; and problems with judgment, concentration, writing, reading, speech, and naming of objects. It discusses…

  17. Donated Blood Won't Transmit Alzheimer's, Parkinson's Disease

    MedlinePlus

    ... fullstory_159577.html Donated Blood Won't Transmit Alzheimer's, Parkinson's Disease Swedish study of nearly 1.5 ... who have received blood transfusions from patients with Alzheimer's or Parkinson's disease," said Dr. Irving Gomolin, a ...

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

    MedlinePlus

    ... with mild Alzheimer's disease may be helped in day-to-day living by a list of daily plans notes ... help some people with mild Alzheimer's disease with day-to-day living. A big calendar, a list ...

  19. Auditory spatial processing in Alzheimer's disease.

    PubMed

    Golden, Hannah L; Nicholas, Jennifer M; Yong, Keir X X; Downey, Laura E; Schott, Jonathan M; Mummery, Catherine J; Crutch, Sebastian J; Warren, Jason D

    2015-01-01

    The location and motion of sounds in space are important cues for encoding the auditory world. Spatial processing is a core component of auditory scene analysis, a cognitively demanding function that is vulnerable in Alzheimer's disease. Here we designed a novel neuropsychological battery based on a virtual space paradigm to assess auditory spatial processing in patient cohorts with clinically typical Alzheimer's disease (n = 20) and its major variant syndrome, posterior cortical atrophy (n = 12) in relation to healthy older controls (n = 26). We assessed three dimensions of auditory spatial function: externalized versus non-externalized sound discrimination, moving versus stationary sound discrimination and stationary auditory spatial position discrimination, together with non-spatial auditory and visual spatial control tasks. Neuroanatomical correlates of auditory spatial processing were assessed using voxel-based morphometry. Relative to healthy older controls, both patient groups exhibited impairments in detection of auditory motion, and stationary sound position discrimination. The posterior cortical atrophy group showed greater impairment for auditory motion processing and the processing of a non-spatial control complex auditory property (timbre) than the typical Alzheimer's disease group. Voxel-based morphometry in the patient cohort revealed grey matter correlates of auditory motion detection and spatial position discrimination in right inferior parietal cortex and precuneus, respectively. These findings delineate auditory spatial processing deficits in typical and posterior Alzheimer's disease phenotypes that are related to posterior cortical regions involved in both syndromic variants and modulated by the syndromic profile of brain degeneration. Auditory spatial deficits contribute to impaired spatial awareness in Alzheimer's disease and may constitute a novel perceptual model for probing brain network disintegration across the Alzheimer's disease

  20. Progenitor endothelial cell involvement in Alzheimer's disease

    SciTech Connect

    Budinger, Thomas F.

    2003-05-01

    There is compelling evidence that endothelial cells of the brain and periphery are dysfunctional in Alzheimer's Disease. There is evidence for a fundamental defect in, or abnormal aging of, endothelial progenitor cells in atherosclerosis. The possibility that endothelial cell defects are a primary cause for Alzheimer's Disease or other dementias can be researched by molecular and cell biology studies as well as cell trafficking studies using recently demonstrated molecular imaging methods. The evidence for abnormal endothelial function and the methods to explore this hypothesis are presented.

  1. Alzheimer's disease dietary supplements in websites.

    PubMed

    Palmour, Nicole; Vanderbyl, Brandy L; Zimmerman, Emma; Gauthier, Serge; Racine, Eric

    2013-12-01

    Consumer demand for health information and health services has rapidly evolved to capture and even propel the movement to online health information seeking. Seventeen percent (52 million) of health information internet users will look for information about memory loss, dementia and Alzheimer's disease (AD) (Fox Pew Internet & American life project: Online health search. Report. Pew Research Center. http://pewinternet.org/Reports/2006/Online-Health-Search-2006.aspx 2006, Pew Research Center. http://pewinternet.org/Reports/2011/HealthTopics.aspx 2011). We examined the content of the 25 most frequently retrieved websites marketing AD dietary supplements. We found that the majority of websites and their products claimed AD-related benefits, including improvement and enhancement of function, treatment for AD, prevention of AD, maintenance of function, delayed progression of AD, and decreased symptoms. Supplements were described as effective, natural, powerful or strong, dependable and pure or of high quality. Peer reviewed references to proper scientific studies were infrequent on websites. Statements highlighting the risks of dietary supplements were as common as statements mitigating or minimizing these risks. Different strategies were used to promote supplements such as popular appeals and testimonials. Further enforcement of relevant policy is needed and preparation of clinicians to deal with requests of patients and caregivers is indicated. PMID:23765585

  2. 7 Warning Signs of Alzheimer's | Alzheimer's disease | NIH MedlinePlus the Magazine

    MedlinePlus

    ... brain have shrunk (above right). Understanding Alzheimer's–Free Videos Can Help The NIHSeniorHealth Web site ( www.nihseniorhealth.gov ) offers a collection of free instructional videos to help the public understand Alzheimer's disease, how ...

  3. Brain capillaries in Alzheimer's disease.

    PubMed

    Baloyannis, Stavros J

    2015-01-01

    Alzheimer's disease is the most common cause of irreversible dementia, affecting mostly the presenile and senile age, shaping a tragic profile in the epilogue of the life of the suffering people. Due to the severity and the social impact of the disease an ongoing research activity is in climax nowadays, associated with many legal, social, ethical, humanitarian, philosophical and economic considerations. From the neuropathological point of view the disease is characterized by dendritic pathology, loss of synapses and dendritic spines, affecting mostly selective neuronal networks of critical importance for memory and cognition, such as the basal forebrain cholinergic system, the medial temporal regions, the hippocampus and many neocortical association areas. Tau pathology consisted of intracellular accumulation of neurofibrillary tangles of hyperphosphorilated tau protein and accumulation of Aβ-peptide's deposits, defined as neuritic plaques, are the principal neuropathological diagnostic criteria of the disease. The neurotoxic properties of the oligomerics of the Aβ-peptide and tau mediated neurodegeneration are among the main causative factors of impaired synaptic plasticity, neuronal loss, dendritic alterations and tremendous synaptic loss. The gradual degeneration of the organelles, particularly mitochondria, smooth endoplasmic reticulum and Golgi apparatus, visualized clearly by electron microscopy (EM), emphasize the importance of the oxidative stress and amyloid toxicity in the pathogenetic cascade of the disease. The vascular factor may be an important component of the whole spectrum of the pathogenesis of AD. It is of substantial importance the concept that the structural alterations of the brain capillaries, may contribute in the pathology of AD, given that the disruption of the BBB may induce exacerbation of AD pathology, by promoting inflammation around the blood capillaries and in the neuropile space diffusely. From the morphological point of view

  4. Physiological genomics analysis for Alzheimer's disease.

    PubMed

    Wiwanitkit, Viroj

    2013-01-01

    Alzheimer's disease is a common kind of dementia. This disorder can be detected in all countries around the world. This neurological disorder affects millions of population and becomes an important concern in modern neurology. There are many researches on the pathogenesis of Alzheimer's disease. Although it has been determined for a long time, there is no clear-cut that this is a case with genetic disorder or not. A physiological genomics is a new application that is useful for track function to genes within the human genome and can be applied for answering the problem of underlying pathobiology of complex diseases. The physiogenomics can be helpful for study of systemic approach on the pathophysiology, and genomics might provide useful information to better understand the pathogenesis of Alzheimer's disease. The present advent in genomics technique makes it possible to trace for the underlying genomics of disease. In this work, physiological genomics analysis for Alzheimer's disease was performed. The standard published technique is used for assessment. According to this work, there are 20 identified physiogenomics relationship on several chromosomes. Considering the results, the HADH2 gene on chromosome X, APBA1 gene on chromosome 9, AGER gene on chromosome 6, GSK3B gene on chromosome 3, CDKHR1 gene on chromosome 17, APPBP1 gene on chromosome 16, APBA2 gene on chromosome 15, GAL gene on chromosome 11, and APLP2 gene on chromosome 11 have the highest physiogenomics score (9.26) while the CASP3 gene on chromosome 4 and the SNCA gene on chromosome 4 have the lowest physiogenomics score (7.44). The results from this study confirm that Alzheimer's disease has a polygenomic origin. PMID:23661967

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

    PubMed

    Ridge, Perry G; Mukherjee, Shubhabrata; Crane, Paul K; Kauwe, John S K

    2013-01-01

    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. PMID:24244562

  6. Metaphor Comprehension in Alzheimer's Disease: Novelty Matters

    ERIC Educational Resources Information Center

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

    2008-01-01

    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…

  7. Famous forgetters: notable people and Alzheimer's disease.

    PubMed

    Jones, Jeffrey M; Jones, Joni L

    2010-03-01

    As life expectancy continues to increase, Alzheimer's disease (AD) has become much more prevalent and as yet there is no cure. This has given rise to the situation Tithonus faced in Greek mythology of living longer but not staying young. In this article, the authors explore this phenomenon while reviewing some notable people and AD. PMID:19949162

  8. Ideational Action Impairments in Alzheimer's Disease

    ERIC Educational Resources Information Center

    Chainay, H.; Louarn, C.; Humphreys, G. W.

    2006-01-01

    We report data from a group of patients with mild Alzheimer's disease on a range of tasks requiring either stored semantic knowledge about objects (e.g., naming object use) or the execution of action to objects (e.g., miming and using objects). We found that the patients were impaired at miming in response to objects, even when they could describe…

  9. Alzheimer's disease: diverse aspects of mitochondrial malfunctioning

    PubMed Central

    Santos, Renato X; Correia, Sónia C; Wang, Xinglong; Perry, George; Smith, Mark A; Moreira, Paula I; Zhu, Xiongwei

    2010-01-01

    Alzheimer's disease is a progressive neurodegenerative disorder, either assuming a sporadic, age-associated, late-onset form, or a familial form, with early onset, in a smaller fraction of the cases. Whereas in the familial cases several mutations have been identified in genes encoding proteins related with the pathogenesis of the disease, for the sporadic form several causes have been proposed and are currently under debate. Mitochondrial dysfunction has surfaced as one of the most discussed hypotheses acting as a trigger for the pathogenesis of Alzheimer's disease. Mitochondria assume central functions in the cell, including ATP production, calcium homeostasis, reactive oxygen species generation, and apoptotic signaling. Although their role as the cause of the disease may be controversial, there is no doubt that mitochondrial dysfunction, abnormal mitochondrial dynamics and degradation by mitophagy occur during the disease process, contributing to its onset and progression. PMID:20661404

  10. Why do we get Alzheimer's disease?

    SciTech Connect

    Wyss-Coray, Tony

    2006-10-02

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

  11. Why Do We Get Alzheimer's Disease?

    SciTech Connect

    Wyss-Coray, Tony

    2006-01-02

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

  12. Graphomotor perseveration and wandering in Alzheimer's disease.

    PubMed

    Ryan, J P; McGowan, J; McCaffrey, N; Ryan, G T; Zandi, T; Brannigan, G G

    1995-10-01

    Perseveration, spatial orientation, and attention/concentration were assessed in 15 patients with a probable diagnosis of senile dementia of the Alzheimer's type. Subjects were divided into two groups, wanderers and nonwanderers, based on caregiver ratings using a modified version of the Caregiver Checklist. Graphic productions of wanderers on the Bender Visual Motor Gestalt Test and Clock Drawing Test displayed greater total perseveration and more recurrent and continuous perseverations than those of nonwanderers. Spatial orientation and attention/concentration were similar between groups. These preliminary results suggest that graphomotor perseverations exhibited during the mild to moderate stages may serve as a marker for wandering in Alzheimer's disease. PMID:8561833

  13. Genetic defect causing familial Alzheimer's disease maps on chromosome 21

    SciTech Connect

    St. George-Hyslop, P.H.; Tanzi, R.E.; Polinsky, R.J.; Haines, J.L.; Nee, L.; Watkins, P.C.; Myers, R.H.; Feldman, R.G.; Pollen, D.; Drachman, D.; Growdon, J.

    1987-02-20

    Alzheimer's disease is a leading cause of morbidity and mortality among the elderly. Several families have been described in which Alzheimer's disease is caused by an autosomal dominant gene defect. The chromosomal location of this defective gene has been discovered by using genetic linkage to DNA markers on chromosome 21. The localization on chromosome 21 provides an explanation for the occurrence of Alzheimer's disease-like pathology in Down syndrome. Isolation and characterization of the gene at this locus may yield new insights into the nature of the defect causing familial Alzheimer's disease and possibly, into the etiology of all forms of Alzheimer's disease.

  14. A multi-center randomized proof-of-concept clinical trial applying [¹⁸F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer's disease.

    PubMed

    Tzimopoulou, Sofia; Cunningham, Vincent J; Nichols, Thomas E; Searle, Graham; Bird, Nick P; Mistry, Prafull; Dixon, Ian J; Hallett, William A; Whitcher, Brandon; Brown, Andrew P; Zvartau-Hind, Marina; Lotay, Narinder; Lai, Robert Y K; Castiglia, Mary; Jeter, Barbara; Matthews, Julian C; Chen, Kewei; Bandy, Dan; Reiman, Eric M; Gold, Michael; Rabiner, Eugenii A; Matthews, Paul M

    2010-01-01

    Here we report the first multi-center clinical trial in Alzheimer's disease (AD) using fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARγ agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Secondary objectives included testing for reduction in the progression of brain atrophy and improvement in cognition. Active treatment was associated with a sustained but not statistically significant trend from the first month for higher mean values in Kiindex and CMRgluindex, novel quantitative indices related to the combined forward rate constant for [18F]FDG uptake and to the rate of cerebral glucose utilization, respectively. However, neither these nor another analytical approach recently validated using data from the Alzheimer's Disease Neuroimaging Initiative indicated that active treatment decreased the progression of decline in brain glucose metabolism. Rates of brain atrophy were similar between active and placebo groups and measures of cognition also did not suggest clear group differences. Our study demonstrates the feasibility of using [18F]FDG-PET as part of a multi-center therapeutics trial. It suggests that Rosiglitazone is associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1 year follow up in the symptomatic stages of AD. PMID:20930300

  15. Cognitive Correlates of Metamemory in Alzheimer's Disease

    PubMed Central

    Shaked, Danielle; Farrell, Meagan; Huey, Edward; Metcalfe, Janet; Cines, Sarah; Karlawish, Jason; Sullo, Elisabeth; Cosentino, Stephanie

    2014-01-01

    Objective Metamemory, or knowledge of one's memory abilities, is often impaired in individuals with Alzheimer's disease (AD), although the basis of this metacognitive deficit has not been fully articulated. Behavioral and imaging studies have produced conflicting evidence regarding the extent to which specific cognitive domains (i.e., executive functioning (EF), memory) and brain regions contribute to memory awareness. The primary aim of this study was to disentangle the cognitive correlates of metamemory in AD by examining the relatedness of objective metamemory performance to cognitive tasks grouped by domain (EF or memory) as well as by preferential hemispheric reliance defined by task modality (verbal or nonverbal). Method 89 participants with mild AD recruited at Columbia University Medical Center and the University of Pennsylvania underwent objective metamemory and cognitive testing. Partial correlations were used to assess the relationship between metamemory and four cognitive variables, adjusted for recruitment site. Results The significant correlates of metamemory included nonverbal fluency (r = .27 p = .02) and nonverbal memory (r = .24, p = .04). Conclusions Our findings suggest that objectively measured metamemory in a large sample of individuals with mild AD is selectively related to a set of inter-domain nonverbal tasks. The association between metamemory and the nonverbal tasks may implicate a shared reliance on a right-sided cognitive network that spans frontal and temporal regions. PMID:24819066

  16. SPECT in Alzheimer`s disease and the dementias

    SciTech Connect

    Bonte, F.J.

    1991-12-31

    Among 90 patients with a clinical diagnosis of Alzheimer`s disease (AD), two subgroups were identified for special study, including 42 patients who had a history of dementia in one or more first-degree relatives, and 14 who had a diagnosis of early AD. Of the 42 patients with a family history of dementia, 34 out of the 35 patients whose final clinical diagnosis was possible or probable AD had positive SPECT rCBF studies. Studies in the 14 patients thought to have very early AD were positive in 11 cases. This finding suggests that altered cortical physiology, and hence, rCBF, occurs quite early in the course of AD, perhaps before the onset of symptoms. It is possible that Xenon 133 rCBF studies might be used to detect the presence of subclinical AD in a population of individuals at risk to this disorder. Despite the drawbacks of a radionuclide with poor photon energy, Xenon 133, with its low cost and round-the-clock availability, deserves further study. Although the physical characteristics of Xenon 127 might make it preferable as a SPECT tracer, it is still not regularly available, and some instrument systems are not designed to handle its higher photon energies.

  17. Alzheimer's disease: current knowledge, management and research

    PubMed Central

    Gauthier, S; Panisset, M; Nalbantoglu, J; Poirier, J

    1997-01-01

    Alzheimer's disease is a common neurological condition, appearing as early as age 40 but increasing dramatically in incidence over age 85. Different genetic factors are at play, modified by events over a lifetime. Clinical diagnosis is possible through careful history taking with a reliable informant and a minimum number of laboratory tests. A relatively predictable natural history can be observed, with progression through stages of cognitive loss, functional impairment and behavioural disinhibition or apathy. New medications such as donepezil offer hope for improving or stabilizing symptoms. Such treatment can be administered by primary care physicians with experience in the diagnosis and management of Alzheimer's disease. Disease stabilization, or even prevention, may be possible in the future. PMID:9347775

  18. Losing one's memory in early Alzheimer's disease.

    PubMed

    Parsons-Suhl, Karen; Johnson, Mary E; McCann, Judy J; Solberg, Shirley

    2008-01-01

    A Heideggerian hermeneutical phenomenological research method was used to investigate the experience of memory loss in twelve individuals with early Alzheimer's disease or mild cognitive impairment. Data analysis proceeded as described by Diekelmann, Allen, and Tanner (1989), and incorporated the methods of Benner (1994), Thomas and Pollio (2002), and van Manen (1990). Three constitutive patterns with relational themes were identified. The first pattern, experiencing breakdown, consisted of two themes: awakening to breakdown and living with forgetting. The second pattern, temporality, consisted of three themes: being in the nothing, forgetting the past, and looking ahead. The third pattern, managing forgetting, consisted of the themes: remembering with cues, writing things down, recognizing what made remembering better or worse, and using laughter. The finding show that early Alzheimer's disease is more than an illness of cognitive losses and that forgetting is significant in light of the meaning that it has within everyday life. PMID:18174533

  19. Screening for new agonists against Alzheimer's disease.

    PubMed

    Zheng, Huiqin; Wei, Dong-Qing; Zhang, Rui; Wang, Chunfang; Wei, Huachun; Chou, Kuo-Chen

    2007-09-01

    To find new drug candidates for treating Alzheimer's disease, we used the similarity search technique and GTS-21 as a template to search the Traditional Chinese Medicines Database. The high-score molecules thus obtained were compared with the template through the flexible alignment. Those molecules which had good alignment with GTS-21 were selected for conducting the docking studies aimed at the alpha7 nicotinic acetylcholine receptor. The CHARMM22 force field was taken to compute the partial charge and the TABU search was adopted to operate the docking process. The docking results thus obtained were used to compare with that of GTS-21. Those molecules which had better docking results than that of GTS-21 were singled out for further consideration. Finally, it was found through an in-depth structural analysis that Mol 7235 might be a promising candidate for further modification by experiments to make it become an effective drug for treating Alzheimer's disease. PMID:17897076

  20. Alzheimer's disease: An acquired neurodegenerative laminopathy

    PubMed Central

    Frost, Bess

    2016-01-01

    ABSTRACT The nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope. For most cell types, this depiction is accurate. In other cell types and in some pathological conditions, however, the smooth nuclear exterior is interrupted by tubular invaginations of the nuclear envelope, often referred to as a “nucleoplasmic reticulum,” into the deep nuclear interior. We have recently reported a significant expansion of the nucleoplasmic reticulum in postmortem human Alzheimer's disease brain tissue. We found that dysfunction of the nucleoskeleton, a lamin-rich meshwork that coats the inner nuclear membrane and associated invaginations, is causal for Alzheimer's disease-related neurodegeneration in vivo. Additionally, we demonstrated that proper function of the nucleoskeleton is required for survival of adult neurons and maintaining genomic architecture. Here, we elaborate on the significance of these findings in regard to pathological states and physiological aging, and discuss cellular causes and consequences of nuclear envelope invagination. PMID:27167528

  1. Alzheimer's disease. Physician-patient communication.

    PubMed Central

    Orange, J. B.; Molloy, D. W.; Lever, J. A.; Darzins, P.; Ganesan, C. R.

    1994-01-01

    The number of cognitively impaired elderly in Canada has increased greatly during the past two decades; nearly all have Alzheimer's disease (AD). The memory problems and changes in language and communication of these patients place tremendous strain on physicians who are searching for a differential diagnosis and are trying to communicate with them. Reviewing the salient language and communication features of AD patients leads to strategies for improving effective physician-patient communication. PMID:8019193

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

    NASA Astrophysics Data System (ADS)

    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.

  3. Calmodulin Binding Proteins and Alzheimer's Disease.

    PubMed

    O'Day, Danton H; Eshak, Kristeen; Myre, Michael A

    2015-01-01

    The small, calcium-sensor protein, calmodulin, is ubiquitously expressed and central to cell function in all cell types. Here the literature linking calmodulin to Alzheimer's disease is reviewed. Several experimentally-verified calmodulin-binding proteins are involved in the formation of amyloid-β plaques including amyloid-β protein precursor, β-secretase, presenilin-1, and ADAM10. Many others possess potential calmodulin-binding domains that remain to be verified. Three calmodulin binding proteins are associated with the formation of neurofibrillary tangles: two kinases (CaMKII, CDK5) and one protein phosphatase (PP2B or calcineurin). Many of the genes recently identified by genome wide association studies and other studies encode proteins that contain putative calmodulin-binding domains but only a couple (e.g., APOE, BIN1) have been experimentally confirmed as calmodulin binding proteins. At least two receptors involved in calcium metabolism and linked to Alzheimer's disease (mAchR; NMDAR) have also been identified as calmodulin-binding proteins. In addition to this, many proteins that are involved in other cellular events intimately associated with Alzheimer's disease including calcium channel function, cholesterol metabolism, neuroinflammation, endocytosis, cell cycle events, and apoptosis have been tentatively or experimentally verified as calmodulin binding proteins. The use of calmodulin as a potential biomarker and as a therapeutic target is discussed. PMID:25812852

  4. The superficial white matter in Alzheimer's disease.

    PubMed

    Phillips, Owen R; Joshi, Shantanu H; Piras, Fabrizio; Orfei, Maria Donata; Iorio, Mariangela; Narr, Katherine L; Shattuck, David W; Caltagirone, Carlo; Spalletta, Gianfranco; Di Paola, Margherita

    2016-04-01

    White matter abnormalities have been shown in the large deep fibers of Alzheimer's disease patients. However, the late myelinating superficial white matter comprised of intracortical myelin and short-range association fibers has not received much attention. To investigate this area, we extracted a surface corresponding to the superficial white matter beneath the cortex and then applied a cortical pattern-matching approach which allowed us to register and subsequently sample diffusivity along thousands of points at the interface between the gray matter and white matter in 44 patients with Alzheimer's disease (Age: 71.02 ± 5.84, 16M/28F) and 47 healthy controls (Age 69.23 ± 4.45, 19M/28F). In patients we found an overall increase in the axial and radial diffusivity across most of the superficial white matter (P < 0.001) with increases in diffusivity of more than 20% in the bilateral parahippocampal regions and the temporal and frontal lobes. Furthermore, diffusivity correlated with the cognitive deficits measured by the Mini-Mental State Examination scores (P < 0.001). The superficial white matter has a unique microstructure and is critical for the integration of multimodal information during brain maturation and aging. Here we show that there are major abnormalities in patients and the deterioration of these fibers relates to clinical symptoms in Alzheimer's disease. PMID:26801955

  5. Improving Alzheimer's disease phase II clinical trials.

    PubMed

    Greenberg, Barry D; Carrillo, Maria C; Ryan, J Michael; Gold, Michael; Gallagher, Kim; Grundman, Michael; Berman, Robert M; Ashwood, Timothy; Siemers, Eric R

    2013-01-01

    Over the past 30 years, many drugs have been studied as possible treatments for Alzheimer's disease, but only four have demonstrated sufficient efficacy to be approved as treatments, of which three are in the same class. This lack of success has raised questions both in the pharmaceutical industry and academia about the future of Alzheimer's disease therapy. The high cost and low success rate of drug development across many disease areas can be attributed, in large part, to late-stage clinical failures (Schachter and Ramoni, Nat Rev Drug Discov 2007;6:107-8). Thus, identifying in phase II, or preferably phase I, drugs that are likely to fail would have a dramatic impact on the costs associated with developing new drugs. With this in mind, the Alzheimer's Association convened a Research Roundtable on June 23 and 24, 2011, in Washington, DC, bringing together scientists from academia, industry, and government regulatory agencies to discuss strategies for improving the probability of phase II trial results predicting success when considering the go/no-go decision-making process leading to the initiation of phase III. PMID:23164548

  6. Reversal of cognitive decline in Alzheimer's disease

    PubMed Central

    Bredesen, Dale E.; Amos, Edwin C.; Canick, Jonathan; Ackerley, Mary; Raji, Cyrus; Fiala, Milan; Ahdidan, Jamila

    2016-01-01

    Alzheimer's disease is one of the most significant healthcare problems nationally and globally. Recently, the first description of the reversal of cognitive decline in patients with early Alzheimer's disease or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment), was published [1]. The therapeutic approach used was programmatic and personalized rather than monotherapeutic and invariant, and was dubbed metabolic enhancement for neurodegeneration (MEND). Patients who had had to discontinue work were able to return to work, and those struggling at work were able to improve their performance. The patients, their spouses, and their co-workers all reported clear improvements. Here we report the results from quantitative MRI and neuropsychological testing in ten patients with cognitive decline, nine ApoE4+ (five homozygous and four heterozygous) and one ApoE4−, who were treated with the MEND protocol for 5-24 months. The magnitude of the improvement is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective. These results have far-reaching implications for the treatment of Alzheimer's disease, MCI, and SCI; for personalized programs that may enhance pharmaceutical efficacy; and for personal identification of ApoE genotype. PMID:27294343

  7. Cancer linked to Alzheimer disease but not vascular dementia

    PubMed Central

    Roe, C M.; Fitzpatrick, A L.; Xiong, C; Sieh, W; Kuller, L; Miller, J P.; Williams, M M.; Kopan, R; Behrens, M I.; Morris, J C.

    2010-01-01

    Objective: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD). Methods: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study–Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer. Results: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20–0.84) and pure AD (HR = 0.31, 95% CI = 0.12–0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52–0.997) and pure AD (HR = 0.57; 95% CI = 0.36–0.90) among white subjects after adjustment for demographics, number of APOE ε4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD. Conclusions: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration. GLOSSARY 3MSE = modified Mini-Mental State Examination; AD = Alzheimer disease; ADDTC = Alzheimer Disease Diagnostic and Treatment Centers; CHD = coronary heart

  8. International Alzheimer's Disease Research Portfolio (IADRP) aims to capture global Alzheimer's disease research funding.

    PubMed

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

    2014-05-01

    Alzheimer's disease (AD) is a recognized international public health crisis. There is an urgent need for public and private funding agencies around the world to coordinate funding strategies and leverage existing resources to enhance and expand support of AD research. To capture and compare their existing investments in AD research and research-related resources, major funding organizations are starting to utilize the Common Alzheimer's Disease Research Ontology (CADRO) to categorize their funding information. This information is captured in the International Alzheimer's Disease Research Portfolio (IADRP) for further analysis. As of January, 2014, over fifteen organizations from the US, Canada, Europe and Australia have contributed their information. The goal of the IADRP project is to enable funding organizations to assess the changing landscape of AD research and coordinate strategies, leverage resources, and avoid duplication of effort. PMID:24780512

  9. Biomarkers for Alzheimer's disease therapeutic trials.

    PubMed

    Hampel, Harald; Wilcock, Gordon; Andrieu, Sandrine; Aisen, Paul; Blennow, Kaj; Broich, K; Carrillo, Maria; Fox, Nick C; Frisoni, Giovanni B; Isaac, Maria; Lovestone, Simon; Nordberg, Agneta; Prvulovic, David; Sampaio, Christina; Scheltens, Philip; Weiner, Michael; Winblad, Bengt; Coley, Nicola; Vellas, Bruno

    2011-12-01

    The development of disease-modifying treatments for Alzheimer's disease requires innovative trials with large numbers of subjects and long observation periods. The use of blood, cerebrospinal fluid or neuroimaging biomarkers is critical for the demonstration of disease-modifying therapy effects on the brain. Suitable biomarkers are those which reflect the progression of AD related molecular mechanisms and neuropathology, including amyloidogenic processing and aggregation, hyperphosphorylation, accumulation of tau and neurofibrillary tangles, progressive functional, metabolic and structural decline, leading to neurodegeneration, loss of brain tissue and cognitive symptoms. Biomarkers should be used throughout clinical trial phases I-III of AD drug development. They can be used to enhance inclusion and exclusion criteria, or as baseline predictors to increase the statistical power of trials. Validated and qualified biomarkers may be used as outcome measures to detect treatment effects in pivotal clinical trials. Finally, biomarkers can be used to identify adverse effects. Questions regarding which biomarkers should be used in clinical trials, and how, are currently far from resolved. The Oxford Task Force continues and expands the work of our previous international expert task forces on disease-modifying trials and on endpoints for Alzheimer's disease clinical trials. The aim of this initiative was to bring together a selected number of key international opinion leaders and experts from academia, regulatory agencies and industry to condense the current knowledge and state of the art regarding the best use of biological markers in Alzheimer's disease therapy trials and to propose practical recommendations for the planning of future AD trials. PMID:21130138

  10. Degree of Bilingualism Predicts Age of Diagnosis of Alzheimer's Disease in Low-Education but Not in Highly Educated Hispanics

    ERIC Educational Resources Information Center

    Gollan, Tamar H.; Salmon, David P.; Montoya, Rosa I.; Galasko, Douglas R.

    2011-01-01

    The current study investigated the relationship between bilingual language proficiency and onset of probable Alzheimer's disease (AD) in 44 Spanish-English bilinguals at the UCSD Alzheimer's Disease Research Center. Degree of bilingualism along a continuum was measured using Boston Naming Test (BNT) scores in each language. Higher degrees of…

  11. Short-term memory binding deficits in Alzheimer's disease.

    PubMed

    Parra, Mario A; Abrahams, Sharon; Fabi, Katia; Logie, Robert; Luzzi, Simona; Della Sala, Sergio

    2009-04-01

    Alzheimer's disease impairs long term memories for related events (e.g. faces with names) more than for single events (e.g. list of faces or names). Whether or not this associative or 'binding' deficit is also found in short-term memory has not yet been explored. In two experiments we investigated binding deficits in verbal short-term memory in Alzheimer's disease. Experiment 1: 23 patients with Alzheimer's disease and 23 age and education matched healthy elderly were recruited. Participants studied visual arrays of objects (six for healthy elderly and four for Alzheimer's disease patients), colours (six for healthy elderly and four for Alzheimer's disease patients), unbound objects and colours (three for healthy elderly and two for Alzheimer's disease patients in each of the two categories), or objects bound with colours (three for healthy elderly and two for Alzheimer's disease patients). They were then asked to recall the items verbally. The memory of patients with Alzheimer's disease for objects bound with colours was significantly worse than for single or unbound features whereas healthy elderly's memory for bound and unbound features did not differ. Experiment 2: 21 Alzheimer's disease patients and 20 matched healthy elderly were recruited. Memory load was increased for the healthy elderly group to eight items in the conditions assessing memory for single or unbound features and to four items in the condition assessing memory for the binding of these features. For Alzheimer's disease patients the task remained the same. This manipulation permitted the performance to be equated across groups in the conditions assessing memory for single or unbound features. The impairment in Alzheimer's disease patients in recalling bound objects reported in Experiment 1 was replicated. The binding cost was greater than that observed in the healthy elderly group, who did not differ in their performance for bound and unbound features. Alzheimer's disease grossly impairs the

  12. Biomarkers for Microglial Activation in Alzheimer's Disease

    PubMed Central

    Lautner, Ronald; Mattsson, Niklas; Schöll, Michael; Augutis, Kristin; Blennow, Kaj; Olsson, Bob; Zetterberg, Henrik

    2011-01-01

    Intensive research over the last decades has provided increasing evidence for neuroinflammation as an integral part in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Inflammatory responses in the central nervous system (CNS) are initiated by activated microglia, representing the first line of the innate immune defence of the brain. Therefore, biochemical markers of microglial activation may help us understand the underlying mechanisms of neuroinflammation in AD as well as the double-sided qualities of microglia, namely, neuroprotection and neurotoxicity. In this paper we summarize candidate biomarkers of microglial activation in AD along with a survey of recent neuroimaging techniques. PMID:22114747

  13. Mapping the road forward in Alzheimer's disease.

    PubMed

    Holtzman, David M; Goate, Alison; Kelly, Jeffrey; Sperling, Reisa

    2011-12-21

    Alzheimer's disease (AD) is the most common cause of dementia and will lead to a worldwide public health crisis if it continues unchecked. Despite tremendous advances in our scientific understanding of AD, we still do not have effective ways to delay, prevent, or slow this disease. At the 2011 Abelson meeting, a diverse group of scientists discussed current challenges in the AD field and made recommendations in the areas of genetics, clinical trials, protein aggregation, and the cell biology of the nervous system. We hope these recommendations will boost research progress in AD and increase the likelihood of developing effective therapies in the near future. PMID:22190237

  14. Early neuroimaging diagnosis of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Jiao, Jianling; Liu, Timon C.; Li, Yan; Liu, Songhao

    2002-04-01

    Neuroimaging has played an important role in evaluating the Alzheimer's disease (AD) patients, and its uses are growing. Magnetic resonance imaging (MRI) may show the presence of cerebral infarcts and white matter disease. Single photon emission computed tomography (SPECT) and positron emission tomography (PET), which visualize such cerebral functions as glucose metabolism and blood flow, may provide positive evidence to support the diagnosis of AD. Electrical impedance tomography (EIT) is a recently developed technique which enables the internal impedance of an object to be imaged noninvasively.

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

    PubMed Central

    Racchi, Marco; Uberti, Daniela; Govoni, Stefano; Memo, Maurizio; Lanni, Cristina; Vasto, Sonya; Candore, Giuseppina; Caruso, Calogero; Romeo, Loriana; Scapagnini, Giovanni

    2008-01-01

    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. PMID:18700965

  16. Alzheimer's disease: is a vaccine possible?

    PubMed

    Alves, R P S; Yang, M J; Batista, M T; Ferreira, L C S

    2014-06-01

    The cause of Alzheimer's disease is still unknown, but the disease is distinctively characterized by the accumulation of β-amyloid plaques and neurofibrillary tangles in the brain. These features have become the primary focus of much of the research looking for new treatments for the disease, including immunotherapy and vaccines targeting β-amyloid in the brain. Adverse effects observed in a clinical trial based on the β-amyloid protein were attributed to the presence of the target antigen and emphasized the relevance of finding safer antigen candidates for active immunization. For this kind of approach, different vaccine formulations using DNA, peptide, and heterologous prime-boost immunization regimens have been proposed. Promising results are expected from different vaccine candidates encompassing B-cell epitopes of the β-amyloid protein. In addition, recent results indicate that targeting another protein involved in the etiology of the disease has opened new perspectives for the effective prevention of the illness. Collectively, the evidence indicates that the idea of finding an effective vaccine for the control of Alzheimer's disease, although not without challenges, is a possibility. PMID:24878604

  17. Alzheimer's disease: is a vaccine possible?

    PubMed Central

    Alves, R.P.S.; Yang, M.J.; Batista, M.T.; Ferreira, L.C.S.

    2014-01-01

    The cause of Alzheimer's disease is still unknown, but the disease is distinctively characterized by the accumulation of β-amyloid plaques and neurofibrillary tangles in the brain. These features have become the primary focus of much of the research looking for new treatments for the disease, including immunotherapy and vaccines targeting β-amyloid in the brain. Adverse effects observed in a clinical trial based on the β-amyloid protein were attributed to the presence of the target antigen and emphasized the relevance of finding safer antigen candidates for active immunization. For this kind of approach, different vaccine formulations using DNA, peptide, and heterologous prime-boost immunization regimens have been proposed. Promising results are expected from different vaccine candidates encompassing B-cell epitopes of the β-amyloid protein. In addition, recent results indicate that targeting another protein involved in the etiology of the disease has opened new perspectives for the effective prevention of the illness. Collectively, the evidence indicates that the idea of finding an effective vaccine for the control of Alzheimer's disease, although not without challenges, is a possibility. PMID:24878604

  18. Treatment of Alzheimer Disease With CT Scans

    PubMed Central

    Moore, Eugene R.; Hosfeld, Victor D.; Nadolski, David L.

    2016-01-01

    Alzheimer disease (AD) primarily affects older adults. This neurodegenerative disorder is the most common cause of dementia and is a leading source of their morbidity and mortality. Patient care costs in the United States are about 200 billion dollars and will more than double by 2040. This case report describes the remarkable improvement in a patient with advanced AD in hospice who received 5 computed tomography scans of the brain, about 40 mGy each, over a period of 3 months. The mechanism appears to be radiation-induced upregulation of the patient’s adaptive protection systems against AD, which partially restored cognition, memory, speech, movement, and appetite. PMID:27103883

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

    PubMed

    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. PMID:27060329

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

    PubMed

    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. PMID:26011650

  1. Caregivers of loved ones with Alzheimer's disease.

    PubMed

    Callan, Judith A; Howland, Robert H

    2009-11-01

    Olivia is a 74-year-old caregiver for her husband of 50 years, Jim. In addition to the usual custodial requirements, she has assumed management of their finances, medical care, and home. During the past year, Jim's sleep has become severely disrupted, such that his nights and days are switched, and he has demonstrated periodic behavioral problems, such as emotional lability and threatening to hit Olivia when he becomes frustrated. Prior to Jim's diagnosis with Alzheimer's disease, Olivia led a very active social life. She has become socially isolated and frequently feels depressed, overwhelmed, and impatient with Jim. PMID:19921756

  2. Advances in the prevention of Alzheimer's Disease

    PubMed Central

    Mangialasche, Francesca; Kivipelto, Miia

    2015-01-01

    Alzheimer's disease (AD), the leading cause of dementia, has reached epidemic proportions, with major social, medical and economical burdens. With no currently available curative treatments, both the World Health Organization and the G8 Dementia Summit recently identified dementia and AD prevention as a major public health priority. Dementia and AD have a wide range of risk factors (genetic, vascular/metabolic and lifestyle-related), which often co-occur and thus interact with each other. Previous intervention efforts aimed at preventing dementia and AD focused on the management of single risk factors, with relatively modest findings. Also, the effect of risk factors depends on age at exposure, indicating that the timing of preventive interventions needs to be carefully considered. In view of the complex multifactorial nature of AD, as well as its long pre-clinical (asymptomatic) phase, interventions simultaneously targeting multiple risk factors and disease mechanisms at an early stage of the disease are most likely to be effective. Three large European multidomain prevention trials have been launched with the goal of preventing cognitive decline, dementia and AD in older adults with different risk profiles. Pharmacological trials are also shifting towards prevention of Alzheimer dementia, by targeting at-risk individuals prior to the onset of cognitive symptoms. The current review will summarize and discuss the evidence on risk and protective factors from observational studies, ongoing lifestyle-related and pharmacological randomized controlled trials (RCTs), as well as future directions for dementia and AD prevention. PMID:26097723

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

    PubMed

    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. PMID:21406339

  4. Novel targets for Alzheimer's disease treatment

    PubMed Central

    Grill, Joshua D.; Cummings, Jeffrey L.

    2014-01-01

    Summary Alzheimer's disease (AD) is a progressive neurodegenerative disease for which no cure exists. There is substantial need for new therapies that offer improved symptomatic benefit and disease-slowing capabilities. In recent decades there has been substantial progress in understanding the molecular and cellular changes associated with AD pathology. This has resulted in identification of a large number of new drug targets. These targets include but are not limited to therapies that aim to prevent production of or remove the beta amyloid (Aβ) protein that accumulates in neuritic plaques; prevent the hyperphosphorylation and aggregation into paired helical filaments of the microtubule-associated protein tau; and aim to keep neurons alive and functioning normally in the face of these pathologic challenges. We provide a review of these targets for drug development. PMID:20420492

  5. Alzheimer's disease: The role for neurosurgery

    PubMed Central

    Pereira, Julio Leonardo Barbosa; Downes, Angela; Gorgulho, Alessandra; Patel, Vishal; Malkasian, Dennis; De Salles, Antonio

    2014-01-01

    Dementia, most commonly caused by Alzheimer's disease (AD), affects approximately 35 million people worldwide, with the incidence expected to increase as the population ages. After decades of investigation, AD is now understood to be a complex disease that affects behavior and cognition through several mechanisms: Disrupted neuronal communication, abnormal regional tissue metabolism, and impaired cellular repair. Existing therapies have demonstrated limited efficacy, which has spurred the search for specific disease markers and predictors as well as innovative therapeutic options. Deep brain stimulation (DBS) of the memory circuits is one such option, with early studies suggesting that modulation of neural activity in these networks may improve cognitive function. Encapsulated cell biodelivery (ECB) is a device that delivers nerve growth factor to the cholinergic basal forebrain to potentially improve cognitive decline in AD patients. This review discusses the pathogenesis of AD, novel neuroimaging and biochemical markers, and the emerging role for neurosurgical applications such as DBS and ECB. PMID:25289167

  6. Glucose Metabolism: A Sweet Relief of Alzheimer's Disease.

    PubMed

    Duran-Aniotz, Claudia; Hetz, Claudio

    2016-09-12

    Patients and individuals at risk for Alzheimer's disease show reduced glucose metabolism in the brain. A new study takes advantage of a fly model of Alzheimer's disease to demonstrate that enhancing glucose uptake in neurons has strong neuroprotective effects involving improved proteostasis. PMID:27623263

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

  11. Aging and Alzheimer's Disease: Lessons from the Nun Study.

    ERIC Educational Resources Information Center

    Snowdon, David A.

    1997-01-01

    Describes a woman who maintained high cognitive test scores until her death at 101 years of age despite anatomical evidence of Alzheimer's disease. The woman was part of a larger "Nun Study" in which 678 sisters donated their brains to teach others about the etiology of aging and Alzheimer's disease. Findings are discussed. (RJM)

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

    PubMed

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

    2012-11-01

    In this review we summarize the epidemiological, cross-sectional, and interventional studies examining the association between physical activity and brain volume, function, and risk for Alzheimer's disease. The epidemiological literature provides compelling evidence that greater amounts of physical activity are associated with a reduced risk of dementia in late life. In addition, randomized interventions using neuroimaging tools have reported that participation in physical activity increases the size of prefrontal and hippocampal brain areas, which may lead to a reduction in memory impairments. Consistent with these findings, longitudinal studies using neuroimaging tools also find that the volume of prefrontal and hippocampal brain areas are larger in individuals who engaged in more physical activity earlier in life. We conclude from this review that there is convincing evidence that physical activity has a consistent and robust association with brain regions implicated in age-related cognitive decline and Alzheimer's disease. In addition to summarizing this literature we provide recommendations for future research on physical activity and brain health. PMID:23085449

  13. Alzheimer's Disease, Drosophila melanogaster and Polyphenols.

    PubMed

    Jimenez-Del-Rio, Marlene; Velez-Pardo, Carlos

    2015-01-01

    Alzheimer's disease (AD) is an insidious neurological disorder that affects memory, one of the human brain's main cognitive functions. Around 5.2 million Americans currently have AD, and the number threatens to climb to 7 million by 2020. Our native country, Colombia, is no exception with an estimated 260,000 individuals to be affected by AD in 2020. A large, genetically-isolated community in Antioquia, Colombia, with early-onset familial Alzheimer's disease due to a presenilin-1 mutation is ideally suited for the study of molecular mechanisms of AD, and hence accelerate the discovery of new or alternative treatment approaches. In this regard, polyphenols--also known as polyhydroxyphenols--have shown antioxidant activity, gene regulation, metal chelator and anti-amyloidogenic aggregation effects. However, further in vitro and in vivo investigations are warranted to validate their use in clinical trials. Drosophila melanogaster is increasingly being used as a valid in vivo model of AD. Here, we summarise data published within the past 16 years (1998-2014) on the molecular biology of AD and the use of polyphenols in the fly to understand the molecular actions and feasibility of these compounds in the treatment of AD. PMID:26092625

  14. The link between cholesterol and Alzheimer's disease.

    PubMed

    Sjögren, Magnus; Blennow, Kaj

    2005-01-01

    A leading hypothesis on the pathophysiology of Alzheimer's disease (AD) is the mis-metabolism of amyloid precursor protein. This mis-metabolism causes the 42-amino acid form of A beta(Abeta42) to form oligomers that in turn start a chain of events leading to the accumulation of amyloid plaques. Vascular factors such as hypertension, hypercholesterolemia and diabetes as well as the inheritance of the epsilon4 allele of the ApoE gene are risk factors for AD. These risks are thought to promote the production of beta-amyloid (Abeta). An association between cholesterol and the development of AD was suggested in 1994 and since then, research has confirmed a link between cholesterol and the development of AD. A high cholesterol level in mid-life is a risk for AD and statins i.e. cholesterol-lowering drugs, reduce this risk. Statins inhibit enzymes involved in the endogenous synthesis of cholesterol and evidence is mounting that they also affect enzymes in Abeta metabolism i.e. beta-secretase. This normalises the breakdown of the precursor of Abeta, amyloid precursor protein, thereby promoting the nonamyloidogenic pathway. This review focusses on the link between cholesterol and Alzheimer's disease. PMID:16156481

  15. Early onset Alzheimer's disease and oxidative stress.

    PubMed

    Meraz-Ríos, Marco Antonio; Franco-Bocanegra, Diana; Toral Rios, Danira; Campos-Peña, Victoria

    2014-01-01

    Alzheimer's disease (AD) is the most common cause of dementia in elderly adults. It is estimated that 10% of the world's population aged more than 60-65 years could currently be affected by AD, and that in the next 20 years, there could be more than 30 million people affected by this pathology. One of the great challenges in this regard is that AD is not just a scientific problem; it is associated with major psychosocial and ethical dilemmas and has a negative impact on national economies. The neurodegenerative process that occurs in AD involves a specific nervous cell dysfunction, which leads to neuronal death. Mutations in APP, PS1, and PS2 genes are causes for early onset AD. Several animal models have demonstrated that alterations in these proteins are able to induce oxidative damage, which in turn favors the development of AD. This paper provides a review of many, although not all, of the mutations present in patients with familial Alzheimer's disease and the association between some of these mutations with both oxidative damage and the development of the pathology. PMID:24669286

  16. Chronic Traumatic Encephalopathy Presenting as Alzheimer's Disease in a Retired Soccer Player.

    PubMed

    Grinberg, Lea T; Anghinah, Renato; Nascimento, Camila Fernandes; Amaro, Edson; Leite, Renata P; Martin, Maria da Graça M; Naslavsky, Michel S; Takada, Leonel T; Filho, Wilson Jacob; Pasqualucci, Carlos A; Nitrini, Ricardo

    2016-07-29

    The relationship between soccer and chronic traumatic encephalopathy (CTE) is not well established. We report clinicopathological correlations in an 83-year-old retired center-back soccer player, with no history of concussion, manifesting typical Alzheimer-type dementia. Examination revealed mixed pathology including widespread CTE, moderate Alzheimer's disease, hippocampal sclerosis, and TDP-43 proteinopathy. This case adds to a few CTE cases described in soccer players. Furthermore, it corroborates that CTE may present clinically as typical Alzheimer-type dementia. Further studies investigating the extent to which soccer is a risk for CTE are needed. PMID:27472879

  17. Can apolipoproteins and complement factors be biomarkers of Alzheimer's disease?

    PubMed

    Manral, Pallavi; Sharma, Pratibha; Hariprasad, Gururao; Chandralekha; Tripathi, Manjari; Srinivasan, Alagiri

    2012-10-01

    Alzheimer's disease is the most common cause of dementia in elderly persons. Quick diagnosis of Alzheimer's disease will allow treatments that may help slow its progression. The correlation between cerebrospinal fluid (CSF) parameters and progression of Alzheimer's disease is higher than and independent of other risk factors. We have compared sixteen CSF samples of clinically diagnosed Alzheimer's disease patients with non demented subjects using proteomics approach. Apolipoprotein E, apolipoprotein J, complement C4b, hemopexin and complement factor B were identified as differentially expressed proteins. Pathway analyses show that these proteins have interacting partners in Alzheimer's and apoptotic pathways. The possible roles of these proteins in relation to the disease are discussed. PMID:22631439

  18. Diminished glucose transport and phosphorylation in Alzheimer`s disease determined by dynamic FDG-PET

    SciTech Connect

    Piert, M.; Koeppe, R.A.; Giordani, B.; Berent, S.; Kuhl, D.E.

    1996-02-01

    Using dynamic [{sup 18}F] fluorodeoxyglucose (FDG) and PET, kinetic rate constants that describe influx (K{sub 1}) and efflux (k{sub 2}) of FDG as well s phosphorylation (k{sub 3}) and dephosphorylation (k{sub 4}) were determined in patients with probable Alzheimer`s disease and similarly aged normal controls. The regional cerebral metabolic rate for glucose (CMR{sub glu}) was calculated from individually fitted rate constants in frontal, temporal, parietal and occipital cerebral cortex, caudate nucleus, putamen, thalamus and cerebellar cortex. Dynamic PET scans were obtained in normal controls (n = 10, mean age = 67) and Alzheimer`s disease patients (n = 8, mean age = 67) for 60 min following injection of 10 mCi of FDG. The Alzheimer`s disease group was characterized by decreases of the CMR{sub glu} ranging from 13.3% in the frontal to 40.9% in the parietal cortex, which achieved significance in all regions except the thalamus. K{sub 1} was significantly reduced in the parietal (p < 0.01) and temporal cortices (p < 0.005), temporal and occipital cortex, and in the putamen and cerebellum (p < 0.05). The rate constants k{sub 2} and k{sub 4} were unchanged in the Alzheimer`s disease group. These data suggest that hypometabolism in Alzheimer`s disease is related to reduced glucose phosphorylation activity as well as diminished glucose transport, particularly in the most metabolically affected areas of the brain, the parietal and temporal cortex. 60 refs., 2 figs., 2 tabs.

  19. The Impact of Alzheimer's Disease in an Aging Rural Population.

    PubMed

    Minkemeyer, Vivian; Wellman, Courtney; Goebel, Lynne

    2016-01-01

    West Virginia already has a large elderly population, and it is expected to increase along with the elderly population of the nation as a whole. Since the most important risk factor for Alzheimer's disease is older age, it is not surprising that the prevalence of Alzheimer's disease is projected to increase significantly over the next thirty-five years. This paper discusses the prevalence of Alzheimer's disease in West Virginia, programs available to assist people and caregivers affected by the disease, and the associated economic burden of the disease. PMID:27301161

  20. Symptoms, Diagnosis and Treatment | Alzheimer's disease | NIH MedlinePlus the Magazine

    MedlinePlus

    ... of this page please turn Javascript on. Feature: Alzheimer's Disease Symptoms, Diagnosis and Treatment Past Issues / Fall ... 10 to 20 years before symptoms appear and Alzheimer's disease is diagnosed. Mild Alzheimer's dementia Memory problems ...

  1. GM1 ganglioside and Alzheimer's disease.

    PubMed

    Yanagisawa, Katsuhiko

    2015-05-01

    Assembly and deposition of amyloid ß-protein (Aß) is an invariable and fundamental event in the pathological process of Alzheimer's disease (AD). To decipher the AD pathogenesis and also to develop disease-modifying drugs for AD, clarification of the molecular mechanism underlying the Aß assembly into amyloid fibrils in the brain has been a crucial issue. GM1-ganglioside-bound Aß (GAß), with unique molecular characteristics such as having an altered conformation and the capability to accelerate Aß assembly, was discovered in an autopsied brain showing early pathological changes of AD in 1995. On the basis of these findings, it was hypothesized that GAß is an endogenous seed for amyloid fibril formation in the AD brain. A body of evidence that supports this GAß hypothesis has been growing over this past 20 years. In this article, seminal GAß studies that have been carried out to date, including recent ones using unique animal models, are reviewed. PMID:25903682

  2. Drug Development for Alzheimer's Disease: Recent Progress

    PubMed Central

    Ji, Wonjin

    2010-01-01

    Alzheimer's disease, the most common cause of dementia, is characterized by two major pathological hallmarks: amyloid plaques and neurofibrillary tangles. Based on these two indicators, an amyloid cascade hypothesis was proposed, and accordingly, most current therapeutic approaches are now focused on the removal of β-amyloid peptides (Aβ from the brain. Additionally, strategies for blocking tau hyperphosphorylation and aggregation have been suggested, including the development of drugs that can block the formation of tangles. However, there are no true disease-modifying drugs in the current market, though many drugs based on theories other than Aβ and tau pathology are under development. The purpose of this review was to provide information on the current development of AD drugs and to discuss the issues related to drug development. PMID:22110351

  3. Commentary: is Alzheimer's disease uniquely human?

    PubMed Central

    Finch, Caleb E.; Austad, Steven N.

    2015-01-01

    That Alzheimer's disease (AD) might be a human-specific disease was hypothesized by Rapoport in 1989. Apes and humans share an identical amyloid beta (Aβ) peptide amino acid sequence and accumulate considerable Aβ deposits after age 40 years, an age when amyloid plaques are uncommon in humans. Despite their early Aβ buildup, ape brains have not shown evidence dystrophic neurites near plaques. Aging great ape brains also have few neurofibrillary tangles, with one exception of 1 obese chimpanzee euthanized after a stroke who displayed abundant neurofibrillary tangles, but without the typical AD distribution. We discuss the need for more exacting evaluation of neuron density with age, and note husbandry issues that may allow great apes to live to greater ages. We remain reserved about expectations for fully developed AD-like pathology in the great apes of advanced ages and cautiously support Rapoport's hypothesis. PMID:25533426

  4. Metabolic profiling of Alzheimer's disease brains

    NASA Astrophysics Data System (ADS)

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

    2013-08-01

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

  5. [Treatment of Alzheimer's disease and future approaches].

    PubMed

    Forette, Françoise; Hauw, Jean-Jacques

    2010-01-01

    The progressive neuronal loss in Alzheimer's disease leads to neurochemical abnormalities which provide the basis for symptomatic treatments. Four cholinesterase inhibitors were released in this indication. Meta-analyses have confirmed a beneficial effect on cognitive functioning and activities of daily living. The NMDA receptor antagonist, memantine, was also approved for the treatment of moderate to severe and may be associated. Progress in the patho-physiology of the disease offers some hope of new treatments acting on the cerebral lesions. The amyloid hypothesis allowed the emergence of active or passive immunotherapies, and of secretase inhibitors or modulators. Recent studies have targeted the P tau protein. The brain plasticity and the uses of stem cells offer more distant hope. PMID:21144478

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

    PubMed

    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. PMID:22675311

  7. Helping People with Alzheimer's Disease Stay Physically Active

    MedlinePlus

    ... Free Stuff Be a Partner Helping People with Alzheimer's Disease Stay Physically Active Regular physical activity has many benefits for people with Alzheimer’s disease. Exercise helps keep muscles, joints, and the ...

  8. What Do We Know About Preventing Alzheimer's? | NIH MedlinePlus the Magazine

    MedlinePlus

    ... read Participating in Alzheimer's Research: For Yourself and Future Generations http://www.nia.nih.gov/alzheimers/publication/participating-alzheimers-research/introduction . You can also contact the NIA Alzheimer's Disease Education and Referral (ADEAR) Center at 1-800- ...

  9. Physical Mistreatment in Persons with Alzheimer's Disease

    PubMed Central

    VandeWeerd, Carla; Paveza, Gregory J.; Walsh, Margaret; Corvin, Jaime

    2013-01-01

    Physical mistreatment has been estimated to affect 2 million older persons each year and dramatically affects health outcomes. While researchers have attempted to examine risk factors for specific forms of abuse, many have been able to focus on only victim or perpetrator characteristics, or a limited number of psychosocial variables at any one time. Additionally, data on risk factors for subgroups such as persons with Alzheimer's disease who may have heightened and/or unique risk profiles has also been limited. This paper examines risk for physical violence in caregiver/patient dyads who participated in the Aggression and Violence in Community-Based Alzheimer's Families Grant. Data were collected via in-person interview and mailed survey and included demographics as well as measures of violence, physical and emotional health, and health behaviors. Logistic regression analysis indicated that caregivers providing care to elders with high levels of functional impairment or dementia symptoms, or who had alcohol problems, were more likely to use violence as a conflict resolution strategy, as were caregivers who were providing care to elders who used violence against them. By contrast, caregivers with high self-esteem were less likely to use violence as a conflict resolution strategy. Significant interaction effects were also noted. PMID:23577255

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

    PubMed

    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. PMID:26616239

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

    PubMed

    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. PMID:24535580

  12. Graphical neuroimaging informatics: application to Alzheimer's disease.

    PubMed

    Van Horn, John Darrell; Bowman, Ian; Joshi, Shantanu H; Greer, Vaughan

    2014-06-01

    The Informatics Visualization for Neuroimaging (INVIZIAN) framework allows one to graphically display image and meta-data information from sizeable collections of neuroimaging data as a whole using a dynamic and compelling user interface. Users can fluidly interact with an entire collection of cortical surfaces using only their mouse. In addition, users can cluster and group brains according in multiple ways for subsequent comparison using graphical data mining tools. In this article, we illustrate the utility of INVIZIAN for simultaneous exploration and mining a large collection of extracted cortical surface data arising in clinical neuroimaging studies of patients with Alzheimer's Disease, mild cognitive impairment, as well as healthy control subjects. Alzheimer's Disease is particularly interesting due to the wide-spread effects on cortical architecture and alterations of volume in specific brain areas associated with memory. We demonstrate INVIZIAN's ability to render multiple brain surfaces from multiple diagnostic groups of subjects, showcase the interactivity of the system, and showcase how INVIZIAN can be employed to generate hypotheses about the collection of data which would be suitable for direct access to the underlying raw data and subsequent formal statistical analysis. Specifically, we use INVIZIAN show how cortical thickness and hippocampal volume differences between group are evident even in the absence of more formal hypothesis testing. In the context of neurological diseases linked to brain aging such as AD, INVIZIAN provides a unique means for considering the entirety of whole brain datasets, look for interesting relationships among them, and thereby derive new ideas for further research and study. PMID:24203652

  13. Alzheimer disease and pre-emptive suicide.

    PubMed

    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. PMID:23842079

  14. Domain adaptation for Alzheimer's disease diagnostics.

    PubMed

    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. PMID:27262241

  15. Sleep disturbances in Alzheimer's and Parkinson's diseases.

    PubMed

    Rothman, Sarah M; Mattson, Mark P

    2012-09-01

    Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders and exact a burden on our society greater than cardiovascular disease and cancer combined. While cognitive and motor symptoms are used to define AD and PD, respectively, patients with both disorders exhibit sleep disturbances including insomnia, hypersomnia and excessive daytime napping. The molecular basis of perturbed sleep in AD and PD may involve damage to hypothalamic and brainstem nuclei that control sleep-wake cycles. Perturbations in neurotransmitter and hormone signaling (e.g., serotonin, norepinephrine and melatonin) and the neurotrophic factor BDNF likely contribute to the disease process. Abnormal accumulations of neurotoxic forms of amyloid β-peptide, tau and α-synuclein occur in brain regions involved in the regulation of sleep in AD and PD patients, and are sufficient to cause sleep disturbances in animal models of these neurodegenerative disorders. Disturbed regulation of sleep often occurs early in the course of AD and PD, and may contribute to the cognitive and motor symptoms. Treatments that target signaling pathways that control sleep have been shown to retard the disease process in animal models of AD and PD, suggesting a potential for such interventions in humans at risk for or in the early stages of these disorders. PMID:22552887

  16. The news advances on Alzheimer's disease's therapeutics.

    PubMed

    Sun, H-Q; Zhang, X; Huang, W-J; Chen, W-W

    2016-05-01

    Alzheimer's disease (AD) is a multifaceted disorder, characterized by the failure of memory and dementia. AD affects mostly elder above 65 years of age and is confirmed by post-mortem detection in the brain, of extracellular senile plaques of amyloid-beta (Aβ) and intracellular neurofibrillary tangles. These pathological hallmarks appear in the brain when the disease is already installed. The difficulty of earlier diagnosis and possibly, the poor understanding of the disease etiology, limit the benefits afforded by available treatments. Indeed, several putative drugs resulting from thorough investigations in preclinical studies have failed to produce clinical results, suggesting the development of further therapeutic alternatives. Recently, the regular practice of physical activity has been shown as one of the effective preventive or curative mean against AD. This finding rekindles the debate on the place of the intrinsic vascular component in the AD pathogenesis which is an aspect of the disease often considered as a distinct pathology. A new integrative conception of the disease may offer an advantage to current therapies which may gain in potency if combined in a multi-target manner to yield true improvements. This review will revisit the pathophysiology of AD and discuss the advanced therapeutics currently in use. PMID:27212186

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

    PubMed

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

    2014-01-01

    The brain transcriptome of Alzheimer's disease (AD) reflects the prevailing disease mechanism at the gene expression level. However, thousands of genes have been reported to be dysregulated in AD brains in existing studies, and the consistency or discrepancy among these studies has not been thoroughly examined. Toward this end, we conducted a comprehensive survey of the brain transcriptome datasets for AD and other neurological diseases. We first demonstrated that the frequency of observed dysregulation in AD was highly correlated with the reproducibility of the dysregulation. Based on this observation, we selected 100 genes with the highest frequency of dysregulation to illustrate the core perturbation in AD brains. The dysregulation of these genes was validated in several independent datasets for AD. We further identified 12 genes with strong correlation of gene expression with disease progression. The relevance of these genes to disease progression was also validated in an independent dataset. Interestingly, we found a transcriptional "cushion" for these 100 genes in the less vulnerable visual cortex region, which may be a critical component of the protection mechanism for less vulnerable brain regions. To facilitate the research in this field, we have provided the expression information of ~8000 relevant genes on a publicly accessible web server AlzBIG (http://alz.big.ac.cn). PMID:24662101

  18. Hypothalamic digoxin, hemispheric chemical dominance, and Alzheimer's disease.

    PubMed

    Kurup, Ravi Kumar; Kurup, Parameswara Achutha

    2003-03-01

    This study assessed the changes in the isoprenoid pathway and the consequences of its dysfunction in Alzheimer's disease (AD). The isoprenoid pathway and digoxin status were also studied for comparison in individuals of differing hemispheric dominance to find the role of cerebral dominance in the genesis of Alzheimer's disease. There was elevation in plasma HMG CoA reductase activity, serum digoxin, and dolichol levels, and a reduction in serum magnesium, RBC membrane Na(+)-K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, strychnine, nicotine, and quinolinic acid were elevated, while serum tyrosine, morphine, dopamine, and noradrenaline were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins, and serum glycolipids were elevated in Alzheimer's disease. HDL cholesterol was reduced and free fatty acids increased. The RBC membrane glycosaminoglycans, hexose, and fucose residues of glycoproteins and cholesterol were reduced, while phospholipid increased. The activity of all free radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in Alzheimer's disease, while the concentration of lipid peroxidation products and NO increased. The hypomagnesemia-related NMDA excitotoxicity, ubiquinone deficiency related mitochondrial dysfunction, and altered glycoconjugates/lysosomal stability could contribute to the pathogenesis of Alzheimer's disease. The biochemical patterns, including hyperdigoxinemia observed in Alzheimer's disease, correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance is a predisposing factor for Alzheimer's disease. PMID:12803139

  19. Sexual Concerns of Male Spouses of Female Alzheimer's Disease Patients.

    ERIC Educational Resources Information Center

    Litz, Brett T.; And Others

    1990-01-01

    Presents case study which highlights attendant cognitive changes that occur in Alzheimer's patient, presenting caregiver with challenges to couple's sexual functioning. Describes man who reported erectile dysfunction directly stemming from stressful changes that had occurred in his relationship to his wife who had Alzheimer's disease. General…

  20. Synaptic Cell Adhesion Molecules in Alzheimer's Disease

    PubMed Central

    Leshchyns'ka, Iryna

    2016-01-01

    Alzheimer's disease (AD) is a neurodegenerative brain disorder associated with the loss of synapses between neurons in the brain. Synaptic cell adhesion molecules are cell surface glycoproteins which are expressed at the synaptic plasma membranes of neurons. These proteins play key roles in formation and maintenance of synapses and regulation of synaptic plasticity. Genetic studies and biochemical analysis of the human brain tissue, cerebrospinal fluid, and sera from AD patients indicate that levels and function of synaptic cell adhesion molecules are affected in AD. Synaptic cell adhesion molecules interact with Aβ, a peptide accumulating in AD brains, which affects their expression and synaptic localization. Synaptic cell adhesion molecules also regulate the production of Aβ via interaction with the key enzymes involved in Aβ formation. Aβ-dependent changes in synaptic adhesion affect the function and integrity of synapses suggesting that alterations in synaptic adhesion play key roles in the disruption of neuronal networks in AD. PMID:27242933

  1. Mitochondria, Cognitive Impairment, and Alzheimer's Disease

    PubMed Central

    Mancuso, M.; Calsolaro, V.; Orsucci, D.; Carlesi, C.; Choub, A.; Piazza, S.; Siciliano, G.

    2009-01-01

    To date, the beta amyloid (Aβ) cascade hypothesis remains the main pathogenetic model of Alzheimer's disease (AD), but its role in the majority of sporadic AD cases is unclear. The “mitochondrial cascade hypothesis” could explain many of the biochemical, genetic, and pathological features of sporadic AD. Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure, increased oxidative stress, and accumulation of Aβ, which in a vicious cycle reinforce the mtDNA damage and the oxidative stress. Despite the evidence of mitochondrial dysfunction in AD, no causative mutations in the mtDNA have been detected so far. Indeed, results of studies on the role of mtDNA haplogroups in AD are controversial. In this review we discuss the role of the mitochondria, and especially of the mtDNA, in the cascade of events leading to neurodegeneration, dementia, and AD. PMID:20798880

  2. Mitochondria, cognitive impairment, and Alzheimer's disease.

    PubMed

    Mancuso, M; Calsolaro, V; Orsucci, D; Carlesi, C; Choub, A; Piazza, S; Siciliano, G

    2009-01-01

    To date, the beta amyloid (Abeta) cascade hypothesis remains the main pathogenetic model of Alzheimer's disease (AD), but its role in the majority of sporadic AD cases is unclear. The "mitochondrial cascade hypothesis" could explain many of the biochemical, genetic, and pathological features of sporadic AD. Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure, increased oxidative stress, and accumulation of Abeta, which in a vicious cycle reinforce the mtDNA damage and the oxidative stress. Despite the evidence of mitochondrial dysfunction in AD, no causative mutations in the mtDNA have been detected so far. Indeed, results of studies on the role of mtDNA haplogroups in AD are controversial. In this review we discuss the role of the mitochondria, and especially of the mtDNA, in the cascade of events leading to neurodegeneration, dementia, and AD. PMID:20798880

  3. Nutrition and the risk of Alzheimer's disease.

    PubMed

    Hu, Nan; Yu, Jin-Tai; Tan, Lin; Wang, Ying-Li; Sun, Lei; Tan, Lan

    2013-01-01

    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. PMID:23865055

  4. Implicit verbal memory in Alzheimer's disease.

    PubMed

    Russo, R; Spinnler, H

    1994-09-01

    Word stem completion and word identification were used in two repetition priming experiments to evaluate the implicit memory performance of Alzheimer's disease (AD) patients. This issue was also approached using various meta-analyses combining and contrasting previously reported data. While the experimental results suggested that AD patients present preserved repetition priming in both tasks, the meta-analytic approach showed an impairment in stem completion in comparison to word identification. Converging evidence cautiously suggested to accept the results of the meta-analysis. The above dissociation has been interpreted as showing differences in the specific contribution of data- and conceptually-driven processes in the two implicit tasks. A further meta-analysis on the effect of reduced perceptual availability of the study material on the same two tasks indicated that this variable affected repetition priming in word identification more heavily than in stem completion. The impact of such a dissociation on theories of implicit memory is discussed. PMID:7805380

  5. Traditional Chinese medicines and Alzheimer's disease.

    PubMed

    Wu, Tzong-Yuan; Chen, Chih-Ping; Chen, Chip-Ping; Jinn, Tzyy-Rong

    2011-06-01

    Traditional Chinese medicines have been widely investigated for the treatment of Alzheimer's disease (AD) because none of the current therapies-either the cholinesterase inhibitors or antagonist of N-methyl-d-aspartate receptors-has profound effects on halting the progression of AD. In recent years, scientists have isolated many active compounds from herbs, which can alleviate dementia and neurodegenerative syndrome with fewer side effects than conventional drugs and, thus, are regarded as promising drug candidates for AD therapy. In this review, we summarize the latest research progress on six herbs for AD therapy-Huperzia serrata, Amaryllidaceae family, Ginkgo biloba, Uncaria rhynchophylla, Polygala tenuifolia, and Salvia officinalis-and focus on the analysis of their active components and possible mechanisms of pharmacological actions on AD. PMID:21791295

  6. Alzheimer's disease and other dementias in Canada.

    PubMed

    Wong, Suzy L; Gilmour, Heather; Ramage-Morin, Pamela L

    2016-05-18

    This article provides information on Alzheimer's disease and other dementias, using the 2010/2011 Canadian Community Health Survey, the 2011/2012 Survey of Neurological Conditions in Institutions in Canada, and the 2011 Survey on Living with Neurological Conditions in Canada. Among Canadians aged 45 or older, an estimated 0.8% in private households and 45% in long-term residential care facilities had a diagnosis of dementia. Prevalence rose with age. The vast majority of people with dementia in private households received assistance with medical care (81%), housework and home maintenance (83%), meal preparation (88%), emotional support (90%), transportation (92%), and managing care (92%). Among those receiving assistance, 85% relied, at least in part, on family, friends or neighbours. The primary caregiver tended to be a spouse (46%) or an adult child (44%), most of whom were daughters (71%). The majority of primary caregivers lived in the same household (83%) and provided daily care (86%). PMID:27192206

  7. Emotional Working Memory in Alzheimer's Disease Patients

    PubMed Central

    Satler, Corina; Tomaz, Carlos

    2011-01-01

    Background Few studies have assessed whether emotional content affects processes supporting working memory in Alzheimer disease (AD) patients. Methods We assessed 22 AD patients and 40 elderly controls (EC) with a delayed matching and non-matching to sample task (DMST/DNMST), and a spatial-delayed recognition span task (SRST; unique/varied) using emotional stimuli. Results AD patients showed decreased performance on both tasks compared with EC. With regard to the valence of the stimuli, we did not observe significant performance differences between groups in the DMST/DNMST. However, both groups remembered a larger number of negative than positive or neutral pictures on unique SRST. Conclusion The results suggest that AD patients show a relative preservation of working memory for emotional information, particularly for negative stimuli. PMID:22163239

  8. Alzheimer's disease: recent advances and future perspectives.

    PubMed

    Ubhi, Kiren; Masliah, Eliezer

    2013-01-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory deficits and other cognitive disturbances. Neuropathologically, AD is characterized by the progressive loss of basal forebrain cholinergic neurons that innervate the hippocampus and cortex and the abnormal extracellular accumulation of amyloid-β and intracellular tau protein. Current research on AD is focused on the mechanisms underlying the abnormal oligomerization, fibrillation, and accumulation of the amyloid-β and tau proteins, mechanisms that may alter the dynamics of this accumulation and on experimental therapeutics approaches aimed at the clearance of the abnormally folded proteins and other potentially neuroprotective interventions. This review will summarize the main areas of investigation in AD and present ways forward for future work. PMID:22810100

  9. New Acetylcholinesterase Inhibitors for Alzheimer's Disease

    PubMed Central

    Mehta, Mona; Adem, Abdu; Sabbagh, Marwan

    2012-01-01

    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. PMID:22216416

  10. Anosognosia and procedural learning in Alzheimer's disease.

    PubMed

    Starkstein, S E; Sabe, L; Cuerva, A G; Kuzis, G; Leiguarda, R

    1997-04-01

    Awareness of cognitive deficits may rely on the implicit learning of intellectual limitations, and anosognosia in Alzheimer's disease (AD) may result from deficits in implicit learning. To examine this hypothesis, a consecutive series of 55 patients with probable AD were divided into groups with mild (n = 13), severe (n = 12), or no anosognosia (n = 30) and were assessed with a neuropsychological battery that included tests of declarative and procedural learning. Whereas there were no significant between-group differences in tests of declarative learning (the Buschke Selective Reminding Test and the Benton Visual Retention Test), patients with severe anosognosia showed a significantly worse performance on procedural learning (as measured with the Maze Learning Test) and a test assessing set shifting abilities (the Wisconsin Card Sorting Test) than AD patients without anosognosia. The authors' results suggest that deficits in procedural learning and anosognosia in AD may result from dysfunction in habit-learning systems. PMID:9150509

  11. The Role of PGRN in Alzheimer's Disease.

    PubMed

    Jing, Hua; Tan, Meng-Shan; Yu, Jin-Tai; Tan, Lan

    2016-08-01

    Progranulin (PGRN), a multifunctional growth factor expressed in various tissues, is involved in a diversity of physiologic and pathological processes, including cell proliferation, wound healing, and modulation of inflammation. Interest in the role of progranulin in the brain has increased dramatically since mutations in GRN, which encodes for the protein PGRN, are associated with the pathogenesis of Alzheimer's disease (AD). A great many of studies suggest that PGRN participates in AD pathogenesis through diverse pathways, including Aβ deposition and clearance, intraneuronal deposition of phosphorylated tau, neuroinflammation, and neuronal survival. Decreased GRN mRNA levels can be detected in the parietal lobe of patients clinically diagnosed with AD; more importantly, emerging data support that serum or plasma PGRN can act as a biomarker for AD. By understanding PGRN in a wider context, we may be better able to depict its role in AD and then provide a therapeutic strategy for AD. PMID:26215834

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

    PubMed

    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. PMID:19214750

  13. Language impairment in Alzheimer's disease and benefits of acetylcholinesterase inhibitors.

    PubMed

    Ferris, Steven H; Farlow, Martin

    2013-01-01

    Alzheimer's disease is characterized by progressively worsening deficits in several cognitive domains, including language. Language impairment in Alzheimer's disease primarily occurs because of decline in semantic and pragmatic levels of language processing. Given the centrality of language to cognitive function, a number of language-specific scales have been developed to assess language deficits throughout progression of the disease and to evaluate the effects of pharmacotherapy on language function. Trials of acetylcholinesterase inhibitors, used for the treatment of clinical symptoms of Alzheimer's disease, have generally focused on overall cognitive effects. However, in the current report, we review data indicating specific beneficial effects of acetylcholinesterase inhibitors on language abilities in patients with Alzheimer's disease, with a particular focus on outcomes among patients in the moderate and severe disease stages, during which communication is at risk and preservation is particularly important. PMID:23946647

  14. Effective pharmacological management of Alzheimer's disease.

    PubMed

    Atri, Alireza

    2011-11-01

    Alzheimer's dementia represents organ failure of the brain. It denotes a clinical milestone that is the result of a pathological process, Alzheimer's disease (AD), which over 1 or more decades has wrought insidious destruction, and finally overwhelmed the brain's capacities to compensate. It is incurable, progressive, and follows an individual pace and course. AD is particularly demanding and devastating to family and caregivers, and patients, all of whom suffer psychologically and emotionally. The cholinesterase inhibitors (ChEIs) donepezil, galantamine, and rivastigmine and the N-methyl- D-aspartate receptor antagonist memantine are approved by the US Food and Drug Administration for AD; they are often used in combination once the disease reaches moderate stages. The relatively good safety profile of these medications, along with their efficacy in alleviating symptoms, is supported by several level-I evidence-grade, short-term, randomized, placebo-controlled trials (RCTs). However, these studies are of limited value in assessing the real-world clinical and economic impact of AD therapies. Long-term, observational studies can provide complementary information to results from short-term clinical trials and more accurately assess practical long-term benefits, risks, costs, and effects on clinically meaningful end points. There is now accumulating and convergent evidence from short- and long-term RCTs, longer-term open-label extensions of RCTs, and long-term observational studies that ChEIs and memantine reduce decline in cognition and daily function, and delay nursing home placement. Optimal care in AD is multifactorial; it includes early diagnosis and multidisciplinary care with educational and nonpharmacological interventions, while ensuring safety, treating comorbidities, caring for caregivers, and appropriate initiation and maintenance of combination therapy. PMID:22214392

  15. Brain atrophy in Alzheimer's Disease and aging.

    PubMed

    Pini, Lorenzo; Pievani, Michela; Bocchetta, Martina; Altomare, Daniele; Bosco, Paolo; Cavedo, Enrica; Galluzzi, Samantha; Marizzoni, Moira; Frisoni, Giovanni B

    2016-09-01

    Thanks to its safety and accessibility, magnetic resonance imaging (MRI) is extensively used in clinical routine and research field, largely contributing to our understanding of the pathophysiology of neurodegenerative disorders such as Alzheimer's disease (AD). This review aims to provide a comprehensive overview of the main findings in AD and normal aging over the past twenty years, focusing on the patterns of gray and white matter changes assessed in vivo using MRI. Major progresses in the field concern the segmentation of the hippocampus with novel manual and automatic segmentation approaches, which might soon enable to assess also hippocampal subfields. Advancements in quantification of hippocampal volumetry might pave the way to its broader use as outcome marker in AD clinical trials. Patterns of cortical atrophy have been shown to accurately track disease progression and seem promising in distinguishing among AD subtypes. Disease progression has also been associated with changes in white matter tracts. Recent studies have investigated two areas often overlooked in AD, such as the striatum and basal forebrain, reporting significant atrophy, although the impact of these changes on cognition is still unclear. Future integration of different MRI modalities may further advance the field by providing more powerful biomarkers of disease onset and progression. PMID:26827786

  16. Role of physical exercise in Alzheimer's disease

    PubMed Central

    CHEN, WEI-WEI; ZHANG, XIA; HUANG, WEN-JUAN

    2016-01-01

    The benefits of physical exercise on the brain and general wellness are well recognised, but not particularly well known to the general public. Understanding the importance of integrating active behavior for overall health is crucial at any age and particularly for the elderly who are at risk of developing Alzheimer's disease (AD), a disease mainly affecting individuals aged >65 years. AD is a neurodegenerative disease characterized by extracellular senile plaques of amyloid-β, intracellular neurofibrillary tangles of the protein tau, brain atrophy and dementia. The beneficial effects of physical exercise have been observed on the maintenance of brain size and efficiency for the prevention of AD risks, such as obesity, hypertension and stroke. These effects are extended to individuals with, or at risk of dementia and other age-related neurodegenerative disorders. Accordingly, although extensive studies are required to fully understand the mechanisms by which physical exercise procures beneficial effects, data suggest the relevance of integrating physical exercise in the prevention and/or cure of AD, disease whose incidence is predicted to increase in the future. Such an increase, may pose medical, social and economical challenges for populations and the health care system worldwide. In the present review we assess the positive aspects of physical exercise with regard to prevention and cure of AD. PMID:27073621

  17. Biomaterials for the Treatment of Alzheimer's Disease.

    PubMed

    Hadavi, Darya; Poot, André A

    2016-01-01

    Alzheimer's disease (AD) as a progressive and fatal neurodegenerative disease represents a huge unmet need for treatment. The low efficacy of current treatment methods is not only due to low drug potency but also due to the presence of various obstacles in the delivery routes. One of the main barriers is the blood-brain barrier. The increasing prevalence of AD and the low efficacy of current therapies have increased the amount of research on unraveling of disease pathways and development of treatment strategies. One of the interesting areas for the latter subject is biomaterials and their applications. This interest originates from the fact that biomaterials are very useful for the delivery of therapeutic agents, such as drugs, proteins, and/or cells, in order to treat diseases and regenerate tissues. Recently, manufacturing of nano-sized delivery systems has increased the efficacy and delivery potential of biomaterials. In this article, we review the latest developments with regard to the use of biomaterials for the treatment of AD, including nanoparticles and liposomes for delivery of therapeutic compounds and scaffolds for cell delivery strategies. PMID:27379232

  18. Pharmacotherapies for Alzheimer's disease: beyond cholinesterase inhibitors.

    PubMed

    Tayeb, Haythum O; Yang, Hyun Duk; Price, Bruce H; Tarazi, Frank I

    2012-04-01

    Alzheimer's disease (AD) is the most common cause of memory impairment and dementia in the elderly. AD is pathologically characterized by extracellular deposits of beta-amyloid (Aβ) peptide, neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, neuronal loss, and neurotransmitter dysfunction. Clinically, AD is characterized by progressive cognitive decline that usually starts with memory impairment and progresses to cause a more generalized cognitive dysfunction, behavioral dysregulation, and neuropsychiatric symptoms. These symptoms collectively lead to a progressive and relentless decline in the ability to perform functions of daily living, eventually leading to total incapacitation. The incidence and prevalence of AD are expected to exponentially increase with the aging of the population. Currently approved treatments, including the acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine and rivastigmine, and the N-methyl-D-aspartate (NMDA) antagonist memantine, do not halt the progression of the disease, and have provided marginal therapeutic benefits. Accordingly, there is an urgent need to develop novel and effective medications for AD that go beyond AChEIs and NMDA antagonists. Modern research has focused on discovering effective disease-modifying therapies, which specifically target the pathophysiologic cascade, hoping to delay the onset of the disease and slow its progression. In this review, different pharmacological drugs and therapeutic approaches will be discussed, with an emphasis on novel therapies that are currently being investigated in clinical trials. PMID:22198801

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

    PubMed

    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. PMID:25619854

  20. Disease-modifying trials in Alzheimer's disease: a European task force consensus.

    PubMed

    Vellas, Bruno; Andrieu, Sandrine; Sampaio, Cristina; Wilcock, Gordon

    2007-01-01

    After symptomatic treatments, the new target for therapeutic approaches in Alzheimer's disease is the development of disease-modifying drugs. The concept of disease modification in Alzheimer's disease is controversial and the design of these trials raises many questions. Which populations should be studied? For how long? With which principal and secondary endpoints? Are surrogate markers available? Here, we present a European consensus on disease-modifying trials in Alzheimer's disease, agreed under the auspices of the European Alzheimer's Disease Consortium and based on the European perspective of the concept of disease modification, study designs, the role for biomarkers, risk benefit, and pharmacoeconomic issues. PMID:17166802

  1. Building a roadmap for developing combination therapies for Alzheimer's disease.

    PubMed

    Perry, Daniel; Sperling, Reisa; Katz, Russell; Berry, Donald; Dilts, David; Hanna, Debra; Salloway, Stephen; Trojanowski, John Q; Bountra, Chas; Krams, Michael; Luthman, Johan; Potkin, Steven; Gribkoff, Val; Temple, Robert; Wang, Yaning; Carrillo, Maria C; Stephenson, Diane; Snyder, Heather; Liu, Enchi; Ware, Tony; McKew, John; Fields, F Owen; Bain, Lisa J; Bens, Cynthia

    2015-03-01

    Combination therapy has proven to be an effective strategy for treating many of the world's most intractable diseases. A growing number of investigators in academia, industry, regulatory agencies, foundations and advocacy organizations are interested in pursuing a combination approach to treating Alzheimer's disease. A meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer's Disease Coalition, the Critical Path Institute and the Alzheimer's Association addressed challenges in designing clinical trials to test multiple treatments in combination and outlined a roadmap for making such trials a reality. PMID:25708309

  2. Crowdsourced estimation of cognitive decline and resilience in Alzheimer's disease.

    PubMed

    Allen, Genevera I; Amoroso, Nicola; Anghel, Catalina; Balagurusamy, Venkat; Bare, Christopher J; Beaton, Derek; Bellotti, Roberto; Bennett, David A; Boehme, Kevin L; Boutros, Paul C; Caberlotto, Laura; Caloian, Cristian; Campbell, Frederick; Chaibub Neto, Elias; Chang, Yu-Chuan; Chen, Beibei; Chen, Chien-Yu; Chien, Ting-Ying; Clark, Tim; Das, Sudeshna; Davatzikos, Christos; Deng, Jieyao; Dillenberger, Donna; Dobson, Richard J B; Dong, Qilin; Doshi, Jimit; Duma, Denise; Errico, Rosangela; Erus, Guray; Everett, Evan; Fardo, David W; Friend, Stephen H; Fröhlich, Holger; Gan, Jessica; St George-Hyslop, Peter; Ghosh, Satrajit S; Glaab, Enrico; Green, Robert C; Guan, Yuanfang; Hong, Ming-Yi; Huang, Chao; Hwang, Jinseub; Ibrahim, Joseph; Inglese, Paolo; Iyappan, Anandhi; Jiang, Qijia; Katsumata, Yuriko; Kauwe, John S K; Klein, Arno; Kong, Dehan; Krause, Roland; Lalonde, Emilie; Lauria, Mario; Lee, Eunjee; Lin, Xihui; Liu, Zhandong; Livingstone, Julie; Logsdon, Benjamin A; Lovestone, Simon; Ma, Tsung-Wei; Malhotra, Ashutosh; Mangravite, Lara M; Maxwell, Taylor J; Merrill, Emily; Nagorski, John; Namasivayam, Aishwarya; Narayan, Manjari; Naz, Mufassra; Newhouse, Stephen J; Norman, Thea C; Nurtdinov, Ramil N; Oyang, Yen-Jen; Pawitan, Yudi; Peng, Shengwen; Peters, Mette A; Piccolo, Stephen R; Praveen, Paurush; Priami, Corrado; Sabelnykova, Veronica Y; Senger, Philipp; Shen, Xia; Simmons, Andrew; Sotiras, Aristeidis; Stolovitzky, Gustavo; Tangaro, Sabina; Tateo, Andrea; Tung, Yi-An; Tustison, Nicholas J; Varol, Erdem; Vradenburg, George; Weiner, Michael W; Xiao, Guanghua; Xie, Lei; Xie, Yang; Xu, Jia; Yang, Hojin; Zhan, Xiaowei; Zhou, Yunyun; Zhu, Fan; Zhu, Hongtu; Zhu, Shanfeng

    2016-06-01

    Identifying accurate biomarkers of cognitive decline is essential for advancing early diagnosis and prevention therapies in Alzheimer's disease. The Alzheimer's disease DREAM Challenge was designed as a computational crowdsourced project to benchmark the current state-of-the-art in predicting cognitive outcomes in Alzheimer's disease based on high dimensional, publicly available genetic and structural imaging data. This meta-analysis failed to identify a meaningful predictor developed from either data modality, suggesting that alternate approaches should be considered for prediction of cognitive performance. PMID:27079753

  3. Acupuncture and moxibustion reduces neuronal edema in Alzheimer's disease rats

    PubMed Central

    Zhou, Hua; Sun, Guojie; Kong, Lihong; Du, Yanjun; Shen, Feng; Wang, Shuju; Chen, Bangguo; Zeng, Xiaoling

    2014-01-01

    To examine the possible correlation of aberrant Wnt signaling and pathological changes in Alzheimer's disease, we established a rat model of Alzheimer's disease and measured axin and β-catenin expression in the hippocampus. Rats were pretreated with moxibustion or electroacupuncture, or both, at Baihui (GV20) and Shenshu (BL23). Axin expression was lower, β-catenin expression was greater, and neuronal cytoplasmic edema was visibly prevented in the rats that had received the pretreatments. Our results suggest that the mechanism underlying the neuroprotective effect of acupuncture and moxibustion in Alzheimer's disease is associated with axin and β-catenin expression in the Wnt signal transduction pathway. PMID:25206919

  4. Perception of Alzheimer Disease in Iranian Traditional Medicine

    PubMed Central

    Saifadini, Rostam; Tajadini, Haleh; Choopani, Rasool; Mehrabani, Mitra; Kamalinegad, Mohamad; Haghdoost, Aliakbar

    2016-01-01

    Context: Alzheimer disease (AD) is the most common cause of dementia. In regards to the world’s aging population, control and treatment of AD will be one of the major concerns of global public health in the next century. Alzheimer disease was not mentioned with the same phrase or its equivalent in traditional medical texts. The main of present paper was to investigate symptoms and causes of alzheimer disease from the view point of Iranian traditional medicine. Evidence Acquisition: In this qualitative study, we searched reliable sources of Iranian traditional medicine such as Canon of Medicide by Avicenna (Al-Quanon fi- tibb), Aghili cure by Aghili’s (Molajat-E-aghili), Tib-E-Akbari, Exire -E-Aazam and Sharh-E-Asbab and some reliable resources of neurology were probed base on keywords to find a disease that had the most overlap in terms of symptoms with alzheimer disease. By taking from the relevant materials, the extracted texts were compared and analyzed. Results: Findings showed that alzheimer disease has the most overlap with Nesyan (fisad-e-zekr, fisad-e-fekr and fisad-e-takhayol) symptoms in Iranian traditional medicine. Although this is not a perfect overlap and there are causes, including coldness and dryness of the brain or coldness and wetness that could also lead to alzheimer disease according to Iranian traditional medicine. Conclusions: According to Iranian traditional medicine, The brain dystemperement is considered the main causes of alzheimer disease. By correcting the brain dystemperement, alzheimer can be well managed. This study helps to suggest a better strategy for preventing and treating alzheimer in the future. PMID:27247784

  5. Evaluation of Cerebrospinal Fluid Assay Variability in Alzheimer's Disease

    PubMed Central

    White, Matthew T.; Shaw, Leslie M.; Xie, Sharon X.

    2016-01-01

    SUMMARY Studies of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have indicated that much of the variability observed in the biomarkers may be due to measurement error. Biomarkers are often obtained with measurement error, which may make the diagnostic biomarker appear less effective than it truly is. In the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, technical replicates of CSF biomarkers are available; the National Alzheimer's Coordinating Center database contains longitudinal replicates of CSF biomarkers. We focus on the area under the receiver operating characteristic curve (AUC) as the measure of diagnostic effectiveness for differentiating AD from normal cognition using CSF biomarkers and compare AUC estimates obtained by a more standard, naïve method (which uses a single observation per subject and ignores measurement error) to a maximum likelihood (ML) based method (which uses all replicates per subject and adjusts for measurement error). The choice of analysis method depends upon the noise to signal ratio (i.e., the magnitude of the measurement error variability relative to the true biomarker variability); moderate to high ratios may significantly bias the naïve AUC estimate, and the ML-based method would be preferred. The noise to signal ratios were low for the ADNI biomarkers but high for the tTau and pTau biomarkers in NACC. Correspondingly, the naïve and ML-based AUC estimates were nearly identical in the ADNI data but dissimilar for the tTau and pTau biomarkers in the NACC data. Therefore, using the naïve method is adequate for analysis of CSF biomarkers in the ADNI study, but the ML method is recommended for the NACC data. PMID:26890778

  6. Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease

    PubMed Central

    Fagan, Anne M.; Perrin, Richard; Arnold, Steven E.; Grossman, Murray; Xiong, Chengjie; Craig-Schapiro, Rebecca; Clark, Christopher M.; Pickering, Eve; Kuhn, Max; Chen, Yu; Van Deerlin, Vivianna M.; McCluskey, Leo; Elman, Lauren; Karlawish, Jason; Chen-Plotkin, Alice; Hurtig, Howard I.; Siderowf, Andrew; Swenson, Frank; Lee, Virginia M.-Y.; Morris, John C.

    2012-01-01

    Objectives: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI). Methods: Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. Conclusion: Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study. PMID:22855860

  7. Randomized controlled trials for Alzheimer disease and Parkinson disease.

    PubMed

    Lauretani, Fulvio; Ticinesi, Andrea; Meschi, Tiziana; Teresi, Giulio; Ceda, Gian Paolo; Maggio, Marcello

    2016-01-01

    The continuous increase in elderly and oldest-old population, and subsequent rise in prevalence of chronic neurological diseases like Alzheimer's disease (AD) and Parkinson's disease (PD), are a major challenge for healthcare systems. These two conditions are the most prevalent neurodegenerative diseases in older persons and physicians should engage treatment for these patients. In this field, Randomized Clinical Trials (RCTs) specifically focused on elderly populations are still lacking. The aim of this study was to identify RCTs conducted among AD and PD and to examine the difference between mean age of enrollment and incidence of these two neurodegenerative diseases. We found that the scenario is different between PD and AD. In particular, the enrollment for PD trials seems to include younger persons than AD, although the incidence of both diseases is similar and highest after 80 years old. The consequence of these results could influence conclusive guidelines of treatment in older parkinsonian patients. PMID:27100346

  8. Cholinesterase inhibitors: cardioprotection in Alzheimer's disease.

    PubMed

    Monacelli, Fiammetta; Rosa, Gianmarco

    2014-01-01

    Alzheimer's disease is a life shortening disease, and the lack of disease modifying therapy implies a huge impact on life expectancy as well as an outgrowing financial and socioeconomic burden. Cholinesterase inhibitors (ChEIs) represent the first line symptomatic therapy, whose benefit to harm ratio is still a matter of debate. Acetylcholinesterase enzyme is a core interest for pharmacological and toxicological research to unmask the fine balance between therapeutic drug efficacy, tolerability, safety, and detrimental effects up to adverse drug reaction. So far, a body of evidence advocated that an increased vagal tone was associated to an increased risk of gastrointestinal and cardiac side effects (negative chronotropic, arrhytmogenic, hypotensive effects), able to hamper ChEIs effects on cognition, reducing administration feasibility and compliance, especially in older and comorbid patients. Conversely, a growing body of evidence is indicating a protective role of ChEIs on overall cardiovascular mortality in patients with dementia, through a series of in vitro and in vivo investigations. The present review is aimed to report the up to date literature in the controversial field of ChEIs and cardioprotection in dementia, offering a state of the art, which may constitute the conceptual framework to be enlarged in order to build higher evidence. Chronic vagal nerve stimulation acted upon by donepezil might improve long term survival through pharmacological properties apart from cholinesterase inhibition, able to offer cardioprotection, abating the overall cardiovascular risk, and, thus profiling a new line of therapeutic intervention for ChEI drug class. PMID:25024324

  9. Body fluid biomarkers in Alzheimer's disease.

    PubMed

    Lu, Huan; Zhu, Xi-Chen; Jiang, Teng; Yu, Jin-Tai; Tan, Lan

    2015-04-01

    A heterogeneous and slowly progressive disease with extracellular amyloid-β (Aβ) deposits and intracellular hyperphosphorylated tau protein aggregates, Alzheimer's disease (AD) is already a hard nut to crack, featured with cognitive decline and memory lapse. Body fluid biomarkers are proved to be useful in exploring further study of AD, might benefit for a full comprehension of the etiopathogenesis, an improved precision of the prognosis and diagnosis, and a positive response of treatments. The cerebrospinal fluid biomarkers Aβ, total tau, and hyperphosphorylated tau reflect the main pathologic changes of AD. We also review data from several novel biomarkers, such as, β-site APP cleaving enzyme 1, soluble amyloid precursor proteins α and β, soluble Aβ oligomers and so on, which are associated with the occurrence and deterioration of this disease and couldn't be ignored. The rationale for the clinical use of those biomarkers, the challenges faced with and the properties of the most appropriate biomarkers are also summarized in the paper. We aim to find several ideal biomarkers to improve the diagnosis and optimize the treatment respectively. PMID:25992369

  10. Astrocytes in physiological aging and Alzheimer's disease.

    PubMed

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

    2016-05-26

    Astrocytes are fundamental for homoeostasis, defence and regeneration of the central nervous system. Loss of astroglial function and astroglial reactivity contributes to the aging of the brain and to neurodegenerative diseases. Changes in astroglia in aging and neurodegeneration are highly heterogeneous and region-specific. In animal models of Alzheimer's disease (AD) astrocytes undergo degeneration and atrophy at the early stages of pathological progression, which possibly may alter the homeostatic reserve of the brain and contribute to early cognitive deficits. At later stages of AD reactive astrocytes are associated with neurite plaques, the feature commonly found in animal models and in human diseased tissue. In animal models of the AD reactive astrogliosis develops in some (e.g. in the hippocampus) but not in all regions of the brain. For instance, in entorhinal and prefrontal cortices astrocytes do not mount gliotic response to emerging β-amyloid deposits. These deficits in reactivity coincide with higher vulnerability of these regions to AD-type pathology. Astroglial morphology and function can be regulated through environmental stimulation and/or medication suggesting that astrocytes can be regarded as a target for therapies aimed at the prevention and cure of neurodegenerative disorders. PMID:25595973

  11. Entorhinal cortex thickness predicts cognitive decline in Alzheimer's disease.

    PubMed

    Velayudhan, Latha; Proitsi, Petroula; Westman, Eric; Muehlboeck, J-Sebastian; Mecocci, Patrizia; Vellas, Bruno; Tsolaki, Magda; Kłoszewska, Iwona; Soininen, Hilkka; Spenger, Christian; Hodges, Angela; Powell, John; Lovestone, Simon; Simmons, Andrew

    2013-01-01

    Biomarkers for Alzheimer's disease (AD) based on non-invasive methods are highly desirable for diagnosis, disease progression, and monitoring therapeutics. We aimed to study the use of hippocampal volume, entorhinal cortex (ERC) thickness, and whole brain volume (WBV) as predictors of cognitive change in patients with AD. 120 AD subjects, 106 mild cognitive impairment (MCI), and 99 non demented controls (NDC) from the multi-center pan-European AddNeuroMed study underwent MRI scanning at baseline and clinical evaluations at quarterly follow-up up to 1 year. The rate of cognitive decline was estimated using cognitive outcomes, Mini-Mental State Examination (MMSE) and Alzheimer disease assessment scale-cognitive (ADAS-cog) by fitting a random intercept and slope model. AD subjects had smaller ERC thickness and hippocampal and WBV volumes compared to MCI and NDC subjects. Within the AD group, ERC > WBV was significantly associated with baseline cognition (MMSE, ADAS-cog) and disease severity (Clinical Dementia Rating). Baseline ERC thickness was associated with both longitudinal MMSE and ADAS-cog score changes and WBV with ADAS-cog decline. These data indicate that AD subjects with thinner ERC had lower baseline cognitive scores, higher disease severity, and predicted greater subsequent cognitive decline at one year follow up. ERC is a region known to be affected early in the disease. Therefore, the rate of atrophy in this structure is expected to be higher since neurodegeneration begins earlier. Focusing on structural analyses that predict decline can identify those individuals at greatest risk for future cognitive loss. This may have potential for increasing the efficacy of early intervention. PMID:23047370

  12. Role of RAGE in Alzheimer's Disease.

    PubMed

    Cai, Zhiyou; Liu, Nannuan; Wang, Chuanling; Qin, Biyong; Zhou, Yingjun; Xiao, Ming; Chang, Liying; Yan, Liang-Jun; Zhao, Bin

    2016-05-01

    Receptor for advanced glycation end products (RAGE) is a receptor of the immunoglobulin super family that plays various important roles under physiological and pathological conditions. Compelling evidence suggests that RAGE acts as both an inflammatory intermediary and a critical inducer of oxidative stress, underlying RAGE-induced Alzheimer-like pathophysiological changes that drive the process of Alzheimer's disease (AD). A critical role of RAGE in AD includes beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangles, failure of synaptic transmission, and neuronal degeneration. The steady-state level of Aβ depends on the balance between production and clearance. RAGE plays an important role in the Aβ clearance. RAGE acts as an important transporter via regulating influx of circulating Aβ into brain, whereas the efflux of brain-derived Aβ into the circulation via BBB is implemented by LRP1. RAGE could be an important contributor to Aβ generation via enhancing the activity of β- and/or γ-secretases and activating inflammatory response and oxidative stress. However, sRAGE-Aβ interactions could inhibit Aβ neurotoxicity and promote Aβ clearance from brain. Meanwhile, RAGE could be a promoting factor for the synaptic dysfunction and neuronal circuit dysfunction which are both the material structure of cognition, and the physiological and pathological basis of cognition. In addition, RAGE could be a trigger for the pathogenesis of Aβ and tau hyper-phosphorylation which both participate in the process of cognitive impairment. Preclinical and clinical studies have supported that RAGE inhibitors could be useful in the treatment of AD. Thus, an effective measure to inhibit RAGE may be a novel drug target in AD. PMID:26175217

  13. Evidence for a membrane defect in Alzheimer disease brain

    NASA Technical Reports Server (NTRS)

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

    1992-01-01

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

  14. Allelic association at the D14S43 locus in early onset Alzheimer`s disease

    SciTech Connect

    Brice, A.; Tardieu, S.; Campion, D.; Martinez, M.

    1995-04-24

    The D14S43 marker is closely linked to the major gene for early onset autosomal dominant Alzheimer`s disease on chromosome 14. Allelic frequencies at the D14S43 locus were compared in 113 familial and isolated cases of early onset Alzheimer`s disease (<60 years of age at onset) (EOAD) and 109 unaffected individuals of the same geographic origin. Allele 7 was significantly (P = 0.033) more frequent in type 1 EOAD patients (13.2%), defined by the presence of at least another first degree relative with EOAD, than in controls (4.1%). Since an autosomal dominant gene is probably responsible for type 1 patients, allelic association may reflect linkage disequilibrium at the D14S43 locus. This would mean that some patients share a common ancestral mutation. However, since multiple tests were carried out, this result must be interpreted with caution, and needs confirmation in an independent sample. 16 refs., 2 tabs.

  15. Association of apolipoprotein E allele {epsilon}4 with late-onset sporadic Alzheimer`s disease

    SciTech Connect

    Lucotte, G.; David, F.; Berriche, S.

    1994-09-15

    Apolipoprotein E, type {epsilon}4 allele (ApoE {epsilon}4), is associated with late-onset sporadic Alzheimer`s disease (AD) in French patients. The association is highly significant (0.45 AD versus 0.12 controls for {epsilon}4 allele frequencies). These data support the involvement of ApoE {epsilon}4 allele as a very important risk factor for the clinical expression of AD. 22 refs., 1 fig., 3 tabs.

  16. Support for an hypothesis linking Alzheimer`s disease and Down syndrome

    SciTech Connect

    Geller, L.N.; Benjamin, M.B.; Dressler, D.

    1994-09-01

    A connection between Alzheimer`s disease (AD) and Down syndrome (trisomy 21) is indicated by the fact that Down syndrome individuals develop AD neuropathology by the third or fourth decade of life. One explanation for the connection between AD and Down syndrome would be that the overexpression of a gene or genes on chromosome 21 results in Alzheimer`s disease, the most likely candidate being the amyloid precursor protein (APP) gene. However, mutations in the APP gene have been found to be associated with only a very small percentage of familial AD cases. An alternative cause of some Alzheimer`s disease cases may be sporadic trisomy of chromosome 21, resulting from mutations or toxins that cause chromosome nondisjunction. Several predictions can be made based on this hypothesis. One prediction is that there should be more trisomy 21 in cells from AD individuals than from unaffected controls. Using quantitative fluorescence in situ hybridization to compare the number of trisomy chromosome 21 cells in cultured fibroblasts from AD and unaffected individuals, we have shown that there are a significantly larger number of trisomy 21 cells from AD individuals. Another prediction is that a defect in the mitotic spindle apparatus could be the underlying cause of the aneuploidy. Cultured lymphoblasts from AD and unaffected individuals were briefly exposed to the microtubule-disrupting agent colchicine. As assayed by the subsequent appearance of metaphase chromosomes showing centromere separation, cells from AD patients were significantly more sensitive to colchicine treatment compared to cells from unaffected individuals, supporting the prediction of an altered spindle apparatus. Finally, we would predict that both types of patients should share some physical symptoms. We have also found that AD, like Down`s patients, are hypersensitive to the effect of the cholinergic antagonist, tropicamide, on pupil dilation, which may serve as a diagnostic test for Alzheimer`s disease.

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

    PubMed

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

    2016-07-01

    Alzheimer's disease is a major worldwide health problem with no effective therapy. Deep brain stimulation (DBS) has emerged as a useful therapy for certain movement disorders and is increasingly being investigated for treatment of other neural circuit disorders. Here we review the rationale for investigating DBS as a therapy for Alzheimer's disease. Phase I clinical trials of DBS targeting memory circuits in Alzheimer's disease patients have shown promising results in clinical assessments of cognitive function, neurophysiological tests of cortical glucose metabolism, and neuroanatomical volumetric measurements showing reduced rates of atrophy. These findings have been supported by animal studies, where electrical stimulation of multiple nodes within the memory circuit have shown neuroplasticity through stimulation-enhanced hippocampal neurogenesis and improved performance in memory tasks. The precise mechanisms by which DBS may enhance memory and cognitive functions in Alzheimer's disease patients and the degree of its clinical efficacy continue to be examined in ongoing clinical trials. PMID:26443701

  18. Mediterranean diet and Alzheimer disease mortality

    PubMed Central

    Scarmeas, Nikolaos; Luchsinger, Jose A.; Mayeux, Richard; Stern, Yaakov

    2009-01-01

    Background We previously reported that the Mediterranean diet (MeDi) is related to lower risk for Alzheimer disease (AD). Whether MeDi is associated with subsequent AD course and outcomes has not been investigated. Objectives To examine the association between MeDi and mortality in patients with AD. Methods A total of 192 community-based individuals in New York who were diagnosed with AD were prospectively followed every 1.5 years. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of mortality in Cox models that were adjusted for period of recruitment, age, gender, ethnicity, education, APOE genotype, caloric intake, smoking, and body mass index. Results Eighty-five patients with AD (44%) died during the course of 4.4 (±3.6, 0.2 to 13.6) years of follow-up. In unadjusted models, higher adherence to MeDi was associated with lower mortality risk (for each additional MeDi point hazard ratio 0.79; 95% CI 0.69 to 0.91; p = 0.001). This result remained significant after controlling for all covariates (0.76; 0.65 to 0.89; p = 0.001). In adjusted models, as compared with AD patients at the lowest MeDi adherence fertile, those at the middle fertile had lower mortality risk (0.65; 0.38 to 1.09; 1.33 years’ longer survival), whereas subjects at the highest fertile had an even lower risk (0.27; 0.10 to 0.69; 3.91 years’ longer survival; p for trend = 0.003). Conclusion Adherence to the Mediterranean diet (MeDi) may affect not only risk for Alzheimer disease (AD) but also subsequent disease course: Higher adherence to the MeDi is associated with lower mortality in AD. The gradual reduction in mortality risk for higher MeDi adherence tertiles suggests a possible dose–response effect. PMID:17846408

  19. The episodic buffer and learning in early Alzheimer's disease.

    PubMed

    Germano, Carmela; Kinsella, Glynda J; Storey, Elsdon; Ong, Ben; Ames, David

    2008-08-01

    The role of working memory, specifically the episodic buffer, in the learning performance of patients with very mild (n = 18) and mild (n = 12) Alzheimer's disease as compared with healthy older adults (n = 29) was investigated using a series of word-lists that were manipulated (clustered, unclustered) to explore the impact of strategic organizational skills under varying attention conditions (full, divided). Results indicated that the learning performance for all three groups under full attention was better than that under divided attention, but only for the clustered word-lists. Moreover, in contrast to the mild Alzheimer's disease group, both the healthy older controls and the very mild Alzheimer's disease group demonstrated better performance on clustered word-lists than on unclustered lists, suggesting active strategic organizational skills, even at delayed free recall. The overall pattern of results indicates a staging of working-memory impairment in early Alzheimer's disease. PMID:18612873

  20. Ayurvedic medicinal plants for Alzheimer's disease: a review

    PubMed Central

    2012-01-01

    Alzheimer's disease is an age-associated, irreversible, progressive neurodegenerative disease that is characterized by severe memory loss, unusual behavior, personality changes, and a decline in cognitive function. No cure for Alzheimer's exists, and the drugs currently available to treat the disease have limited effectiveness. It is believed that therapeutic intervention that could postpone the onset or progression of Alzheimer's disease would dramatically reduce the number of cases in the next 50 years. Ayurvedic medicinal plants have been the single most productive source of leads for the development of drugs, and over a hundred new products are already in clinical development. Indeed, several scientific studies have described the use of various Ayurvedic medicinal plants and their constituents for treatment of Alzheimer's disease. Although the exact mechanism of their action is still not clear, phytochemical studies of the different parts of the plants have shown the presence of many valuable compounds, such as lignans, flavonoids, tannins, polyphenols, triterpenes, sterols, and alkaloids, that show a wide spectrum of pharmacological activities, including anti-inflammatory, anti-amyloidogenic, anti-cholinesterase, hypolipidemic, and antioxidant effects. This review gathers research on various medicinal plants that have shown promise in reversing the Alzheimer's disease pathology. The report summarizes information concerning the phytochemistry, biological, and cellular activities and clinical applications of these various plants in order to provide sufficient baseline information that could be used in drug discovery campaigns and development process, thereby providing new functional leads for Alzheimer's disease. PMID:22747839

  1. An Interdisciplinary Outreach Model of African American Recruitment for Alzheimer's Disease Research

    ERIC Educational Resources Information Center

    Williams, Monique M.; Meisel, Marie M.; Williams, James; Morris, John C.

    2011-01-01

    Purpose: The African American Outreach Satellite (Satellite) provides educational outreach to facilitate African American recruitment for longitudinal studies at the Washington University Alzheimer's Disease Research Center (ADRC). This descriptive article characterizes the Satellite's recruitment methods, plan for community engagement, results of…

  2. Vascular contributions to cognitive impairment and dementia including Alzheimer's disease.

    PubMed

    Snyder, Heather M; Corriveau, Roderick A; Craft, Suzanne; Faber, James E; Greenberg, Steven M; Knopman, David; Lamb, Bruce T; Montine, Thomas J; Nedergaard, Maiken; Schaffer, Chris B; Schneider, Julie A; Wellington, Cheryl; Wilcock, Donna M; Zipfel, Gregory J; Zlokovic, Berislav; Bain, Lisa J; Bosetti, Francesca; Galis, Zorina S; Koroshetz, Walter; Carrillo, Maria C

    2015-06-01

    Scientific evidence continues to demonstrate the linkage of vascular contributions to cognitive impairment and dementia such as Alzheimer's disease. In December, 2013, the Alzheimer's Association, with scientific input from the National Institute of Neurological Disorders and Stroke and the National Heart, Lung and Blood Institute from the National Institutes of Health, convened scientific experts to discuss the research gaps in our understanding of how vascular factors contribute to Alzheimer's disease and related dementia. This manuscript summarizes the meeting and the resultant discussion, including an outline of next steps needed to move this area of research forward. PMID:25510382

  3. Potential predictors of hippocampal atrophy in Alzheimer's disease.

    PubMed

    Dhikav, Vikas; Anand, Kuljeet

    2011-01-01

    The hippocampus is a vulnerable and plastic brain structure that is damaged by a variety of stimuli, e.g. hypoxia, hypoperfusion, hypoglycaemia, stress and seizures. Alzheimer's disease is a common and important disorder in which hippocampal atrophy is reported. Indeed, the available evidence suggests that hippocampal atrophy is the starting point of the pathogenesis of Alzheimer's disease and a significant number of patients with hippocampal atrophy will develop Alzheimer's disease. Studies indicate that hippocampal atrophy has functional consequences, e.g. cognitive impairment. Deposition of tau protein, formation of neurofibrillary tangles and accumulation of β-amyloid (Aβ) contributes to hippocampal atrophy together with damage caused by several other factors. Some of the factors associated with the development of hippocampal atrophy in Alzheimer's disease have been identified, e.g. hypertension, diabetes mellitus, hyperlipidaemia, seizures, affective disturbances and stress, and more is being learnt about other factors. Hypertension can potentially damage the hippocampus through ischaemia caused by atherosclerosis and cerebral amyloid angiopathy. Diabetes can produce hippocampal lesions via both vascular and non-vascular pathologies and can reduce the threshold for hippocampal damage. Carriers of the apolipoprotein E (ApoE)-ε4 genotype have been shown to have greater mesial temporal atrophy and poorer memory functions than non-carriers. In addition to giving rise to abnormal lipid metabolism, the ApoE-ε4 allele can affect the course of Alzheimer's disease via both Aβ-dependent and -independent pathways. Repetitive seizures can increase Aβ-peptide production and cause neurotransmission dysfunction and cytoskeletal abnormalities or a combination of these. Affective disturbances and stress are proposed to increase corticosteroid-induced hippocampal damage in many different ways. In the absence of any specific markers for predicting Alzheimer's disease

  4. Origins of delusions in Alzheimer's disease.

    PubMed

    Reeves, Suzanne J; Gould, Rebecca L; Powell, John F; Howard, Robert J

    2012-11-01

    Research over the past two decades supports a shared aetiology for delusions in Alzheimer's disease (AD) and schizophrenia. Functional networks involved in salience attribution and belief evaluation have been implicated in the two conditions, and striatal D2/3 receptors are increased to a comparable extent. Executive/frontal deficits are common to both disorders and predict emergent symptoms. Putative risk genes for schizophrenia, which may modify the AD process, have been more strongly implicated in delusions than those directly linked with late-onset AD. Phenotypic correlates of delusions in AD may be dependent upon delusional subtype. Persecutory delusions occur early in the disease and are associated with neurochemical and neuropathological changes in frontostriatal circuits. In contrast, misidentification delusions are associated with greater global cognitive deficits and advanced limbic pathology. It is unclear whether the two subtypes are phenomenologically and biologically distinct or are part of a continuum, in which misidentification delusions manifest increasingly as the pathological process extends. This has treatment implications, particularly if they are found to have discrete chemical and/or pathological markers. PMID:22910677

  5. Seizures and epilepsy in Alzheimer's disease.

    PubMed

    Friedman, Daniel; Honig, Lawrence S; Scarmeas, Nikolaos

    2012-04-01

    Many studies have shown that patients with Alzheimer's disease (AD) are at increased risk for developing seizures and epilepsy. However, reported prevalence and incidence of seizures and relationship of seizures to disease measures such as severity, outcome, and progression vary widely between studies. We performed a literature review of the available clinical and epidemiological data on the topic of seizures in patients with AD. We review seizure rates and types, risk factors for seizures, electroencephalogram (EEG) studies, and treatment responses. Finally, we consider limitations and methodological issues. There is considerable variability in the reported prevalence and incidence of seizures in patients with AD-with reported lifetime prevalence rates of 1.5-64%. More recent, prospective, and larger studies in general report lower rates. Some, but not all, studies have noted increased seizure risk with increasing dementia severity or with younger age of AD onset. Generalized convulsive seizures are the most commonly reported type, but often historical information is the only basis used to determine seizure type and the manifestation of seizures may be difficult to distinguish from other behaviors common in demented patients. EEG has infrequently been performed and reported. Data on treatment of seizures in AD are extremely limited. Similarly, the relationship between seizures and cognitive impairment in AD is unclear. We conclude that the literature on seizures and epilepsy in AD, including diagnosis, risk factors, and response to treatment suffers from methodological limitations and gaps. PMID:22070283

  6. Early detection of Alzheimer's disease using neuroimaging.

    PubMed

    Mosconi, Lisa; Brys, Miroslaw; Glodzik-Sobanska, Lidia; De Santi, Susan; Rusinek, Henry; de Leon, Mony J

    2007-01-01

    Neuroimaging is being increasingly used to complement clinical assessments in the early detection of Alzheimer's disease (AD). Structural magnetic resonance imaging (MRI) and metabolic positron emission tomography (FDG-PET) are the most clinically used and promising modalities to detect brain abnormalities in individuals who might be at risk for AD but who have not yet developed symptoms. The knowledge of established risk factors for AD enabled investigators to develop enrichment strategies for longitudinal imaging studies to reduce the sample sizes and study duration. The present review focuses on the results obtained by MRI and FDG-PET studies that examined the preclinical AD stages in several at risk populations: (1) individuals from families with autosomal dominant early-onset AD (FAD), (2) patients with mild cognitive impairment (MCI), particularly in memory, who are at very high risk for declining to AD with an estimated decline rate of 10-30% per year, (3) normal young and middle-age subjects carriers of known susceptibility genes for late-onset AD such as the Apolipoprotein E (ApoE) E4 allele, and (4) as age is the main risk factor for AD, normal elderly individuals followed to the onset of MCI and AD. Overall, these studies show that the use of imaging for the early detection of AD is successful even in the earlier stages of disease when clinical symptoms are not fully expressed and the regional brain damage may be limited. PMID:16839732

  7. Association between alcohol and Alzheimer's disease

    PubMed Central

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

    2016-01-01

    Alzheimer's disease (AD) is a neurodegenerative disease characterized by dense deposition of amyloid-β (Aβ) protein in the brain, failure of the memory and dementia. At present, there is no cure for AD and current treatments only provide a temporary reduction of symptoms. Thus, there is a need for effective preventive/curative strategic approaches. Accordingly, epidemiological studies have reported a reduction in the prevalence of AD in individuals ingesting low amounts of alcohol, while a moderate consumption of ethanol may protect against Aβ. These data are conflicting with other observations that assigned detrimental effects of heavy alcohol use on brain function, which are apparently similar to those observed in AD. These discrepancies questioned whether or not alcohol is a protective agent against the development of AD, whether the probable protective effects are influenced by the quantity and/or frequency of drinking. These issues are addressed in this review with the aim to suggest the real risk of alcohol for developing or preventing AD. PMID:27588045

  8. Linking multiple pathogenic pathways in Alzheimer's disease.

    PubMed

    Bou Khalil, Rami; Khoury, Elie; Koussa, Salam

    2016-06-22

    Alzheimer's disease (AD) is a chronic neurodegenerative disorder presenting as progressive cognitive decline with dementia that does not, to this day, benefit from any disease-modifying drug. Multiple etiologic pathways have been explored and demonstrate promising solutions. For example, iron ion chelators, such as deferoxamine, are a potential therapeutic solution around which future studies are being directed. Another promising domain is related to thrombin inhibitors. In this minireview, a common pathophysiological pathway is suggested for the pathogenesis of AD to prove that all these mechanisms converge onto the same cascade of neuroinflammatory events. This common pathway is initiated by the presence of vascular risk factors that induce brain tissue hypoxia, which leads to endothelial cell activation. However, the ensuing hypoxia stimulates the production and release of reactive oxygen species and pro-inflammatory proteins. Furthermore, the endothelial activation may become excessive and dysfunctional in predisposed individuals, leading to thrombin activation and iron ion decompartmentalization. The oxidative stress that results from these modifications in the neurovascular unit will eventually lead to neuronal and glial cell death, ultimately leading to the development of AD. Hence, future research in this field should focus on conducting trials with combinations of potentially efficient treatments, such as the combination of intranasal deferoxamine and direct thrombin inhibitors. PMID:27354962

  9. Role of oxidative stress in Alzheimer's disease

    PubMed Central

    HUANG, WEN-JUAN; ZHANG, XIA; CHEN, WEI-WEI

    2016-01-01

    Alzheimer's disease (AD) is the most common cause of disability in individuals aged >65 years worldwide. AD is characterized by the abnormal deposition of amyloid β (Aβ) peptide, and intracellular accumulation of neurofibrillary tangles of hyperphosphorylated τ protein and dementia. The neurotoxic oligomer Aβ peptide, which is the neuropathological diagnostic criterion of the disease, together with τ protein, are mediators of the neurodegeneration that is among the main causative factors. However, these phenomena are mainly initiated and enhanced by oxidative stress, a process referring to an imbalance between antioxidants and oxidants in favour of oxidants. This imbalance can occur as a result of increased free radicals or a decrease in antioxidant defense, free radicals being a species that contains one or more unpaired electrons in its outer shell. The major source of potent free radicals is the reduction of molecular oxygen in water, that initially yields the superoxide radical, which produces hydrogen peroxide by the addition of an electron. The reduction of hydrogen peroxide produces highly reactive hydroxyl radicals, termed reactive oxygen species (ROS) that can react with lipids, proteins, nucleic acids, and other molecules and may also alter their structures and functions. Thus, tissues and organs, particularly the brain, a vulnerable organ, are affected by ROS due to its composition. The brain is largely composed of easily oxidizable lipids while featuring a high oxygen consumption rate. The current review examined the role of oxidative stress in AD. PMID:27123241

  10. Impairment of homonymous processing in Alzheimer's disease.

    PubMed

    Piccirilli, Massimo; D'Alessandro, Patrizia; Micheletti, Norma; Macone, Sara; Scarponi, Laura; Arcelli, Paola; Petrillo, Stefania Maria; Silvestrini, Mauro; Luzzi, Simona

    2015-08-01

    An important issue in research on language is how concepts are represented and associated with each other in the brain. Many investigations have focused on language ambiguity and the phenomenon of homonymy in which a single lexical item, presenting the same form, is related to different meanings. Our study aims to test the hypothesis that weak association of meaning characterizing homonyms may be especially prone to brain damage. To verify this hypothesis a test of attribution of the meaning of homonymous words, the Humpty Dumpty (HD) test, was applied to 50 patients with Alzheimer's disease (AD) and 50 healthy subjects. Results show that AD patients are impaired in the HD test in an early phase of disease and that performance correlates with naming ability and phonological fluency. The data are in keeping with a growing body of literature that supports dual impairment to the semantic system in AD, i.e., to semantic knowledge and active processing and access to the semantic field. The evaluation of the ability to resolve homonymous ambiguity, using the HD test, may provide a useful and quick clinical tool to detect the anomalies of the semantic network linked to either a loss of the core system where meaning of words is stored or an impairment of the access to an intact semantic representation. PMID:25630454

  11. Retinal microvascular network attenuation in Alzheimer's disease

    PubMed Central

    Williams, Michael A.; McGowan, Amy J.; Cardwell, Chris R.; Cheung, Carol Y.; Craig, David; Passmore, Peter; Silvestri, Giuliana; Maxwell, Alexander P.; McKay, Gareth J.

    2015-01-01

    Introduction Cerebral small-vessel disease has been implicated in the development of Alzheimer's disease (AD). The retinal microvasculature enables the noninvasive visualization and evaluation of the systemic microcirculation. We evaluated retinal microvascular parameters in a case-control study of AD patients and cognitively normal controls. Methods Retinal images were computationally analyzed and quantitative retinal parameters (caliber, fractal dimension, tortuosity, and bifurcation) measured. Regression models were used to compute odds ratios (OR) and confidence intervals (CI) for AD with adjustment for confounders. Results Retinal images were available in 213 AD participants and 294 cognitively normal controls. Persons with lower venular fractal dimension (OR per standard deviation [SD] increase, 0.77 [CI: 0.62–0.97]) and lower arteriolar tortuosity (OR per SD increase, 0.78 [CI: 0.63–0.97]) were more likely to have AD after appropriate adjustment. Discussion Patients with AD have a sparser retinal microvascular network and retinal microvascular variation may represent similar pathophysiological events within the cerebral microvasculature of patients with AD. PMID:26634224

  12. Integrated cortical structural marker for Alzheimer's disease.

    PubMed

    Ming, Jing; Harms, Michael P; Morris, John C; Beg, M Faisal; Wang, Lei

    2015-01-01

    In this article, we propose an approach to integrate cortical morphology measures for improving the discrimination of individuals with and without very mild Alzheimer's disease (AD). FreeSurfer was applied to scans collected from 83 participants with very mild AD and 124 cognitively normal individuals. We generated cortex thickness, white matter convexity (aka "sulcal depth"), and white matter surface metric distortion measures on a normalized surface atlas in this first study to integrate high resolution gray matter thickness and white matter surface geometric measures in identifying very mild AD. Principal component analysis was applied to each individual structural measure to generate eigenvectors. Discrimination power based on individual and combined measures are compared, based on stepwise logistic regression and 10-fold cross-validation. Global AD likelihood index and surface-based likelihood maps were also generated. Our results show complementary patterns on the cortical surface between thickness, which reflects gray matter atrophy, convexity, which reflects white matter sulcal depth changes and metric distortion, which reflects white matter surface area changes. The classifier integrating all 3 types of surface measures significantly improved classification performance compared with classification based on single measures. The principal component analysis-based approach provides a framework for achieving high discrimination power by integrating high-dimensional data, and this method could be very powerful in future studies for early diagnosis of diseases that are known to be associated with abnormal gyral and sulcal patterns. PMID:25444604

  13. Deregulation of sphingolipid metabolism in Alzheimer's disease

    PubMed Central

    He, Xingxuan; Huang, Yu; Li, Bin; Gong, Cheng-Xing; Schuchman, Edward H.

    2010-01-01

    Abnormal sphingolipid metabolism has been previously reported in Alzheimer's disease (AD). To extend these findings, several sphingolipids and sphingolipid hydrolases were analyzed in brain samples from AD patients and age-matched normal individuals. We found a pattern of elevated acid sphingomyelinase (ASM) and acid ceramidase (AC) expression in AD, leading to a reduction in sphingomyelin and elevation of ceramide. More sphingosine also was found in the AD brains, although sphingosine-1-phosphate (S1P) levels were reduced. Notably, significant correlations were observed between the brain ASM and S1P levels and the levels of amyloid beta peptide (Aβ) and phosphorylated tau protein. Based on these findings, neuronal cell cultures were treated with Aβ oligomers, which were found to activate ASM, increase ceramide, and induce apoptosis. Pre-treatment of the neurons with purified, recombinant AC prevented the cells from undergoing Aβ-induced apoptosis. We propose that ASM activation is an important pathological event leading to AD, perhaps due to Aβ deposition. The downstream consequences of ASM activation are elevated ceramide, activation of ceramidases, and production of sphingosine. The reduced levels of S1P in the AD brain, together with elevated ceramide, likely contribute to the disease pathogenesis. PMID:18547682

  14. Stem cell strategies for Alzheimer's disease therapy.

    PubMed

    Sugaya, K; Alvarez, A; Marutle, A; Kwak, Y D; Choumkina, E

    2006-06-01

    We have found much evidence that the brain is capable of regenerating neurons after maturation. In our previous study, human neural stem cells (HNSCs) transplanted into aged rat brains differentiated into neural cells and significantly improved the cognitive functions of the animals, indicating that HNSCs may be a promising candidate for cell-replacement therapies for neurodegenerative diseases including Alzheimer's disease (AD). However, ethical and practical issues associated with HNSCs compel us to explore alternative strategies. Here, we report novel technologies to differentiate adult human mesenchymal stem cells, a subset of stromal cells in the bone marrow, into neural cells by modifying DNA methylation or over expression of nanog, a homeobox gene expressed in embryonic stem cells. We also report peripheral administrations of a pyrimidine derivative that increases endogenous stem cell proliferation improves cognitive function of the aged animal. Although these results may promise a bright future for clinical applications used towards stem cell strategies in AD therapy, we must acknowledge the complexity of AD. We found that glial differentiation takes place in stem cells transplanted into amyloid-( precursor protein (APP) transgenic mice. We also found that over expression of APP gene or recombinant APP treatment causes glial differentiation of stem cells. Although further detailed mechanistic studies may be required, RNA interference of APP or reduction of APP levels in the brain can significantly reduced glial differentiation of stem cells and may be useful in promoting neurogenesis after stem cell transplantation. PMID:16953146

  15. Brain injury, neuroinflammation and Alzheimer's disease

    PubMed Central

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

    2013-01-01

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

  16. [Development of new drugs for Alzheimer's disease].

    PubMed

    Tabira, Takeshi

    2010-07-01

    Currently, only donepezil is available for the treatment of Alzheimer disease (AD) in Japan. Clinical trials of galantamine, rivastigmine, and memantine have been completed in Japan, and patients are awaiting government approval for the use of these drugs. The herbal medicine yokukansan was found to be effective for behavioral and psychological symptoms of dementia (BPSD) in patients, and juzentaihoto was found to reduce AD pathology in a mouse model. In addition, muscarinic and nicotinic acetylcholine receptor agonists, serotonergic agonists, other drugs are being developed. These medicines have little effect on the improvement of cognitive functions. The anti-histamine dimebolin was expected to have a significant effect on the improvement of cognitive functions, but unfortunately, it was rejected during phase III clinical trials. Disease modifying drugs such as alpha-secretase activators, beta- and gamma-secretase inhibitors or modulators, inhibitors of Abeta and tau aggregation, enhancers of Abeta degradation, immunotherapies to remove Abeta oligomers and fibrils, and neurotrophic factors are being developed. Some of these drugs are in phase III clinical trials and are expected to be available for clinical use in the near future. PMID:20675883

  17. Alzheimer disease immunotherapeutics: then and now.

    PubMed

    Jindal, Harashish; Bhatt, Bhumika; Sk, Shashikantha; Singh Malik, Jagbir

    2014-01-01

    Dementia is a public health priority and one of the major contributors to morbidity and global non-communicable disease burden, thus necessitating the need for significant health-care interventions. Alzheimer disease (AD) is the most common cause of dementia and may contribute to 60-70% of cases. The cause and progression of AD are not well understood but have been thought to be due at least in part to protein misfolding (proteopathy) manifest as plaque accumulation of abnormally folded β-amyloid and tau proteins in brain. There are about 8 million new cases per year. The total number of people with dementia is projected to almost double every 20 years, to 66 million in 2030 and 115 million in 2050. Immunotherapy in AD aimed at β-amyloid covers 2 types of vaccination: active vaccination against Aβ42 in which patients receive injections of the antigen itself, or passive vaccination in which patients receive injections of monoclonal antibodies (mAb) against Aβ42. Three of the peptide vaccines for active immunizations, CAD106, ACC001, and Affitope, are in phase 2 clinical trials. Three of the mAbs solanezumab, gantenerumab, and crenezumab, are or were in phase 2 and 3 clinical studies. While the phase 3 trials failed, one of these may have shown a benefit at least in mild forms of AD. There is a need for a greater initiative in the development of immunotherapeutics. Several avenues have been explored and still to come. PMID:25483498

  18. Alzheimer disease immunotherapeutics: Then and now

    PubMed Central

    Jindal, Harashish; Bhatt, Bhumika; Sk, Shashikantha; Singh Malik, Jagbir

    2014-01-01

    Dementia is a public health priority and one of the major contributors to morbidity and global non-communicable disease burden, thus necessitating the need for significant health-care interventions. Alzheimer disease (AD) is the most common cause of dementia and may contribute to 60–70% of cases. The cause and progression of AD are not well understood but have been thought to be due at least in part to protein misfolding (proteopathy) manifest as plaque accumulation of abnormally folded β-amyloid and tau proteins in brain. There are about 8 million new cases per year. The total number of people with dementia is projected to almost double every 20 years, to 66 million in 2030 and 115 million in 2050. Immunotherapy in AD aimed at β-amyloid covers 2 types of vaccination: active vaccination against Aβ42 in which patients receive injections of the antigen itself, or passive vaccination in which patients receive injections of monoclonal antibodies (mAb) against Aβ42. Three of the peptide vaccines for active immunizations, CAD106, ACC001, and Affitope, are in phase 2 clinical trials. Three of the mAbs solanezumab, gantenerumab, and crenezumab, are or were in phase 2 and 3 clinical studies. While the phase 3 trials failed, one of these may have shown a benefit at least in mild forms of AD. There is a need for a greater initiative in the development of immunotherapeutics. Several avenues have been explored and still to come. PMID:25483498

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

    PubMed

    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

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

    PubMed

    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

  1. Targeting the β secretase BACE1 for Alzheimer's disease therapy.

    PubMed

    Yan, Riqiang; Vassar, Robert

    2014-03-01

    The β secretase, widely known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), initiates the production of the toxic amyloid β (Aβ) that plays a crucial early part in Alzheimer's disease pathogenesis. BACE1 is a prime therapeutic target for lowering cerebral Aβ concentrations in Alzheimer's disease, and clinical development of BACE1 inhibitors is being intensely pursued. Although BACE1 inhibitor drug development has proven challenging, several promising BACE1 inhibitors have recently entered human clinical trials. The safety and efficacy of these drugs are being tested at present in healthy individuals and patients with Alzheimer's disease, and will soon be tested in individuals with presymptomatic Alzheimer's disease. Although hopes are high that BACE1 inhibitors might be efficacious for the prevention or treatment of Alzheimer's disease, concerns have been raised about potential mechanism-based side-effects of these drugs. The potential of therapeutic BACE1 inhibition might prove to be a watershed in the treatment of Alzheimer's disease. PMID:24556009

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

    PubMed

    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'. PMID:26025658

  3. Altered Superficial White Matter on Tractography MRI in Alzheimer's Disease

    PubMed Central

    Reginold, William; Luedke, Angela C.; Itorralba, Justine; Fernandez-Ruiz, Juan; Islam, Omar; Garcia, Angeles

    2016-01-01

    Background/Aims Superficial white matter provides extensive cortico-cortical connections. This tractography study aimed to assess the diffusion characteristics of superficial white matter tracts in Alzheimer's disease. Methods Diffusion tensor 3T magnetic resonance imaging scans were acquired in 24 controls and 16 participants with Alzheimer's disease. Neuropsychological test scores were available in some participants. Tractography was performed by the Fiber Assignment by Continuous Tracking (FACT) method. The superficial white matter was manually segmented and divided into frontal, parietal, temporal and occipital lobes. The mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AxD) and fractional anisotropy (FA) of these tracts were compared between controls and participants with Alzheimer's disease and correlated with available cognitive tests while adjusting for age and white matter hyperintensity volume. Results Alzheimer's disease was associated with increased MD (p = 0.0011), increased RD (p = 0.0019) and increased AxD (p = 0.0017) in temporal superficial white matter. In controls, superficial white matter was associated with the performance on the Montreal Cognitive Assessment, Stroop and Trail Making Test B tests, whereas in Alzheimer's disease patients, it was not associated with the performance on cognitive tests. Conclusion Temporal lobe superficial white matter appears to be disrupted in Alzheimer's disease. PMID:27489557

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

    PubMed

    Ridge, Perry G; Koop, Andre; Maxwell, Taylor J; Bailey, Matthew H; Swerdlow, Russell H; Kauwe, John S K; Honea, Robyn A

    2013-01-01

    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. PMID:24040196

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

    PubMed

    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. PMID:27026590

  6. [From physiopathology to treatment of Alzheimer's disease].

    PubMed

    Delacourte, A

    2006-10-01

    The natural and molecular history of familial or sporadic Alzheimer's disease (AD) shows that APP (amyloid protein precursor) dysfunction is a consensual central etiological factor in Alzheimer's disease (AD). This is demonstrated by 1) genetic defects involving APP gene or APP dysfunction (such as PS1 or PS2), leading to the formation of neocortical amyloid plaques in familial AD; 2) transgenic mice with these mutated genes that develop plaques; 3) both sporadic and familial AD develop plaques. But two alternatives to explain the physiopathology can be proposed: a gain of toxic function of AB peptide (reflected by the amyloid cascade hypothesis) or a loss of function of APP, a ubiquitous and well conserved protein with numerous possible neurotrophic activities. On the other hand, AD is also characterized by another inescapable degenerating process: tauopathy, an intraneuronal aggregation of tau proteins into neurofibrillary tangles. Remarkably enough, progression of tauopathy in neocortical areas fully explains the progressive clinical deficits of AD, from memory loss to aphasia, apraxia, agnosia. Also one has to bare in mind that most demented patients and most dementing neurodegenerative disorders have a tauopathy. From that, it is concluded that APP an Tau are solid therapeutic targets. But if we know that APP and Tau dysfunctions interact to boost neurodegeneration in AD, we still do no know what are the intraneuronal signaling pathways to activate or to inhibit to stop the degenerating process. There are many hypotheses and many possible approaches: the inhibition of toxicity of plaque, of AB protofibrils, or of AB oligomers inside or outside the neuron, using vaccination or ligands (Alzhemed). On the other hand, modulation of secretases that cleave APP by inhibiting those involved in the amyloidogenic pathway or by stimulating those of the non-amyloidogenic pathway, is a major route of research. Also modulation of kinases or phosphatases possibly involved in

  7. Effective Diagnosis of Alzheimer's Disease by Means of Association Rules

    NASA Astrophysics Data System (ADS)

    Chaves, R.; Ramírez, J.; Górriz, J. M.; López, M.; Salas-Gonzalez, D.; Illán, I.; Segovia, F.; Padilla, P.

    In this paper we present a novel classification method of SPECT images for the early diagnosis of the Alzheimer's disease (AD). The proposed method is based on Association Rules (ARs) aiming to discover interesting associations between attributes contained in the database. The system uses firstly voxel-as-features (VAF) and Activation Estimation (AE) to find tridimensional activated brain regions of interest (ROIs) for each patient. These ROIs act as inputs to secondly mining ARs between activated blocks for controls, with a specified minimum support and minimum confidence. ARs are mined in supervised mode, using information previously extracted from the most discriminant rules for centering interest in the relevant brain areas, reducing the computational requirement of the system. Finally classification process is performed depending on the number of previously mined rules verified by each subject, yielding an up to 95.87% classification accuracy, thus outperforming recent developed methods for AD diagnosis.

  8. The circadian system in Alzheimer's disease: disturbances, mechanisms, and opportunities.

    PubMed

    Coogan, Andrew N; Schutová, Barbora; Husung, Susanne; Furczyk, Karolina; Baune, Bernhard T; Kropp, Peter; Häßler, Frank; Thome, Johannes

    2013-09-01

    Alzheimer's disease (AD) is a devastating neurodegenerative condition associated with severe cognitive and behavioral impairments. Circadian rhythms are recurring cycles that display periods of approximately 24 hours and are driven by an endogenous circadian timekeeping system centered on the suprachiasmatic nucleus of the hypothalamus. We review the compelling evidence that circadian rhythms are significantly disturbed in AD and that such disturbance is of significant clinical importance in terms of behavioral symptoms. We also detail findings from neuropathological studies of brain areas associated with the circadian system in postmortem studies, the use of animal models of AD in the investigation of circadian processes, and the evidence that chronotherapeutic approaches aimed at bolstering weakened circadian rhythms in AD produce beneficial outcomes. We argue that further investigation in such areas is warranted and highlight areas for future research that might prove fruitful in ultimately providing new treatment options for this most serious and intractable of conditions. PMID:23273723

  9. Pulse pressure correlates with leukoaraiosis in Alzheimer disease.

    PubMed

    Lee, Ae Young; Jeong, Seong-Hae; Choi, Byung Hee; Sohn, Eun Hee; Chui, Helena

    2006-01-01

    The relation between pulse pressure (PP) and Alzheimer disease (AD) remains unclear. We performed this study to investigate the relation between PP and AD and the impact of PP to impair cognitive performance on this relationship. It is a cross-sectional study from the Neurology Memory Clinic of Chungnam National University Hospital and five senior welfare centers in the city of Taejon, Korea. A cohort of 75 patients with AD and 117 control subjects were enrolled for the study. PP was significantly higher whereas mean arterial pressure (MAP) was lower in patients with AD than those of control subjects. Elevated serum total cholesterol (TC) level was significantly associated with both PP and MAP in control subjects as well as patients with AD. We found a significant relationship between PP and cerebral white matter changes (WMCs) in AD. PP changes correlate with leukoaraiosis in AD. PMID:16139378

  10. Virological and Immunological Characteristics of Human Cytomegalovirus Infection Associated With Alzheimer Disease

    PubMed Central

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

    2013-01-01

    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. PMID:23661800

  11. Imaging of Leukocyte Trafficking in Alzheimer's Disease.

    PubMed

    Pietronigro, Enrica; Zenaro, Elena; Constantin, Gabriela

    2016-01-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder and is characterized by a progressive decline of cognitive functions. The neuropathological features of AD include amyloid beta (Aβ) deposition, intracellular neurofibrillary tangles derived from the cytoskeletal hyperphosphorylated tau protein, amyloid angiopathy, the loss of synapses, and neuronal degeneration. In the last decade, inflammation has emerged as a key feature of AD, but most studies have focused on the role of microglia-driven neuroinflammation mechanisms. A dysfunctional blood-brain barrier has also been implicated in the pathogenesis of AD, and several studies have demonstrated that the vascular deposition of Aβ induces the expression of adhesion molecules and alters the expression of tight junction proteins, potentially facilitating the transmigration of circulating leukocytes. Two-photon laser scanning microscopy (TPLSM) has become an indispensable tool to dissect the molecular mechanisms controlling leukocyte trafficking in the central nervous system (CNS). Recent TPLSM studies have shown that vascular deposition of Aβ in the CNS promotes intraluminal neutrophil adhesion and crawling on the brain endothelium and also that neutrophils extravasate in the parenchyma preferentially in areas with Aβ deposits. These studies have also highlighted a role for LFA-1 integrin in neutrophil accumulation in the CNS of AD-like disease models, revealing that LFA-1 inhibition reduces the corresponding cognitive deficit and AD neuropathology. In this article, we consider how current imaging techniques can help to unravel new inflammation mechanisms in the pathogenesis of AD and identify novel therapeutic strategies to treat the disease by interfering with leukocyte trafficking mechanisms. PMID:26913031

  12. Early neuropsychological detection of Alzheimer's disease.

    PubMed

    Bastin, C; Salmon, E

    2014-11-01

    Lifestyle modification offers a promising way of preventing or delaying Alzheimer's disease (AD). In particular, nutritional interventions can contribute to decrease the risk of dementia. The efficacy of such interventions should be assessed in individuals thought to be prone to AD. It is therefore necessary to identify markers that may help detecting AD as early as possible. This review will focus on subtle neuropsychological changes that may already exist in the predementia phase, and that could point to individuals at risk of dementia. Episodic memory decline appears consistently as the earliest sign of incipient typical AD. An episodic memory test that ensures deep encoding of information and assesses retrieval with free as well as cued recall appears as a useful tool to detect patients at an early stage of AD. Beyond the memory domain, category verbal fluency has been shown to decline early and to predict progression to AD. Moreover, in line with current diagnosis criteria for prodromal AD, combining neuropsychological scores and neuroimaging data allows a better discrimination of future AD patients than neuroimaging or neuropsychological data alone. Altogether, the detection of cognitive changes that are predictive of the typical form of probable AD already in the predementia stage points to at risk people who are the best target for therapeutic interventions, such as nutrition or physical exercise counseling or dietary interventions. PMID:25182019

  13. The NLRP3 inflammasome in Alzheimer's disease.

    PubMed

    Tan, Meng-Shan; Yu, Jin-Tai; Jiang, Teng; Zhu, Xi-Chen; Tan, Lan

    2013-12-01

    Innate immunity and inflammatory response plays an important role in the pathogenesis of Alzheimer's disease (AD). As the major resident immune cells in the brain, microglial cells constantly survey the microenvironment and are activated by and recruited to senile plaques. Subsequently, they can phagocytose amyloid-β (Aβ) and secrete pro-inflammatory cytokines that influence the surrounding brain tissue. Recently, a wealth of information linking the microglia-specific activation of NLRP3 inflammasome to AD pathogenesis has emerged. We review here the activation mechanisms of NLRP3 inflammasome in microglia and several downstream effects in the brain, demonstrating that toxic Aβ peptide can light a fire in NLRP3 inflammasome and eventually induce AD pathology and tissue damage. More importantly, it has been demonstrated that inhibition of NLRP3 could largely protect from memory loss and decrease Aβ deposition in AD transgenic mouse model. So, we further discuss the recent advances and challenges in targeting NLRP3 inflammasome for AD therapy. PMID:23686772

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

    PubMed

    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. PMID:27395465

  15. Retrieval monitoring and anosognosia in Alzheimer's disease.

    PubMed

    Gallo, David A; Chen, Jennifer M; Wiseman, Amy L; Schacter, Daniel L; Budson, Andrew E

    2007-09-01

    This study explored the relationship between episodic memory and anosognosia (a lack of deficit awareness) among patients with mild Alzheimer's disease (AD). Participants studied words and pictures for subsequent memory tests. Healthy older adults made fewer false recognition errors when trying to remember pictures compared with words, suggesting that the perceptual distinctiveness of picture memories enhanced retrieval monitoring (the distinctiveness heuristic). In contrast, although participants with AD could discriminate between studied and nonstudied items, they had difficulty recollecting the specific presentation formats (words or pictures), and they had limited use of the distinctiveness heuristic. Critically, the demands of the memory test modulated the relationship between memory accuracy and anosognosia. Greater anosognosia was associated with impaired memory accuracy when participants with AD tried to remember words but not when they tried to remember pictures. These data further delineate the retrieval monitoring difficulties among individuals with AD and suggest that anosognosia measures are most likely to correlate with memory tests that require the effortful retrieval of nondistinctive information. PMID:17784804

  16. [Car driving, cognitive aging and Alzheimer disease].

    PubMed

    Fabrigoule, Colette; Lafont, Sylviane

    2015-10-01

    Older drivers are more numerous on the roads. They are expert drivers, but with increasing age certain physiological changes can interfere with driving, which is a complex activity of daily living. Older drivers are involved in fewer accidents than younger drivers, but they have a higher accident rate per kilometer driven. The elderly are heavily represented in the balance sheet of road deaths, being motorists or pedestrians. This high mortality is largely explained by their physical frailty. In the presence of deficits, self-regulation of driving habits, changes/reductions or stopping in driving activity occur in the elderly. But cognitive deficits are associated with an increased risk of accidents. Among drivers with Alzheimer's disease, there is a heterogeneity of driving ability, making difficult the advisory role of a physician for driving. A protocol for physicians was developed to assess cognitive impairments that may affect driving in an elderly patient. The car plays an important role in the autonomy of the elderly and patient advice on stopping driving should take into account the risk/benefit ratio. PMID:26009241

  17. Cannabinoids in late-onset Alzheimer's disease.

    PubMed

    Ahmed, Aia; van der Marck, M A; van den Elsen, Gah; Olde Rikkert, Mgm

    2015-06-01

    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 medicinal uses of cannabinoids, the bioactive components of the cannabis plant, including the treatment of LOAD and other physical conditions that are common in older people. Several in vitro and in vivo studies have demonstrated that cannabinoids can reduce oxidative stress, neuroinflammation, and the formation of amyloid plaques and neurofibrillary tangles, the key hallmarks of LOAD. In addition, in population-based studies, cannabinoids reduced dementia-related symptoms (e.g., behavioral disturbances). The current article provides an overview of the potential of cannabinoids in the treatment of LOAD and related neuropsychiatric symptoms in older people. We also discuss the efficacy, safety, and pharmacokinetics of cannabinoid-based drugs in older people with dementia. PMID:25788394

  18. Intracellular Calcium Dysregulation: Implications for Alzheimer's Disease

    PubMed Central

    Magi, Simona; Castaldo, Pasqualina; Macrì, Maria Loredana; Maiolino, Marta; Matteucci, Alessandra; Bastioli, Guendalina; Gratteri, Santo; Lariccia, Vincenzo

    2016-01-01

    Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive neuronal loss. AD is associated with aberrant processing of the amyloid precursor protein, which leads to the deposition of amyloid-β plaques within the brain. Together with plaques deposition, the hyperphosphorylation of the microtubules associated protein tau and the formation of intraneuronal neurofibrillary tangles are a typical neuropathological feature in AD brains. Cellular dysfunctions involving specific subcellular compartments, such as mitochondria and endoplasmic reticulum (ER), are emerging as crucial players in the pathogenesis of AD, as well as increased oxidative stress and dysregulation of calcium homeostasis. Specifically, dysregulation of intracellular calcium homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Aberrant calcium signaling has been considered a phenomenon mainly related to the dysfunction of intracellular calcium stores, which can occur in both neuronal and nonneuronal cells. This review reports the most recent findings on cellular mechanisms involved in the pathogenesis of AD, with main focus on the control of calcium homeostasis at both cytosolic and mitochondrial level. PMID:27340665

  19. Pathophysiological Links Among Hypertension and Alzheimer's Disease.

    PubMed

    Carnevale, Daniela; Perrotta, Marialuisa; Lembo, Giuseppe; Trimarco, Bruno

    2016-03-01

    Genetic Alzheimer's disease (AD) accounts for only few AD cases and is almost exclusively associated to increased amyloid production in the brain. Instead, the majority of patients is affected with the AD sporadic form with typical alterations of clearance mechanisms of the brain. Most studies use engineered animal models that mimic genetic AD. Since it is emerging the existence of a pathophysiological link between cardiovascular risk factors and AD etiology, the strategy to develop animal models of vascular related AD pathology could be the key toward developing novel successful therapies. On this issue, we have demonstrated that mice that have been chronically subjected to high blood pressure show deposition of amyloid aggregates, the main histological feature of AD, and loss of memory in specific tasks. More importantly, we have identified that the hypertensive challenge increases the expression of the receptor for advanced glycated end products (RAGE), leading to beta-amyloid (Aβ) deposition and learning impairment. Here, we review different murine models of hypertension, induced either pharmacologically or mechanically, leading in the long time to plaque formation in the brain parenchyma and around blood vessels. The major findings obtained till now in this particular experimental setting allow us to suggest that this appears to be a unique possibility to study the pathogenetic mechanisms of sporadic AD triggered by vascular risk factors. PMID:26054481

  20. Retinoids as potential targets for Alzheimer's disease.

    PubMed

    Sodhi, Rupinder K; Singh, Nirmal

    2014-05-01

    Vitamin A and its derivatives, the retinoids, modulate several physiological and pathological processes through their interactions with nuclear retinoid receptor proteins termed as retinoic acid receptors (RARs) and retinoid X receptors (RXRs). An increasing body of evidence signifies the existence of retinoid signaling in diverse brain areas including cortex, amygdala, hypothalamus, hippocampus, and striatum suggesting its involvement in adult brain functions. Defective retinoid signaling has been evidenced in the pathology of Alzheimer's disease. Reports demonstrate that vitamin A deprived mice exhibit serious defects in spatial learning and memory signifying its importance in the maintenance of memory functions. Retinoid signaling impacts the development of AD pathology through multiple pathways. Ligand activation of RAR and RXR in APP/PS1 transgenic mice ameliorated the symptoms of AD and reduced amyloid accumulation and tau hyperphosphorylation. Retinoids also reduce the production of pro-inflammatory cytokines and chemokines by astrocytes and the microglia. Studies also suggest that neuronal cell lines treated with retinoid agonists exhibit an up-regulation in the expression and activity of choline acetyltransferase (ChAT). Reports depict that retinoic acid isomers enhance, the expression of genes linked with cholesterol efflux e.g. apoe, abca-1 and abcg-1 proteins in astrocytes. Furthermore numerous studies also indicate antioxidant potential of retinoids. Through this review we concisely summarize the biology of retinoids, emphasizing on their probable neuroprotective mechanisms that will help to elucidate the pivotal role of these receptors in AD pathology. PMID:24582848

  1. Endoplasmic reticulum dysfunction in Alzheimer's disease.

    PubMed

    Li, Jie-Qiong; Yu, Jin-Tai; Jiang, Teng; Tan, Lan

    2015-02-01

    The endoplasmic reticulum (ER) serves many crucial cellular functions. However, when misfolded or unfolded proteins accumulated in the ER, the stress of ER will be induced. Meanwhile, the intracellular signaling network, which is called unfolded protein response, will also be activated to cope with. Those unfolded proteins can be recognized by three kinds of stress sensors which are IRE1, PERK, and ATF6. Based on lots of medical reports, ER stress in postmortem brains from Alzheimer's disease (AD) patients, animals, and vitro models have indicated that ER dysfunction might work as an important part in causing AD. In this review, we demonstrated that the effect of ER stress contributed to the pathogenesis of AD. ER stress associates almost the whole brain pathology processes which can be observed in AD, such as gene mutation of presenilin1, the abnormal clipped mRNA of presenilin2, β-amyloid production, tau phosphorylation, and cell death. The status of ER stress and unfolded protein response in the pathogenesis of AD also suggests they can be used as potential therapeutic agents. PMID:24715417

  2. Reduced hippocampal glutamate in Alzheimer disease.

    PubMed

    Rupsingh, R; Borrie, M; Smith, M; Wells, J L; Bartha, R

    2011-05-01

    Altered neurometabolic profiles have been detected in Alzheimer disease (AD) using (1)H magnetic resonance spectroscopy (MRS), but no definitive biomarker of mild cognitive impairment (MCI) or AD has been established. This study used MRS to compare hippocampal metabolite levels between normal elderly controls (NEC) and subjects with MCI and AD. Short echo-time (TE=46 ms) (1)H spectra were acquired at 4T from the right hippocampus of 23 subjects with AD, 12 subjects with MCI and 15 NEC. Absolute metabolite levels and metabolite ratios were compared between groups using a multivariate analysis of covariance (covariates: age, sex) followed by post hoc Tukey's test (p<0.05 significant). Subjects with AD had decreased glutamate (Glu) as well as decreased Glu/creatine (Cr), Glu/myo-inositol (mI), Glu/N-acetylaspartate (NAA), and NAA/Cr ratios compared to NEC. Subjects with AD also had decreased Glu/mI ratio compared to MCI. There were no differences between subjects with MCI and NEC. Therefore, in addition to NAA/Cr, decreased hippocampal Glu may be an indicator of AD. PMID:19501936

  3. Alzheimer's disease: inside, outside, upside down.

    PubMed

    Yan, S D; Schmidt, A M; Stern, D

    2001-01-01

    Neurotoxicity of beta-amyloid peptide (A beta) in Alzheimer's disease (AD) is usually thought to arise from the nonspecific effects of high concentrations of A beta on vulnerable neurons, resulting in membrane destabilization and increasing intracellular calcium concentration. This review advances the hypothesis that at early stages of AD, when A beta is present in lower amounts, its ability to perturb the function of cellular targets is mediated by specific cofactors present on the cell surface and intracellularly. Receptor for advanced glycation endproducts (RAGE) is a cell-surface receptor which binds A beta and amplifies its effects on cells in the nanomolar range. The intracellular enzyme A beta-binding alcohol dehydrogenase (ABAD) is likely to engage nascent A beta formed in the endoplasmic reticulum, and to mediate cell stress from this site. The analysis of A beta interaction with RAGE and ABAD, as well as other cofactors, provides insight into new mechanisms and, potentially, identifies therapeutic targets relevant to neuronal dysfunction in AD. PMID:11447831

  4. "Is dopamine involved in Alzheimer's disease?".

    PubMed

    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 highly toxic effect on neurotransmission pathways, such as those mediated by Acetylcholine. The interaction of Aβ oligomers with these neurotansmitters systems would in turn induce cell dysfunction, neurotransmitters signaling imbalance and finally lead to the appearance of neurological signs. In this perspective, it is still debated how and if these mechanisms may also engage the dopaminergic system in AD. Recent experimental work revealed that the dopaminergic system may well be involved in the occurrence of cognitive decline, often being predictive of rapidly progressive forms of AD. However, a clear idea on the role of the dopamine system in AD is still missing. Here we review the more recent evidences supporting the notion that the dopaminergic dysfunction has a pathogenic role in cognitive decline symptoms of AD. PMID:25309431

  5. Auditory confrontation naming in Alzheimer's disease.

    PubMed

    Brandt, Jason; Bakker, Arnold; Maroof, David Aaron

    2010-11-01

    Naming is a fundamental aspect of language and is virtually always assessed with visual confrontation tests. Tests of the ability to name objects by their characteristic sounds would be particularly useful in the assessment of visually impaired patients, and may be particularly sensitive in Alzheimer's disease (AD). We developed an auditory naming task, requiring the identification of the source of environmental sounds (i.e., animal calls, musical instruments, vehicles) and multiple-choice recognition of those not identified. In two separate studies mild-to-moderate AD patients performed more poorly than cognitively normal elderly on the auditory naming task. This task was also more difficult than two versions of a comparable visual naming task, and correlated more highly with Mini-Mental State Exam score. Internal consistency reliability was acceptable, although ROC analysis revealed auditory naming to be slightly less successful than visual confrontation naming in discriminating AD patients from normal participants. Nonetheless, our auditory naming task may prove useful in research and clinical practice, especially with visually impaired patients. PMID:20981630

  6. CARS microscopy of Alzheimer's diseased brain tissue

    NASA Astrophysics Data System (ADS)

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

    2014-02-01

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

  7. Tropisetron and its targets in Alzheimer's disease.

    PubMed

    Hashimoto, Kenji

    2015-01-01

    Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Despite this, there are no drugs for preventing the onset of AD. Preclinical studies suggest that the interaction between amyloid-β peptides (Aβ) and the α7 nicotinic acetylcholine receptor (α7 nAChR) plays a key role in AD pathology, and that α7 nAChR agonists could act as potential therapeutic drugs for AD. A recent study demonstrated that tropisetron, a potent α7 nAChR agonist and serotonin 5-hydroxytryptamine3 receptor antagonist, also bound to the ectodomain of amyloid precursor protein. Furthermore, tropisetron promoted greater improvements in memory than current AD therapeutic drugs, such as memantine and donepezil. Positron emission tomography studies detected Aβ deposition and inflammation in the brains of subjects with amnestic mild cognitive impairment (MCI) before the onset of AD. Given the role of α7 nAChR in Aβ deposition and inflammation, tropisetron represents an attractive potential therapeutic drug to delay or prevent MCI and AD. Additionally as this drug is used internationally to treat chemotherapy-induced emesis, its safety record is already known. PMID:25399811

  8. Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

    PubMed Central

    Goedert, Michel; Ghetti, Bernardino; Spillantini, Maria Grazia

    2012-01-01

    Frontotemporal dementia (FTD) comprises a group of behavioral, language, and movement disorders. On the basis of the nature of the characteristic protein inclusions, frontotemporal lobar degeneration (FTLD) can be subdivided into the common FTLD-tau and FTLD-TDP as well as the less common FTLD-FUS and FTLD-UPS. Approximately 10% of cases of FTD are inherited in an autosomal-dominant manner. Mutations in seven genes cause FTD, with those in tau (MAPT), chromosome 9 open reading frame 72 (C9ORF72), and progranulin (GRN) being the most common. Mutations in MAPT give rise to FTLD-tau and mutations in C9ORF72 and GRN to FTLD-TDP. The other four genes are transactive response–DNA binding protein-43 (TARDBP), fused in sarcoma (FUS), valosin-containing protein (VCP), and charged multivesicular body protein 2B (CHMP2B). Mutations in TARDBP and VCP give rise to FTLD-TDP, mutations in FUS to FTLD-FUS, and mutations in CHMP2B to FTLD-UPS. The discovery that mutations in MAPT cause neurodegeneration and dementia has important implications for understanding Alzheimer disease. PMID:22355793

  9. Brainstem morphological changes in Alzheimer's disease.

    PubMed

    Lee, Ji Han; Ryan, John; Andreescu, Carmen; Aizenstein, Howard; Lim, Hyun Kook

    2015-05-01

    As brainstem nuclei are interconnected with several cortical structures and regulate several autonomic, cognitive, and behavioral functions, it might be important to place the brainstem within an important pathologic core in the progression of Alzheimer's disease (AD). Although there have been several postmortem studies reporting neuropathological alterations of the brainstem in AD, there has been no in-vivo structural neuroimaging study of the brainstem in the patients with AD. The aim of this study was to investigate differences in the brainstem volume and shape between patients with AD and elderly normal controls. Fifty AD patients (the Clinical Dementia Rating Scale ≥ 1) and 50 normal controls were recruited, and the brainstem volumes and deformations were compared between the AD and the controls. Patients with AD showed significant total volume [(mean ± SD) 21007 ± 1640 mm] reduction in the brainstem compared with the controls [(mean ± SD) 22530 ± 1750 mm] (P<0.001). In addition, AD patients showed significant brainstem deformations in the upper posterior brainstem corresponding to the midbrain compared with the healthy individuals (false discovery rate corrected P<0.05). This study is the first to explore brainstem volume change and deformations in AD. These structural changes in the midbrain areas might be at the core of the underlying neurobiological mechanisms of brainstem dysfunction with relevance to their various cognitive and behavioral symptoms such as memory impairment, sleep, and emotional disturbance in AD. However, further longitudinal studies might be needed to confirm these findings. PMID:25830491

  10. Microglia in Alzheimer's disease: A multifaceted relationship.

    PubMed

    ElAli, Ayman; Rivest, Serge

    2016-07-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting elderly people worldwide, which is mainly characterized by cerebral amyloid-beta (Aβ) plaque deposition and neurofibrillary tangle formation. The interest in microglia arose from the overwhelming experimental evidence that outlined a key role of neuroinflammation in AD pathology. Microglia constitute the powerhouse of the innate immune system in the brain. It is now widely accepted that microglia are myeloid-derived cells that infiltrate the developing brain at the early embryonic stages, and acquire a highly ramified phenotype postnatally. Microglia use these dynamic ramifications as sentinels to sense and detect any occurring alteration in brain homeostasis. Once a danger signal is detected, microglia get activated by acquiring a less ramified phenotype, and mount adequate responses that range from phagocyting cell debris to secreting inflammatory and trophic factors. Earlier reports have demonstrated, unequivocally, that microglia surround Aβ plaques and internalize Aβ microaggregates. However, the implication of these observations in AD pathology, and consequently treatment, is still a matter of debate. Nonetheless, targeting the activity of these cells constituted a convergent point in this debate. Unfortunately, the conflicting experimental findings obtained following the modulation of microglial activity in AD, further fueled the debate. This review aims at providing an overview regarding what we know about the implication of microglia in AD pathology, and treatment. The emerging role of monocytes is also discussed. PMID:26254232

  11. 5-HT6 receptors and Alzheimer's disease

    PubMed Central

    2013-01-01

    During the past 20 years, the 5-HT6 receptor has received increasing attention and become a promising target for improving cognition. Several studies with structurally different compounds have shown that not only antagonists but also 5-HT6 receptor agonists improve learning and memory in animal models. A large number of publications describing the development of ligands for this receptor have come to light, and it is now quite evident that 5-HT6 receptors have great pharmaceutical potential in terms of related patents. However, 5-HT6 receptor functionality is much more complex than initially defined. According to the existing data, different cellular pathways may be activated, depending on the drug being used. This article reviews preclinical and clinical evidence of the effects that 5-HT6 receptor compounds have on cognition. In addition, the biochemical and neurochemical mechanisms of action through which 5-HT6 receptor compounds can influence cognition will be described. Overall, several 5-HT6-targeted compounds can reasonably be regarded as powerful drug candidates for the treatment of Alzheimer's disease. PMID:23607787

  12. Lewy Body Pathology in Familial Alzheimer Disease

    PubMed Central

    Leverenz, James B.; Fishel, Mark A.; Peskind, Elaine R.; Montine, Thomas J.; Nochlin, David; Steinbart, Ellen; Raskind, Murray A.; Schellenberg, Gerard D.; Bird, Thomas D.; Tsuang, Debby

    2006-01-01

    Background The origin and significance of Lewy bodies and neurites (Lewy body pathology [LBP]) in Alzheimer disease (AD) are poorly understood. Objective To examine LBP in the brainstem, limbic cortex, and neocortex of a large number of familial AD cases with mutations in 2 presenilin (PSEN) genes. Methods Twenty-five familial AD cases with 9 known PSEN 1 mutations and 14 familial AD cases with a single PSEN 2 mutation (N141I) were examined for LBP using α-synuclein immunohistochemistry and sampling of multiple brainstem and cortical regions. Results The amygdala was the most vulnerable site for LBP. In fact, virtually all (24 [96%] of 25 cases) of the PSEN 1 mutation cases had LBP in the amygdala. The PSEN 1 mutation cases also had more frequent LBP in the amygdala and neocortex than those with the PSEN 2 mutation. However, within families with a single mutation of either PSEN 1 or PSEN 2, there was frequent variability of the LBP. Conclusion These findings suggest that there are genetic influences on the presence of LBP in familial AD as demonstrated by the differences between PSEN 1 and PSEN 2 mutation cases. PMID:16533963

  13. Spatial Navigation in Preclinical Alzheimer's Disease.

    PubMed

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

    2016-02-01

    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

  14. [Immunotherapy for Alzheimer's disease targeting Aβ].

    PubMed

    Tabira, Takeshi

    2016-03-01

    Active and passive immunization of Alzheimer model mice with Aβ showed clearance of aggregated amyloid β deposits and improved memory and learning. Although human trial was halted because of autoimmune encephalitis, the trial revealed that immunization with Aβ also deleted amyloid deposits in humans without clinical benefit. On these proof of concept, several clinical trials using monoclonal antibodies are on-going. Although solanezumab which recognizes Aβ monomer turned out ineffective in the primary endpoint, it showed significant beneficial effect in mild AD cases in the secondary outcome. Solanezumab is now on a large scale phase III trial in mild AD cases in the world. If it turns out to be effective, it will be the first disease modifying drug for AD in a few years. However, since monoclonal antibodies are extremely expensive, less expensive and long acting active immunization will be widely accepted. More effective and sophisticated vaccines such as DNA vaccine and recombinant viral vaccines will be utilized in future. PMID:27025080

  15. Neuroinflammation and Copper in Alzheimer's Disease

    PubMed Central

    Alukaidey, Lobna; White, Anthony R.

    2013-01-01

    Inflammation is the innate immune response to infection or tissue damage. Initiation of proinflammatory cascades in the central nervous system (CNS) occurs through recognition of danger associated molecular patterns by cognate immune receptors expressed on inflammatory cells and leads to rapid responses to remove the danger stimulus. The presence of activated microglia and astrocytes in the vicinity of amyloid plaques in the brains of Alzheimer's disease (AD) patients and mouse models implicates inflammation as a contributor to AD pathogenesis. Activated microglia play a critical role in amyloid clearance, but chronic deregulation of CNS inflammatory pathways results in secretion of neurotoxic mediators that ultimately contribute to neurodegeneration in AD. Copper (Cu) homeostasis is profoundly affected in AD, and accumulated extracellular Cu drives Aβ aggregation, while intracellular Cu deficiency limits bioavailable Cu required for CNS functions. This review presents an overview of inflammatory events that occur in AD in response to Aβ and highlights recent advances on the role of Cu in modulation of beneficial and detrimental inflammatory responses in AD. PMID:24369524

  16. Copper Chelation in Alzheimer's Disease Protein

    NASA Astrophysics Data System (ADS)

    Rose, Frisco; Hodak, Miroslav; Bernholc, Jerry

    2013-03-01

    Alzheimer's disease (AD) is a neurodegenerative disorder affecting millions of people in the U.S. AD is primarily characterized at the cellular level by densely tangled fibrils of amyloid- β protein. These protein clusters have been found in association with elevated levels of multiple transition metals, with copper being the most egregious. Interestingly, metal chelation has shown promise in attenuating the symptoms of AD in recent clinical studies. We investigate this process by constructing an atomistic model of the amyloid- β-copper complex and profile the energetic viability in each of its subsequent disassociation stages. Our results indicate that five energetic barriers must be overcome for full metal chelation. The energy barriers are biologically viable in the presence water mediated bond and proton transfer between the metal and the protein. We model the chelation reaction using a consecutive path nudged elastic band method implemented in our ab initio real-space multi-grid code to obtain a viable sequence. This reaction model details a physically consistent explanation of the chelation process that could lead to the discovery of more effective chelation agents in the treatment of AD.

  17. Common polygenic variation enhances risk prediction for Alzheimer's disease.

    PubMed

    Escott-Price, Valentina; Sims, Rebecca; Bannister, Christian; Harold, Denise; Vronskaya, Maria; Majounie, Elisa; Badarinarayan, Nandini; Morgan, Kevin; Passmore, Peter; Holmes, Clive; Powell, John; Brayne, Carol; Gill, Michael; Mead, Simon; Goate, Alison; Cruchaga, Carlos; Lambert, Jean-Charles; van Duijn, Cornelia; Maier, Wolfgang; Ramirez, Alfredo; Holmans, Peter; Jones, Lesley; Hardy, John; Seshadri, Sudha; Schellenberg, Gerard D; Amouyel, Philippe; Williams, Julie

    2015-12-01

    The identification of subjects at high risk for Alzheimer's disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer's disease and the accuracy of Alzheimer's disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer's Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer's disease (P = 4.9 × 10(-26)). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 × 10(-19)). The best prediction accuracy AUC = 78.2% (95% confidence interval 77-80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer's disease has a significant polygenic component, which has predictive utility for Alzheimer's disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes. PMID:26490334

  18. Structural imaging biomarkers of Alzheimer's disease: predicting disease progression.

    PubMed

    Eskildsen, Simon F; Coupé, Pierrick; Fonov, Vladimir S; Pruessner, Jens C; Collins, D Louis

    2015-01-01

    Optimized magnetic resonance imaging (MRI)-based biomarkers of Alzheimer's disease (AD) may allow earlier detection and refined prediction of the disease. In addition, they could serve as valuable tools when designing therapeutic studies of individuals at risk of AD. In this study, we combine (1) a novel method for grading medial temporal lobe structures with (2) robust cortical thickness measurements to predict AD among subjects with mild cognitive impairment (MCI) from a single T1-weighted MRI scan. Using AD and cognitively normal individuals, we generate a set of features potentially discriminating between MCI subjects who convert to AD and those who remain stable over a period of 3 years. Using mutual information-based feature selection, we identify 5 key features optimizing the classification of MCI converters. These features are the left and right hippocampi gradings and cortical thicknesses of the left precuneus, left superior temporal sulcus, and right anterior part of the parahippocampal gyrus. We show that these features are highly stable in cross-validation and enable a prediction accuracy of 72% using a simple linear discriminant classifier, the highest prediction accuracy obtained on the baseline Alzheimer's Disease Neuroimaging Initiative first phase cohort to date. The proposed structural features are consistent with Braak stages and previously reported atrophic patterns in AD and are easy to transfer to new cohorts and to clinical practice. PMID:25260851

  19. Tocopherol (vitamin E) in Alzheimer's disease and other neurodegenerative disorders.

    PubMed

    Berman, Karen; Brodaty, Henry

    2004-01-01

    In this article, we review the evidence that tocopherol (vitamin E) may have a role to play in the prevention and treatment of Alzheimer's disease and other neurological diseases. The theoretical rationale for the effectiveness of tocopherol as treatment and/or prevention of Alzheimer's disease is based on its antioxidant properties. Results from animal and in vitro studies provide evidence to support use of tocopherol for prevention and treatment of degenerative neurological diseases. Furthermore, several, but not all, epidemiological, cross-sectional, prospective studies indicate that tocopherol may have protective effects in Alzheimer's disease, although dietary and supplemental forms of the vitamin may differ in their efficacy. Mixed results have been obtained from clinical trials. Evidence of the use of tocopherol as a protective measure or as therapy in neurological diseases other than Alzheimer's disease is less compelling. To date, there are no clear-cut answers as to whether tocopherol is worth prescribing, but current clinical practice favours its use in the treatment of Alzheimer's disease. PMID:15377170

  20. Metabolic profiling distinguishes three subtypes of Alzheimer's disease

    PubMed Central

    Bredesen, Dale E.

    2015-01-01

    The cause of Alzheimer's disease is incompletely defined, and no truly effective therapy exists. However, multiple studies have implicated metabolic abnormalities such as insulin resistance, hormonal deficiencies, and hyperhomocysteinemia. Optimizing metabolic parameters in a comprehensive way has yielded cognitive improvement, both in symptomatic and asymptomatic individuals. Therefore, expanding the standard laboratory evaluation in patients with dementia may be revealing. Here I report that metabolic profiling reveals three Alzheimer's disease subtypes. The first is inflammatory, in which markers such as hs-CRP and globulin:albumin ratio are increased. The second type is non-inflammatory, in which these markers are not increased, but other metabolic abnormalities are present. The third type is a very distinctive clinical entity that affects relatively young individuals, extends beyond the typical Alzheimer's disease initial distribution to affect the cortex widely, is characterized by early non-amnestic features such as dyscalculia and aphasia, is often misdiagnosed or labeled atypical Alzheimer's disease, typically affects ApoE4-negative individuals, and is associated with striking zinc deficiency. Given the involvement of zinc in multiple Alzheimer's-related metabolic processes, such as insulin resistance, chronic inflammation, ADAM10 proteolytic activity, and hormonal signaling, this syndrome of Alzheimer's-plus with low zinc (APLZ) warrants further metabolic, genetic, and epigenetic characterization. PMID:26343025

  1. Metabolic profiling distinguishes three subtypes of Alzheimer's disease.

    PubMed

    Bredesen, Dale E

    2015-08-01

    The cause of Alzheimer's disease is incompletely defined, and no truly effective therapy exists. However, multiple studies have implicated metabolic abnormalities such as insulin resistance, hormonal deficiencies, and hyperhomocysteinemia. Optimizing metabolic parameters in a comprehensive way has yielded cognitive improvement, both in symptomatic and asymptomatic individuals. Therefore, expanding the standard laboratory evaluation in patients with dementia may be revealing. Here I report that metabolic profiling reveals three Alzheimer's disease subtypes. The first is inflammatory, in which markers such as hs-CRP and globulin:albumin ratio are increased. The second type is non-inflammatory, in which these markers are not increased, but other metabolic abnormalities are present. The third type is a very distinctive clinical entity that affects relatively young individuals, extends beyond the typical Alzheimer's disease initial distribution to affect the cortex widely, is characterized by early non-amnestic features such as dyscalculia and aphasia, is often misdiagnosed or labeled atypical Alzheimer's disease, typically affects ApoE4-negative individuals, and is associated with striking zinc deficiency. Given the involvement of zinc in multiple Alzheimer's-related metabolic processes, such as insulin resistance, chronic inflammation, ADAM10 proteolytic activity, and hormonal signaling, this syndrome of Alzheimer's-plus with low zinc (APLZ) warrants further metabolic, genetic, and epigenetic characterization. PMID:26343025

  2. Homonymous Hemianopsia Associated with Probable Alzheimer's Disease.

    PubMed

    Ishiwata, Akiko; Kimura, Kazumi

    2016-01-01

    Posterior cortical atrophy (PCA) is a rare neurodegenerative disorder that has cerebral atrophy in the parietal, occipital, or occipitotemporal cortices and is characterized by visuospatial and visuoperceptual impairments. The most cases are pathologically compatible with Alzheimer's disease (AD). We describe a case of PCA in which a combination of imaging methods, in conjunction with symptoms and neurological and neuropsychological examinations, led to its being diagnosed and to AD being identified as its probable cause. Treatment with donepezil for 6 months mildly improved alexia symptoms, but other symptoms remained unchanged. A 59-year-old Japanese woman with progressive alexia, visual deficit, and mild memory loss was referred to our neurologic clinic for the evaluation of right homonymous hemianopsia. Our neurological examination showed alexia, constructional apraxia, mild disorientation, short-term memory loss, and right homonymous hemianopsia. These findings resulted in a score of 23 (of 30) points on the Mini-Mental State Examination. Occipital atrophy was identified, with magnetic resonance imaging (MRI) showing left-side dominance. The MRI data were quantified with voxel-based morphometry, and PCA was diagnosed on the basis of these findings. Single photon emission computed tomography with (123)I-N-isopropyl-p-iodoamphetamine showed hypoperfusion in the corresponding voxel-based morphometry occipital lobes. Additionally, the finding of hypoperfusion in the posterior associate cortex, posterior cingulate gyrus, and precuneus was consistent with AD. Therefore, the PCA was considered to be a result of AD. We considered Lewy body dementia as a differential diagnosis because of the presence of hypoperfusion in the occipital lobes. However, the patient did not meet the criteria for Lewy body dementia during the course of the disease. We therefore consider including PCA in the differential diagnoses to be important for patients with visual deficit, cognitive

  3. 2009 Alzheimer's disease facts and figures.

    PubMed

    2009-05-01

    Alzheimer's disease (AD) is the sixth leading cause of all deaths in the United States, and the fifth leading cause of death in Americans aged 65 and older. Whereas other major causes of death have been on the decrease, deaths attributable to AD have been rising dramatically. Between 2000 and 2006, heart-disease deaths decreased nearly 12%, stroke deaths decreased 18%, and prostate cancer-related deaths decreased 14%, whereas deaths attributable to AD increased 47%. An estimated 5.3 million Americans have AD; the approximately 200,000 persons under age 65 years with AD comprise the younger-onset AD population. Every 70 seconds, someone in America develops AD; by 2050, this time is expected to decrease to every 33 seconds. Over the coming decades, the "baby-boom" population is projected to add 10 million people to these numbers. In 2050, the incidence of AD is expected to approach nearly a million people per year, with a total estimated prevalence of 11 to 16 million people. Significant cost implications related to AD and other dementias include an estimated $148 billion annually in direct (Medicare/Medicaid) and indirect (e.g., decreased business productivity) costs. Not included in these figures is the $94 billion in unpaid services to individuals with AD provided annually by an estimated 10 million caregivers. Mild cognitive impairment (MCI) is an important component in the continuum from healthy cognition to dementia. Understanding which individuals with MCI are at highest risk for eventually developing AD is key to our ultimate goal of preventing AD. This report provides information meant to increase an understanding of the public-health impact of AD, including incidence and prevalence, mortality, lifetime risks, costs, and impact on family caregivers. This report also sets the stage for a better understanding of the relationship between MCI and AD. PMID:19426951

  4. Stereological quantification of the cerebellum in patients with Alzheimer's disease.

    PubMed

    Andersen, Kjeld; Andersen, Birgitte Bo; Pakkenberg, Bente

    2012-01-01

    Nonquantitative studies indicate that the cerebellum is neuropathologically affected in Alzheimer's disease; however, no quantitative studies on the subject have yet been conducted. Ten cerebella from elderly female subjects with severe Alzheimer's disease and 10 age- and gender-matched controls were examined. The cerebellum was divided into 5 regions and the Purkinje and granule cell number and density, cortical volume, molecular and granular layer volume and thickness, white matter volume, surface area, and the Purkinje cell gradient were stereologically estimated. There was no significant difference between the groups in Purkinje or granule cell number or density, and no overall difference in Purkinje cell gradient. However, there was a significant 12.7% reduction in total cerebellar volume in the Alzheimer's group and significant localized differences between the groups regarding other parameters. The relative lack of neuropathological changes in the cerebellum of severely demented Alzheimer's patients suggests that neuronal cell bodies on a global scale apparently still are intact. PMID:20728248

  5. Developmental Disabilities and Alzheimer's Disease...What You Should Know.

    ERIC Educational Resources Information Center

    Arc, Arlington, TX.

    This booklet provides an overview of Alzheimer's disease along with a description of the disease, how to find out if someone has it, and how it affects adults with developmental disabilities. It also provides information on what to do and suggests where to seek help. Specific sections discuss: (1) the etiology of the disease; (2) symptoms of…

  6. When Memories Disappear | Alzheimer's disease | NIH MedlinePlus the Magazine

    MedlinePlus

    ... please turn Javascript on. Feature: Alzheimer's Disease When Memories Disappear Understanding and Dealing with Alzheimer's Disease Past ... progressive brain disease that slowly destroys a person's memory, thinking skills, and the ability to perform simple, ...

  7. Evidence of neuronal oxidative damage in Alzheimer's disease.

    PubMed Central

    Good, P. F.; Werner, P.; Hsu, A.; Olanow, C. W.; Perl, D. P.

    1996-01-01

    Oxidative stress has been proposed as a pathogenetic mechanism in Alzheimer's disease. One mechanism of oxidative damage is the nitration of tyrosine residues in proteins, mediated by peroxynitrite breakdown. Peroxynitrite, a reaction product of nitric oxide and superoxide radicals, has been implicated in N-methyl-D-aspartate receptor-mediated excitotoxic damage. Reported evidence of oxidative stress in Alzheimer's disease includes increased iron, alterations in protective enzymes, and markers of oxidative damage to proteins and lipids. In this report, we demonstrate the presence of nitrotyrosine in neurofibrillary tangles of Alzheimer's disease. Nitrotyrosine was not detected in controls lacking neurofibrillary tangles. Immunolabeling was demonstrated to be specific nitrotyrosine in a series of control experiments. These observations link oxidative stress with a key pathological lesion of Alzheimer's disease, the neurofibrillary tangle, and demonstrate a pathogenetic mechanism in common with the other major neurodegenerative diseases of aging, Parkinson's disease and amyotrophic lateral sclerosis. These findings further implicate nitric oxide expression and excitotoxicity in the pathogenesis of cell death in Alzheimer's disease. Images Figure 1 Figure 2 PMID:8686745

  8. Accumulation of murine amyloid-β mimics early Alzheimer's disease.

    PubMed

    Krohn, Markus; Bracke, Alexander; Avchalumov, Yosef; Schumacher, Toni; Hofrichter, Jacqueline; Paarmann, Kristin; Fröhlich, Christina; Lange, Cathleen; Brüning, Thomas; von Bohlen Und Halbach, Oliver; Pahnke, Jens

    2015-08-01

    Amyloidosis mouse models of Alzheimer's disease are generally established by transgenic approaches leading to an overexpression of mutated human genes that are known to be involved in the generation of amyloid-β in Alzheimer's families. Although these models made substantial contributions to the current knowledge about the 'amyloid hypothesis' of Alzheimer's disease, the overproduction of amyloid-β peptides mimics only inherited (familiar) Alzheimer's disease, which accounts for <1% of all patients with Alzheimer's disease. The inherited form is even regarded a 'rare' disease according to the regulations for funding of the European Union (www.erare.eu). Here, we show that mice that are double-deficient for neprilysin (encoded by Mme), one major amyloid-β-degrading enzyme, and the ABC transporter ABCC1, a major contributor to amyloid-β clearance from the brain, develop various aspects of sporadic Alzheimer's disease mimicking the clinical stage of mild cognitive impairment. Using behavioural tests, electrophysiology and morphological analyses, we compared different ABC transporter-deficient animals and found that alterations are most prominent in neprilysin × ABCC1 double-deficient mice. We show that these mice have a reduced probability to survive, show increased anxiety in new environments, and have a reduced working memory performance. Furthermore, we detected morphological changes in the hippocampus and amygdala, e.g. astrogliosis and reduced numbers of synapses, leading to defective long-term potentiation in functional measurements. Compared to human, murine amyloid-β is poorly aggregating, due to changes in three amino acids at N-terminal positions 5, 10, and 13. Interestingly, our findings account for the action of early occurring amyloid-β species/aggregates, i.e. monomers and small amyloid-β oligomers. Thus, neprilysin × ABCC1 double-deficient mice present a new model for early effects of amyloid-β-related mild cognitive impairment that allows

  9. Memory binding and white matter integrity in familial Alzheimer's disease.

    PubMed

    Parra, Mario A; Saarimäki, Heini; Bastin, Mark E; Londoño, Ana C; Pettit, Lewis; Lopera, Francisco; Della Sala, Sergio; Abrahams, Sharon

    2015-05-01

    Binding information in short-term and long-term memory are functions sensitive to Alzheimer's disease. They have been found to be affected in patients who meet criteria for familial Alzheimer's disease due to the mutation E280A of the PSEN1 gene. However, only short-term memory binding has been found to be affected in asymptomatic carriers of this mutation. The neural correlates of this dissociation are poorly understood. The present study used diffusion tensor magnetic resonance imaging to investigate whether the integrity of white matter structures could offer an account. A sample of 19 patients with familial Alzheimer's disease, 18 asymptomatic carriers and 21 non-carrier controls underwent diffusion tensor magnetic resonance imaging, neuropsychological and memory binding assessment. The short-term memory binding task required participants to detect changes across two consecutive screens displaying arrays of shapes, colours, or shape-colour bindings. The long-term memory binding task was a Paired Associates Learning Test. Performance on these tasks were entered into regression models. Relative to controls, patients with familial Alzheimer's disease performed poorly on both memory binding tasks. Asymptomatic carriers differed from controls only in the short-term memory binding task. White matter integrity explained poor memory binding performance only in patients with familial Alzheimer's disease. White matter water diffusion metrics from the frontal lobe accounted for poor performance on both memory binding tasks. Dissociations were found in the genu of corpus callosum which accounted for short-term memory binding impairments and in the hippocampal part of cingulum bundle which accounted for long-term memory binding deficits. The results indicate that white matter structures in the frontal and temporal lobes are vulnerable to the early stages of familial Alzheimer's disease and their damage is associated with impairments in two memory binding functions known to

  10. Advances in Raman spectroscopy for the diagnosis of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Sudworth, Caroline D.; Archer, John K. J.; Black, Richard A.; Mann, David

    2006-02-01

    Within the next 50 years Alzheimer's disease is expected to affect 100 million people worldwide. The progressive decline in the mental health of the patient is caused by severe brain atrophy generated by the breakdown and aggregation of proteins, resulting in β-amyloid plaques and neurofibrillary tangles. The greatest challenge to Alzheimer's disease lies in the pursuit of an early and definitive diagnosis, in order that suitable treatment can be administered. At the present time, definitive diagnosis is restricted to post-mortem examination. Alzheimer's disease also remains without a long-term cure. This research demonstrates the potential role of Raman spectroscopy, combined with principle components analysis (PCA), as a diagnostic method. Analyses of ethically approved ex vivo post-mortem brain tissues (originating from frontal and occipital lobes) from control (3 normal elderly subjects and 3 Huntingdon's disease subjects) and Alzheimer's disease (12 subjects) brain sections, and a further set of 12 blinded samples are presented. Spectra originating from these tissues are highly reproducible, and initial results indicate a vital difference in protein content and conformation, relating to the abnormally high levels of aggregated proteins in the diseased tissues. Further examination of these spectra using PCA allows for the separation of control from diseased tissues. The validation of the PCA models using blinded samples also displays promise for the identification of Alzheimer's disease, in conjunction with secondary information regarding other brain diseases and dementias. These results provide a route for Raman spectroscopy as a possible non-invasive, non-destructive tool for the early diagnosis of Alzheimer's disease.

  11. Alzheimer's Disease and Glaucoma: Imaging the Biomarkers of Neurodegenerative Disease

    PubMed Central

    Valenti, Denise A.

    2010-01-01

    Imaging through the visual system in Alzheimer's disease, with the technology currently in widespread use for the diagnosis and management of eye disease such as glaucoma and macular degeneration, is proving to be promising. In vivo cross-section imaging during an annual comprehensive eye exam has been available for a decade for glaucoma and macular degeneration, and this same imaging, using Optical Coherence Tomography, has been demonstrated to show deficits specific to AD and mild cognitive impairment. These deficits are in the form of nerve fiber layer tissue drop out in the retina and optic nerve. The retrograde loss of nerve fiber layer tissue in the retina and optic nerve may be an early biomarker of AD, and these deficits in the nerve fiber layer of the retina and optic nerve may be the earliest sign of AD, even prior to damage to the hippocampal region that impacts memory. PMID:21253485

  12. Impaired lysosomal cobalamin transport in Alzheimer's disease.

    PubMed

    Zhao, Hua; Li, Hongyun; Ruberu, Kalani; Garner, Brett

    2015-01-01

    Cobalamin (vitamin B12) is required for erythrocyte formation and DNA synthesis and it plays a crucial role in maintaining neurological function. As a coenzyme for methionine synthase and methylmalonyl-CoA mutase, cobalamin utilization depends on its efficient transit through the intracellular lysosomal compartment and subsequent delivery to the cytosol and mitochondria. Lysosomal function deteriorates in Alzheimer's disease (AD). Lysosomal acidification is defective in AD and lysosomal proteolysis is disrupted by AD-related presenilin 1 mutation. In this study, we propose that AD related lysosomal dysfunction may impair lysosomal cobalamin transport. The experiments use in vitro and in vivo models of AD to define how lysosomal dysfunction directly affects cobalamin utilization. SH-SY5Y-AβPP mutant cells were treated with a proteasome inhibitor to induce lysosomal amyloid-β accumulation. We metabolically labeled these cells with [57Co] cobalamin and isolated purified lysosomes, mitochondria, and cytosol fractions. The results indicated that proteasome inhibition was associated with lysosomal amyloid-β accumulation and a doubling of lysosomal [57Co] cobalamin levels. We also used AβPPxPS1 transgenic AD mice that were intraperitoneally injected with [57Co] cobalamin. The amount of [57Co] cobalamin in the major organs of these mice was measured and the subcellular [57Co] cobalamin distribution in the brain was assessed. The results demonstrated that lysosomal [57Co] cobalamin level was significantly increased by 56% in the AβPPxPS1 AD mouse brains as compared to wild type control mice. Together these data provide evidence that lysosomal cobalamin may be impaired in AD in association with amyloid-β accumulation. PMID:25125476

  13. Microglial dysfunction connects depression and Alzheimer's disease.

    PubMed

    Santos, Luís Eduardo; Beckman, Danielle; Ferreira, Sergio T

    2016-07-01

    Alzheimer's disease (AD) and major depressive disorder (MDD) are highly prevalent neuropsychiatric conditions with intriguing epidemiological overlaps. Depressed patients are at increased risk of developing late-onset AD, and around one in four AD patients are co-diagnosed with MDD. Microglia are the main cellular effectors of innate immunity in the brain, and their activation is central to neuroinflammation - a ubiquitous process in brain pathology, thought to be a causal factor of both AD and MDD. Microglia serve several physiological functions, including roles in synaptic plasticity and neurogenesis, which may be disrupted in neuroinflammation. Following early work on the 'sickness behavior' of humans and other animals, microglia-derived inflammatory cytokines have been shown to produce depressive-like symptoms when administered exogenously or released in response to infection. MDD patients consistently show increased circulating levels of pro-inflammatory cytokines, and anti-inflammatory drugs show promise for treating depression. Activated microglia are abundant in the AD brain, and concentrate around senile plaques, hallmark lesions composed of aggregated amyloid-β peptide (Aβ). The Aβ burden in affected brains is regulated largely by microglial clearance, and the complex activation state of microglia may be crucial for AD progression. Intriguingly, recent reports have linked soluble Aβ oligomers, toxins that accumulate in AD brains and are thought to cause memory impairment, to increased brain cytokine production and depressive-like behavior in mice. Here, we review recent findings supporting the inflammatory hypotheses of AD and MDD, focusing on microglia as a common player and therapeutic target linking these devastating disorders. PMID:26612494

  14. Apolipoprotein E: Risk factor for Alzheimer disease

    SciTech Connect

    Tsai, M.S.; Thibodeau, S.N.; Tangalos, E.G.; Petersen, R.C.; Kokmen, E.; Smith, G.E.; Schaid, D.J.; Ivnik, R.J. )

    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.

  15. Hormone therapy and Alzheimer disease dementia

    PubMed Central

    Shao, Huibo; Breitner, John C.S.; Whitmer, Rachel A.; Wang, Junmin; Hayden, Kathleen; Wengreen, Heidi; Corcoran, Chris; Tschanz, JoAnn; Norton, Maria; Munger, Ron; Welsh-Bohmer, Kathleen

    2012-01-01

    Objectives: Observational studies suggest reduced risk of Alzheimer disease (AD) in users of hormone therapy (HT), but trials show higher risk. We examined whether the association of HT with AD varies with timing or type of HT use. Methods: Between 1995 and 2006, the population-based Cache County Study followed 1,768 women who had provided a detailed history on age at menopause and use of HT. During this interval, 176 women developed incident AD. Cox proportional hazard models evaluated the association of HT use with AD, overall and in relation to timing, duration of use, and type (opposed vs unopposed) of HT. Results: Women who used any type of HT within 5 years of menopause had 30% less risk of AD (95% confidence interval 0.49–0.99), especially if use was for 10 or more years. By contrast, AD risk was not reduced among those who had initiated HT 5 or more years after menopause. Instead, rates were increased among those who began “opposed” estrogen-progestin compounds within the 3 years preceding the Cache County Study baseline (adjusted hazard ratio 1.93; 95% confidence interval 0.94–3.96). This last hazard ratio was similar to the ratio of 2.05 reported in randomized trial participants assigned to opposed HT. Conclusions: Association of HT use and risk of AD may depend on timing of use. Although possibly beneficial if taken during a critical window near menopause, HT (especially opposed compounds) initiated in later life may be associated with increased risk. The relation of AD risk to timing and type of HT deserves further study. PMID:23100399

  16. Antihypertensive drugs decrease risk of Alzheimer disease

    PubMed Central

    Xia, Jin; Yao, Wenliang; Furberg, Curt D.; Xue, Qian-Li; Mercado, Carla I.; Fitzpatrick, Annette L.; Fried, Linda P.; Kawas, Claudia H.; Sink, Kaycee M.; Williamson, Jeff D.; DeKosky, Steven T.; Carlson, Michelle C.

    2013-01-01

    Objectives: The aim of this study was to determine whether use of diuretics, angiotensin-1 receptor blockers (ARB), angiotensin-converting enzyme inhibitors (ACE-I), calcium channel blockers (CCB), or β-blockers (BB) was associated with a reduced risk of Alzheimer disease (AD) dementia in participants with normal cognition or mild cognitive impairment (MCI). Methods: Secondary longitudinal data analysis of the Ginkgo Evaluation of Memory Study in older adults at least 75 years of age with normal cognition (n = 1,928) or MCI (n = 320) over a median 6.1-year period using Cox proportional hazard models after adjusting for confounders. Results: Diuretic use was reported by 15.6%, ARB 6.1%, ACE-I 15.1%, CCB 14.8%, and BB 20.5%. Of the 2,248 participants, 290 (13%) developed AD dementia. Hazard ratio for incident AD dementia among participants with normal cognition was 0.51 in diuretic (95% confidence interval [CI] 0.31–0.82), 0.31 in ARB (95% CI 0.14–0.68), 0.50 in ACE-I (95% CI 0.29–0.83), 0.62 in CCB (95% CI 0.35–1.09), and 0.58 in BB (95% CI 0.36–0.93) users and was not significantly altered when mean systolic blood pressure was above 140 mm Hg. In participants with MCI, only diuretic use was associated with decreased risk (hazard ratio = 0.38, 95% CI 0.20–0.73). Conclusions: Diuretic, ARB, and ACE-I use was, in addition to and/or independently of mean systolic blood pressure, associated with reduced risk of AD dementia in participants with normal cognition, while only diuretic use was associated with reduced risk in participants with MCI. PMID:23911756

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

    PubMed

    Ossenkoppele, Rik; Pijnenburg, Yolande A L; Perry, David C; Cohn-Sheehy, Brendan I; Scheltens, Nienke M E; Vogel, Jacob W; Kramer, Joel H; van der Vlies, Annelies E; La Joie, Renaud; Rosen, Howard J; van der Flier, Wiesje M; Grinberg, Lea T; Rozemuller, Annemieke J; Huang, Eric J; van Berckel, Bart N M; Miller, Bruce L; Barkhof, Frederik; Jagust, William J; Scheltens, Philip; Seeley, William W; Rabinovici, Gil D

    2015-09-01

    A 'frontal variant of Alzheimer's disease' has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimer's disease pathology. The description of this rare Alzheimer's disease phenotype has been limited to case reports and small series, and many clinical, neuroimaging and neuropathological characteristics are not well understood. In this retrospective study, we included 55 patients with Alzheimer's disease with a behavioural-predominant presentation (behavioural Alzheimer's disease) and a neuropathological diagnosis of high-likelihood Alzheimer's disease (n = 17) and/or biomarker evidence of Alzheimer's disease pathology (n = 44). In addition, we included 29 patients with autopsy/biomarker-defined Alzheimer's disease with a dysexecutive-predominant syndrome (dysexecutive Alzheimer's disease). We performed structured chart reviews to ascertain clinical features. First symptoms were more often cognitive (behavioural Alzheimer's disease: 53%; dysexecutive Alzheimer's disease: 83%) than behavioural (behavioural Alzheimer's disease: 25%; dysexecutive Alzheimer's disease: 3%). Apathy was the most common behavioural feature, while hyperorality and perseverative/compulsive behaviours were less prevalent. Fifty-two per cent of patients with behavioural Alzheimer's disease met diagnostic criteria for possible behavioural-variant frontotemporal dementia. Overlap between behavioural and dysexecutive Alzheimer's disease was modest (9/75 patients). Sixty per cent of patients with behavioural Alzheimer's disease and 40% of those with the dysexecutive syndrome carried at least one APOE ε4 allele. We also compared neuropsychological test performance and brain atrophy (applying voxel-based morphometry) with matched autopsy/biomarker-defined typical (amnestic-predominant) Alzheimer's disease (typical Alzheimer's disease, n = 58), autopsy-confirmed/Alzheimer's disease biomarker-negative behavioural variant frontotemporal dementia (n = 59

  18. Dietary and lifestyle guidelines for the prevention of Alzheimer's disease.

    PubMed

    Barnard, Neal D; Bush, Ashley I; Ceccarelli, Antonia; Cooper, James; de Jager, Celeste A; Erickson, Kirk I; Fraser, Gary; Kesler, Shelli; Levin, Susan M; Lucey, Brendan; Morris, Martha Clare; Squitti, Rosanna

    2014-09-01

    Risk of developing Alzheimer's disease is increased by older age, genetic factors, and several medical risk factors. Studies have also suggested that dietary and lifestyle factors may influence risk, raising the possibility that preventive strategies may be effective. This body of research is incomplete. However, because the most scientifically supported lifestyle factors for Alzheimer's disease are known factors for cardiovascular diseases and diabetes, it is reasonable to provide preliminary guidance to help individuals who wish to reduce their risk. At the International Conference on Nutrition and the Brain, Washington, DC, July 19-20, 2013, speakers were asked to comment on possible guidelines for Alzheimer's disease prevention, with an aim of developing a set of practical, albeit preliminary, steps to be recommended to members of the public. From this discussion, 7 guidelines emerged related to healthful diet and exercise habits. PMID:24913896

  19. A test of lens opacity as an indicator of preclinical Alzheimer Disease.

    PubMed

    Bei, Ling; Shui, Ying-Bo; Bai, Fang; Nelson, Suzanne K; Van Stavern, Gregory P; Beebe, David C

    2015-11-01

    Previous studies reported that characteristic lens opacities were present in Alzheimer Disease (AD) patients postmortem. We therefore determined whether cataract grade or lens opacity is related to the risk of Alzheimer dementia in participants who have biomarkers that predict a high risk of developing the disease. AD biomarker status was determined by positron emission tomography-Pittsburgh compound B (PET-PiB) imaging and cerebrospinal fluid (CSF) levels of Aβ42. Cognitively normal participants with a clinical dementia rating of zero (CDR = 0; N = 40) or with slight evidence of dementia (CDR = 0.5; N = 2) were recruited from longitudinal studies of memory and aging at the Washington University Knight Alzheimer's Disease Research Center. The age, sex, race, cataract type and cataract grade of all participants were recorded and an objective measure of lens light scattering was obtained for each eye using a Scheimpflug camera. Twenty-seven participants had no biomarkers of Alzheimer dementia and were CDR = 0. Fifteen participants had biomarkers indicating increased risk of AD, two of which were CDR = 0.5. Participants who were biomarker positive were older than those who were biomarker negative. Biomarker positive participants had more advanced cataracts and increased cortical light scattering, none of which reached statistical significance after adjustment for age. We conclude that cataract grade or lens opacity is unlikely to provide a non-invasive measure of the risk of developing Alzheimer dementia. PMID:25773986

  20. Joint Modeling of Transitional Patterns of Alzheimer's Disease

    PubMed Central

    Liu, Wei; Zhang, Bo; Zhang, Zhiwei; Zhou, Xiao-Hua

    2013-01-01

    While the experimental Alzheimer's drugs recently developed by pharmaceutical companies failed to stop the progression of Alzheimer's disease, clinicians strive to seek clues on how the patients would be when they visit back next year, based upon the patients' current clinical and neuropathologic diagnosis results. This is related to how to precisely identify the transitional patterns of Alzheimer's disease. Due to the complexities of the diagnosis of Alzheimer's disease, the condition of the disease is usually characterized by multiple clinical and neuropathologic measurements, including Clinical Dementia Rating (CDRGLOB), Mini-Mental State Examination (MMSE), a score derived from the clinician judgement on neuropsychological tests (COGSTAT), and Functional Activities Questionnaire (FAQ). In this research article, we investigate a class of novel joint random-effects transition models that are used to simultaneously analyze the transitional patterns of multiple primary measurements of Alzheimer's disease and, at the same time, account for the association between the measurements. The proposed methodology can avoid the bias introduced by ignoring the correlation between primary measurements and can predict subject-specific transitional patterns. PMID:24073268

  1. Preserved painting creativity in an artist with Alzheimer's disease.

    PubMed

    Fornazzari, L R

    2005-06-01

    Creativity in any of its forms, either visual, musical, literary or performing arts, may be conceived as a cognitive capability, and should be actively explored in relation to patients with Alzheimer disease and related dementias, even when other cognitive functions do not allow us to even communicate with them. We are reporting the case of a talented artist with the diagnosis of early onset Alzheimer disease (AD) with progressive cognitive impairment but with preservation of her creativity until very late in the course of the disease. PMID:15885044

  2. 2010 Alzheimer's disease facts and figures.

    PubMed

    2010-03-01

    Alzheimer's disease (AD) is the seventh leading cause of all deaths in the United States and is virtually tied with the sixth leading cause of death-diabetes. AD is the fifth leading cause of death in Americans aged 65 and older. Although other major causes of death have been on the decrease, deaths because of AD have been rising dramatically. Between 2000 and 2006, heart disease deaths decreased 11.1%, stroke deaths decreased 18.2%, and prostate cancer-related deaths decreased 8.7%, whereas deaths because of AD increased 46.1%. Older African-Americans and Hispanics are more likely than older white Americans to have AD or other dementia. Current estimates are that African-Americans are about 2 times more likely, and Hispanics about 1.5 times more likely, than their white counterparts to have these conditions. However, the relationship of race and ethnicity to the development of AD and other dementias is complex and not fully understood. In 2009, nearly 11 million family and other unpaid caregivers provided an estimated 12.5 billion hours of care to persons with AD and other dementias; this care is valued at nearly $144 billion. Medicare payments for services to beneficiaries aged 65 years and older with AD and other dementias are three times higher than for beneficiaries without these conditions. Total payments for 2010 for health care and long-term care services for people aged 65 and older with AD and other dementias are expected to be $172 billion (not including the contributions of unpaid caregivers). An estimated 5.3 million Americans have AD; approximately 200,000 persons under age 65 with AD comprise the younger-onset AD population. Every 70 seconds, someone in America develops AD; by 2050 the time of every 70 seconds is expected to decrease to every 33 seconds. Over the coming decades, the baby boom population is projected to add 10 million people to these numbers. In 2050, the incidence of AD is expected to approach nearly a million people per year, with a

  3. 2011 Alzheimer's disease facts and figures.

    PubMed

    2011-03-01

    Alzheimer's disease (AD) is the sixth leading cause of all deaths in the United States and is the fifth leading cause of death in Americans aged ≥65 years. Although other major causes of death have been on the decrease, deaths because of AD have been rising dramatically. Between 2000 and 2008 (preliminary data), heart disease deaths decreased by 13%, stroke deaths by 20%, and prostate cancer-related deaths by 8%, whereas deaths because of AD increased by 66%. An estimated 5.4 million Americans have AD; approximately 200,000 people aged <65 years with AD comprise the younger-onset AD population. Every 69 seconds, someone in America develops AD; by 2050, the time is expected to accelerate to every 33 seconds. Over the coming decades, the baby boom population is projected to add 10 million people to these numbers. In 2050, the incidence of AD is expected to approach nearly a million people per year, with a total estimated prevalence of 11 to 16 million people. Dramatic increases in the numbers of "oldest-old" (those aged ≥85 years) across all racial and ethnic groups will also significantly affect the numbers of people living with AD. In 2010, nearly 15 million family and other unpaid caregivers provided an estimated 17 billion hours of care to people with AD and other dementias, a contribution valued at more than $202 billion. Medicare payments for services to beneficiaries aged ≥65 years with AD and other dementias are almost 3 times higher than for beneficiaries without these conditions. Total payments in 2011 for health care, long-term care, and hospice services for people aged ≥65years with AD and other dementias are expected to be $183 billion (not including the contributions of unpaid caregivers). This report provides information to increase understanding of the public health effect of AD, including incidence and prevalence, mortality, health expenditures and costs of care, and effect on caregivers and society in general. The report also examines the

  4. 2012 Alzheimer's disease facts and figures.

    PubMed

    2012-01-01

    This report provides information to increase understanding of the public health impact of Alzheimer's disease (AD). Topics addressed include incidence, prevalence, mortality rates, health expenditures and costs of care, and effect on caregivers and society. The report also explores issues that arise when people with AD and other dementias live alone. The characteristics, risks, and unmet needs of this population are described. An estimated 5.4 million Americans have AD, including approximately 200,000 age <65 years who comprise the younger-onset AD population. Over the coming decades, the aging of the baby boom generation is projected to result in an additional 10 million people with AD. Today, someone in America develops AD every 68 seconds. By 2050, there is expected to be one new case of AD every 33 seconds, or nearly a million new cases per year, and AD prevalence is projected to be 11 million to 16 million. Dramatic increases in the number of "oldest-old" (those age ≥85 years) across all racial and ethnic groups are expected to contribute to the increased prevalence of AD. AD is the sixth leading cause of death in the United States and the fifth leading cause of death in Americans age ≥65 years. Although the proportions of deaths due to other major causes of death have decreased in the last several years, the proportion due to AD has risen significantly. Between 2000 and 2008, the proportion of deaths due to heart disease, stroke, and prostate cancer decreased by 13%, 20%, and 8%, respectively, whereas the proportion due to AD increased by 66%. In 2011, more than 15 million family members and other unpaid caregivers provided an estimated 17.4 billion hours of care to people with AD and other dementias, a contribution valued at more than $210 billion. Medicare payments for services to beneficiaries age ≥65 years with AD and other dementias are three times as great as payments for beneficiaries without these conditions, and Medicaid payments are 19 times

  5. Alzheimer's Disease. LC Science Tracer Bullet 87-2.

    ERIC Educational Resources Information Center

    Sammons, Vivian O., Comp.

    Alzheimer's disease is characterized by a degeneration and shrinkage of brain tissue; the symptoms include progressive memory loss, bizarre behavior, difficulty in speaking and walking, incontinence, and confusion. Positive diagnosis is possible only upon examination of brain tissue at autopsy. The disease affects not only the patient but also the…

  6. Pituitary gland levels of mercury, selenium, iron, and zinc in an Alzheimer`s disease study

    SciTech Connect

    Cornett, C.R.; Markesbery, W.R.; Wekstein, D.R.; Ehmann, W.D.

    1996-12-31

    Mercury, iron, selenium, and zinc imbalances have been observed in comparisons between Alzheimer`s disease (AD) and control subject brains. Analyses of the pituitary gland have demonstrated that this organ retains relatively high concentrations of trace elements, including mercury, iron, and zinc. Our previous work has shown that the pituitary glands of AD and control subjects are typically higher in these trace elements than brain samples from the same subject. Instrumental neutron activation analysis (INAA) was used to compare the pituitary trace element levels of AD and control subjects. This study also describes the intrasubject relationships of brain trace element levels to those in the pituitary gland of AD and control subjects.

  7. Family Study of Platelet Membrane Fluidity in Alzheimer's Disease

    NASA Astrophysics Data System (ADS)

    Zubenko, George S.; Wusylko, Michael; Cohen, Bruce M.; Boller, Francois; Teply, Ivana

    1987-10-01

    The fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene in labeled platelet membranes, an index of membrane fluidity, identifies a prominent subgroup of patients with Alzheimer's disease who manifest distinct clinical features. In a family study, the prevalence of this platelet membrane abnormality was 3.2 to 11.5 times higher in asymptomatic, first-degree relatives of probands with Alzheimer's disease than in neurologically healthy control subjects chosen without regard to family history of dementia. The pattern of the platelet membrane abnormality within families was consistent with that of a fully penetrant autosomal dominant trait. Thus, this abnormality of platelet membranes may be an inherited factor that is related to the development of Alzheimer's disease.

  8. Peripheral glucose metabolism and insulin sensitivity in Alzheimer's disease.

    PubMed

    Kilander, L; Boberg, M; Lithell, H

    1993-04-01

    Twenty-four patients with Alzheimer's disease and matched controls were examined with reference to metabolic parameters such as peripheral insulin and glucose metabolism, serum lipid concentrations and blood pressure levels. Blood glucose levels and insulin response were measured during an intravenous glucose tolerance test and peripheral insulin sensitivity was estimated with the hyperinsulinemic euglycemic clamp technique. There were no differences recorded between the two groups in glucose metabolism, triglyceride, cholesterol or HDL-cholesterol levels. The patients with Alzheimer's disease had significantly lower blood pressure levels, which partly could be explained by ongoing treatment with neuroleptics and antidepressives. Previous findings of higher insulin levels in Alzheimer's disease could not be verified. PMID:8503259

  9. Pre-moxibustion and moxibustion prevent Alzheimer's disease

    PubMed Central

    Du, Yanjun; Liu, Ruolan; Sun, Guojie; Meng, Peiyan; Song, Jie

    2013-01-01

    The Alzheimer's disease model in Wistar rats was established by injection of amyloid β-peptide (Aβ1–42) into the hippocampal CA1 region. Rats were treated with suspended moxibustion on Baihui (GV20) and Shenshu (BL23) acupoints. Prior to and post Aβ1–42 exposure. Results showed no evidence of apoptosis in hippocampal neurons, a significantly reduced apoptosis rate of neurons and improved learning and memory abilities were observed in the Alzheimer's disease model. In particular, moxibustion prior to Aβ1–42 exposure was more effective than moxibustion after Aβ1–42 exposure in protecting the neuronal structure and lowering the apoptosis rate. Our findings indicate that a combination of preventive and therapeutic moxibustion has a beneficial effect for the prevention of Alzheimer's disease development. PMID:25206602

  10. Inhalational Alzheimer's disease: an unrecognized - and treatable - epidemic.

    PubMed

    Bredesen, Dale E

    2016-02-01

    Alzheimer's disease is one of the most significant healthcare problems today, with a dire need for effective treatment. Identifying subtypes of Alzheimer's disease may aid in the development of therapeutics, and recently three different subtypes have been described: type 1 (inflammatory), type 2 (non-inflammatory or atrophic), and type 3 (cortical). Here I report that type 3 Alzheimer's disease is the result of exposure to specific toxins, and is most commonly inhalational (IAD), a phenotypic manifestation of chronic inflammatory response syndrome (CIRS), due to biotoxins such as mycotoxins. The appropriate recognition of IAD as a potentially important pathogenetic condition in patients with cognitive decline offers the opportunity for successful treatment of a large number of patients whose current prognoses, in the absence of accurate diagnosis, are grave. PMID:26870879

  11. Inhalational Alzheimer's disease: an unrecognized—and treatable—epidemic

    PubMed Central

    Bredesen, Dale E.

    2016-01-01

    Alzheimer's disease is one of the most significant healthcare problems today, with a dire need for effective treatment. Identifying subtypes of Alzheimer's disease may aid in the development of therapeutics, and recently three different subtypes have been described: type 1 (inflammatory), type 2 (non-inflammatory or atrophic), and type 3 (cortical). Here I report that type 3 Alzheimer's disease is the result of exposure to specific toxins, and is most commonly inhalational (IAD), a phenotypic manifestation of chronic inflammatory response syndrome (CIRS), due to biotoxins such as mycotoxins. The appropriate recognition of IAD as a potentially important pathogenetic condition in patients with cognitive decline offers the opportunity for successful treatment of a large number of patients whose current prognoses, in the absence of accurate diagnosis, are grave. PMID:26870879

  12. Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention

    PubMed Central

    Qiu, Chengxuan; Kivipelto, Miia; von Strauss, Eva

    2009-01-01

    More than 25 million people in the world today are affected by dementia, most suffering from Alzheimer's disease. In both developed and developing nations, Alzheimer's disease has had tremendous impact on the affected individuals, caregivers, and society. The etiological factors, other than older age and genetic susceptibility, remain to be determined. Nevertheless, increasing evidence strongly points to the potential risk roles of vascular risk factors and disorders (eg, cigarette smoking, midlife high blood pressure and obesity, diabetes, and cerebrovascular lesions) and the possible beneficial roles of psychosocial factors (eg, high education, active social engagement, physical exercise, and mentally stimulating activity) in the pathogenetic process and clinical manifestation of the dementing disorders. The long-term multidomain interventions toward the optimal control of multiple vascular risk factors and the maintenance of socially integrated lifestyles and mentally stimulating activities are expected to reduce the risk or postpone the clinical onset of dementia, including Alzheimer's disease. PMID:19585947

  13. Caring for a Person with Alzheimer's Disease

    MedlinePlus

    ... gov/alzheimers, or www.alz.org . Use search engines to find more information. • Talk about AD with ... All guns and other weapons,scissors,and knives • Gasoline cans and other dangerous items in the garage ...

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

    MedlinePlus

    ... 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 ...

  15. The Valsalva maneuver and Alzheimer's disease: is there a link?

    PubMed

    Wostyn, Peter; Audenaert, Kurt; De Deyn, Peter Paul

    2009-02-01

    Recent research findings provide evidence for Alzheimer's disease-related changes in brain diseases, such as normal pressure hydrocephalus and traumatic brain injury, and in glaucoma at the level of the retinal ganglion cells. This is a group of diseases that affect central nervous system tissue and are characterized by elevation of intracranial or intraocular pressure and/or local shear stress and strain. This strengthens the possibility that Alzheimer-type changes in these diseases may result at least in part from exposure of central nervous system tissue to elevated mechanical load. As activities or diseases with significant Valsalva effort can generate increased intracranial pressures, we hypothesize that individuals who frequently perform strong Valsalva maneuvers (e.g., long hours of repetitive heavy lifting, sequences of blows during the playing of a wind instrument, forceful and repetitive cough, bearing-down efforts during parturition) may be more susceptible to developing Alzheimer's disease. In this paper, we discuss three hypotheses about the mechanisms by which extensive use of the Valsalva maneuver might contribute to the neuropathogenesis of Alzheimer's disease: via mechanical stress-induced events in the hippocampus and/or via changes in the secretory process of the choroid plexus and/or via hemodynamic changes in cerebral blood flow. If confirmed, this hypothesis could have implications in clinical practice. PMID:19199876

  16. The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

    PubMed Central

    Craddock, Travis J. A.; Tuszynski, Jack A.; Chopra, Deepak; Casey, Noel; Goldstein, Lee E.; Hameroff, Stuart R.; Tanzi, Rudolph E.

    2012-01-01

    Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-β protein (Aβ), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Aβ accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aβ and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aβ-amyloid deposits (Aβ oligomers and plaques) not only drives Aβ aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal Aβ deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Aβ amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on β-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized

  17. Statistical physics approaches to Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Peng, Shouyong

    Alzheimer's disease (AD) is the most common cause of late life dementia. In the brain of an AD patient, neurons are lost and spatial neuronal organizations (microcolumns) are disrupted. An adequate quantitative analysis of microcolumns requires that we automate the neuron recognition stage in the analysis of microscopic images of human brain tissue. We propose a recognition method based on statistical physics. Specifically, Monte Carlo simulations of an inhomogeneous Potts model are applied for image segmentation. Unlike most traditional methods, this method improves the recognition of overlapped neurons, and thus improves the overall recognition percentage. Although the exact causes of AD are unknown, as experimental advances have revealed the molecular origin of AD, they have continued to support the amyloid cascade hypothesis, which states that early stages of aggregation of amyloid beta (Abeta) peptides lead to neurodegeneration and death. X-ray diffraction studies reveal the common cross-beta structural features of the final stable aggregates-amyloid fibrils. Solid-state NMR studies also reveal structural features for some well-ordered fibrils. But currently there is no feasible experimental technique that can reveal the exact structure or the precise dynamics of assembly and thus help us understand the aggregation mechanism. Computer simulation offers a way to understand the aggregation mechanism on the molecular level. Because traditional all-atom continuous molecular dynamics simulations are not fast enough to investigate the whole aggregation process, we apply coarse-grained models and discrete molecular dynamics methods to increase the simulation speed. First we use a coarse-grained two-bead (two beads per amino acid) model. Simulations show that peptides can aggregate into multilayer beta-sheet structures, which agree with X-ray diffraction experiments. To better represent the secondary structure transition happening during aggregation, we refine the

  18. Globalization of Alzheimer's disease clinical trials

    PubMed Central

    2011-01-01

    Alzheimer's disease (AD) therapies are increasingly being tested in global clinical trials. A search of ClincalTrials.gov revealed that of 269 currently active trials, 28% are currently being conducted in the United States; the majority of trials and the majority of trial sites are ex-US. The US has the largest number of trial sites of any single country; cumulatively, nearly half of all sites are outside the US. The US conducts more trials in all phases of drug development but has a greater proportion of phase 3 trials. The increasing importance of global participants in clinical trials emphasizes the importance of considering the ethnic and international factors that may influence trial outcome. The International Conference on Harmonization guidelines divide ethnic factors that may affect drug development into intrinsic and extrinsic influences. These include language, cultural factors, educational levels, the general level of health and standard of care, as well as nutrition and diet. Ethnic influences on pharmacokinetics are known for some metabolic pathways. The biology of AD may also differ among the world's populations. The frequency of the apolipoprotein e4 allele, a major risk factor for AD, differs internationally. Genetic variations might also affect inflammatory, excitotoxic, and oxidative components of AD. Diagnostic standards and experience vary from country to country. Levels of practitioner training and experience, diagnostic approaches to AD, and attitudes regarding aging and AD may differ. Experience and sophistication with regard to clinical trial conduct also vary within and between countries. Experience with conducting the necessary examinations, as well as the linguistic and cultural validity of instrument translations, may affect trial outcomes. Operational and regulatory aspects of clinical trials vary and provide important barriers to seamless conduct of multiregional clinical trials. Collection and testing of biological samples, continuous

  19. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease.

    PubMed

    Yan, S D; Chen, X; Fu, J; Chen, M; Zhu, H; Roher, A; Slattery, T; Zhao, L; Nagashima, M; Morser, J; Migheli, A; Nawroth, P; Stern, D; Schmidt, A M

    1996-08-22

    Amyloid-beta peptide is central to the pathology of Alzheimer's disease, because it is neurotoxic--directly by inducing oxidant stress, and indirectly by activating microglia. A specific cell-surface acceptor site that could focus its effects on target cells has been postulated but not identified. Here we present evidence that the 'receptor for advanced glycation end products' (RAGE) is such a receptor, and that it mediates effects of the peptide on neurons and microglia. Increased expressing of RAGE in Alzheimer's disease brain indicates that it is relevant to the pathogenesis of neuronal dysfunction and death. PMID:8751438

  20. Dementia pugilistica with clinical features of Alzheimer's disease.

    PubMed

    Areza-Fegyveres, Renata; Rosemberg, Sergio; Castro, Rosa Maria R P S; Porto, Claudia Sellitto; Bahia, Valéria Santoro; Caramelli, Paulo; Nitrini, Ricardo

    2007-09-01

    A 61-year-old ex-boxer presented with a three-year history of progressive memory decline. During a seven-year follow-up period, there was a continuous cognitive decline, very similar to that usually observed in Alzheimer's disease. Parkinsonian, pyramidal or cerebellar signs were conspicuously absent. Neuropathological examination revealed the typical features of dementia pugilistica: cavum septi pellucidi with multiple fenestrations, numerous neurofibrillary tangles in the cerebral isocortex and hippocampus (and rare senile plaques). Immunohistochemistry disclosed a high number of tau protein deposits and scarce beta-amyloid staining. This case shows that dementia pugilistica may present with clinical features practically undistinguishable from Alzheimer's disease. PMID:17952290

  1. Hippocampal shape analysis in Alzheimer's disease using functional data analysis.

    PubMed

    Epifanio, Irene; Ventura-Campos, Noelia

    2014-02-28

    The hippocampus is one of the first affected regions in Alzheimer's disease. The left hippocampi of control subjects, patients with mild cognitive impairment and patients with Alzheimer's disease are represented by spherical harmonics. Functional data analysis is used in the hippocampal shape analysis. Functional principal component analysis and functional independent component analysis are defined for multivariate functions with two arguments. A functional linear discriminant function is also defined. Comparisons with other approaches are carried out. Our functional approach gives promising results, especially in shape classification. PMID:24105806

  2. Amyloid imaging with PET in early Alzheimer disease diagnosis.

    PubMed

    Rowe, Christopher C; Villemagne, Victor L

    2013-05-01

    In vivo imaging of amyloid-β (Aβ) with positron emission tomography has moved from the research arena into clinical practice. Clinicians working with cognitive decline and dementia must become familiar with its benefits and limitations. Amyloid imaging allows earlier diagnosis of Alzheimer disease and better differential diagnosis of dementia and provides prognostic information for mild cognitive impairment. It also has an increasingly important role in therapeutic trial recruitment and for evaluation of anti-Aβ treatments. Longitudinal observations are required to elucidate the role of Aβ deposition in the course of Alzheimer disease and provide information needed to fully use the prognostic power of this investigation. PMID:23642577

  3. 2014 Alzheimer's disease facts and figures.

    PubMed

    2014-03-01

    This report discusses the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality rates, costs of care, and overall effect on caregivers and society. It also examines the impact of AD on women compared with men. An estimated 5.2 million Americans have AD. Approximately 200,000 people younger than 65 years with AD comprise the younger onset AD population; 5 million are age 65 years or older. By mid-century, fueled in large part by the baby boom generation, the number of people living with AD in the United States is projected to grow by about 9 million. Today, someone in the country develops AD every 67 seconds. By 2050, one new case of AD is expected to develop every 33 seconds, or nearly a million new cases per year, and the total estimated prevalence is expected to be 13.8 million. In 2010, official death certificates recorded 83,494 deaths from AD, making AD the sixth leading cause of death in the United States and the fifth leading cause of death in Americans aged 65 years or older. Between 2000 and 2010, the proportion of deaths resulting from heart disease, stroke, and prostate cancer decreased 16%, 23%, and 8%, respectively, whereas the proportion resulting from AD increased 68%. The actual number of deaths to which AD contributes (or deaths with AD) is likely much larger than the number of deaths from AD recorded on death certificates. In 2014, an estimated 700,000 older Americans will die with AD, and many of them will die from complications caused by AD. In 2013, more than 15 million family members and other unpaid caregivers provided an estimated 17.7 billion hours of care to people with AD and other dementias, a contribution valued at more than $220 billion. Average per-person Medicare payments for services to beneficiaries aged 65 years and older with AD and other dementias are more than two and a half times as great as payments for all beneficiaries without these conditions, and Medicaid payments are 19 times as

  4. Vitamin E and memantine in Alzheimer's disease: Clinical trial methods and baseline data

    PubMed Central

    Dysken, Maurice W.; Guarino, Peter D.; Asthana, Sanjay; Sano, Mary; Vertrees, Julia E.; Schellenberg, Gerard D.; Love, Susan.; Llorente, Maria; Pallaki, Muralidhar; Vatassery, Govind

    2014-01-01

    Objective To describe the methods and baseline characteristics of a VA Cooperative Studies Program trial designed to compare the effectiveness of 1) alpha-tocopherol, a vitamin E antioxidant, 2) memantine (Namenda®), an NMDA antagonist, 3) their combination, and 4) placebo in delaying clinical progression in Alzheimer disease. Design Multi-center, randomized, placebo controlled trial Setting 14 VA medical centers. Patients 613 patients with a diagnosis of possible or probable Alzheimer's disease of mild-to-moderate severity defined as a Mini-Mental State Examination (MMSE) total score between 12 and 26 inclusive who were taking an acetylcholinesterase inhibitor. Intervention : 2,000 IU/day of alpha-tocopherol + placebo, 20 mg/day of memantine + placebo, 2,000 IU/day of alpha-tocopherol + 20 mg/day of memantine, or double placebo. Main Outcome Measures The primary outcome is the Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory (ADCS-ADL). Secondary outcome measures include the MMSE, the Alzheimer's Disease Assessment Scale - Cognitive portion, the Dependence Scale, the Neuropsychiatric Inventory, and the Caregiver Activity Survey. Results The majority of the enrolled patients were male (97%), white (86%) with a mean age of 79. The mean scores of the ADCS-ADL, and MMSE, at entry were 57, and 21, respectively. Conclusion This large multicenter trial will address the unanswered question of the long-term safety and effectiveness of alpha-tocopherol, memantine and their combination in patients with mild-to-moderate Alzheimer's disease taking an acetylcholinesterase inhibitor. The results are expected in early 2013. PMID:23583234

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

    PubMed

    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. PMID:25510383

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

    PubMed Central

    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

    2016-01-01

    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. PMID:25510383

  7. The Worldwide Alzheimer's Disease Neuroimaging Initiative: An update.

    PubMed

    Hendrix, James A; Finger, Brad; Weiner, Michael W; Frisoni, Giovanni B; Iwatsubo, Takeshi; Rowe, Christopher C; Kim, Seong Yoon; Guinjoan, Salvador M; Sevlever, Gustavo; Carrillo, Maria C

    2015-07-01

    The Alzheimer's Disease Neuroimaging Initiative (ADNI), launched in 2004, has worked to accelerate drug development by validating imaging and blood/cerebrospinal fluid biomarkers for Alzheimer's disease clinical treatment trials. ADNI is a naturalistic (nontreatment) multisite longitudinal study. A true public-private partnership, the initiative has set a new standard for data sharing without embargo and for the use of biomarkers in dementia research. The ADNI effort in North America is not the only such effort in the world. The Alzheimer's Association recognized these global efforts and formed Worldwide ADNI (WW-ADNI). By creating a platform for international collaboration and cooperation, WW-ADNI's goals are to harmonize projects and results across geographical regions and to facilitate data management and availability to investigators around the world. WW-ADNI projects include those based in North America, Europe, Japan, Australia, Korea, and Argentina. PMID:26194318

  8. 2013 Alzheimer's disease facts and figures.

    PubMed

    2013-03-01

    This report provides information to increase understanding of the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality rates, health expenditures and costs of care, and effect on caregivers and society in general. It also explores the roles and unique challenges of long-distance caregivers, as well as interventions that target those challenges. An estimated 5.2 million Americans have AD. Approximately 200,000 people younger than 65 years with AD comprise the younger onset AD population; 5 million comprise the older onset AD population. Throughout the coming decades, the baby boom generation is projected to add about 10 million to the total number of people in the United States with AD. Today, someone in America develops AD every 68 seconds. By 2050, one new case of AD is expected to develop every 33 seconds, or nearly a million new cases per year, and the total estimated prevalence is expected to be 13.8 million. AD is the sixth leading cause of death in the United States and the fifth leading cause of death in Americans age 65 years or older. Between 2000 and 2010, the proportion of deaths resulting from heart disease, stroke, and prostate cancer decreased 16%, 23%, and 8%, respectively, whereas the proportion resulting from AD increased 68%. The number of deaths from AD as determined by official death certificates (83,494 in 2010) likely underrepresents the number of AD-related deaths in the United States. A projected 450,000 older Americans with AD will die in 2013, and a large proportion will die as a result of complications of AD. In 2012, more than 15 million family members and other unpaid caregivers provided an estimated 17.5 billion hours of care to people with AD and other dementias, a contribution valued at more than $216 billion. Medicare payments for services to beneficiaries age 65 years and older with AD and other dementias are three times as great as payments for beneficiaries without these conditions, and

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

    SciTech Connect

    Campion, D.; Martinez, M.; Babron, M.C.

    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.

  10. Plasma β-amyloid in Alzheimer's disease and vascular disease.

    PubMed

    Janelidze, Shorena; Stomrud, Erik; Palmqvist, Sebastian; Zetterberg, Henrik; van Westen, Danielle; Jeromin, Andreas; Song, Linan; Hanlon, David; Tan Hehir, Cristina A; Baker, David; Blennow, Kaj; Hansson, Oskar

    2016-01-01

    Implementation of amyloid biomarkers in clinical practice would be accelerated if such biomarkers could be measured in blood. We analyzed plasma levels of Aβ42 and Aβ40 in a cohort of 719 individuals (the Swedish BioFINDER study), including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer's disease (AD) dementia and cognitively healthy elderly, using a ultrasensitive immunoassay (Simoa platform). There were weak positive correlations between plasma and cerebrospinal fluid (CSF) levels for both Aβ42 and Aβ40, and negative correlations between plasma Aβ42 and neocortical amyloid deposition (measured with PET). Plasma levels of Aβ42 and Aβ40 were reduced in AD dementia compared with all other diagnostic groups. However, during the preclinical or prodromal AD stages (i.e. in amyloid positive controls, SCD and MCI) plasma concentration of Aβ42 was just moderately decreased whereas Aβ40 levels were unchanged. Higher plasma (but not CSF) levels of Aβ were associated with white matter lesions, cerebral microbleeds, hypertension, diabetes and ischemic heart disease. In summary, plasma Aβ is overtly decreased during the dementia stage of AD indicating that prominent changes in Aβ metabolism occur later in the periphery compared to the brain. Further, increased levels of Aβ in plasma are associated with vascular disease. PMID:27241045

  11. The US economic and social costs of Alzheimer's disease revisited.

    PubMed Central

    Ernst, R L; Hay, J W

    1994-01-01

    OBJECTIVEs. An earlier paper estimated the per-case and national incidence costs of Alzheimer's disease for 1983. This paper updates the estimates of costs per case to 1991 and presents new national prevalence estimates of the economic and social costs of the disease. METHODS. All data for the cost estimates were taken from published sources or provided by other researchers. RESULTS. At midrange values of the estimated cost and epidemiological parameters, the discounted (at 4%) direct and total costs of Alzheimer's disease were $47,581 and $173,932 per case, respectively. The estimated 1991 national direct and total prevalence costs were $20.6 billion and $67.3 billion, respectively. Assuming conservatively that the prevalence of the disease remains constant, the estimated discounted present values of the direct and total costs of all current and future generations of Alzheimer's patients are $536 billion and $1.75 trillion, respectively. CONCLUSIONS. The $536 billion and $1.75 trillion figures are minimum estimates of the long-term dollar losses to the US economy in 1991 caused by Alzheimer's disease. PMID:8059882

  12. Cortical responses to sustained and divided attention in Alzheimer's disease.

    PubMed

    Johannsen, P; Jakobsen, J; Bruhn, P; Gjedde, A

    1999-09-01

    Neuropsychological data suggests that divided attention is more impaired than sustained attention during the early phases of Alzheimer's disease. The purpose of the present study was to compare cerebral activation patterns during sustained and divided attention between Alzheimer patients and healthy elderly. The O-15-water PET activation method was used to map sustained and divided attention in 16 patients with Alzheimer's disease (mean age +/- SD: 68 +/- 5 years; MMSE: 11-25, mean +/- SD = 19.5 +/- 4.9) and in 16 healthy age-matched control subjects. After stereotactical normalization, voxel-by-voxel t statistics was used to assess the significance of activated brain areas and to compare activations between patients and control subjects. In the healthy elderly, sustained and divided attention both elicited activation of the right inferior parietal lobule, and the right middle frontal gyrus, whereas the anterior cingulate gyrus was activated during sustained attention only. Only medial frontal structures (Brodmann Area (BA) 32/34) were activated in Alzheimer patients, and both frontal (BA-10), posterior cingulate (BA-23/31), and subcortical sites were deactivated. Compared to the healthy elderly, the activations in the patients of the right medial (BA-11) superior (BA-10) and inferior (BA-47) frontal gyri, the right middle temporal (BA-20), and the left lingual (BA-17) gyri were significantly reduced. More cortical sites differed statistically between Alzheimer patients and control subjects during divided than during sustained attention. The activation pattern elicited by attention supports the neuropsychological data that divided attention is more impaired than sustained attention in early Alzheimer's disease. PMID:10458942

  13. Assessing Impact on Family Caregivers to Alzheimer's Disease Patients.

    ERIC Educational Resources Information Center

    Talkington-Boyer, Shannon; Snyder, Douglas K.

    1994-01-01

    Examined impact of caregiving among 110 caregivers to aging family member with Alzheimer's disease. Family caregivers' appraisals along dimensions of subjective burden, negative impact, caregiving satisfaction, and caregiver mastery were correlated with extent of memory and behavior problems of patient and caregivers' coping style, locus of…

  14. Awareness of Deficit in Alzheimer's Disease: Relation to Caregiver Burden.

    ERIC Educational Resources Information Center

    Seltzer, Benjamin; And Others

    1997-01-01

    Analyzes caregiver burden in relation to Alzheimer patients' awareness of their own deficits. Results suggest that caregiver burden was associated with impaired patient awareness of memory deficit independent of disease stage and dementia severity, suggesting that impaired awareness may be an important mediator of caregiver burden. (RJM)

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

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-04

    ... individuals of their memories and leads to progressive mental and physical impairments. This eventually fatal... to learn more about Alzheimer's disease and what they can do to support their families, friends, and... States of America the two hundred and thirty-fifth. (Presidential Sig.) [FR Doc. 2010-28062 Filed...

  16. Coping with Specific Stressors in Alzheimer's Disease Caregiving.

    ERIC Educational Resources Information Center

    Williamson, Gail M.; Schulz, Richard

    1993-01-01

    Examined strategies used by 170 Alzheimer's disease caregivers to cope with memory deficits, communication impairments, and decline of loved one. Wishfulness was related to more depressed affect, regardless of stressor type. Relaxation in response to memory deficits, and acceptance in dealing with communication impairments and decline of loved one…

  17. Alzheimer's Disease and Hippocampal Adult Neurogenesis; Exploring Shared Mechanisms

    PubMed Central

    Hollands, Carolyn; Bartolotti, Nancy; Lazarov, Orly

    2016-01-01

    New neurons incorporate into the granular cell layer of the dentate gyrus throughout life. Neurogenesis is modulated by behavior and plays a major role in hippocampal plasticity. Along with older mature neurons, new neurons structure the dentate gyrus, and determine its function. Recent data suggest that the level of hippocampal neurogenesis is substantial in the human brain, suggesting that neurogenesis may have important implications for human cognition. In support of that, impaired neurogenesis compromises hippocampal function and plays a role in cognitive deficits in Alzheimer's disease mouse models. We review current work suggesting that neuronal differentiation is defective in Alzheimer's disease, leading to dysfunction of the dentate gyrus. Additionally, alterations in critical signals regulating neurogenesis, such as presenilin-1, Notch 1, soluble amyloid precursor protein, CREB, and β-catenin underlie dysfunctional neurogenesis in Alzheimer's disease. Lastly, we discuss the detectability of neurogenesis in the live mouse and human brain, as well as the therapeutic implications of enhancing neurogenesis for the treatment of cognitive deficits and Alzheimer's disease. PMID:27199641

  18. Language Impairment in Alzheimer's Disease and Vascular Dementia.

    ERIC Educational Resources Information Center

    Lempinen, Maire; And Others

    A study of 21 patients with Alzheimer's Disease and 25 with vascular dementia, the two most common forms of dementia, investigated language impairments in the dementia syndrome to see if analysis of language disturbances is helpful in differential diagnosis. Diagnostic assessment included a neurological examination, detailed medical history,…

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

    ERIC Educational Resources Information Center

    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…

  20. [Awareness and understanding of consent in Alzheimer's disease].

    PubMed

    Bouyer, C; Teulon, M; Toullat, G; Gil, R

    2015-02-01

    Before a patient can take part in a clinical research, French legislation requires his/her free, express and informed consent. In the same way, the information must be given in a clear, fair and appropriate manner. However, in the context of Alzheimer's disease, one might wonder about the patient's capacity to consent. The goal of our research was to study the capacity to provide informed consent in a group of patients with mild Alzheimer's disease and in a control group, using two specialized clinical vignettes inspired by Marson's studies. The aim of the study was to assess discernment in capacity to consent to a treatment and to determinate the possible links between impaired capacities to consent and cognitive and behavioral impairments involved in Alzheimer's disease. The data collected confirm that the capacity to make and maintain a choice is preserved while the capacities to appreciate the consequences of choosing a treatment, to reason and to understand the treatment situation are already impaired in mild Alzheimer's disease. The impairment of these capacities can be linked to dysexecutive syndrome, apathy and impaired self-awareness. Caregivers and family should take into account the risk of weakened capacities of discernment as soon as possible. PMID:25535110

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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,…

  3. Voice Onset Time Production in Speakers with Alzheimer's Disease

    ERIC Educational Resources Information Center

    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…

  4. Semantic Priming for Coordinate Distant Concepts in Alzheimer's Disease Patients

    ERIC Educational Resources Information Center

    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…

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

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-04

    ... From the Federal Register Online via the Government Publishing Office #0; #0; #0; Presidential Documents #0; #0; #0;#0;Federal Register / Vol. 76 , No. 214 / Friday, November 4, 2011 / Presidential Documents#0;#0; ] Proclamation 8745 of November 1, 2011 National Alzheimer's Disease Awareness Month, 2011 By the President of the United States of America...

  6. Emotional reactivity and awareness of task performance in Alzheimer's disease.

    PubMed

    Mograbi, Daniel C; Brown, Richard G; Salas, Christian; Morris, Robin G

    2012-07-01

    Lack of awareness about performance in tasks is a common feature of Alzheimer's disease. Nevertheless, clinical anecdotes have suggested that patients may show emotional or behavioural responses to the experience of failure despite reporting limited awareness, an aspect which has been little explored experimentally. The current study investigated emotional reactions to success or failure in tasks despite unawareness of performance in Alzheimer's disease. For this purpose, novel computerised tasks which expose participants to systematic success or failure were used in a group of Alzheimer's disease patients (n=23) and age-matched controls (n=21). Two experiments, the first with reaction time tasks and the second with memory tasks, were carried out, and in each experiment two parallel tasks were used, one in a success condition and one in a failure condition. Awareness of performance was measured comparing participant estimations of performance with actual performance. Emotional reactivity was assessed with a self-report questionnaire and rating of filmed facial expressions. In both experiments the results indicated that, relative to controls, Alzheimer's disease patients exhibited impaired awareness of performance, but comparable differential reactivity to failure relative to success tasks, both in terms of self-report and facial expressions. This suggests that affective valence of failure experience is processed despite unawareness of task performance, which might indicate implicit processing of information in neural pathways bypassing awareness. PMID:22609573

  7. Roles of sigma-1 receptors in Alzheimer's disease.

    PubMed

    Jin, Jia-Li; Fang, Min; Zhao, Yan-Xin; Liu, Xue-Yuan

    2015-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of senile dementia all over the world. Still no existing drugs can effectively reverse the cognitive impairment. However, Sigma-1 (σ-1) receptors have been long implicated in multiple neurological and psychiatric conditions over these years. In this review, we discuss the current understanding of σ-1 receptor functions. Through regulation of lipid rafts, secretases, kinases, neuroceptors and ion channels, σ-1 receptors can influence cellular signal transduction, TCA cycle, oxidative stress, neuron plasticity and neurotransmitter release etc. Based on this, we suggest the key cellular mechanisms linking σ-1 receptor to Alzheimer's disease. Besides, we detail the evidences showing that σ-1 receptors agonists, being the promising compounds for treatment of cognitive dysfunction, exhibit robust neuroprotection and anti-amnesia effect against Aβ neurotoxicity in the progress of Alzheimer's disease. The evidence comes from animal models, preclinical studies in humans and full clinical trials. In addition, the questions to be solved regarding this receptor are also presented. When concerned with NMDAR, σ-1 receptor activation may result in two totally different influences on AD. Utilization of σ-1 agents early in AD remains an overlooked therapeutic opportunity. This article may pave the way for further studies about sigma-1 receptor on Alzheimer's disease. PMID:26131055

  8. The Effect of Alzheimer's Disease and Aging on Conceptual Combination

    ERIC Educational Resources Information Center

    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…

  9. [Treatment of patients with Alzheimer's disease: a breakthrough or not?].

    PubMed

    van Marum, Rob J

    2015-01-01

    The results of an open-label extension study of the Expedition I and II studies with solanezumab in patients with Alzheimer's disease, neither of which had shown an effect on cognition and functional ability, were recently presented at the Alzheimer's Association International Conference in Toronto. Placebo and intervention patients with mild Alzheimer's disease from both studies were offered the option of continuing with solanezumab for 2 additional years. The data from this group were re-analysed using a new analysis technique, the so-called 'delayed start analysis'. On the basis of the re-analysis it was concluded that solanezumab does show disease-modifying activity and should be considered a promising candidate for treatment of Alzheimer's disease in the near future. This conclusion, however, is poorly supported by the data presented in the study. A more definite positioning of solanezumab will not be possible until data from the ongoing Expedition III study becomes available in 2017 at the earliest. PMID:26271177

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

    ERIC Educational Resources Information Center

    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…

  11. Alzheimer's disease: the silver tsunami of the 21(st) century.

    PubMed

    Sarkar, Ankita; Irwin, Madison; Singh, Aditi; Riccetti, Matthew; Singh, Amit

    2016-05-01

    Alzheimer's disease (AD), a fatal progressive neurodegenerative disorder, has no cure to date. One of the causes of AD is the accumulation of amyloid-beta 42 (Aβ42) plaques, which result in the onset of neurodegeneration. It is not known how these plaques trigger the onset of neurodegeneration. There are several animal models developed to (i) study etiology of disease, (ii) look for genetic modifiers, and (iii) identify chemical inhibitors that can block neurodegeneration and help to find cure for this disease. An insect model of Drosophila melanogaster has also provided new insights into the disease. Here we will discuss the utility of the Drosophila eye model to study Alzheimer's disease. PMID:27335537

  12. Alzheimer's disease: the silver tsunami of the 21st century

    PubMed Central

    Sarkar, Ankita; Irwin, Madison; Singh, Aditi; Riccetti, Matthew; Singh, Amit

    2016-01-01

    Alzheimer's disease (AD), a fatal progressive neurodegenerative disorder, has no cure to date. One of the causes of AD is the accumulation of amyloid-beta 42 (Aβ42) plaques, which result in the onset of neurodegeneration. It is not known how these plaques trigger the onset of neurodegeneration. There are several animal models developed to (i) study etiology of disease, (ii) look for genetic modifiers, and (iii) identify chemical inhibitors that can block neurodegeneration and help to find cure for this disease. An insect model of Drosophila melanogaster has also provided new insights into the disease. Here we will discuss the utility of the Drosophila eye model to study Alzheimer's disease. PMID:27335537

  13. Beyond amyloid: getting real about nonamyloid targets in Alzheimer's disease.

    PubMed

    Herrup, Karl; Carrillo, Maria C; Schenk, Dale; Cacace, Angela; Desanti, Susan; Fremeau, Robert; Bhat, Ratan; Glicksman, Marcie; May, Patrick; Swerdlow, Russell; Van Eldik, Linda J; Bain, Lisa J; Budd, Samantha

    2013-07-01

    For decades, researchers have focused primarily on a pathway initiated by amyloid beta aggregation, amyloid deposition, and accumulation in the brain as the key mechanism underlying the disease and the most important treatment target. However, evidence increasingly suggests that amyloid is deposited early during the course of disease, even prior to the onset of clinical symptoms. Thus, targeting amyloid in patients with mild to moderate Alzheimer's disease (AD), as past failed clinical trials have done, may be insufficient to halt further disease progression. Scientists are investigating other molecular and cellular pathways and processes that contribute to AD pathogenesis. Thus, the Alzheimer's Association's Research Roundtable convened a meeting in April 2012 to move beyond amyloid and explore AD as a complex multifactorial disease, with the goal of using a more inclusive perspective to identify novel treatment strategies. PMID:23809366

  14. Pharmacological strategies for the prevention of Alzheimer's disease.

    PubMed

    Doraiswamy, P Murali; Xiong, Glen L

    2006-01-01

    This review examines key pharmacological strategies that have been clinically studied for the primary or secondary prevention of Alzheimer's disease. Much information (neuropsychological, genetic and imaging) is already available to characterise an individual's risk for developing Alzheimer's disease. However, regulatory pathways for obtaining a prevention indication are less well charted, and such trials tend to involve 3- to 7-year studies of 1000 - 5000 individuals, depending on baseline status. Treatments developed for prevention will also need to have superior safety. For these reasons, > 100 proprietary pharmacological products are currently being developed for an Alzheimer's disease treatment, but only a few are being studied for prevention. Randomised trial data are available for antihypertensive agents (calcium channel blockers, angiotensin-converting enzyme inhibitors), pravastatin, simvastatin, conjugated oestrogen, raloxifene, rofecoxib, CX516 (AMPA agonist) and cholinesterase inhibitors regarding efficacy for Alzheimer's disease prevention. At least four large prevention trials of conjugated oestrogen, selenium and vitamin E, Ginkgo biloba and statins are currently underway. Strategies using other agents have not yet been evaluated in Alzheimer's disease prevention clinical trials. These include anti-amyloid antibodies, active immunisation, selective secretase inhibitors and modulators, microtubule stabilisers (e.g., paclitaxel), R-flurbiprofen, xaliproden, ONO-2506, FK962 (somatostatin releaser), SGS 742 (GABA(B) antagonist), TCH 346 (apoptosis inhibitor), Alzhemedtrade mark, phophodiesterase inhibitors, rosiglitazone, leuprolide, interferons, metal-protein attenuating compounds (e.g., PBT2), CX717, rasagaline, huperzine A, antioxidants and memantine. Studies combining lifestyle modification and drug therapy have not been conducted. Full validation of surrogate markers for disease progression (such as amyloid imaging) should further facilitate drug

  15. Alzheimer's disease risk genes and mechanisms of disease pathogenesis

    PubMed Central

    Karch, Celeste M.; Goate, Alison M.

    2014-01-01

    Here, we review the genetic risk factors for late onset Alzheimer's disease (AD) and their role in AD pathogenesis. Recent advances in our understanding of the human genome, namely technological advances in methods to analyze millions of polymorphisms in thousands of subjects, have revealed new genes associated with AD risk: ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5D, MS4A, MEF2C, NME8, PICALM, PTK2B, SLC24H4 RIN3, SORL1, ZCWPW1. Emerging technologies to analyze the entire genome in large datasets have also revealed coding variants that increase AD risk: PLD3 and TREM2. We review the relationship between these AD risk genes and the cellular and neuropathological features of AD. Together, understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to date. PMID:24951455

  16. [Development of Disease-modifying Therapy for Alzheimer's Disease].

    PubMed

    Akiyama, Haruhiko

    2016-04-01

    The development of disease-modifying therapy (DMT) that can arrest the pathological processes of Alzheimer's disease (AD) has emerged as one of the highest priorities of medical research. Two pathological hallmarks, amyloid-beta (Abeta) protein deposition and tau accumulation, are the major targets of DMT. Immunotherapy for Abeta removal and secretase inhibitors/modulators that reduce total or accumulation-prone Abeta are candidate DMTs against Abeta. Compounds that prevent tau aggregation are also under development. Clinical trials that test the efficacy of these DMT candidates are in preparation or ongoing. Recent studies of biomarkers of AD brain lesions have indicated that Abeta and tau accumulation appears 10 to 30 years before the occurrence of dementia and gradually propagate to reach the level that causes symptoms. Therefore, efficacy of DMT has to be evaluated in the preclinical stage of AD. The incidence of preclinical AD in the cognitively normal, aged population are estimated to be around 19%. Thus, currently available biomarkers, amyloid/tau PET imaging and cerebrospinal fluid measurements of Abeta and tau, are, perhaps, too invasive and costly. An international collaborative effort is needed to overcome this issue. PMID:27056864

  17. Distinct mechanisms of impairment in cognitive ageing and Alzheimer's disease.

    PubMed

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

    2008-06-01

    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 heading discrimination task requiring subjects to determine direction of simulated self-movement from left or right offset optic flow fields of several sizes (25 degrees, 40 degrees or 60 degrees in diameter) to 18 Alzheimer's disease subjects (mean age = 75.3, 55% female), 21 older adult control subjects (mean age = 72.4, 67% female), and 26 younger control subjects (mean age = 26.5, 63% female). We also administered computerized measures of processing speed and divided and selective attention, and psychophysical measures of visual motion perception to all subjects. Both older groups showed significant difficulty in judging the direction of virtual self-movement [F(2,194) = 40.5, P < 0.001] and optic flow stimulus size had little effect on heading discrimination for any group. Both older groups showed impairments on measures of divided [F(2,62) = 22.2, P < 0.01] and selective [F(2,62) = 63.0, P < 0.001] attention relative to the younger adult control group, while the Alzheimer's disease group showed a selective impairment in outward optic flow perception [F(2,64) = 6.3, P = 0.003] relative to both control groups. Multiple linear regression revealed distinct attentional and perceptual contributions to heading discrimination performance for the two older groups. In older adult control subjects, poorer heading discrimination was attributable to attentional deficits (R(2) adj = 0.41, P = 0.001) whereas, in Alzheimer's disease patients, it was largely attributable to deficits of visual motion perception (R(2) adj = 0.57, P < 0.001). These findings suggest that successive attentional and perceptual deficits play independent roles in

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

    PubMed

    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 < 0.0001), disinhibition (16% versus 2%, P = 0.009), irritability (48% versus 9%, P = 0.0001), sleep changes (28% versus 7%, P = 0.003), and agitation (24% versus 6%, P = 0.008) were more common and

  19. Effect of Psychotropic Drugs on Development of Diabetes Mellitus in Patients With Alzheimer's Disease

    PubMed Central

    Chang, Ki Jung; Hong, Chang Hyung; Lee, Yunhwan; Lee, Kang Soo; Roh, Hyun Woong; Back, Joung Hwan; Jung, Young Ki; Lim, Ki Young; Noh, Jai Sung; Kim, Hyun Chung; Choi, Seong Hye; Kim, Seong Yoon; Na, Duk L.; Seo, Sang Won; Lee, Soojin; Son, Sang Joon

    2015-01-01

    Abstract We aimed to examine risk of diabetes mellitus (DM) among older adults with Alzheimer's disease receiving 3 types of psychotropic drugs, that is, antipsychotics, antidepressants, and sedative anxiolytics. We retrospectively analyzed data from a hospital-based Clinical Research Center for Dementia of South Korea (CREDOS) study conducted between January 1, 2008 and December 31, 2012. Participants (n = 3042) with Alzheimer's disease were aged 65 or older and had no preexisting history of DM. Development of DM was identified using claims for initiating at least 1 prescription of antidiabetic medications or a diagnosis of DM during the follow-up period. Cox proportional hazards regression was used to demonstrate the Hazard ratio of DM in use of each psychotropic drug. Among the 3042 participants, 426 patients (14.0%) developed DM, representing an incidence rate of 5.2/100 person-years during an average 2.9 years of follow-up period. Among the 3 types of psychotropic drugs, antipsychotic users had a significantly higher risk of DM (hazard ratio = 1.74, 95% confidence interval = 1.10, 2.76) than nonusers, after adjusting covariates. Antidepressants and sedative anxiolytics did not achieve statistical significance. These results suggested that the diabetes risk was elevated in Alzheimer patients on antipsychotic treatment. Therefore, patients with Alzheimer's disease receiving antipsychotic treatment should be carefully monitored for the development of DM. PMID:26061313

  20. Pathomechanisms of atrophy in insular cortex in Alzheimer's disease.

    PubMed

    Moon, Yeonsil; Moon, Won-Jin; Han, Seol-Heui

    2015-08-01

    The insular cortex is associated with neuropsychiatric symptoms, changes in cardiovascular and autonomic control, and mortality in Alzheimer's dementia. However, the insular cortex does not provide information on the contribution of the other cortices to cognitive decline. We hypothesized that the factors that affect to atrophy in insular cortex are different from other cortical regions. A total of 42 patients with probable Alzheimer's dementia were included in the analyses. The manual drawing of regions of interest was used to detect insular cortex located in the deep gray matter and to avoid coatrophy. Covariates, which could affect to the atrophy of the cerebral cortex, were selected based on previous studies. Any of the demographic factors, vascular risk factors, and the severity scales of dementia was not associated with any insular volume ratio. We suggest that the pathomechanisms of atrophy in insular cortex are different from those of other cortex regions in Alzheimer's disease. PMID:25596207

  1. Early probable Alzheimer's disease and awareness context theory.

    PubMed

    Hutchinson, S A; Leger-Krall, S; Wilson, H S

    1997-11-01

    The purpose of this research was to explore the explanatory value of Awareness Context Theory for social interactional issues in early probable Alzheimer's Disease (AD). Glaser and Strauss's Awareness Context Theory [Glaser and Strauss (1965) Awareness of Dying, Aldine, New York] served as the framework for the analysis of interview data from 14 early probable AD clients and 14 family caregivers, a written autobiographical account, a fictionalized account, observations of a family care-giver focus group, and excerpts that focused on early AD from field notes recorded during two years of participant observation at a specialized AD daycare center and a family caregiver support group. Initial open-ended study questions focused on the experience of early AD from the diverse perspectives represented in the data. After preliminary analysis of data suggesting emergent fit with Awareness Context Theory, questions were refocused to address awareness contexts. Data were coded and analyzed for fit with the theory. Awareness Context Theory provided a useful heuristic for thinking about the nuances and complexities of social interaction in early AD. Attention to awareness contexts should enable health care providers to suggest interventions to improve caregiver-client interactions. PMID:9351157

  2. Subregional Basal Forebrain Atrophy in Alzheimer's Disease: A Multicenter Study

    PubMed Central

    Kilimann, Ingo; Grothe, Michel; Heinsen, Helmut; Alho, Eduardo Joaquim Lopez; Grinberg, Lea; Amaro, Edson; dos Santos, Gláucia Aparecida Bento; da Silva, Rafael Emídio; Mitchell, Alex J.; Frisoni, Giovanni B.; Bokde, Arun L.W.; Fellgiebel, Andreas; Filippi, Massimo; Hampel, Harald; Klöppel, Stefan; Teipel, Stefan J.

    2014-01-01

    Histopathological studies in Alzheimer's disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically manifest AD (n = 134) and 148 cognitively healthy controls. Atrophy was determined using voxel-based and region-of-interest based analyses of high-dimensionally normalized MRI scans using a newly created map of the BFCS based on postmortem in cranio MRI and histology. The AD group showed significant volume reductions of all subregions of the BFCS, which were most pronounced in the posterior nucleus basalis Meynert (NbM). The mild cognitive impairment-AD group showed pronounced volume reductions in the posterior NbM, but preserved volumes of anterior-medial regions. Diagnostic accuracy of posterior NbM volume was superior to hippocampus volume in both groups, despite higher multicenter variability of the BFCS measurements. The data of our study suggest that BFCS morphometry may provide an emerging biomarker in AD. PMID:24503619

  3. Masitinib for the treatment of mild to moderate Alzheimer's disease.

    PubMed

    Folch, Jaume; Petrov, Dmitry; Ettcheto, Miren; Pedrós, Ignacio; Abad, Sonia; Beas-Zarate, Carlos; Lazarowski, Alberto; Marin, Miguel; Olloquequi, Jordi; Auladell, Carme; Camins, Antoni

    2015-06-01

    Alzheimer's disease (AD) is a degenerative neurological disorder that is the most common cause of dementia and disability in older patients. Available treatments are symptomatic in nature and are only sufficient to improve the quality of life of AD patients temporarily. A potential strategy, currently under investigation, is to target cell-signaling pathways associated with neurodegeneration, in order to decrease neuroinflammation, excitotoxicity, and to improve cognitive functions. Current review centers on the role of neuroinflammation and the specific contribution of mast cells to AD pathophysiology. The authors look at masitinib therapy and the evidence presented through preclinical and clinical trials. Dual actions of masitinib as an inhibitor of mast cell-glia axis and a Fyn kinase blocker are discussed in the context of AD pathology. Masitinib is in Phase III clinical trials for the treatment of malignant melanoma, mastocytosis, multiple myeloma, gastrointestinal cancer and pancreatic cancer. It is also in Phase II/III clinical trials for the treatment of multiple sclerosis, rheumatoid arthritis and AD. Additional research is warranted to better investigate the potential effects of masitinib in combination with other drugs employed in AD treatment. PMID:25961655

  4. Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer's disease.

    PubMed

    Atamna, Hani; Frey, William H

    2007-09-01

    Several studies have demonstrated aberrations in the Electron Transport Complexes (ETC) and Krebs (TCA) cycle in Alzheimer's disease (AD) brain. Optimal activity of these key metabolic pathways depends on several redox active centers and metabolites including heme, coenzyme Q, iron-sulfur, vitamins, minerals, and micronutrients. Disturbed heme metabolism leads to increased aberrations in the ETC (loss of complex IV), dimerization of APP, free radical production, markers of oxidative damage, and ultimately cell death all of which represent key cytopathologies in AD. The mechanism of mitochondrial dysfunction in AD is controversial. The observations that Abeta is found both in the cells and in the mitochondria and that Abeta binds with heme may provide clues to this mechanism. Mitochondrial Abeta may interfere with key metabolites or metabolic pathways in a manner that overwhelms the mitochondrial mechanisms of repair. Identifying the molecular mechanism for how Abeta interferes with mitochondria and that explains the established key cytopathologies in AD may also suggest molecular targets for therapeutic interventions. Below we review recent studies describing the possible role of Abeta in altered energy production through heme metabolism. We further discuss how protecting mitochondria could confer resistance to oxidative and environmental insults. Therapies targeted at protecting mitochondria may improve the clinical outcome of AD patients. PMID:17625988

  5. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective.

    PubMed

    Tanzi, Rudolph E; Bertram, Lars

    2005-02-25

    From Alois Alzheimer's description of Auguste D.'s brain in 1907 to George Glenner's biochemical dissection of beta-amyloid in 1984, the "amyloid hypothesis" of Alzheimer's disease has continued to gain support over the past two decades, particularly from genetic studies. Here we assess the amyloid hypothesis based on both known and putative Alzheimer's disease genes. PMID:15734686

  6. Mitochondria-Targeted Protective Compounds in Parkinson's and Alzheimer's Diseases

    PubMed Central

    Fernández-Moriano, Carlos; González-Burgos, Elena; Gómez-Serranillos, M. Pilar

    2015-01-01

    Mitochondria are cytoplasmic organelles that regulate both metabolic and apoptotic signaling pathways; their most highlighted functions include cellular energy generation in the form of adenosine triphosphate (ATP), regulation of cellular calcium homeostasis, balance between ROS production and detoxification, mediation of apoptosis cell death, and synthesis and metabolism of various key molecules. Consistent evidence suggests that mitochondrial failure is associated with early events in the pathogenesis of ageing-related neurodegenerative disorders including Parkinson's disease and Alzheimer's disease. Mitochondria-targeted protective compounds that prevent or minimize mitochondrial dysfunction constitute potential therapeutic strategies in the prevention and treatment of these central nervous system diseases. This paper provides an overview of the involvement of mitochondrial dysfunction in Parkinson's and Alzheimer's diseases, with particular attention to in vitro and in vivo studies on promising endogenous and exogenous mitochondria-targeted protective compounds. PMID:26064418

  7. [The trend of developing new disease-modifying drugs in Alzheimer's disease].

    PubMed

    Arai, Hiroyuki; Furukawa, Katsutoshi; Tomita, Naoki; Ishiki, Aiko; Okamura, Nobuyuki; Kudo, Yukitsuka

    2016-03-01

    Development of symptomatic treatment of Alzheimer s disease by cholinesterase inhibitors like donepezil was successful. However, it is a disappointment that development of disease-modifying drugs such as anti-amyloid drug based on amyloid-cascade theory has been interrupted or unsuccessful. Therefore, we have to be more cautious regarding inclusion criteria for clinical trials of new drugs. We agree that potentially curative drugs should be started before symptoms begin as a preemptive therapy or prevention trial. The concept of personalized medicine also is important when ApoE4-related amyloid reducing therapy is considered. Unfortunately, Japanese-ADNI has suffered a setback since 2014. However, Ministry of Health, Labour and Welfare gave a final remark that there was nothing wrong in the data managing process in the J-ADNI data center. We should pay more attention to worldwide challenges of speeding up new drug development. PMID:27025078

  8. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease

    PubMed Central

    Tobinick, Edward L; Gross, Hyman

    2008-01-01

    Background Recent clinical studies point to rapid and sustained clinical, cognitive, and behavioral improvement in both Alzheimer's disease and primary progressive aphasia following weekly perispinal administration of etanercept, a TNF-alpha inhibitor that acts by blocking the binding of this cytokine to its receptors. This outcome is concordant with recent basic science studies suggesting that TNF-alpha functions in vivo as a gliotransmitter that regulates synaptic function in the brain. We hypothesized that perispinal etanercept had the potential to improve verbal function in Alzheimer's disease, so we included several standarized measures of verbal ability to evaluate language skills in a clinical trial of perispinal etanercept for Alzheimer's disease. Methods This was a prospective, single-center, open-label, pilot study, in which 12 patients with mild-to-severe Alzheimer's disease were administered etanercept, 25–50 mg, weekly by perispinal administration for six months. Two additional case studies are presented. Results Two-tailed, paired t-tests were conducted comparing baseline performance to 6-month performance on all neuropsychological measures. Test batteries included the California Verbal Learning Test-Second Edition, Adult Version; Logical Memory I and II(WMS-LM-II) from the Wechsler Memory Scale-Abbreviated; the Comprehensive Trail Making Test (TMT); Boston Naming Test; and letter(FAS) and category verbal fluency. All measures revealed a significant effect except for the Boston Naming Test and the TMT-4, with WMS-LM-II being marginally significant at p = .05. The FAS test for letter fluency was most highly significant with a p < 0.0007. In addition, rapid improvement in verbal fluency and aphasia in two patients with dementia, beginning minutes after perispinal etanercept administration, is documented. Conclusion In combination with the previously reported results of perispinal etanercept in Alzheimer's disease and primary progressive aphasia, these

  9. Friend or foe? Targeting microglia in Alzheimer's disease.

    PubMed

    Dhib-Jalbut, Suhayl

    2016-10-01

    Inflammation is believed to be a component of a number of degenerative brain diseases including Alzheimer's disease. A recent article by Fu and colleagues (2016) demonstrated that the cytokine IL-33 can modulate microglia in an animal model of AD to become better scavengers of beta-amyloid and less pro-inflammatory. The findings have potential therapeutic implications for a number of brain conditions. PMID:27442003

  10. Understanding suffering: Utermohlen's self-portraits and Alzheimer's disease.

    PubMed

    Harrison, Elizabeth M

    2013-01-01

    Human suffering is a universal experience simply defined as, or associated with, physical or psychological pain and distress. Faculty seeks ways to help its students understand and ease their patients' suffering. The author uses Alzheimer's disease as an exemplar of suffering and describes a creative teaching strategy using 9 self-portraits that chronicle American-born artist William Utermohlen's deterioration from the disease. PMID:23222627

  11. Revisiting rodent models: Octodon degus as Alzheimer's disease model?

    PubMed

    Steffen, Johannes; Krohn, Markus; Paarmann, Kristin; Schwitlick, Christina; Brüning, Thomas; Marreiros, Rita; Müller-Schiffmann, Andreas; Korth, Carsten; Braun, Katharina; Pahnke, Jens

    2016-01-01

    Alzheimer's disease primarily occurs as sporadic disease and is accompanied with vast socio-economic problems. The mandatory basic research relies on robust and reliable disease models to overcome increasing incidence and emerging social challenges. Rodent models are most efficient, versatile, and predominantly used in research. However, only highly artificial and mostly genetically modified models are available. As these 'engineered' models reproduce only isolated features, researchers demand more suitable models of sporadic neurodegenerative diseases. One very promising animal model was the South American rodent Octodon degus, which was repeatedly described as natural 'sporadic Alzheimer's disease model' with 'Alzheimer's disease-like neuropathology'. To unveil advantages over the 'artificial' mouse models, we re-evaluated the age-dependent, neurohistological changes in young and aged Octodon degus (1 to 5-years-old) bred in a wild-type colony in Germany. In our hands, extensive neuropathological analyses of young and aged animals revealed normal age-related cortical changes without obvious signs for extensive degeneration as seen in patients with dementia. Neither significant neuronal loss nor enhanced microglial activation were observed in aged animals. Silver impregnation methods, conventional, and immunohistological stains as well as biochemical fractionations revealed neither amyloid accumulation nor tangle formation. Phosphoepitope-specific antibodies against tau species displayed similar intraneuronal reactivity in both, young and aged Octodon degus.In contrast to previous results, our study suggests that Octodon degus born and bred in captivity do not inevitably develop cortical amyloidosis, tangle formation or neuronal loss as seen in Alzheimer's disease patients or transgenic disease models. PMID:27566602

  12. Loss of endophilin-B1 exacerbates Alzheimer's disease pathology.

    PubMed

    Wang, David B; Kinoshita, Yoshito; Kinoshita, Chizuru; Uo, Takuma; Sopher, Bryce L; Cudaback, Eiron; Keene, C Dirk; Bilousova, Tina; Gylys, Karen; Case, Amanda; Jayadev, Suman; Wang, Hong-Gang; Garden, Gwenn A; Morrison, Richard S

    2015-07-01

    Endophilin-B1, also known as Bax-interacting factor 1 (Bif-1, and encoded by SH3GLB1), is a multifunctional protein involved in apoptosis, autophagy and mitochondrial function. We recently described a unique neuroprotective role for neuron-specific alternatively spliced isoforms of endophilin-B1. To examine whether endophilin-B1-mediated neuroprotection could be a novel therapeutic target for Alzheimer's disease we used a double mutant amyloid precursor protein and presenilin 1 (APPswe/PSEN1dE9) mouse model of Alzheimer's disease and observed that expression of neuron-specific endophilin-B1 isoforms declined with disease progression. To determine if this reduction in endophilin-B1 has a functional role in Alzheimer's disease pathogenesis, we crossed endophilin-B1(-/-) mice with APPswe/PSEN1dE9 mice. Deletion of endophilin-B1 accelerated disease onset and progression in 6-month-old APPswe/PSEN1dE9/endophilin-B1(-/-) mice, which showed more plaques, astrogliosis, synaptic degeneration, cognitive impairment and mortality than APPswe/PSEN1dE9 mice. In mouse primary cortical neuron cultures, overexpression of neuron-specific endophilin-B1 isoforms protected against amyloid-β-induced apoptosis and mitochondrial dysfunction. Additionally, protein and mRNA levels of neuron-specific endophilin-B1 isoforms were also selectively decreased in the cerebral cortex and in the synaptic compartment of patients with Alzheimer's disease. Flow sorting of synaptosomes from patients with Alzheimer's disease demonstrated a negative correlation between amyloid-β and endophilin-B1 levels. The importance of endophilin-B1 in neuronal function was further underscored by the development of synaptic degeneration and cognitive and motor impairment in endophilin-B1(-/-) mice by 12 months. Our findings suggest that endophilin-B1 is a key mediator of a feed-forward mechanism of Alzheimer's disease pathogenesis where amyloid-β reduces neuron-specific endophilin-B1, which in turn enhances amyloid

  13. Insight into the Molecular Imaging of Alzheimer's Disease

    PubMed Central

    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

  14. Fluorescence tomography in a murine model of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Raymond, Scott B.; Kumar, Anand T. N.; Dunn, Andrew K.; Boas, David A.; Bacskai, Brian J.

    2007-02-01

    Noninvasive molecular imaging of amyloid plaques in murine Alzheimer's disease models would accelerate drug development and basic Alzheimer's research. Amyloid plaques differ from traditional fluorescent targets in size and spatial distribution and therefore present a unique challenge for biomarker development and tomography. To study imaging feasibility and establish biomarker criteria, we developed a digital mouse head model from a 100 μm-resolution, digital, segmented mouse atlas1. The cortical region of the brain was filled with a spatially uniform distribution of plaques that had different fluorescent properties from the surrounding brain tissue, similar to current transgenic mouse models of Alzheimer's disease. Fluorescence was simulated with a Monte Carlo algorithm using different plaque densities, detection geometries, and background fluorescence. Our preliminary results demonstrated that shielding effects might require nonlinear reconstruction algorithms and that background fluorescence would seriously hinder quantitative burden estimation. The Monte Carlo based approach presented here offers a powerful way to study the feasibility of non-invasive imaging in murine Alzheimer's models and to optimize experimental conditions.

  15. Disrupted modular brain dynamics reflect cognitive dysfunction in Alzheimer's disease.

    PubMed

    de Haan, W; van der Flier, W M; Koene, T; Smits, L L; Scheltens, P; Stam, C J

    2012-02-15

    The relation between pathology and cognitive dysfunction in dementia is still poorly understood, although disturbed communication between different brain regions is almost certainly involved. In this study we combine magneto-encephalography (MEG) and network analysis to investigate the role of functional sub-networks (modules) in the brain with regard to cognitive failure in Alzheimer's disease. Whole-head resting-state (MEG) was performed in 18 Alzheimer patients (age 67 ± 9, 6 females, MMSE 23 ± 5) and 18 healthy controls (age 66 ± 9, 11 females, MMSE 29 ± 1). We constructed functional brain networks based on interregional synchronization measurements, and performed graph theoretical analysis with a focus on modular organization. The overall modular strength and the number of modules changed significantly in Alzheimer patients. The parietal cortex was the most highly connected network area, but showed the strongest intramodular losses. Nonetheless, weakening of intermodular connectivity was even more outspoken, and more strongly related to cognitive impairment. The results of this study demonstrate that particularly the loss of communication between different functional brain regions reflects cognitive decline in Alzheimer's disease. These findings imply the relevance of regarding dementia as a functional network disorder. PMID:22154957

  16. 100 Years of Alzheimer's disease (1906-2006).

    PubMed

    Lage, José Manuel Martínez

    2006-01-01

    As we commemorate the first centennial since Alzheimer's disease (AD) was first diagnosed, this article casts back into the past while also looking to the future. It reflects on the life of Alois Alzheimer (1864-1915) and the scientific work he undertook in describing the disorder suffered by Auguste D. from age 51 to 56 and the neuropathological findings revealed by her brain, reminding us of the origin of the eponym. It highlights how, throughout the 1960's, the true importance of AD as the major cause of late life dementia ultimately came to light and narrates the evolution of the concepts related to AD throughout the years and its recognition as a major public health problem. Finally, the article pays homage to the work done by the Alzheimer's Association and the research undertaken at the Alzheimer's Disease Centres within the framework of the National Institute on Aging (NIA) Program, briefly discussing the long road travelled in the fight against AD in the past 25 years and the scientific odyssey that we trust will result in finding a cure. PMID:17004362

  17. A family living with Alzheimer's disease: The communicative challenges.

    PubMed

    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. PMID:24339113

  18. Cascading network failure across the Alzheimer's disease spectrum.

    PubMed

    Jones, David T; Knopman, David S; Gunter, Jeffrey L; Graff-Radford, Jonathan; Vemuri, Prashanthi; Boeve, Bradley F; Petersen, Ronald C; Weiner, Michael W; Jack, Clifford R

    2016-02-01

    Complex biological systems are organized across various spatiotemporal scales with particular scientific disciplines dedicated to the study of each scale (e.g. genetics, molecular biology and cognitive neuroscience). When considering disease pathophysiology, one must contemplate the scale at which the disease process is being observed and how these processes impact other levels of organization. Historically Alzheimer's disease has been viewed as a disease of abnormally aggregated proteins by pathologists and molecular biologists and a disease of clinical symptoms by neurologists and psychologists. Bridging the divide between these scales has been elusive, but the study of brain networks appears to be a pivotal inroad to accomplish this task. In this study, we were guided by an emerging systems-based conceptualization of Alzheimer's disease and investigated changes in brain networks across the disease spectrum. The default mode network has distinct subsystems with unique functional-anatomic connectivity, cognitive associations, and responses to Alzheimer's pathophysiology. These distinctions provide a window into the systems-level pathophysiology of Alzheimer's disease. Using clinical phenotyping, metadata, and multimodal neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative, we characterized the pattern of default mode network subsystem connectivity changes across the entire disease spectrum (n = 128). The two main findings of this paper are (i) the posterior default mode network fails before measurable amyloid plaques and appears to initiate a connectivity cascade that continues throughout the disease spectrum; and (ii) high connectivity between the posterior default mode network and hubs of high connectivity (many located in the frontal lobe) is associated with amyloid accumulation. These findings support a system model best characterized by a cascading network failure-analogous to cascading failures seen in power grids triggered by local

  19. Alzheimer's Disease Mechanisms and Emerging Roads to Novel Therapeutics.

    PubMed

    Sala Frigerio, Carlo; De Strooper, Bart

    2016-07-01

    Ten years of remarkable progress in understanding the fundamental biochemistry of Alzheimer's disease have been followed by ten years of remarkable and increasing clinical insight into the natural progression of the disorder. The concept of a long, intermediary, prodromal phase between the first appearance of amyloid plaques and tangles and the manifestation of dementia is now well established. The major challenge for the next decade is to chart the many cellular processes that underlie this phase and link the biochemical alterations to the clinical manifestation of Alzheimer's disease. We discuss here how genetics, new cell culture systems, and improved animal models will fuel this work. We anticipate that the resulting novel insights will provide a basis for further drug development for this terrible disease. PMID:27050320

  20. The fine-tuning of proteolytic pathways in Alzheimer's disease.

    PubMed

    Cecarini, Valentina; Bonfili, Laura; Cuccioloni, Massimiliano; Mozzicafreddo, Matteo; Angeletti, Mauro; Keller, Jeffrey N; Eleuteri, Anna Maria

    2016-09-01

    Several integrated proteolytic systems contribute to the maintenance of cellular homeostasis through the continuous removal of misfolded, aggregated or oxidized proteins and damaged organelles. Among these systems, the proteasome and autophagy play the major role in protein quality control, which is a fundamental issue in non-proliferative cells such as neurons. Disturbances in the functionality of these two pathways are frequently observed in neurodegenerative diseases, like Alzheimer's disease, and reflect the accumulation of protease-resistant, deleterious protein aggregates. In this review, we explored the sophisticated crosstalk between the ubiquitin-proteasome system and autophagy in the removal of the harmful structures that characterize Alzheimer's disease neurons. We also dissected the role of the numerous shuttle factors and chaperones that, directly or indirectly interacting with ubiquitin and LC3, are used for cargo selection and delivery to one pathway or the other. PMID:27120560

  1. Drawing Disorders in Alzheimer's Disease and Other Forms of Dementia.

    PubMed

    Trojano, Luigi; Gainotti, Guido

    2016-04-21

    Drawing is a multicomponential process that can be impaired by many kinds of brain lesions. Drawing disorders are very common in Alzheimer's disease and other forms of dementia, and can provide clinical information for the distinction of the different dementing diseases. In our review we started from an overview of the neural and cognitive bases of drawing, and from a recollection of the drawing tasks more frequently used for assessing individuals with dementia. Then, we analyzed drawing disorders in dementia, paying special attention to those observed in Alzheimer's disease, from the prodromal stages of the amnesic mild cognitive impairment to the stages of full-blown dementia, both in the sporadic forms with late onset in the entorhino-hippocampal structures and in those with early onset in the posterior neocortical structures. We reviewed the drawing features that could differentiate Alzheimer's disease from vascular dementia and from the most frequent forms of degenerative dementia, namely frontotemporal dementia and Lewy body disease. Finally, we examined some peculiar aspects of drawing disorders in dementia, such as perseverations, rotations, and closing-in. We argue that a careful analysis of drawing errors helps to differentiate the different forms of dementia more than overall accuracy in drawing. PMID:27104898

  2. Studying infrared light therapy for treating Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    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. Bioinformatics methods in drug repurposing for Alzheimer's disease.

    PubMed

    Siavelis, John C; Bourdakou, Marilena M; Athanasiadis, Emmanouil I; Spyrou, George M; Nikita, Konstantina S

    2016-03-01

    Alarming epidemiological features of Alzheimer's disease impose curative treatment rather than symptomatic relief. Drug repurposing, that is reappraisal of a substance's indications against other diseases, offers time, cost and efficiency benefits in drug development, especially when in silico techniques are used. In this study, we have used gene signatures, where up- and down-regulated gene lists summarize a cell's gene expression perturbation from a drug or disease. To cope with the inherent biological and computational noise, we used an integrative approach on five disease-related microarray data sets of hippocampal origin with three different methods of evaluating differential gene expression and four drug repurposing tools. We found a list of 27 potential anti-Alzheimer agents that were additionally processed with regard to molecular similarity, pathway/ontology enrichment and network analysis. Protein kinase C, histone deacetylase, glycogen synthase kinase 3 and arginase inhibitors appear consistently in the resultant drug list and may exert their pharmacologic action in an epidermal growth factor receptor-mediated subpathway of Alzheimer's disease. PMID:26197808

  4. Near-infrared fluorescent probes for imaging of amyloid plaques in Alzheimer׳s disease.

    PubMed

    Tong, Hongjuan; Lou, Kaiyan; Wang, Wei

    2015-01-01

    One of the early pathological hallmarks of Alzheimer׳s disease (AD) is the deposition of amyloid-β (Aβ) plaques in the brain. There has been a tremendous interest in the development of Aβ plaques imaging probes for early diagnosis of AD in the past decades. Optical imaging, particularly near-infrared fluorescence (NIRF) imaging, has emerged as a safe, low cost, real-time, and widely available technique, providing an attractive approach for in vivo detection of Aβ plaques among many different imaging techniques. In this review, we provide a brief overview of the state-of-the-art development of NIRF Aβ probes and their in vitro and in vivo applications with special focus on design strategies and optical, binding, and brain-kinetic properties. PMID:26579421

  5. Apolipoprotein E in the genetics and epidemiology of Alzheimer`s disease

    SciTech Connect

    Hardy, J.

    1995-10-09

    The role of apolipoprotein E (ApoE) alleles and isoforms in the etiology and pathogenesis of Alzheimer`s disease is discussed. The possibility that ApoE itself is not involved in the disease pathogenesis but is merely in genetic disequilibrium with the real locus is discussed and dismissed. The data showing that the {epsilon}4 allele is associated with an increased risk of developing the disease and with an earlier onset age are reviewed. The data showing that, at least in some circumstances, the {epsilon}2 allele is associated with a decrease in the risk of developing the disease, and with a later onset age are also reviewed. Data from the genetic analysis of other disorders are reviewed and presented, and it is suggested that the genetic data support the notion that the role of ApoE in the etiology of the disease directly relates to {beta}-amyloid deposition and plaque formation. This suggestion is in concordance with the most likely mechanism for the role of P-amyloid precursor protein gene mutations as other risk factors for the disease. 68 refs.

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

    PubMed

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

    2016-01-01

    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. PMID:26919851

  7. Construction of a yeast artificial chromosome contig encompassing the chromosome 14 Alzheimer`s disease locus

    SciTech Connect

    Sharma, V.; Bonnycastle, L.; Poorkai, P.

    1994-09-01

    We have constructed a yeast artificial chromosome (YAC) contig of chromosome 14q24.3 which encompasses the chromosome 14 Alzheimer`s disease locus (AD3). Determined by linkage analysis of early-onset Alzheimer`s disease kindreds, this interval is bounded by the genetic markers D14S61-D14S63 and spans approximately 15 centimorgans. The contig consists of 29 markers and 74 YACs of which 57 are defined by one or more sequence tagged sites (STSs). The STS markers comprise 5 genes, 16 short tandem repeat polymorphisms and 8 cDNA clones. An additional number of genes, expressed sequence tags and cDNA fragments have been identified and localized to the contig by hybridization and sequence analysis of anonymous clones isolated by cDNA direct selection techniques. A minimal contig of about 15 YACs averaging 0.5-1.5 megabase in length will span this interval and is, at first approximation, in rough agreement with the genetic map. For two regions of the contig, our coverage has relied on L1/THE fingerprint and Alu-PCR hybridization data of YACs provided by CEPH/Genethon. We are currently developing sequence tagged sites from these to confirm the overlaps revealed by the fingerprint data. Among the genes which map to the contig are transforming growth factor beta 3, c-fos, and heat shock protein 2A (HSPA2). C-fos is not a candidate gene for AD3 based on the sequence analysis of affected and unaffected individuals. HSPA2 maps to the proximal edge of the contig and Calmodulin 1, a candidate gene from 4q24.3, maps outside of the region. The YAC contig is a framework physical map from which cosmid or P1 clone contigs can be constructed. As more genes and cDNAs are mapped, a highly resolved transcription map will emerge, a necessary step towards positionally cloning the AD3 gene.

  8. Animal models in the drug discovery pipeline for Alzheimer's disease

    PubMed Central

    Van Dam, Debby; De Deyn, Peter Paul

    2011-01-01

    With increasing feasibility of predicting conversion of mild cognitive impairment to dementia based on biomarker profiling, the urgent need for efficacious disease-modifying compounds has become even more critical. Despite intensive research, underlying pathophysiological mechanisms remain insufficiently documented for purposeful target discovery. Translational research based on valid animal models may aid in alleviating some of the unmet needs in the current Alzheimer's disease pharmaceutical market, which includes disease-modification, increased efficacy and safety, reduction of the number of treatment unresponsive patients and patient compliance. The development and phenotyping of animal models is indeed essential in Alzheimer's disease-related research as valid models enable the appraisal of early pathological processes – which are often not accessible in patients, and subsequent target discovery and evaluation. This review paper summarizes and critically evaluates currently available animal models, and discusses their value to the Alzheimer drug discovery pipeline. Models dealt with include spontaneous models in various species, including senescence-accelerated mice, chemical and lesion-induced rodent models, and genetically modified models developed in Drosophila melanogaster, Caenorhabditis elegans, Danio rerio and rodents. Although highly valid animal models exist, none of the currently available models recapitulates all aspects of human Alzheimer's disease, and one should always be aware of the potential dangers of uncritical extrapolating from model organisms to a human condition that takes decades to develop and mainly involves higher cognitive functions. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21371009

  9. Attention and executive deficits in Alzheimer's disease. A critical review.

    PubMed

    Perry, R J; Hodges, J R

    1999-03-01

    In this review we summarize the progress that has been made in the research on attentional and executive deficits in Alzheimer's disease. Like memory, attention is now recognized as consisting of subtypes that differ in their function and anatomical basis. We base our review upon a classification of three subtypes of attention: selective, sustained and divided. This model derives from lesion studies, animal electrophysiological recordings and functional imaging. We examine how these subcomponents of attention can be reconciled with neuropsychological models of attentional control, particularly the Supervisory Attentional System and the Central Executive System of Shallice and Baddeley, respectively. We also discuss the relationship of attention to the concept of executive function. Current evidence suggests that after an initial amnesic stage in Alzheimer's disease, attention is the first non-memory domain to be affected, before deficits in language and visuospatial functions. This is consistent with the possibility that difficulties with activities of daily living, which occur in even mildly demented patients, may be related to attentional deficits. It appears that divided attention and aspects of selective attention, such as set-shifting and response selection, are particularly vulnerable while sustained attention is relatively preserved in the early stages. The phenomenon of cognitive slowing in Alzheimer's disease and normal ageing emphasizes the need to discriminate quantitative changes in attention dysfunction from qualitative changes which may be specifically related to the disease process. The neuropathological basis of these attentional deficits remains unsettled, with two competing hypotheses: spread of pathology from the medial temporal to basal forebrain structures versus corticocortical tract disconnection. Finally we discuss the difficulties of comparing evidence across studies and look at the implications for the design of future studies and future

  10. Caloric restriction: beneficial effects on brain aging and Alzheimer's disease.

    PubMed

    Van Cauwenberghe, Caroline; Vandendriessche, Charysse; Libert, Claude; Vandenbroucke, Roosmarijn E

    2016-08-01

    Dietary interventions such as caloric restriction (CR) extend lifespan and health span. Recent data from animal and human studies indicate that CR slows down the aging process, benefits general health, and improves memory performance. Caloric restriction also retards and slows down the progression of different age-related diseases, such as Alzheimer's disease. However, the specific molecular basis of these effects remains unclear. A better understanding of the pathways underlying these effects could pave the way to novel preventive or therapeutic strategies. In this review, we will discuss the mechanisms and effects of CR on aging and Alzheimer's disease. A potential alternative to CR as a lifestyle modification is the use of CR mimetics. These compounds mimic the biochemical and functional effects of CR without the need to reduce energy intake. We discuss the effect of two of the most investigated mimetics, resveratrol and rapamycin, on aging and their potential as Alzheimer's disease therapeutics. However, additional research will be needed to determine the safety, efficacy, and usability of CR and its mimetics before a general recommendation can be proposed to implement them. PMID:27240590

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

    PubMed

    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. PMID:25456841

  12. Predicting Clinical Scores from Magnetic Resonance Scans in Alzheimer's Disease

    PubMed Central

    Stonnington, Cynthia M.; Chu, Carlton; Klöppel, Stefan; Jack, Clifford R; Ashburner, John; Frackowiak, Richard S.J.

    2010-01-01

    Machine learning and pattern recognition methods have been used to diagnose Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) from individual MRI scans. Another application of such methods is to predict clinical scores from individual scans. Using relevance vector regression (RVR), we predicted individuals' performances on established tests from their MRI T1 weighted image in two independent datasets. From Mayo Clinic, 73 probable AD patients and 91 cognitively normal (CN) controls completed the Mini-Mental State Examination (MMSE), Dementia Rating Scale (DRS), and Auditory Verbal Learning Test (AVLT) within 3 months of their scan. Baseline MRI's from the Alzheimer's disease Neuroimaging Initiative (ADNI) comprised the other dataset; 113 AD, 351 MCI, and 122 CN subjects completed the MMSE and Alzheimer's Disease Assessment Scale—Cognitive subtest (ADAS-cog) and 39 AD, 92 MCI, and 32 CN ADNI subjects completed MMSE, ADAS-cog, and AVLT. Predicted and actual clinical scores were highly correlated for the MMSE, DRS, and ADAS-cog tests (P<.0001). Training with one dataset and testing with another demonstrated stability between datasets. DRS, MMSE, and ADAS-Cog correlated better than AVLT with whole brain grey matter changes associated with AD. This result underscores their utility for screening and tracking disease. RVR offers a novel way to measure interactions between structural changes and neuropsychological tests beyond that of univariate methods. In clinical practice, we envision using RVR to aid in diagnosis and predict clinical outcome. PMID:20347044

  13. Withanolides: Biologically Active Constituents in the Treatment of Alzheimer's Disease.

    PubMed

    Khan, Shahid A; Khan, Sher B; Shah, Zarbad; Asiri, Abdullah M

    2016-01-01

    The use of natural products in drug discovery and development have an important history. Several therapeutic agents have been investigated during the biological screenings of natural compounds. It is well documented that plants are possibly the core of novel substances that led to the discovery of new, novel, and effective therapeutic agents. Therefore, in the last few decades, scientists were thoroughly attempting for the search of benevolent drugs to protect mankind from various diseases and discomforts. The diverse chemical structures of natural products are the key element of their success in modern drug discovery. Cholinesterase enzyme inhibitors (ChEI) are chemicals which inhibit the splitting of cholinesterase enzymes (acetylcholinesterase and butyrylcholinesterase). Acetyl cholinesterase (AChE) and butyrylcholinesterase (BChE) are two types of cholinesterase enzymes that have been identified in vertebrates that are responsible for Alzheimer's disease and related dementia. Withanolides are affective plant secondary metabolites which inhibit acetylcholinesterase and butyrylcholinesterase enzyme and thus possibly will be the future drug for Alzheimer's disease. By viewing the importance of natural products in drug discovery and development, we present here, the importance of withanolides in the treatment of Alzheimer's disease. In this article, we also describe the classification and structural characterization of withanolides. This review comprises of 114 compounds. PMID:26527154

  14. Mortality from Alzheimer's disease in Canada: A multiple-cause-of-death analysis, 2004 to 2011.

    PubMed

    Park, Jungwee

    2016-05-18

    Using multiple-cause-of-death data, this study investigates mortality from Alzheimer's disease. From 2004 through 2011, Alzheimer's disease was coded as a cause of 80,868 deaths-more often the underlying than a contributing cause. The rate of Alzheimer's disease deaths was higher for women and older individuals than for men and younger people, and varied considerably by province/territory. Regardless of whether Alzheimer's disease was coded as the underlying or a contributing cause, on average, two other causes were also listed on the death certificate. When Alzheimer's disease was the underlying cause, cardiovascular diseases were most often listed as a contributing cause; when Alzheimer's disease was a contributing cause, cardiovascular diseases were most often listed as the underlying cause. PMID:27192207

  15. Helping Family and Friends Understand Alzheimer's Disease

    MedlinePlus

    ... Alzheimer’s. You can: • Tell friends and family about Alzheimer’s disease and its effects. • Share articles, websites, and other information about the disease. • Tell them what they can do to help. Let them know you need ... has Alzheimer’s disease, it affects everyone in the family, including children ...

  16. High-resolution PET studies in Alzheimer's disease

    SciTech Connect

    Kumar, A.; Schapiro, M.B.; Grady, C.; Haxby, J.V.; Wagner, E.; Salerno, J.A.; Friedland, R.P.; Rapoport, S.I. )

    1991-01-01

    Forty-seven patients with probable dementia of the Alzheimer type (DAT) and 30 healthy age-matched controls were scanned using (18F)-2-fluoro-2-deoxy-D-glucose on a Scanditronix PC 1024-7B tomograph (inplane resolution = 6 mm, axial resolution = 10 mm). Patients and controls were scanned in the resting state with their eyes patched and ears occluded. The regional cerebral metabolic rates for glucose (rCMRglc) in most major neocortical and subcortical gray matter regions, and certain metabolic ratios (rCMRglc/ calcarine rCMRglc), quantitatively discriminated even the mildly demented patients from healthy controls. The association neocortices showed metabolic abnormalities that were more severe than those in the sensorimotor and calcarine regions. All demented groups showed significant neuropsychological disturbances when compared to healthy controls. These data demonstrated widespread metabolic disturbances, particularly in the association areas, relatively early in Alzheimer's disease, and more profound involvement with disease progression.

  17. Communicative function in patients with questionable Alzheimer's disease.

    PubMed

    Heller, R B; Dobbs, A R; Rule, B G

    1992-09-01

    The communicative skills of patients with questionable Alzheimer's disease (AD) were examined by having patients describe events shown in a silent video cartoon. As anticipated, questionable AD patients provided fewer clauses in their descriptions than did education- and age-matched controls. This finding was independent of differences in word finding ability. More important, the patients failed to describe as many of the thematically important events as did the controls, a difference that affected the overall informativeness of the communication. Even though the patients were sensitive to event importance, there was no evidence of compensation in their descriptions (i.e., a greater concentration of important events). Several interpretations are presented that focus on possible deficits in the pragmatic or semantic systems of language or both as an early symptom of Alzheimer's disease. PMID:1388860

  18. Galantamine: new preparation. The fourth cholinesterase inhibitor for Alzheimer's disease.

    PubMed

    2001-12-01

    (1) The reference symptomatic treatment for mild to moderate Alzheimer's disease is a cholinesterase inhibitor such as donepezil, but efficacy is only moderate and only about 10% of those patients treated actually benefit. (2) Galantamine is the fourth cholinesterase inhibitor to be marketed in France for Alzheimer's disease. The clinical file contains data from five double-blind placebo-controlled trials lasting 3-6 months, but no data comparing galantamine with other drugs. (3) These trials show that about 5-13% of patients treated with galantamine may be improved. (4) Adverse effects are very frequent, and are similar to those of other cholinesterase inhibitors, i.e. nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, etc. (5) For patients who are eligible for drug therapy, the reference treatment is still donepezil, for want of anything better. PMID:11824442

  19. Tibetan medicine “RNSP” in treatment of Alzheimer disease

    PubMed Central

    Shi, Jing-Ming; He, Xue; Lian, Hui-Juan; Yuan, Dong-Ya; Hu, Qun-Ying; Sun, Zheng-Qi; Li, Yan-Song; Zeng, Yu-Wen

    2015-01-01

    Alzheimer disease (Alzheimer Disease, AD) is one of the most common type in senile dementia. Its main pathological features were that a large number of senile plaques gathered in brain extracellular and tangles fibrosis appeared in nerve cells. Currently, the pathogenesis of AD is still uncertain, and scale investigation and combined brain CT, MRI data were analyzed mainly for clinical diagnosis. Mitigation and improvement of the nervous system activity to interfere with the subsequent behavior of the patients are the main methods for treatment. In clinical no drug can really prevent and cure AD. From the view point of Tibetan medicine studies, Tibetan medicine RNSP has effect on improving memory and repairing the neurons in the brain. In this study, we combined the characteristics of AD pathology, pathogenesis, diagnosis and treatment methods to explore the feasibility of Tibetan medicine RNSP for the treatment of AD to provide new ideas for the diagnosis and treatment of AD. PMID:26884898

  20. Challenges, solutions, and recommendations for Alzheimer's disease combination therapy.

    PubMed

    Hendrix, James A; Bateman, Randall J; Brashear, H Robert; Duggan, Cynthia; Carrillo, Maria C; Bain, Lisa J; DeMattos, Ronald; Katz, Russell G; Ostrowitzki, Susanne; Siemers, Eric; Sperling, Reisa; Vitolo, Ottavio V

    2016-05-01

    Given the complex neuropathology Alzheimer's disease (AD), combination therapy may be necessary for effective treatment. However, scientific, pragmatic, regulatory, and business challenges need to be addressed before combination therapy for AD can become a reality. Leaders from academia and industry, along with a former member of the Food and Drug Administration and the Alzheimer's Association, have explored these challenges and here propose a strategy to facilitate proof-of-concept combination therapy trials in the near future. First, a more integrated understanding of the complex pathophysiology and progression of AD is needed to identify the appropriate pathways and the disease stage to target. Once drug candidates are identified, novel clinical trial designs and selection of appropriate outcome assessments will be needed to enable definition and evaluation of the appropriate dose and dosing regimen and determination of efficacy. Success in addressing this urgent problem will only be achieved through collaboration among multiple stakeholders. PMID:27017906

  1. Alzheimer's Disease: Mechanism and Approach to Cell Therapy.

    PubMed

    Amemori, Takashi; Jendelova, Pavla; Ruzicka, Jiri; Urdzikova, Lucia Machova; Sykova, Eva

    2015-01-01

    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. PMID:26556341

  2. Modeling cost-effectiveness of pharmaceuticals in Alzheimer's disease.

    PubMed

    Oremus, Mark; Tarride, Jean-Eric

    2012-06-01

    Alzheimer's disease is a neurodegenerative disorder characterized by cognitive and behavioral deficits. Donepezil and memantine are two medications used to treat the symptoms of cognitive decline in Alzheimer's disease. A modeled cost-effectiveness analysis found that treatment with donepezil to be less costly and more effective than no treatment or treatment with memantine in Germany. However, the model drew on non-German population data and could have been more transparent with regard to 'back-end' processes. In addition, the authors would question the extent to which the differences in effectiveness between treatments would be considered clinically significant. Identifying sources of cost savings for donepezil remains an important issue for future consideration. PMID:22812550

  3. Criminal Behavior in Frontotemporal Dementia and Alzheimer Disease

    PubMed Central

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

    2015-01-01

    Importance Neurodegenerative diseases can cause dysfunction of neural structures involved in judgment, executive function, emotional processing, sexual behavior, violence, and self-awareness. Such dysfunctions can lead to antisocial and criminal behavior that appears for the first time in the adult or middle-aged individual or even later in life. Objective To investigate the frequency and type of criminal behavior among patients with a diagnosed dementing disorder. Design, Setting, and Participants We conducted a retrospective medical record review of 2397 patients who were seen at the University of California, San Francisco, Memory and Aging Center between 1999 and 2012, including 545 patients with Alzheimer disease (AD), 171 patients with behavioral variant of frontotemporal dementia (bvFTD), 89 patients with semantic variant of primary progressive aphasia, and 30 patients with Huntington disease. Patient notes containing specific keywords denoting criminal behavior were reviewed. Data were stratified by criminal behavior type and diagnostic groups. Main Outcomes and Measures Frequencies of criminal behavior and χ2 statistics were calculated. Results Of the 2397 patients studied, 204 (8.5%) had a history of criminal behavior that emerged during their illness. Of the major diagnostic groups, 42 of 545 patients (7.7%) with AD, 64 of 171 patients (37.4%) with bvFTD, 24 of 89 patients (27.0%) with semantic variant of primary progressive aphasia, and 6 of 30 patients (20%) with Huntington disease exhibited criminal behavior. A total of 14% of patients with bvFTD were statistically significantly more likely to present with criminal behavior compared with 2% of patients with AD (P < .001) and 6.4% were statistically significantly more likely to exhibit violence compared with 2% of patients with AD (P = .003). Common manifestations of criminal behavior in the bvFTD group included theft, traffic violations, sexual advances, trespassing, and public urination in contrast

  4. Cohort profile: the Finnish Medication and Alzheimer's disease (MEDALZ) study

    PubMed Central

    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

  5. Functional neuroanatomy of auditory scene analysis in Alzheimer's disease.

    PubMed

    Golden, Hannah L; Agustus, Jennifer L; Goll, Johanna C; Downey, Laura E; Mummery, Catherine J; Schott, Jonathan M; Crutch, Sebastian J; Warren, Jason D

    2015-01-01

    Auditory scene analysis is a demanding computational process that is performed automatically and efficiently by the healthy brain but vulnerable to the neurodegenerative pathology of Alzheimer's disease. Here we assessed the functional neuroanatomy of auditory scene analysis in Alzheimer's disease using the well-known 'cocktail party effect' as a model paradigm whereby stored templates for auditory objects (e.g., hearing one's spoken name) are used to segregate auditory 'foreground' and 'background'. Patients with typical amnestic Alzheimer's disease (n = 13) and age-matched healthy individuals (n = 17) underwent functional 3T-MRI using a sparse acquisition protocol with passive listening to auditory stimulus conditions comprising the participant's own name interleaved with or superimposed on multi-talker babble, and spectrally rotated (unrecognisable) analogues of these conditions. Name identification (conditions containing the participant's own name contrasted with spectrally rotated analogues) produced extensive bilateral activation involving superior temporal cortex in both the AD and healthy control groups, with no significant differences between groups. Auditory object segregation (conditions with interleaved name sounds contrasted with superimposed name sounds) produced activation of right posterior superior temporal cortex in both groups, again with no differences between groups. However, the cocktail party effect (interaction of own name identification with auditory object segregation processing) produced activation of right supramarginal gyrus in the AD group that was significantly enhanced compared with the healthy control group. The findings delineate an altered functional neuroanatomical profile of auditory scene analysis in Alzheimer's disease that may constitute a novel computational signature of this neurodegenerative pathology. PMID:26029629

  6. Functional neuroanatomy of auditory scene analysis in Alzheimer's disease

    PubMed Central

    Golden, Hannah L.; Agustus, Jennifer L.; Goll, Johanna C.; Downey, Laura E.; Mummery, Catherine J.; Schott, Jonathan M.; Crutch, Sebastian J.; Warren, Jason D.

    2015-01-01

    Auditory scene analysis is a demanding computational process that is performed automatically and efficiently by the healthy brain but vulnerable to the neurodegenerative pathology of Alzheimer's disease. Here we assessed the functional neuroanatomy of auditory scene analysis in Alzheimer's disease using the well-known ‘cocktail party effect’ as a model paradigm whereby stored templates for auditory objects (e.g., hearing one's spoken name) are used to segregate auditory ‘foreground’ and ‘background’. Patients with typical amnestic Alzheimer's disease (n = 13) and age-matched healthy individuals (n = 17) underwent functional 3T-MRI using a sparse acquisition protocol with passive listening to auditory stimulus conditions comprising the participant's own name interleaved with or superimposed on multi-talker babble, and spectrally rotated (unrecognisable) analogues of these conditions. Name identification (conditions containing the participant's own name contrasted with spectrally rotated analogues) produced extensive bilateral activation involving superior temporal cortex in both the AD and healthy control groups, with no significant differences between groups. Auditory object segregation (conditions with interleaved name sounds contrasted with superimposed name sounds) produced activation of right posterior superior temporal cortex in both groups, again with no differences between groups. However, the cocktail party effect (interaction of own name identification with auditory object segregation processing) produced activation of right supramarginal gyrus in the AD group that was significantly enhanced compared with the healthy control group. The findings delineate an altered functional neuroanatomical profile of auditory scene analysis in Alzheimer's disease that may constitute a novel computational signature of this neurodegenerative pathology. PMID:26029629

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

    PubMed

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

    2013-03-01

    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 compare the affective processing in 12 people with mild Alzheimer's disease and 12 matched controls. The main finding was that the clinical participants showed reduced activations in regions associated with the motor simulation system (the ventral premotor cortex) and in regions associated with emotional simulation-empathy (the anterior insula and adjacent frontal operculum). This regional decline in blood oxygen level-dependent signals appeared to be lateralized in the left hemisphere and was not related to any structural degeneration in the clinical participants. Furthermore, the regions that showed changes in neural activity differed for the 3 emotional facial expressions studied. Findings of our study indicate that neural changes in regions associated with the motor and emotional simulation systems might play an important role in the development of Alzheimer's disease. PMID:22840336

  8. The clinical use of structural MRI in Alzheimer disease

    PubMed Central

    Frisoni, Giovanni B.; Fox, Nick C.; Jack, Clifford R.; Scheltens, Philip; Thompson, Paul M.

    2010-01-01

    Structural imaging based on magnetic resonance is an integral part of the clinical assessment of patients with suspected Alzheimer dementia. Prospective data on the natural history of change in structural markers from preclinical to overt stages of Alzheimer disease are radically changing how the disease is conceptualized, and will influence its future diagnosis and treatment. Atrophy of medial temporal structures is now considered to be a valid diagnostic marker at the mild cognitive impairment stage. Structural imaging is also included in diagnostic criteria for the most prevalent non-Alzheimer dementias, reflecting its value in differential diagnosis. In addition, rates of whole-brain and hippocampal atrophy are sensitive markers of neurodegeneration, and are increasingly used as outcome measures in trials of potentially disease-modifying therapies. Large multicenter studies are currently investigating the value of other imaging and nonimaging markers as adjuncts to clinical assessment in diagnosis and monitoring of progression. The utility of structural imaging and other markers will be increased by standardization of acquisition and analysis methods, and by development of robust algorithms for automated assessment. PMID:20139996

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

    NASA Astrophysics Data System (ADS)

    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.

  10. Cerebral correlates of psychotic symptoms in Alzheimer's disease

    PubMed Central

    Mega, M.; Lee, L.; Dinov, I.; Mishkin, F.; Toga, A.; Cummings, J.

    2000-01-01

    BACKGROUND—Psychotic symptoms are produced by distributed neuronal dysfunction. Abnormalities of reality testing and false inference implicate frontal lobe abnormalities.
OBJECTIVES—To identify the functional imaging profile of patients with Alzheimer's disease manifesting psychotic symptoms as measured by single photon emission computed tomography (SPECT).
METHODS—Twenty patients with Alzheimer's disease who had SPECT and clinical evaluations were divided into two equal groups with similar mini mental status examination (MMSE), age, sex, and the range of behaviours documented by the neuropsychiatric inventory (NPI), except delusions and hallucinations. SPECT studies, registered to a probabilistic anatomical atlas, were normalised across the combined group mean intensity level, and subjected to a voxel by voxel subtraction of the non-psychotic minus psychotic groups. Subvolume thresholding (SVT) corrected random lobar noise to produce a three dimensional functional significance map.
RESULTS—The significance map showed lower regional perfusion in the right and left dorsolateral frontal, left anterior cingulate, and left ventral striatal regions along with the left pulvinar and dorsolateral parietal cortex, in the psychotic versus non-psychotic group.
CONCLUSION—Patients with Alzheimer's disease who manifest psychosis may have disproportionate dysfunction of frontal lobes and related subcortical and parietal structures.

 PMID:10896687

  11. Regulation of gamma-Secretase in Alzheimer's Disease

    SciTech Connect

    Zhou, Shuxia; Zhou, Hua; Walian, Peter; Jap, Bing

    2007-02-07

    The {gamma}-secretase complex is an intramembrane aspartyl protease that cleaves its substrates along their transmembrane regions. Sequential proteolytic processing of amyloid precursor protein by {beta}- and {gamma}-secretase produces amyloid {beta}-peptides, which are the major components of amyloid plaques in the brains of Alzheimer's disease patients. The {gamma}-secretase complex is therefore believed to be critical in the pathogenesis of Alzheimer's disease. Here we review the range of factors found to affect the nature and degree of {gamma}-secretase complex activity; these include {gamma}-secretase complex assembly and activation, the integral regulatory subunit CD147, transient or weak binding partners, the levels of cholesterol and sphingolipids in cell membranes, and inflammatory cytokines. Integrated knowledge of the molecular mechanisms supporting the actions of these factors is expected to lead to a comprehensive understanding of the functional regulation of the {gamma}-secretase complex, and this, in turn, should facilitate the development of novel therapeutic strategies for the treatment of Alzheimer's disease.

  12. Directed network motifs in Alzheimer's disease and mild cognitive impairment.

    PubMed

    Friedman, Eric J; Young, Karl; Tremper, Graham; Liang, Jason; Landsberg, Adam S; Schuff, Norbert

    2015-01-01

    Directed network motifs are the building blocks of complex networks, such as human brain networks, and capture deep connectivity information that is not contained in standard network measures. In this paper we present the first application of directed network motifs in vivo to human brain networks, utilizing recently developed directed progression networks which are built upon rates of cortical thickness changes between brain regions. This is in contrast to previous studies which have relied on simulations and in vitro analysis of non-human brains. We show that frequencies of specific directed network motifs can be used to distinguish between patients with Alzheimer's disease (AD) and normal control (NC) subjects. Especially interesting from a clinical standpoint, these motif frequencies can also distinguish between subjects with mild cognitive impairment who remained stable over three years (MCI) and those who converted to AD (CONV). Furthermore, we find that the entropy of the distribution of directed network motifs increased from MCI to CONV to AD, implying that the distribution of pathology is more structured in MCI but becomes less so as it progresses to CONV and further to AD. Thus, directed network motifs frequencies and distributional properties provide new insights into the progression of Alzheimer's disease as well as new imaging markers for distinguishing between normal controls, stable mild cognitive impairment, MCI converters and Alzheimer's disease. PMID:25879535

  13. Positron emission tomography in patients with clinically diagnosed Alzheimer's disease.

    PubMed Central

    McGeer, P L; Kamo, H; Harrop, R; Li, D K; Tuokko, H; McGeer, E G; Adam, M J; Ammann, W; Beattie, B L; Calne, D B

    1986-01-01

    Fourteen patients who had clinically diagnosed Alzheimer's disease with mild to severe dementia (mean age 69.1 years) were evaluated by calculation of local cerebral metabolic rate for glucose (LCMR-gl) based on uptake of 18F-2-fluoro-2-deoxyglucose (FDG) detected with positron emission tomography (PET). PET scanning showed that the patients had significantly lower LCMR-gl values than 11 age-matched neurologically normal volunteers (mean age 66.3 years). The differences were most marked in the temporal cortex, followed by the frontal, parietal and occipital cortex. In each case the LCMR-gl value was below the lowest control value in at least one cortical area and usually in several; the reduction in LCMR-gl and the number of regions involved in the patients increased with the severity of the dementia. Deficits noted in neuropsychologic testing generally correlated with those predicted from loss of regional cortical metabolism. The patients with Alzheimer's disease were also examined with magnetic resonance imaging, computed tomography or both; the degree of atrophy found showed only a poor correlation with the neuropsychologic deficit. Significant atrophy was also noted in some of the controls. A detailed analysis of LCMR-gl values in selected cerebral regions of various sizes refuted the hypothesis that the reduction in cortical glucose metabolism in Alzheimer's disease is due to the filling by metabolically inert cerebrospinal fluid of space created by tissue atrophy. Images Fig. 2 Fig. 3 Fig. 4 Fig. 7 Fig. 8 Fig. 9 PMID:3512063

  14. Dynamic self-guiding analysis of Alzheimer's disease

    PubMed Central

    Kurakin, Alexei; Bredesen, Dale E.

    2015-01-01

    We applied a self-guiding evolutionary algorithm to initiate the synthesis of the Alzheimer's disease-related data and literature. A protein interaction network associated with amyloid-beta precursor protein (APP) and a seed model that treats Alzheimer's disease as progressive dysregulation of APP-associated signaling were used as dynamic “guides” and structural “filters” in the recursive search, analysis, and assimilation of data to drive the evolution of the seed model in size, detail, and complexity. Analysis of data and literature across sub-disciplines and system-scale discovery platforms suggests a key role of dynamic cytoskeletal connectivity in the stability, plasticity, and performance of multicellular networks and architectures. Chronic impairment and/or dysregulation of cell adhesions/synapses, cytoskeletal networks, and/or reversible epithelial-to-mesenchymal-like transitions, which enable and mediate the stable and coherent yet dynamic and reconfigurable multicellular architectures, may lead to the emergence and persistence of the disordered, wound-like pockets/microenvironments of chronically disconnected cells. Such wound-like microenvironments support and are supported by pro-inflammatory, pro-secretion, de-differentiated cellular phenotypes with altered metabolism and signaling. The co-evolution of wound-like microenvironments and their inhabitants may lead to the selection and stabilization of degenerated cellular phenotypes, via acquisition of epigenetic modifications and mutations, which eventually result in degenerative disorders such as cancer and Alzheimer's disease. PMID:26041885

  15. [Cognitive plasticity in Alzheimer's disease patients receiving cognitive stimulation programs].

    PubMed

    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. PMID:18674439

  16. An EEG-Based Fuzzy Probability Model for Early Diagnosis of Alzheimer's Disease.

    PubMed

    Chiang, Hsiu-Sen; Pao, Shun-Chi

    2016-05-01

    Alzheimer's disease is a degenerative brain disease that results in cardinal memory deterioration and significant cognitive impairments. The early treatment of Alzheimer's disease can significantly reduce deterioration. Early diagnosis is difficult, and early symptoms are frequently overlooked. While much of the literature focuses on disease detection, the use of electroencephalography (EEG) in Alzheimer's diagnosis has received relatively little attention. This study combines the fuzzy and associative Petri net methodologies to develop a model for the effective and objective detection of Alzheimer's disease. Differences in EEG patterns between normal subjects and Alzheimer patients are used to establish prediction criteria for Alzheimer's disease, potentially providing physicians with a reference for early diagnosis, allowing for early action to delay the disease progression. PMID:27059738

  17. Liposomes for Targeted Delivery of Active Agents against Neurodegenerative Diseases (Alzheimer's Disease and Parkinson's Disease)

    PubMed Central

    Spuch, Carlos; Navarro, Carmen

    2011-01-01

    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. PMID:22203906

  18. Clinical Features of Alzheimer Disease With and Without Lewy Bodies

    PubMed Central

    Chung, Eun Joo; Babulal, Ganesh M.; Monsell, Sarah E.; Cairns, Nigel J.; Roe, Catherine M.; Morris, John C.

    2015-01-01

    IMPORTANCE Lewy bodies are a frequent coexisting pathology in late-onset Alzheimer disease (AD). Previous studies have examined the contribution of Lewy bodies to the clinical phenotype of late-onset AD with variable findings. OBJECTIVE To determine whether the presence of Lewy body pathology influences the clinical phenotype and progression of symptoms in longitudinally assessed participants with AD. DESIGN, SETTING, AND PARTICIPANTS Retrospective clinical and pathological cohort study of 531 deceased participants who met the neuropathologic criteria for intermediate or high likelihood of AD according to the National Institute on Aging–Ronald Reagan Institute guidelines for the neuropathologic diagnosis of AD. All participants had a clinical assessment within 2 years of death. The data were obtained from 34 AD centers maintained by the National Alzheimer Coordinating Center and spanned from September 12, 2005, to April 30, 2013. EXPOSURES Standardized neuropathologic assessment and then brain autopsy after death. MAIN OUTCOMES AND MEASURES Clinical and neuropsychiatric test scores. RESULTS The mean (SD) age at death was statistically significantly younger for participants who had AD with Lewy bodies (77.9 [9.5] years) than for participants who had AD without Lewy bodies (80.2 [11.1] years) (P = .01). The mean (SD) age at onset of dementia symptoms was also younger for participants who had AD with Lewy bodies (70.0 [9.9] years) than for participants who had AD without Lewy bodies (72.2 [12.3] years) (P = .03). More men than women had AD with Lewy bodies (P = .01). The frequency of having at least 1 APOE ε4 allele was higher for participants who had AD with Lewy bodies than for participants who had AD without Lewy bodies (P = .03). After adjusting for age, sex, education, frequency of plaques (neuritic and diffuse), and tangle stage, we found that participants who had AD with Lewy bodies had a statistically significantly higher mean (SD) Neuropsychiatric

  19. 3 CFR 8591 - Proclamation 8591 of October 29, 2010. National Alzheimer's Disease Awareness Month, 2010

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... disease. As we continue our fight against Alzheimer’s disease, we must seek new ways to prevent, delay... Alzheimer's Disease Awareness Month, 2010 8591 Proclamation 8591 Presidential Documents Proclamations Proclamation 8591 of October 29, 2010 Proc. 8591 National Alzheimer's Disease Awareness Month, 2010By...

  20. A diagnostic approach in Alzheimer`s disease using three-dimensional stereotactic surface projections of Fluorine-18-FDG PET

    SciTech Connect

    Minoshima, S.; Frey, K.A.; Koeppe, R.A.

    1995-07-01

    To improve the diagnostic performance of PET as an aid in evaluating patients suspected of having Alzheimer`s disease, the authors developed a fully automated method which generates comprehensive image presentations and objective diagnostic indices. Fluorine-18-fluorodeoxyglucose PET image sets were collected from 37 patients with probable Alzheimer`s disease (including questionable and mild dementia), 22 normal subjects and 5 patients with cerebrovascular disease. Following stereotactic anatomic standardization, metabolic activity on an individual`s PET image set was extracted to a set of predefined surface pixels (three-dimensional stereotactic surface projection, 3D-SSP), which was used in the subsequent analysis. A normal database was created by averaging extracted datasets of the normal subjects. Patients` datasets were compared individually with the normal database by calculating a Z-score on a pixel-by-pixel basis and were displayed in 3D-SSP views for visual inspections. Diagnostic indices were then generated based on averaged Z-scores for the association cortices. Patterns and severities of metabolic reduction in patients with probable Alzheimer`s disease were seen in the standard 3D-SSP views of extracted raw data and statistical Z-scores. When discriminating patients with probable Alzheimer`s disease from normal subjects, diagnostic indices of the parietal association cortex and unilaterally averaged parietal-temporal-frontal cortex showed sensitivities of 95% and 97%, respectively, with a specificity of 100%. Neither index yielded false-positive results for cerebrovascular disease. 3D-SSP enables quantitative data extraction and reliable localization of metabolic abnormalities by means of stereotactic coordinates. The proposed method is a promising approach for interpreting functional brain PET scans. 45 refs., 5 figs.

  1. Boosting brain connectome classification accuracy in Alzheimer's disease using higher-order singular value decomposition

    PubMed Central

    Zhan, Liang; Liu, Yashu; Wang, Yalin; Zhou, Jiayu; Jahanshad, Neda; Ye, Jieping; Thompson, Paul M.

    2015-01-01

    Alzheimer's disease (AD) is a progressive brain disease. Accurate detection of AD and its prodromal stage, mild cognitive impairment (MCI), are crucial. There is also a growing interest in identifying brain imaging biomarkers that help to automatically differentiate stages of Alzheimer's disease. Here, we focused on brain structural networks computed from diffusion MRI and proposed a new feature extraction and classification framework based on higher order singular value decomposition and sparse logistic regression. In tests on publicly available data from the Alzheimer's Disease Neuroimaging Initiative, our proposed framework showed promise in detecting brain network differences that help in classifying different stages of Alzheimer's disease. PMID:26257601

  2. Mitochondrial DNA sequence analysis of four Alzheimer`s and Parkinson`s disease patients

    SciTech Connect

    Brown, M.D.; Shoffner, J.M.; Wallace, D.C.

    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. Mechanisms of Acupuncture Effect on Alzheimer's Disease in Animal- Based Researches.

    PubMed

    Cao, Yan; Zhang, Li-Wen; Wang, Jian; Du, Si-Qi; Xiao, Ling-Yong; Tu, Jian-Feng; Liu, Cun-Zhi

    2016-01-01

    Alzheimer's disease is the most common type of dementia in the aging population worldwide. The etiology and treatment of Alzheimer's disease are still not very clear. Finding a new treatment is urgent due to the increasing population aging. Acupuncture has been practicing in China for more than 3000 years and reported to be beneficial in treating cognitive impairment of Alzheimer's disease. This paper reviews the recent development on the effect of acupuncture on Alzheimer's disease in animal-based researches. It is suggested that acupuncture improves cognitive function of Alzheimer's disease by regulating glucose metabolism, enhancing neurotransmission as well as reducing oxidative stress, Aβ protein deposition, and neuronal apoptosis. However, it is still difficult to clarify which specific signaling pathway contributes to the acupuncture effect. Better designed studies are recommended to investigate the effects of acupuncture on Alzheimer's disease. PMID:26268326

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

    PubMed Central

    Hölscher, Christian

    2014-01-01

    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. PMID:25558231

  5. New Genes Tied to Alzheimer's Disease

    MedlinePlus

    ... disease, including the immune response, inflammation, cellular protein trafficking, and lipid transport. They also add to evidence ... Loss in Cancer Epigenetic Clock Marks Age of Human Tissues and Cells Connect with Us Subscribe to ...

  6. CAP--advancing the evaluation of preclinical Alzheimer disease treatments.

    PubMed

    Reiman, Eric M; Langbaum, Jessica B; Tariot, Pierre N; Lopera, Francisco; Bateman, Randall J; Morris, John C; Sperling, Reisa A; Aisen, Paul S; Roses, Allen D; Welsh-Bohmer, Kathleen A; Carrillo, Maria C; Weninger, Stacie

    2016-01-01

    If we are to find treatments to postpone, reduce the risk of, or completely prevent the clinical onset of Alzheimer disease (AD), we need faster methods to evaluate promising preclinical AD treatments, new ways to work together in support of common goals, and a determination to expedite the initiation and performance of preclinical AD trials. In this article, we note some of the current challenges, opportunities and emerging strategies in preclinical AD treatment. We describe the Collaboration for Alzheimer's Prevention (CAP)-a convening, harmonizing and consensus-building initiative to help stakeholders advance AD prevention research with rigour, care and maximal impact-and we demonstrate the impact of CAP on the goals and design of new preclinical AD trials. PMID:26416539

  7. Is amyloid beta-protein glycated in Alzheimer's disease?

    PubMed

    Tabaton, M; Perry, G; Smith, M; Vitek, M; Angelini, G; Dapino, D; Garibaldi, S; Zaccheo, D; Odetti, P

    1997-03-01

    Recent data suggest that protein glycation is involved in the process of amyloid formation in Alzheimer's disease (AD). To further investigate this issue, we analyzed the presence of advanced glycation end products (AGE) in soluble and insoluble forms of amyloid beta-protein (A beta) as well as in apolipoprotein E (apoE), a protein bound to amyloid deposits. Both proteins were extracted from cerebral cortex obtained from patients with AD and probed by immunoblotting with two antibodies specific for different AGE, already known to immunocytochemically label amyloid plaques. All the AGE antibodies failed to recognize either A beta or apoE, whereas they reacted with synthetic A beta glycated in vitro. These findings indicate that other proteins associated with amyloid deposits are candidates to be modified with AGE in Alzheimer's cerebral tissue. PMID:9141062

  8. The importance of being apt: metaphor comprehension in Alzheimer's disease

    PubMed Central

    Roncero, Carlos; de Almeida, Roberto G.

    2014-01-01

    We investigated the effect of aptness in the comprehension of copular metaphors (e.g., Lawyers are sharks) by Alzheimer's Disease (AD) patients. Aptness is the extent to which the vehicle (e.g., shark) captures salient properties of the topic (e.g., lawyers). A group of AD patients provided interpretations for metaphors that varied both in aptness and familiarity. Compared to healthy controls, AD patients produced worse interpretations, but interpretation ability was related to a metaphor's aptness rather than to its familiarity level, and patients with superior abstraction ability produced better interpretations. Therefore, the ability to construct figurative interpretations for metaphors is not always diminished in AD patients nor is it dependent only on the novelty level of the expression. We show that Alzheimer's patients' capacity to build figurative interpretations for metaphors is related to both item variables, such as aptness, and participant variables, such as abstraction ability. PMID:25520642

  9. Stroke risk interacts with Alzheimer's disease biomarkers on brain aging outcomes.

    PubMed

    Hohman, Timothy J; Samuels, Lauren R; Liu, Dandan; Gifford, Katherine A; Mukherjee, Shubhabrata; Benson, Elleena M; Abel, Ty; Ruberg, Frederick L; Jefferson, Angela L

    2015-09-01

    Alzheimer's disease (AD) biomarkers and stroke risk factors independently predict cognitive impairment, likely through independent disease pathways. However, limited work has sought to describe the dynamic interplay between these important risk factors. This article evaluated the interaction between stroke risk and AD biomarkers on hippocampal volume and cognitive performance. We first evaluated the interaction between stroke risk factors and AD biomarkers using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1202). We then extended our findings to an independent autopsy data set from the National Alzheimer's Coordinating Center (NACC, n = 1122) using measures of AD pathology. Stroke risk was quantified using the Framingham Stroke Risk Profile. In ADNI, stroke risk interacted with tau and amyloid levels in relation to baseline and longitudinal cognitive performance. Similarly, in NACC, stroke risk interacted with amyloid and tau positivity on cognitive performance. The effect of stroke risk factors on cognition was strongest in the absence of AD biomarkers or neuropathology, providing additional evidence that AD biomarkers and stroke risk factors relate to cognition through independent pathways. PMID:26119224

  10. Alzheimer's disease: Unique markers for diagnosis & new treatment modalities

    PubMed Central

    Aggarwal, Neelum T.; Shah, Raj C.; Bennett, David A.

    2015-01-01

    Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease. In humans, AD becomes symptomatic only after brain changes occur over years or decades. Three contiguous phases of AD have been proposed: (i) the AD pathophysiologic process, (ii) mild cognitive impairment due to AD, and (iii) AD dementia. Intensive research continues around the world on unique diagnostic markers and interventions associated with each phase of AD. In this review, we summarize the available evidence and new therapeutic approaches that target both amyloid and tau pathology in AD and discuss the biomarkers and pharmaceutical interventions available and in development for each AD phase. PMID:26609028

  11. Genome-wide profiling of alternative splicing in Alzheimer's disease

    PubMed Central

    Lai, Mitchell K.P.; Esiri, Margaret M.; Tan, Michelle G.K.

    2014-01-01

    Alternative splicing is a highly regulated process which generates transcriptome and proteome diversity through the skipping or inclusion of exons within gene loci. Identification of aberrant alternative splicing associated with human diseases has become feasible with the development of new genomic technologies and powerful bioinformatics. We have previously reported genome-wide gene alterations in the neocortex of a well-characterized cohort of Alzheimer's disease (AD) patients and matched elderly controls using a commercial exon microarray platform [1]. Here, we provide detailed description of analyses aimed at identifying differential alternative splicing events associated with AD. PMID:26484111

  12. Current concepts in Alzheimer's Disease: molecules, models and translational perspectives.

    PubMed

    Rutten, Bart P F; Steinbusch, Harry W M

    2013-01-01

    The field of neuroscience research in AD has been evolving rapidly over the last few years, and has pinpointed a number of candidate targets for molecules with crucial role in the pathophysiology of AD. Recent developments have furthermore enabled new ways of modeling the disease, while an increasing number of preclinically validated targets is currently being taken one step forward and tested in clinical trials. These recent developments are reviewed in the current Special Issues Series on "Current concepts in Alzheimer's disease research: molecules, models and translational perspectives" in a number of state-of-the-art manuscripts. PMID:24148188

  13. Clinical Trial Design Issues in Mild to Moderate Alzheimer Disease

    PubMed Central

    Knopman, David S.

    2009-01-01

    The field of clinical trials and therapeutics in Alzheimer Disease (AD) is little more than 20 years old. Considerable progress has been made in crafting appropriate designs for clinical trials of promising therapeutic agents for AD. This article reviews basic issues in diagnostic criteria, choice of outcome measures, duration of trials and analytic strategies. Through trial and error, a general set of strategies has evolved for the assessment of putative therapies for mild to moderate AD. The experience of the past two decades has set the stage for discovering the next generation of anti-AD drugs and introducing those therapies at milder stages of the disease. PMID:19057167

  14. Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women.

    PubMed Central

    Payami, H.; Zareparsi, S.; Montee, K. R.; Sexton, G. J.; Kaye, J. A.; Bird, T. D.; Yu, C. E.; Wijsman, E. M.; Heston, L. L.; Litt, M.; Schellenberg, G. D.

    1996-01-01

    Late-onset Alzheimer disease (AD) is associated with the apolipoprotein E (APOE)-epsilon4 allele. In late-onset familial AD, women have a significantly higher risk of developing the disease than do men. The aim of this study was to determine whether the gender difference in familial AD is a function of APOE genotype. We studied 58 late-onset familial AD kindreds. Kaplan-Meier survival analysis was used to assess genotype-specific distributions of age at onset. Odds ratios were estimated by logistic regression with adjustment for age and by conditional logistic regression with stratification on families. All methods detected a significant gender difference for the epsilon4 heterozygous genotype. In women, epsilon4 heterozygotes had higher risk than those without epsilon4; there was no significant difference between epsilon4 heterozygotes and epsilon4 homozygotes. In men, epsilon4 heterozygotes had lower risk than epsilon4 homozygotes; there was not significant difference between epsilon4 heterozygotes and those without epsilon4. A direct comparison of epsilon4 heterozygous men and women revealed a significant twofold increased risk in women. We confirmed these results in 15 autopsy-confirmed AD kindreds from the National Cell Repository at Indiana University Alzheimer Disease Center. These observations are consistent with the increased incidence of familial AD in women and may be a critical clue to the role of gender in the pathogenesis of AD. PMID:8644745

  15. Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: A possible clue to the higher incidence of Alzheimer disease in women

    SciTech Connect

    Payami, H.; Zareparsi, S.; Montee, K.R.; Litt, M.

    1996-04-01

    Late-onset Alzheimer disease (AD) is associated with the apolipoprotein E (APOE)-{epsilon}4 allele. In late-onset familial AD, women have a significantly higher risk of developing the disease than do men. The aim of this study was to determine whether the gender difference in familial AD is a function of APOE genotype. We studied 58 late-onset familial AD kindreds. Kaplan-Meier survival analysis was used to assess genotype-specific distributions of age at onset. Odds ratios were estimated by logistic regression with adjustment for age and by conditional logistic regression with stratification on families. All methods detected a significant gender difference for the {epsilon}4 heterozygous genotype. In women, {epsilon}4 heterozygotes had higher risk than those without {epsilon}4; there was no significant difference between {epsilon}4 heterozygotes and {epsilon}4 homozygotes. In men, {epsilon}4 heterozygotes had lower risk than {epsilon}4 homozygotes; there was no significant difference between {epsilon}4 heterozygotes and those without {epsilon}4. A direct comparison of {epsilon}4 heterozygous men and women revealed a significant two-fold increased risk in women. We confirmed these results in 15 autopsy-confirmed AD kindreds from the National Cell Repository at Indiana University Alzheimer Disease Center. These observations are consistent with the increased incidence of familial AD in women and may be a critical clue to the role of gender in the pathogenesis of AD. 53 refs., 2 figs., 2 tabs.

  16. Allele doses of apolipoprotein E type {epsilon}4 in sporadic late-onset Alzheimer`s disease

    SciTech Connect

    Lucotte, G.; Aouizerate, A.; Gerard, N.

    1995-12-18

    Apoliprotein E, type {epsilon}4 allele (ApoE-{epsilon}4) is associated with late-onset sporadic Alzheimer`s disease (AD). We have found that the cumulative probability of remaining unaffected over time decreases for each dose of ApoE-{epsilon}4 in sporadic, late-onset French AD. The effect of genotypes on age at onset of AD was analyzed using the product limit method, to compare unaffected groups during aging. 26 refs., 2 figs., 1 tab.

  17. [Nutritional factors in prevention of Alzheimer's disease].

    PubMed

    Wyka, Joanna

    2012-01-01

    Nutritional patterns affect significantly man's body at each age. The elderly--with their eating habits and diseases they have overcome--often require specific dietary intervention. A proper and well-balanced diet is an important element of lifestyle that may become a factor facilitating the so-called healthy, successful ageing and delay the development of noninfectious, chronic metabolic diseases that are in majority of cases diagnosed in elder people. Neurodegenerative diseases have been classified amongst chronic diseases yet with still controversial etiology. Nevertheless, it is speculated that some nutritional factors, including the appropriate intake of B-group vitamins, antioxidative vitamins and polyunsaturated fatty acids, are likely to play a significant role in their prevention and therapy. A diet rich in vegetables and fruits, whole-meal bread, milk and dairy products as well as containing fish, plant oils and nuts provides all indispensable nutrients. The appropriate merging of these food products into dishes--widely described in literature as the Mediterranean diet--facilitates leading a long life in health. PMID:22928359

  18. The development of new therapeutics for Alzheimer's disease.

    PubMed

    Carter, M D; Simms, G A; Weaver, D F

    2010-10-01

    Existing treatments for Alzheimer's disease (AD) fail to address the underlying pathology of the disease; they merely provide short-lived symptomatic relief. Consequently, the progression of AD is unrelenting, leading to a continual decrease in cognitive abilities. Recent advances in understanding the genetic factors that predispose to AD, as well as in biomarker development, have brought with them the promise of earlier and more reliable diagnosis of this disease. As improvements continue to be made in these areas, the shortcomings of current AD treatments appear all the more acute because opportunities for early intervention are hindered by a lack of "curative" or even disease-modifying drugs. This State of the Art report reviews existing AD therapeutics and highlights recent progress made in the design and development of drugs that are aimed at disrupting AD disease progression by inhibition of the protein misfolding of β-amyloid (Aβ) into neurotoxic oligomeric aggregates. PMID:20811351

  19. Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

    PubMed

    Dubois, Bruno; Hampel, Harald; Feldman, Howard H; Scheltens, Philip; Aisen, Paul; Andrieu, Sandrine; Bakardjian, Hovagim; Benali, Habib; Bertram, Lars; Blennow, Kaj; Broich, Karl; Cavedo, Enrica; Crutch, Sebastian; Dartigues, Jean-François; Duyckaerts, Charles; Epelbaum, Stéphane; Frisoni, Giovanni B; Gauthier, Serge; Genthon, Remy; Gouw, Alida A; Habert, Marie-Odile; Holtzman, David M; Kivipelto, Miia; Lista, Simone; Molinuevo, José-Luis; O'Bryant, Sid E; Rabinovici, Gil D; Rowe, Christopher; Salloway, Stephen; Schneider, Lon S; Sperling, Reisa; Teichmann, Marc; Carrillo, Maria C; Cummings, Jeffrey; Jack, Cliff R

    2016-03-01

    During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations. PMID:27012484

  20. Clinical features of early onset, familial Alzheimer`s disease linked to chromosome 14

    SciTech Connect

    Mullan, M.; Bennett, C.; Figueredo, C.; Crawford, F.

    1995-02-27

    Early onset familial Alzheimer`s disease (AD) has an autosomal dominant mode of inheritance. Two genes are responsible for the majority of cases of this subtype of AD. Mutations in the {beta}-amyloid precursor protein ({beta}APP) gene on chromosome 21 have been shown to completely cosegregate with the disease. We and others have previously described the clinical features of families with {beta}APP mutations at the codon 717 locus in an attempt to define the phenotype associated with a valine to isoleucine (Val {r_arrow} Ile) or a valine to glycine (Val {r_arrow} Gly) change. More recently, a second locus for very early onset disease has been localized to chromosome 14. The results of linkage studies in some families suggesting linkage to both chromosomes have been explained by the suggestion of a second (centromeric) locus on chromosome 21. Here we report the clinical features and genetic analysis of a British pedigree (F74) with early onset AD in which neither the {beta}APP locus nor any other chromosome 21 locus segregates with the disease, but in which good evidence is seen for linkage on the long arm of chromosome 14. In particular we report marker data suggesting that the chromosome 14 disease locus is close to D14S43 and D14S77. Given the likelihood that F74 represents a chromosome 14 linked family, we describe the clinical features and make a limited clinical comparison with the {beta}APP717 Val {r_arrow} Ile and {beta}APP717 Val {r_arrow} Gly encoded families that have been previously described. We conclude that although several previously reported clinical features occur to excess in early onset familial AD, no single clinical feature demarcates either the chromosome 14 or {beta}APP codon 717 mutated families except mean age of onset. 52 refs., 2 figs., 5 tabs.