Sample records for early alzheimer disease

  1. Early-onset Alzheimer's Disease Phenotypes: Neuropsychology and Neural Networks

    ClinicalTrials.gov

    2017-05-11

    Alzheimer Disease, Early Onset; Alzheimer Disease; Alzheimer Disease, Late Onset; Dementia, Alzheimer Type; Logopenic Progressive Aphasia; Primary Progressive Aphasia; Visuospatial/Perceptual Abilities; Posterior Cortical Atrophy; Executive Dysfunction; Corticobasal Degeneration; Ideomotor Apraxia

  2. Biomarkers for early detection of Alzheimer disease.

    PubMed

    Barber, Robert C

    2010-09-01

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

  3. Functional neuroanatomical associations of working memory in early-onset Alzheimer's disease.

    PubMed

    Kobylecki, Christopher; Haense, Cathleen; Harris, Jennifer M; Stopford, Cheryl L; Segobin, Shailendra H; Jones, Matthew; Richardson, Anna M T; Gerhard, Alexander; Anton-Rodriguez, José; Thompson, Jennifer C; Herholz, Karl; Snowden, Julie S

    2018-01-01

    To characterize metabolic correlates of working memory impairment in clinically defined subtypes of early-onset Alzheimer's disease. Established models of working memory suggest a key role for frontal lobe function, yet the association in Alzheimer's disease between working memory impairment and visuospatial and language symptoms suggests that temporoparietal neocortical dysfunction may be responsible. Twenty-four patients with predominantly early-onset Alzheimer's disease were clinically classified into groups with predominantly amnestic, multidomain or visual deficits. Patients underwent neuropsychological evaluation focused on the domains of episodic and working memory, T1-weighted magnetic resonance imaging and brain fluorodeoxyglucose positron emission tomography. Fluorodeoxyglucose positron emission tomography data were analysed by using a region-of-interest approach. Patients with multidomain and visual presentations performed more poorly on tests of working memory compared with amnestic Alzheimer's disease. Working memory performance correlated with glucose metabolism in left-sided temporoparietal, but not frontal neocortex. Carriers of the apolipoprotein E4 gene showed poorer episodic memory and better working memory performance compared with noncarriers. Our findings support the hypothesis that working memory changes in early-onset Alzheimer's disease are related to temporoparietal rather than frontal hypometabolism and show dissociation from episodic memory performance. They further support the concept of subtypes of Alzheimer's disease with distinct cognitive profiles due to prominent neocortical dysfunction early in the disease course. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  4. Operational Thought in Alzheimer's Disease Early Onset and SDAT.

    ERIC Educational Resources Information Center

    Emery, Olga B.; Breslau, Lawrence D.

    For more than a decade it has been convention to assume that senile dementia Alzheimer's type (SDAT) and Alzheimer's disease early onset represent a unitary disease process with only an onset difference. This assumption has been neither confirmed nor disconfirmed. To address this issue, a study was conducted which analyzed the dissolution of…

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

    NASA Astrophysics Data System (ADS)

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

    2015-01-01

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

  6. Converging approaches to understanding early onset familial Alzheimer disease: A First Nation study

    PubMed Central

    Cabrera, Laura Y; Beattie, B Lynn; Dwosh, Emily; Illes, Judy

    2015-01-01

    Objectives: In 2007, a novel pathogenic genetic mutation associated with early onset familial Alzheimer disease was identified in a large First Nation family living in communities across British Columbia, Canada. Building on a community-based participatory study with members of the Nation, we sought to explore the impact and interplay of medicalization with the Nation’s knowledge and approaches to wellness in relation to early onset familial Alzheimer disease. Methods: We performed a secondary content analysis of focus group discussions and interviews with 48 members of the Nation between 2012 and 2013. The analysis focused specifically on geneticization, medicalization, and traditional knowledge of early onset familial Alzheimer disease, as these themes were prominent in the primary analysis. Results: We found that while biomedical explanations of disease permeate the knowledge and understanding of early onset familial Alzheimer disease, traditional concepts about wellness are upheld simultaneously. Conclusion: The analysis brings the theoretical framework of “two-eyed seeing” to the case of early onset familial Alzheimer disease for which the contributions of different ways of knowing are embraced, and in which traditional and western ways complement each other on the path of maintaining wellness in the face of progressive neurologic disease. PMID:27092264

  7. Distinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer's disease.

    PubMed

    Schöll, Michael; Ossenkoppele, Rik; Strandberg, Olof; Palmqvist, Sebastian; Jögi, Jonas; Ohlsson, Tomas; Smith, Ruben; Hansson, Oskar

    2017-09-01

    Patients with Alzheimer's disease can present with different clinical phenotypes. Individuals with late-onset Alzheimer's disease (>65 years) typically present with medial temporal lobe neurodegeneration and predominantly amnestic symptomatology, while patients with early-onset Alzheimer's disease (<65 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early-onset Alzheimer's disease, 21 with late-onset Alzheimer's disease, three with prodromal early-onset Alzheimer's disease and 13 with prodromal late-onset Alzheimer's disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F-AV-1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early- and late-onset Alzheimer's disease exhibit differential regional tau pathology and atrophy patterns. Strong associations of lower age at symptom onset with higher 18F-AV-1451 uptake were observed in several neocortical regions, while higher age did not yield positive associations in neither patient group. Comparing patients with early-onset Alzheimer's disease with controls resulted in significantly higher 18F-AV-1451 retention throughout the neocortex, while comparing healthy controls with late-onset Alzheimer's disease patients yielded a distinct pattern of higher 18F-AV-1451 retention, predominantly confined to temporal lobe regions. When compared against each other, the early-onset Alzheimer's disease group exhibited greater uptake than the late-onset group in prefrontal and premotor, as well as in inferior parietal cortex. These preliminary findings indicate that age may constitute an important contributor to Alzheimer's disease heterogeneity highlighting the potential of tau positron emission tomography to capture phenotypic variation across patients with Alzheimer's disease. © The Author (2017). Published by Oxford

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

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

    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, allelicmore » 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.« less

  10. Whole Exome Analysis of Early Onset Alzheimer’s Disease

    DTIC Science & Technology

    2016-04-01

    Early Onset Alzheimer’s Disease 5a. CONTRACT NUMBER W81XWH-12-1-0013 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR( S ) Margaret A. Pericak...relationship between SORL1, AD, and Parkinsonism . 16 Appendix V: ABCA7 Frameshift Deletion Associated with Alzheimer’s Disease in African Americans...onset Alzheimer disease identified using whole-exome sequencing G. W. Beecham1, B. W. Kunkle1, B. Vardarajan2, P. L. Whitehead1, S . Rolati1, E. R

  11. Early intranasal insulin therapy halts progression of neurodegeneration: progress in Alzheimer's disease therapeutics.

    PubMed

    de la Monte, Suzanne M

    Evaluation of Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial. Arch Neurol . 2011 Sep 12. Alzheimer's disease is associated with brain insulin deficiency and insulin resistance, similar to the problems in diabetes. If insulin could be supplied to the brain in the early stages of Alzheimer's, subsequent neurodegeneration might be prevented. Administering systemic insulin to elderly non-diabetics poses unacceptable risks of inadvertant hypoglycemia. However, intranasal delivery directs the insulin into the brain, avoiding systemic side-effects. This pilot study demonstrates both efficacy and safety of using intranasal insulin to treat early Alzheimer's and mild cognitive impairment, i.e. the precursor to Alzheimer's. Significant improvements in learning, memory, and cognition occured within a few months, but without intranasal insulin, brain function continued to deteriorate in measurable degrees. Intranasal insulin therapy holds promise for halting progression of Alzheimer's disease.

  12. Genetics Home Reference: Alzheimer disease

    MedlinePlus

    ... 65, while the late-onset form appears after age 65. The early-onset form is much less common than the ... familial Alzheimer disease (FAD) Presenile and senile dementia Primary Senile Degenerative Dementia SDAT Related ... autosomal dominant Alzheimer disease Familial Alzheimer disease ...

  13. 78 FR 9396 - Draft Guidance for Industry on Alzheimer's Disease: Developing Drugs for the Treatment of Early...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-08

    ...] Draft Guidance for Industry on Alzheimer's Disease: Developing Drugs for the Treatment of Early Stage Disease; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and... ``Alzheimer's Disease: Developing Drugs for the Treatment of Early Stage Disease.'' This guidance outlines FDA...

  14. [Biomarkers of Alzheimer disease].

    PubMed

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

    2014-01-01

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

  15. Multi-Domain Transfer Learning for Early Diagnosis of Alzheimer's Disease.

    PubMed

    Cheng, Bo; Liu, Mingxia; Shen, Dinggang; Li, Zuoyong; Zhang, Daoqiang

    2017-04-01

    Recently, transfer learning has been successfully applied in early diagnosis of Alzheimer's Disease (AD) based on multi-domain data. However, most of existing methods only use data from a single auxiliary domain, and thus cannot utilize the intrinsic useful correlation information from multiple domains. Accordingly, in this paper, we consider the joint learning of tasks in multi-auxiliary domains and the target domain, and propose a novel Multi-Domain Transfer Learning (MDTL) framework for early diagnosis of AD. Specifically, the proposed MDTL framework consists of two key components: 1) a multi-domain transfer feature selection (MDTFS) model that selects the most informative feature subset from multi-domain data, and 2) a multi-domain transfer classification (MDTC) model that can identify disease status for early AD detection. We evaluate our method on 807 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database using baseline magnetic resonance imaging (MRI) data. The experimental results show that the proposed MDTL method can effectively utilize multi-auxiliary domain data for improving the learning performance in the target domain, compared with several state-of-the-art methods.

  16. Souvenaid®: a new approach to management of early Alzheimer's disease.

    PubMed

    Ritchie, C W; Bajwa, J; Coleman, G; Hope, K; Jones, R W; Lawton, M; Marven, M; Passmore, P

    2014-03-01

    Synaptic loss correlates closely with cognitive deficits in Alzheimer's disease and represents a new target for intervention. Souvenaid® is the first medical nutrition product to be designed to support synapse formation and function in early Alzheimer's disease, and has undergone an extensive, 12-year development programme. The relatively large amount of clinical data available for Souvenaid® is unusual for a medical nutrition product. Souvenaid® contains omega-3 polyunsaturated fatty acids (docosahexaenoic acid and eicosapentaenoic acid), uridine (as uridine monophosphate) and choline which are nutritional precursors required for synaptic membrane phospholipid synthesis, together with phospholipids and other cofactors. Souvenaid® has demonstrated cognitive benefits in patients with mild Alzheimer's disease but not in patients with mild-to-moderate Alzheimer's disease. Two randomised, double-blind, controlled trials (duration 12 and 24 weeks) in patients with mild Alzheimer's disease untreated with acetylcholinesterase inhibitors and/or memantine have demonstrated that Souvenaid® is well tolerated and improves episodic memory performance. The daily intake of Souvenaid® has not been associated with any harmful effects or interactions with medications and none are anticipated. The ongoing, 24-month, European Union-funded LipiDiDiet trial in subjects with prodromal Alzheimer's disease is evaluating the potential benefits of Souvenaid® on memory and in slowing progression to Alzheimer's dementia. If Souvenaid® induces synaptogenesis and improved synaptic function, it may provide benefits in other clinical conditions characterised by neurodegeneration. A number of trials are ongoing and planned to evaluate the potential wider benefits of Souvenaid®.

  17. Early Detection of Amyloid Plaque in Alzheimer’s Disease via X-ray Phase CT

    DTIC Science & Technology

    2016-08-01

    AWARD NUMBER: W81XWH-12-1-0138 TITLE: Early Detection of Amyloid Plaque in Alzheimer’s Disease via X-ray Phase CT PRINCIPAL INVESTIGATOR...NUMBER W81XWH-12-1-0138 Early Detection of Amyloid Plaque in Alzheimer’s Disease via X-ray Phase CT 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6...method for early detection of amyloid plaque in Alzheimer’s disease , with three Specific Aims: #1 Develop and optimize an x-ray PCCT to explore the

  18. Amygdalohippocampal MR volume measurements in the early stages of Alzheimer disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lehericy, S.; Baulac, M.; Chiras, J.

    1994-05-01

    To evaluate the accuracy of hippocampal and amygdala volume measurements in diagnosing patients in the early stages of Alzheimer disease. Measurements of the hippocampal formation, amygdala, amygdalohippocampal complex (the two measurements summed), caudate nucleus, and ventricles, normalized for total intracranial volume, were obtained on coronal sections (1.5 T, 400/13 [repetition time/echo time], 5 mm) of 13 patients in the mild (minimental status {ge} 21) and five patients in the moderate stages of Alzheimer disease (10 < minimental status < 21), and eight age-matched control subjects. For patients with a minimental status score of 21 or greater, atrophy was significant formore » the amygdala and hippocampal formation (-36% and -25% for amygdala/total intracranial volume and hippocampal formation/total intracranial volume, respectively), but not for the caudate nucleus. No significant ventricular enlargement was found. For patients with a minimental status score less than 21, atrophy was more severe in all structures studied (amygdala/total intracranial volume -40%; hippocampal formation/total intracranial volume, -45%; caudate nucleus/total intracranial volume, -21%), and ventricles were enlarged (63%). No overlap was found between Alzheimer disease and control values for the amygdalohippocampal volume, even in the mild stages of the disease. In Alzheimer disease patients, hippocampal formation volumes correlated with the minimental status. Hippocampal and amygdala atrophy is marked and significant in the mild stages of Alzheimer disease. Volumetric measurements of the amygdala and the amygdalohippocampal complex appear more accurate than those of the hippocampal formation alone in distinguishing patients with Alzheimer disease. 46 refs., 8 figs., 2 tabs.« less

  19. Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease.

    PubMed

    Chaudhury, Sultan; Patel, Tulsi; Barber, Imelda S; Guetta-Baranes, Tamar; Brookes, Keeley J; Chappell, Sally; Turton, James; Guerreiro, Rita; Bras, Jose; Hernandez, Dena; Singleton, Andrew; Hardy, John; Mann, David; Morgan, Kevin

    2018-02-01

    Sporadic early-onset Alzheimer's disease (sEOAD) exhibits the symptoms of late-onset Alzheimer's disease but lacks the familial aspect of the early-onset familial form. The genetics of Alzheimer's disease (AD) identifies APOEε4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and multiple genetic loci. Polygenic risk scores (PRSs) accumulate the total risk of a phenotype in an individual based on variants present in their genome. We determined whether sEOAD cases had a higher PRS compared to controls. A cohort of sEOAD cases was genotyped on the NeuroX array, and PRSs were generated using PRSice. The target data set consisted of 408 sEOAD cases and 436 controls. The base data set was collated by the International Genomics of Alzheimer's Project consortium, with association data from 17,008 late-onset Alzheimer's disease cases and 37,154 controls, which can be used for identifying sEOAD cases due to having shared phenotype. PRSs were generated using all common single nucleotide polymorphisms between the base and target data set, PRS were also generated using only single nucleotide polymorphisms within a 500 kb region surrounding the APOE gene. Sex and number of APOE ε2 or ε4 alleles were used as variables for logistic regression and combined with PRS. The results show that PRS is higher on average in sEOAD cases than controls, although there is still overlap among the whole cohort. Predictive ability of identifying cases and controls using PRSice was calculated with 72.9% accuracy, greater than the APOE locus alone (65.2%). Predictive ability was further improved with logistic regression, identifying cases and controls with 75.5% accuracy. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. 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

  1. Bone density and brain atrophy in early Alzheimer's disease.

    PubMed

    Loskutova, Natalia; Honea, Robyn A; Vidoni, Eric D; Brooks, William M; Burns, Jeffrey M

    2009-01-01

    Studies suggest a link between bone loss and Alzheimer's disease. To examine bone mineral density (BMD) in early Alzheimer's disease (AD) and its relationship to brain structure and cognition, we evaluated 71 patients with early stage AD (Clinical Dementia Rating (CDR) 0.5 and 1) and 69 non-demented elderly control participants (CDR 0). Measures included whole body BMD by dual energy x-ray absorptiometry (DXA) and normalized whole brain volumes computed from structural MRI scans. Cognition was assessed with a standard neuropsychological test battery. Mean BMD was lower in the early AD group (1.11 +/- 0.13) compared to the non-demented control group (1.16 +/- 0.12, p = 0.02), independent of age, gender, habitual physical activity, smoking, depression, estrogen replacement, and apolipoprotein E4 carrier status. In the early AD group, BMD was related to whole brain volume (b = 0.18, p = 0.03). BMD was also associated with cognitive performance, primarily in tests of memory (logical memory [b = 0.15, p = 0.04], delayed logical memory [b = 0.16, p = 0.02], and the selective reminding task - free recall [b = 0.18, p = 0.009]). BMD is reduced in the earliest clinical stages of AD and associated with brain atrophy and memory decline, suggesting that central mechanisms may contribute to bone loss in early AD.

  2. [Early episodic memory impairments in Alzheimer's disease].

    PubMed

    Ergis, A-M; Eusop-Roussel, E

    2008-05-01

    Patients with Alzheimer's disease (AD) show early episodic memory impairments. Such deficits reflect specific impairments affecting one or several stages of encoding, storage and retrieval processes. However, AD patients not only have great difficulty retrieving memories and information but also suffer from distortions of memory, as intrusions and false recognitions. Intrusions can be defined as the unintentional recall of inappropriate information in a laboratory-learning tasks such as word-list recall and story recall. False recognition refers to the erroneous recognition of information that was not previously presented. The first objective of this review is to present studies from the literature that allowed a better understanding of the nature of episodic memory deficits in AD, and to examine recent research on false memories. The second part of this review is aimed at presenting recent research conducted on prospective memory (PM) in Alzheimer's disease. Prospective memory situations involve forming intentions and then realizing those intentions at some appropriate time in the future. Everyday examples of prospective memory include remembering to buy bread on the way home from work, remembering to give friends a message upon next encountering them, and remembering to take medication. Patients suffering from AD show difficulties in performing prospective tasks in daily life, according to the complaints of their care givers, and these difficulties are massively present at the first stages of the disease. Nevertheless, very few studies have been dedicated to this subject, although the evaluation of PM could be helpful for the early diagnosis of AD.

  3. An early and late peak in microglial activation in Alzheimer's disease trajectory.

    PubMed

    Fan, Zhen; Brooks, David J; Okello, Aren; Edison, Paul

    2017-03-01

    Amyloid-β deposition, neuroinflammation and tau tangle formation all play a significant role in Alzheimer's disease. We hypothesized that there is microglial activation early on in Alzheimer's disease trajectory, where in the initial phase, microglia may be trying to repair the damage, while later on in the disease these microglia could be ineffective and produce proinflammatory cytokines leading to progressive neuronal damage. In this longitudinal study, we have evaluated the temporal profile of microglial activation and its relationship between fibrillar amyloid load at baseline and follow-up in subjects with mild cognitive impairment, and this was compared with subjects with Alzheimer's disease. Thirty subjects (eight mild cognitive impairment, eight Alzheimer's disease and 14 controls) aged between 54 and 77 years underwent 11C-(R)PK11195, 11C-PIB positron emission tomography and magnetic resonance imaging scans. Patients were followed-up after 14 ± 4 months. Region of interest and Statistical Parametric Mapping analysis were used to determine longitudinal alterations. Single subject analysis was performed to evaluate the individualized pathological changes over time. Correlations between levels of microglial activation and amyloid deposition at a voxel level were assessed using Biological Parametric Mapping. We demonstrated that both baseline and follow-up microglial activation in the mild cognitive impairment cohort compared to controls were increased by 41% and 21%, respectively. There was a longitudinal reduction of 18% in microglial activation in mild cognitive impairment cohort over 14 months, which was associated with a mild elevation in fibrillar amyloid load. Cortical clusters of microglial activation and amyloid deposition spatially overlapped in the subjects with mild cognitive impairment. Baseline microglial activation was increased by 36% in Alzheimer's disease subjects compared with controls. Longitudinally, Alzheimer's disease subjects showed

  4. 7 Warning Signs of Alzheimer's | Alzheimer's disease | NIH MedlinePlus the Magazine

    MedlinePlus

    ... please turn Javascript on. Feature: Alzheimer's Disease 7 Warning Signs of Alzheimer's Past Issues / Fall 2010 Table ... is to alert the public to the early warning signs of Alzheimer's disease. If someone has several ...

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    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 penetrantmore » 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.« less

  6. 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. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  7. A Bayesian Model for the Prediction and Early Diagnosis of Alzheimer's Disease.

    PubMed

    Alexiou, Athanasios; Mantzavinos, Vasileios D; Greig, Nigel H; Kamal, Mohammad A

    2017-01-01

    Alzheimer's disease treatment is still an open problem. The diversity of symptoms, the alterations in common pathophysiology, the existence of asymptomatic cases, the different types of sporadic and familial Alzheimer's and their relevance with other types of dementia and comorbidities, have already created a myth-fear against the leading disease of the twenty first century. Many failed latest clinical trials and novel medications have revealed the early diagnosis as the most critical treatment solution, even though scientists tested the amyloid hypothesis and few related drugs. Unfortunately, latest studies have indicated that the disease begins at the very young ages thus making it difficult to determine the right time of proper treatment. By taking into consideration all these multivariate aspects and unreliable factors against an appropriate treatment, we focused our research on a non-classic statistical evaluation of the most known and accepted Alzheimer's biomarkers. Therefore, in this paper, the code and few experimental results of a computational Bayesian tool have being reported, dedicated to the correlation and assessment of several Alzheimer's biomarkers to export a probabilistic medical prognostic process. This new statistical software is executable in the Bayesian software Winbugs, based on the latest Alzheimer's classification and the formulation of the known relative probabilities of the various biomarkers, correlated with Alzheimer's progression, through a set of discrete distributions. A user-friendly web page has been implemented for the supporting of medical doctors and researchers, to upload Alzheimer's tests and receive statistics on the occurrence of Alzheimer's disease development or presence, due to abnormal testing in one or more biomarkers.

  8. Clinical features of early onset, familial Alzheimer`s disease linked to chromosome 14

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Mullan, M.; Bennett, C.; Figueredo, C.

    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 onsetmore » 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.« less

  9. Magnetic resonance imaging for diagnosis of early Alzheimer's disease.

    PubMed

    Colliot, O; Hamelin, L; Sarazin, M

    2013-10-01

    A major challenge for neuroimaging is to contribute to the early diagnosis of Alzheimer's disease (AD). In particular, magnetic resonance imaging (MRI) allows detecting different types of structural and functional abnormalities at an early stage of the disease. Anatomical MRI is the most widely used technique and provides local and global measures of atrophy. The recent diagnostic criteria of "mild cognitive impairment due to AD" include hippocampal atrophy, which is considered a marker of neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in the hippocampus and throughout the whole brain. Recent modalities such as diffusion-tensor imaging and resting-state functional MRI provide additional measures that could contribute to the early diagnosis but require further validation. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  10. Alzheimer's Disease Early Diagnosis Using Manifold-Based Semi-Supervised Learning.

    PubMed

    Khajehnejad, Moein; Saatlou, Forough Habibollahi; Mohammadzade, Hoda

    2017-08-20

    Alzheimer's disease (AD) is currently ranked as the sixth leading cause of death in the United States and recent estimates indicate that the disorder may rank third, just behind heart disease and cancer, as a cause of death for older people. Clearly, predicting this disease in the early stages and preventing it from progressing is of great importance. The diagnosis of Alzheimer's disease (AD) requires a variety of medical tests, which leads to huge amounts of multivariate heterogeneous data. It can be difficult and exhausting to manually compare, visualize, and analyze this data due to the heterogeneous nature of medical tests; therefore, an efficient approach for accurate prediction of the condition of the brain through the classification of magnetic resonance imaging (MRI) images is greatly beneficial and yet very challenging. In this paper, a novel approach is proposed for the diagnosis of very early stages of AD through an efficient classification of brain MRI images, which uses label propagation in a manifold-based semi-supervised learning framework. We first apply voxel morphometry analysis to extract some of the most critical AD-related features of brain images from the original MRI volumes and also gray matter (GM) segmentation volumes. The features must capture the most discriminative properties that vary between a healthy and Alzheimer-affected brain. Next, we perform a principal component analysis (PCA)-based dimension reduction on the extracted features for faster yet sufficiently accurate analysis. To make the best use of the captured features, we present a hybrid manifold learning framework which embeds the feature vectors in a subspace. Next, using a small set of labeled training data, we apply a label propagation method in the created manifold space to predict the labels of the remaining images and classify them in the two groups of mild Alzheimer's and normal condition (MCI/NC). The accuracy of the classification using the proposed method is 93

  11. Ultra-Early Phase pathologies of Alzheimer's disease and other neurodegenerative diseases.

    PubMed

    Okazawa, Hitoshi

    2017-01-01

    The concept of neurodegenerative diseases and the therapeutics targeting these intractable diseases are changing rapidly. Protein aggregation as the top of pathological cascade is now challenged, and many alternative ideas are proposed. Early molecular pathologies before microscopic detection of diseases protein aggregates, which I propose to call "Ultra-Early Phase pathologies or phase 0 pathologies", are the focus of research that might explain the failures of clinical trials with anti-Aβ antibodies against Alzheimer's disease. In this review article, I summarize the critical issues that should be successfully and consistently answered by a new concept of neurodegeneration. For reevaluating old concepts and reconstructing a new concept of neurodegeneration that will replace the old ones, non-biased comprehensive approaches including proteome combined with systems biology analyses will be a powerful tool. I introduce our recent efforts in this orientation that have reached to the stage of non-clinical proof of concept applicable to clinical trials.

  12. Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the Nun Study.

    PubMed

    Snowdon, D A; Kemper, S J; Mortimer, J A; Greiner, L H; Wekstein, D R; Markesbery, W R

    1996-02-21

    To determine if linguistic ability in early life is associated with cognitive function and Alzheimer's disease in late life. Two measures of linguistic ability in early life, idea density and grammatical complexity, were derived from autobiographies written at a mean age of 22 years. Approximately 58 years later, the women who wrote these autobiographies participated in an assessment of cognitive function, and those who subsequently died were evaluated neuropathologically. Convents in the United States participating in the Nun Study; primarily convents in the Milwaukee, Wis, area. Cognitive function was investigated in 93 participants who were aged 75 to 95 years at the time of their assessments, and Alzheimer's disease was investigated in the 14 participants who died at 79 to 96 years of age. Seven neuropsychological tests and neuropathologically confirmed Alzheimer's disease. Low idea density and low grammatical complexity in autobiographies written in early life were associated with low cognitive test scores in late life. Low idea density in early life had stronger and more consistent associations with poor cognitive function than did low grammatical complexity. Among the 14 sisters who died, neuropathologically confirmed Alzheimer's disease was present in all of those with low idea density in early life and in none of those with high idea density. Low linguistic ability in early life was a strong predictor of poor cognitive function and Alzheimer's disease in late life.

  13. Forecasting Alzheimer's Disease.

    ERIC Educational Resources Information Center

    Fackelmann, Kathleen

    1996-01-01

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

  14. Completed suicide in an autopsy-confirmed case of early onset Alzheimer's disease.

    PubMed

    Hartzell, Jennifer Wiener; Geary, Richard; Gyure, Kymberly; Chivukula, Venkata Ravi; Haut, Marc W

    2018-04-01

    We report a case of a 57-year-old male with clinically diagnosed and autopsy-confirmed early onset Alzheimer's disease who completed suicide by gunshot wound to the chest. This case has several unique aspects that have not been discussed in previous case reports of completed suicide in Alzheimer's disease. In particular, our patient's death was highly planned with successful compensation for his cognitive deficits. After all firearms had been removed from the home as a safety precaution, he obtained a new weapon, hid it and left himself cues to find and use it. The case is discussed in the context of literature differentiating the neural circuitry propagating impulsive versus planned suicidal acts.

  15. The Cognitive and Neural Expression of Semantic Memory Impairment in Mild Cognitive Impairment and Early Alzheimer's Disease

    ERIC Educational Resources Information Center

    Joubert, Sven; Brambati, Simona M.; Ansado, Jennyfer; Barbeau, Emmanuel J.; Felician, Olivier; Didic, Mira; Lacombe, Jacinthe; Goldstein, Rachel; Chayer, Celine; Kergoat, Marie-Jeanne

    2010-01-01

    Semantic deficits in Alzheimer's disease have been widely documented, but little is known about the integrity of semantic memory in the prodromal stage of the illness. The aims of the present study were to: (i) investigate naming abilities and semantic memory in amnestic mild cognitive impairment (aMCI), early Alzheimer's disease (AD) compared to…

  16. Reliable determination of new lipid peroxidation compounds as potential early Alzheimer Disease biomarkers.

    PubMed

    García-Blanco, Ana; Peña-Bautista, Carmen; Oger, Camille; Vigor, Claire; Galano, Jean-Marie; Durand, Thierry; Martín-Ibáñez, Nuria; Baquero, Miguel; Vento, Máximo; Cháfer-Pericás, Consuelo

    2018-07-01

    Lipid peroxidation plays an important role in Alzheimer Disease, so corresponding metabolites found in urine samples could be potential biomarkers. The aim of this work is to develop a reliable ultra-performance liquid chromatography-tandem mass spectrometry analytical method to determine a new set of lipid peroxidation compounds in urine samples. Excellent sensitivity was achieved with limits of detection between 0.08 and 17 nmol L -1 , which renders this method suitable to monitor analytes concentrations in real samples. The method's precision was satisfactory with coefficients of variation around 5-17% (intra-day) and 8-19% (inter-day). The accuracy of the method was assessed by analysis of spiked urine samples obtaining recoveries between 70% and 120% for most of the analytes. The utility of the described method was tested by analyzing urine samples from patients early diagnosed with mild cognitive impairment or mild dementia Alzheimer Disease following the clinical standard criteria. As preliminary results, some analytes (17(RS)-10-epi-SC-Δ 15 -11-dihomo-IsoF, PGE 2 ) and total parameters (Neuroprostanes, Isoprostanes, Isofurans) show differences between the control and the clinical groups. So, these analytes could be potential early Alzheimer Disease biomarkers assessing the patients' pro-oxidant condition. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. Whole Exome Analysis of Early Onset Alzheimer’s Disease

    DTIC Science & Technology

    2013-04-01

    FTD), FTD with Parkinsonism , and early-onset Alzheimer Disease (EOAD)-like presentations. Using whole exome capture with subsequent sequencing, we...dementia. The MAPT R406W mutation is associated with EOAD-like symptoms and Parkinsonism without FTD, as well as distinct cognitive courses. KEY...OUTCOMES: Carney RM, Kohli MA, Kunkle BW, Naj AC, Gilbert JR, Züchner S, PERICAK-VANCE MA, Parkinsonism and distinct dementia patterns in a

  18. The Proteasome and Oxidative Stress in Alzheimer's Disease.

    PubMed

    Bonet-Costa, Vicent; Pomatto, Laura Corrales-Diaz; Davies, Kelvin J A

    2016-12-01

    Alzheimer's disease is a neurodegenerative disorder that is projected to exceed more than 100 million cases worldwide by 2050. Aging is considered the primary risk factor for some 90% of Alzheimer's cases but a significant 10% of patients suffer from aggressive, early-onset forms of the disease. There is currently no effective Alzheimer's treatment and this, coupled with a growing aging population, highlights the necessity to understand the mechanism(s) of disease initiation and propagation. A major hallmark of Alzheimer's disease pathology is the accumulation of amyloid-β (Aβ) aggregates (an early marker of Alzheimer's disease), and neurofibrillary tangles, comprising the hyper-phosphorylated microtubule-associated protein Tau. Recent Advances: Protein oxidation is frequently invoked as a potential factor in the progression of Alzheimer's disease; however, whether it is a cause or a consequence of the pathology is still being debated. The Proteasome complex is a major regulator of intracellular protein quality control and an essential proteolytic enzyme for the processing of both Aβ and Tau. Recent studies have indicated that both protein oxidation and excessive phosphorylation may limit Proteasomal processing of Aβ and Tau in Alzheimer's disease. Thus, the Proteasome may be a key factor in understanding the development of Alzheimer's disease pathology; however, its significance is still very much under investigation. Discovering how the proteasome is affected, regulated, or dysregulated in Alzheimer's disease could be a valuable tool in the efforts to understand and, ultimately, eradicate the disease. Antioxid. Redox Signal. 25, 886-901.

  19. Linguistic ability in early life and the neuropathology of Alzheimer's disease and cerebrovascular disease. Findings from the Nun Study.

    PubMed

    Snowdon, D A; Greiner, L H; Markesbery, W R

    2000-04-01

    Findings from the Nun Study indicate that low linguistic ability in early life has a strong association with dementia and premature death in late life. In the present study, we investigated the relationship of linguistic ability in early life to the neuropathology of Alzheimer's disease and cerebrovascular disease. The analyses were done on a subset of 74 participants in the Nun Study for whom we had handwritten autobiographies completed some time between the ages of 19 and 37 (mean = 23 years). An average of 62 years after writing the autobiographies, when the participants were 78 to 97 years old, they died and their brains were removed for our neuropathologic studies. Linguistic ability in early life was measured by the idea (proposition) density of the autobiographies, i.e., a standard measure of the content of ideas in text samples. Idea density scores from early life had strong inverse correlations with the severity of Alzheimer's disease pathology in the neocortex: Correlations between idea density scores and neurofibrillary tangle counts were -0.59 for the frontal lobe, -0.48 for the temporal lobe, and -0.49 for the parietal lobe (all p values < 0.0001). Idea density scores were unrelated to the severity of atherosclerosis of the major arteries at the base of the brain and to the presence of lacunar and large brain infarcts. Low linguistic ability in early life may reflect suboptimal neurological and cognitive development, which might increase susceptibility to the development of Alzheimer's disease pathology in late life.

  20. Biomarkers for early diagnosis of Alzheimer disease: 'ALZheimer ASsociated gene'--a new blood biomarker?

    PubMed

    Jellinger, Kurt A; Janetzky, Bernd; Attems, Johannes; Kienzl, Elisabeth

    2008-08-01

    Simple, non-invasive tests for an early detection of degenerative dementia by use of biomarkers are urgently required. However, up to the present, no validated extracerebral diagnostic markers (plasma/serum, platelets, urine, connective tissue) for the early diagnosis of Alzheimer disease (AD) are available. In disease stages with evident cognitive disturbances, the clinical diagnosis of probable AD is made with around 90% accuracy using modern clinical, neuropsychological and imaging methods. Diagnostic sensitivity and specificity even in early disease stages are improved by CSF markers, in particular combined tau and amyloid beta peptides (Abeta) and plasma markers (eg, Abeta-42/Abeta-40 ratio). Recently, a novel gene/protein--ALZAS (Alzheimer Associated Protein)--with a 79 amino acid sequence, containing the amyloid beta-42 fragment (Abeta-42), the amyloid precursor protein (APP) transmembrane signal and a 12 amino acid C-terminal, not present in any other known APP alleles, has been discovered on chromosome 21 within the APP region. Reverse transcriptase-PCR revealed the expression of the transcript of this protein in the cortex and hippocampal regions as well as in lymphocytes of human AD patients. The expression of ALZAS is mirrored by a specific autoimmune response in AD patients, directed against the ct-12 end of the ALZAS-peptide but not against the Abeta-sequence. ELISA studies of plasma detected highest titers of ALZAS in patients with mild cognitive impairment (presymptomatic AD), but only moderately increased titers in autopsy-confirmed AD, whereas low or undetectable ct-12 titers were found in cognitively intact age-matched subjects and young controls. The antigen, ALZAS protein, was detected in plasma in later clinical stages of AD. It is suggested that ALZAS represents an indicator in a dynamic equilibrium between both peripheral and brain degenerative changes in AD and may become a useful "non-invasive" diagnostic marker via a simple blood test.

  1. Early- and late-onset Alzheimer disease: Are they the same entity?

    PubMed

    Tellechea, P; Pujol, N; Esteve-Belloch, P; Echeveste, B; García-Eulate, M R; Arbizu, J; Riverol, M

    2018-05-01

    Early-onset Alzheimer disease (EOAD), which presents in patients younger than 65 years, has frequently been described as having different features from those of late-onset Alzheimer disease (LOAD). This review analyses the most recent studies comparing the clinical presentation and neuropsychological, neuropathological, genetic, and neuroimaging findings of both types in order to determine whether EOAD and LOAD are different entities or distinct forms of the same entity. We observed consistent differences between clinical findings in EOAD and in LOAD. Fundamentally, the onset of EOAD is more likely to be marked by atypical symptoms, and cognitive assessments point to poorer executive and visuospatial functioning and praxis with less marked memory impairment. Alzheimer-type features will be more dense and widespread in neuropathology studies, with structural and functional neuroimaging showing greater and more diffuse atrophy extending to neocortical areas (especially the precuneus). In conclusion, available evidence suggests that EOAD and LOAD are 2 different forms of a single entity. LOAD is likely to be influenced by ageing-related processes. Copyright © 2015 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. Magnetic resonance imaging and magnetic resonance spectroscopy for detection of early Alzheimer's disease.

    PubMed

    Westman, Eric; Wahlund, Lars-Olof; Foy, Catherine; Poppe, Michaela; Cooper, Allison; Murphy, Declan; Spenger, Christian; Lovestone, Simon; Simmons, Andrew

    2011-01-01

    Alzheimer's disease is the most common form of neurodegenerative disorder and early detection is of great importance if new therapies are to be effectively administered. We have investigated whether the discrimination between early Alzheimer's disease (AD) and elderly healthy control subjects can be improved by adding magnetic resonance spectroscopy (MRS) measures to magnetic resonance imaging (MRI) measures. In this study 30 AD patients and 36 control subjects were included. High resolution T1-weighted axial magnetic resonance images were obtained from each subject. Automated regional volume segmentation and cortical thickness measures were determined for the images. 1H MRS was acquired from the hippocampus and LCModel was used for metabolic quantification. Altogether, this yielded 58 different volumetric, cortical thickness and metabolite ratio variables which were used for multivariate analysis to distinguish between subjects with AD and Healthy controls. Combining MRI and MRS measures resulted in a sensitivity of 97% and a specificity of 94% compared to using MRI or MRS measures alone (sensitivity: 87%, 76%, specificity: 86%, 83% respectively). Adding the MRS measures to the MRI measures more than doubled the positive likelihood ratio from 6 to 17. Adding MRS measures to a multivariate analysis of MRI measures resulted in significantly better classification than using MRI measures alone. The method shows strong potential for discriminating between Alzheimer's disease and controls.

  3. Difference in imaging biomarkers of neurodegeneration between early and late-onset amnestic Alzheimer's disease.

    PubMed

    Aziz, Anne-Laure; Giusiano, Bernard; Joubert, Sven; Duprat, Lauréline; Didic, Mira; Gueriot, Claude; Koric, Lejla; Boucraut, José; Felician, Olivier; Ranjeva, Jean-Philippe; Guedj, Eric; Ceccaldi, Mathieu

    2017-06-01

    Neuroimaging biomarkers differ between patients with early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD). Whether these changes reflect cognitive heterogeneity or differences in disease severity is still unknown. This study aimed at investigating changes in neuroimaging biomarkers, according to the age of onset of the disease, in mild amnestic Alzheimer's disease patients with positive amyloid biomarkers in cerebrospinal fluid. Both patient groups were impaired on tasks assessing verbal and visual recognition memory. EOAD patients showed greater executive and linguistic deficits, while LOAD patients showed greater semantic memory impairment. In EOAD and LOAD, hypometabolism involved the bilateral temporoparietal junction and the posterior cingulate cortex. In EOAD, atrophy was widespread, including frontotemporoparietal areas, whereas it was limited to temporal regions in LOAD. Atrophic volumes were greater in EOAD than in LOAD. Hypometabolic volumes were similar in the 2 groups. Greater extent of atrophy in EOAD, despite similar extent of hypometabolism, could reflect different underlying pathophysiological processes, different glucose-based compensatory mechanisms or distinct level of premorbid atrophic lesions. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Alzheimer disease.

    PubMed

    Calderon-Garcidueñas, Ana Laura; Duyckaerts, Charles

    2017-01-01

    Alzheimer disease neuropathology is characterized by the extracellular accumulation of Aβ peptide and intracellular aggregation of hyperphosphorylated tau. With the progression of the disease, macroscopic atrophy affects the entorhinal area and hippocampus, amygdala, and associative regions of the neocortex. The locus coeruleus is depigmented. The deposition of Aβ is first made of diffuse deposits. Amyloid focal deposits constitute the core of the senile plaque which also comprises a corona of tau-positive neurites. Aβ deposits are found successively in the neocortex, the hippocampus, the striatum, the mesencephalon, and finally the cerebellum together with the pontine nuclei (Thal phases). Tau pathology affects in a stereotyped order some specific nuclei of the brainstem, the entorhinal area, the hippocampus, and the neocortex - first the associative areas and secondarily the primary cortices (Braak stages). Loss of synapses is observed in association with tau and Aβ pathology; neuronal loss occurs in the most affected areas. Granulovacuolar degeneration and perisomatic granules are also linked to Alzheimer disease pathology. The physiopathology of Alzheimer disease remains unknown. Familial cases suggest that Aβ deposition is the initial step, but tau pathology appears early in the course and seems to be better correlated with the symptoms. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Polygenic Risk Score for Alzheimer's Disease: Implications for Memory Performance and Hippocampal Volumes in Early Life.

    PubMed

    Axelrud, Luiza K; Santoro, Marcos L; Pine, Daniel S; Talarico, Fernanda; Gadelha, Ary; Manfro, Gisele G; Pan, Pedro M; Jackowski, Andrea; Picon, Felipe; Brietzke, Elisa; Grassi-Oliveira, Rodrigo; Bressan, Rodrigo A; Miguel, Eurípedes C; Rohde, Luis A; Hakonarson, Hakon; Pausova, Zdenka; Belangero, Sintia; Paus, Tomas; Salum, Giovanni A

    2018-06-01

    Alzheimer's disease is a heritable neurodegenerative disorder in which early-life precursors may manifest in cognition and brain structure. The authors evaluate this possibility by examining, in youths, associations among polygenic risk score for Alzheimer's disease, cognitive abilities, and hippocampal volume. Participants were children 6-14 years of age in two Brazilian cities, constituting the discovery (N=364) and replication samples (N=352). As an additional replication, data from a Canadian sample (N=1,029), with distinct tasks, MRI protocol, and genetic risk, were included. Cognitive tests quantified memory and executive function. Reading and writing abilities were assessed by standardized tests. Hippocampal volumes were derived from the Multiple Automatically Generated Templates (MAGeT) multi-atlas segmentation brain algorithm. Genetic risk for Alzheimer's disease was quantified using summary statistics from the International Genomics of Alzheimer's Project. Analyses showed that for the Brazilian discovery sample, each one-unit increase in z-score for Alzheimer's polygenic risk score significantly predicted a 0.185 decrement in z-score for immediate recall and a 0.282 decrement for delayed recall. Findings were similar for the Brazilian replication sample (immediate and delayed recall, β=-0.259 and β=-0.232, both significant). Quantile regressions showed lower hippocampal volumes bilaterally for individuals with high polygenic risk scores. Associations fell short of significance for the Canadian sample. Genetic risk for Alzheimer's disease may affect early-life cognition and hippocampal volumes, as shown in two independent samples. These data support previous evidence that some forms of late-life dementia may represent developmental conditions with roots in childhood. This result may vary depending on a sample's genetic risk and may be specific to some types of memory tasks.

  6. Preferential degradation of cognitive networks differentiates Alzheimer's disease from ageing.

    PubMed

    Chhatwal, Jasmeer P; Schultz, Aaron P; Johnson, Keith A; Hedden, Trey; Jaimes, Sehily; Benzinger, Tammie L S; Jack, Clifford; Ances, Beau M; Ringman, John M; Marcus, Daniel S; Ghetti, Bernardino; Farlow, Martin R; Danek, Adrian; Levin, Johannes; Yakushev, Igor; Laske, Christoph; Koeppe, Robert A; Galasko, Douglas R; Xiong, Chengjie; Masters, Colin L; Schofield, Peter R; Kinnunen, Kirsi M; Salloway, Stephen; Martins, Ralph N; McDade, Eric; Cairns, Nigel J; Buckles, Virginia D; Morris, John C; Bateman, Randall; Sperling, Reisa A

    2018-05-01

    Converging evidence from structural, metabolic and functional connectivity MRI suggests that neurodegenerative diseases, such as Alzheimer's disease, target specific neural networks. However, age-related network changes commonly co-occur with neuropathological cascades, limiting efforts to disentangle disease-specific alterations in network function from those associated with normal ageing. Here we elucidate the differential effects of ageing and Alzheimer's disease pathology through simultaneous analyses of two functional connectivity MRI datasets: (i) young participants harbouring highly-penetrant mutations leading to autosomal-dominant Alzheimer's disease from the Dominantly Inherited Alzheimer's Network (DIAN), an Alzheimer's disease cohort in which age-related comorbidities are minimal and likelihood of progression along an Alzheimer's disease trajectory is extremely high; and (ii) young and elderly participants from the Harvard Aging Brain Study, a cohort in which imaging biomarkers of amyloid burden and neurodegeneration can be used to disambiguate ageing alone from preclinical Alzheimer's disease. Consonant with prior reports, we observed the preferential degradation of cognitive (especially the default and dorsal attention networks) over motor and sensory networks in early autosomal-dominant Alzheimer's disease, and found that this distinctive degradation pattern was magnified in more advanced stages of disease. Importantly, a nascent form of the pattern observed across the autosomal-dominant Alzheimer's disease spectrum was also detectable in clinically normal elderly with clear biomarker evidence of Alzheimer's disease pathology (preclinical Alzheimer's disease). At the more granular level of individual connections between node pairs, we observed that connections within cognitive networks were preferentially targeted in Alzheimer's disease (with between network connections relatively spared), and that connections between positively coupled nodes

  7. [Early interventional group therapy for patients with incipient Alzheimer disease and their relatives].

    PubMed

    Scheurich, Armin; Schanz, Benno; Müller, Matthias J; Fellgiebel, Andreas

    2008-06-01

    Pilot study on an early-interventional group therapy for patients with incipient Alzheimer disease and their relatives. The present study investigates whether scientific progress in terms of earlier time of diagnostic certainty can be used for psychoeducation, maintenance of positive activities and prevention of comorbid depressive episodes. 12 patients (66.8 +/- 5.8 years, MMSE 24.0 +/- 4.0) together with 12 relatives have been treated with a bi-weekly group therapy program. For the patients treatment resulted in reduced anxiety, anergia and withdrawal, for their relatives reduced sleep disturbances, irascibility, and aggressiveness have been found. Only one of the patients suffered from a depressive episode. All participants expressed positive feedback and a high level of quality of life. By the straightforward psychosocial intervention it seems possible to use the earlier time of diagnostic certainty for early diagnosed patients suffering from incipient Alzheimer disease. However, results have to be replicated by a controlled, prospective study with larger sample sizes.

  8. Magnetic Resonance Imaging to Detect Early Molecular and Cellular Changes in Alzheimer's Disease.

    PubMed

    Knight, Michael J; McCann, Bryony; Kauppinen, Risto A; Coulthard, Elizabeth J

    2016-01-01

    Recent pharmaceutical trials have demonstrated that slowing or reversing pathology in Alzheimer's disease is likely to be possible only in the earliest stages of disease, perhaps even before significant symptoms develop. Pathology in Alzheimer's disease accumulates for well over a decade before symptoms are detected giving a large potential window of opportunity for intervention. It is therefore important that imaging techniques detect subtle changes in brain tissue before significant macroscopic brain atrophy. Current diagnostic techniques often do not permit early diagnosis or are too expensive for routine clinical use. Magnetic Resonance Imaging (MRI) is the most versatile, affordable, and powerful imaging modality currently available, being able to deliver detailed analyses of anatomy, tissue volumes, and tissue state. In this mini-review, we consider how MRI might detect patients at risk of future dementia in the early stages of pathological change when symptoms are mild. We consider the contributions made by the various modalities of MRI (structural, diffusion, perfusion, relaxometry) in identifying not just atrophy (a late-stage AD symptom) but more subtle changes reflective of early dementia pathology. The sensitivity of MRI not just to gross anatomy but to the underlying "health" at the cellular (and even molecular) scales, makes it very well suited to this task.

  9. Predictors of driving safety in early Alzheimer disease

    PubMed Central

    Dawson, J D.; Anderson, S W.; Uc, E Y.; Dastrup, E; Rizzo, M

    2009-01-01

    Objective: To measure the association of cognition, visual perception, and motor function with driving safety in Alzheimer disease (AD). Methods: Forty drivers with probable early AD (mean Mini-Mental State Examination score 26.5) and 115 elderly drivers without neurologic disease underwent a battery of cognitive, visual, and motor tests, and drove a standardized 35-mile route in urban and rural settings in an instrumented vehicle. A composite cognitive score (COGSTAT) was calculated for each subject based on eight neuropsychological tests. Driving safety errors were noted and classified by a driving expert based on video review. Results: Drivers with AD committed an average of 42.0 safety errors/drive (SD = 12.8), compared to an average of 33.2 (SD = 12.2) for drivers without AD (p < 0.0001); the most common errors were lane violations. Increased age was predictive of errors, with a mean of 2.3 more errors per drive observed for each 5-year age increment. After adjustment for age and gender, COGSTAT was a significant predictor of safety errors in subjects with AD, with a 4.1 increase in safety errors observed for a 1 SD decrease in cognitive function. Significant increases in safety errors were also found in subjects with AD with poorer scores on Benton Visual Retention Test, Complex Figure Test-Copy, Trail Making Subtest-A, and the Functional Reach Test. Conclusion: Drivers with Alzheimer disease (AD) exhibit a range of performance on tests of cognition, vision, and motor skills. Since these tests provide additional predictive value of driving performance beyond diagnosis alone, clinicians may use these tests to help predict whether a patient with AD can safely operate a motor vehicle. GLOSSARY AD = Alzheimer disease; AVLT = Auditory Verbal Learning Test; Blocks = Block Design subtest; BVRT = Benton Visual Retention Test; CFT = Complex Figure Test; CI = confidence interval; COWA = Controlled Oral Word Association; CS = contrast sensitivity; FVA = far visual

  10. Neuropathology of Alzheimer's disease.

    PubMed

    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 rodlike 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. (c) 2010 Mount Sinai School of Medicine.

  11. Driver landmark and traffic sign identification in early Alzheimer's disease.

    PubMed

    Uc, E Y; Rizzo, M; Anderson, S W; Shi, Q; Dawson, J D

    2005-06-01

    To assess visual search and recognition of roadside targets and safety errors during a landmark and traffic sign identification task in drivers with Alzheimer's disease. 33 drivers with probable Alzheimer's disease of mild severity and 137 neurologically normal older adults underwent a battery of visual and cognitive tests and were asked to report detection of specific landmarks and traffic signs along a segment of an experimental drive. The drivers with mild Alzheimer's disease identified significantly fewer landmarks and traffic signs and made more at-fault safety errors during the task than control subjects. Roadside target identification performance and safety errors were predicted by scores on standardised tests of visual and cognitive function. Drivers with Alzheimer's disease are impaired in a task of visual search and recognition of roadside targets; the demands of these targets on visual perception, attention, executive functions, and memory probably increase the cognitive load, worsening driving safety.

  12. TREM2 Variants in Alzheimer's Disease

    PubMed Central

    Guerreiro, Rita; Wojtas, Aleksandra; Bras, Jose; Carrasquillo, Minerva; Rogaeva, Ekaterina; Majounie, Elisa; Cruchaga, Carlos; Sassi, Celeste; Kauwe, John S.K.; Younkin, Steven; Hazrati, Lilinaz; Collinge, John; Pocock, Jennifer; Lashley, Tammaryn; Williams, Julie; Lambert, Jean-Charles; Amouyel, Philippe; Goate, Alison; Rademakers, Rosa; Morgan, Kevin; Powell, John; St. George-Hyslop, Peter; Singleton, Andrew; Hardy, John

    2013-01-01

    BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.) PMID:23150934

  13. The dynamics of Alzheimer's disease biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort.

    PubMed

    Caroli, A; Frisoni, G B

    2010-08-01

    The aim of this study was to investigate the dynamics of four of the most validated biomarkers for Alzheimer's disease (AD), cerebro-spinal fluid (CSF) Abeta 1-42, tau, hippocampal volume, and FDG-PET, in patients at different stage of AD. Two hundred twenty-nine cognitively healthy subjects, 154 mild cognitive impairment (MCI) patients converted to AD, and 193 (95 early and 98 late) AD patients were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. For each biomarker, individual values were Z-transformed and plotted against ADAS-cog scores, and sigmoid and linear fits were compared. For most biomarkers the sigmoid model fitted data significantly better than the linear model. Abeta 1-42 time course followed a steep curve, stabilizing early in the disease course. CSF tau and hippocampal volume changed later showing similar monotonous trends, reflecting disease progression. Hippocampal loss trend was steeper and occurred earlier in time in APOE epsilon4 carriers than in non-carriers. FDG-PET started changing early in time and likely followed a linear decline. In conclusion, this study provides the first evidence in favor of the dynamic biomarker model which has recently been proposed. 2010 Elsevier Inc. All rights reserved.

  14. Predictors of driving safety in early Alzheimer disease.

    PubMed

    Dawson, J D; Anderson, S W; Uc, E Y; Dastrup, E; Rizzo, M

    2009-02-10

    To measure the association of cognition, visual perception, and motor function with driving safety in Alzheimer disease (AD). Forty drivers with probable early AD (mean Mini-Mental State Examination score 26.5) and 115 elderly drivers without neurologic disease underwent a battery of cognitive, visual, and motor tests, and drove a standardized 35-mile route in urban and rural settings in an instrumented vehicle. A composite cognitive score (COGSTAT) was calculated for each subject based on eight neuropsychological tests. Driving safety errors were noted and classified by a driving expert based on video review. Drivers with AD committed an average of 42.0 safety errors/drive (SD = 12.8), compared to an average of 33.2 (SD = 12.2) for drivers without AD (p < 0.0001); the most common errors were lane violations. Increased age was predictive of errors, with a mean of 2.3 more errors per drive observed for each 5-year age increment. After adjustment for age and gender, COGSTAT was a significant predictor of safety errors in subjects with AD, with a 4.1 increase in safety errors observed for a 1 SD decrease in cognitive function. Significant increases in safety errors were also found in subjects with AD with poorer scores on Benton Visual Retention Test, Complex Figure Test-Copy, Trail Making Subtest-A, and the Functional Reach Test. Drivers with Alzheimer disease (AD) exhibit a range of performance on tests of cognition, vision, and motor skills. Since these tests provide additional predictive value of driving performance beyond diagnosis alone, clinicians may use these tests to help predict whether a patient with AD can safely operate a motor vehicle.

  15. Molecular genetics of early-onset Alzheimer's disease revisited.

    PubMed

    Cacace, Rita; Sleegers, Kristel; Van Broeckhoven, Christine

    2016-06-01

    As the discovery of the Alzheimer's disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a apolipoprotein E (APOE) risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Early-onset Alzheimer's disease: nonamnestic subtypes and type 2 AD.

    PubMed

    Mendez, Mario F

    2012-11-01

    Patients with Alzheimer's disease (AD), the most prevalent neurodegenerative dementia, are usually elderly; however, ∼4-5% develop early-onset AD (EOAD) with onset before age 65. Most EOAD is sporadic, but about 5% of patients with EOAD have an autosomal dominant mutation such as Presenilin 1, Presenilin 2, or alterations in the Amyloid Precursor Protein gene. Although most Alzheimer's research has concentrated on older, late-onset AD (LOAD), there is much recent interest and research in EOAD. These recent studies indicate that EOAD is a heterogeneous disorder with significant differences from LOAD. From 22-64% of EOAD patients have a predominant nonamnestic syndrome presenting with deficits in language, visuospatial abilities, praxis, or other non-memory cognition. These nonamnestic patients may differ in several ways from the usual memory or amnestic patients. Patients with nonamnestic EOAD compared to typical amnestic AD have a more aggressive course, lack the apolipoprotein Eɛ4 (APOE ɛ4) susceptibility gene for AD, and have a focus and early involvement of non-hippocampal areas of brain, particularly parietal neocortex. These differences in the EOAD subtypes indicate differences in the underlying amyloid cascade, the prevailing pathophysiological theory for the development of AD. Together the results of recent studies suggest that nonamnestic subtypes of EOAD constitute a Type 2 AD distinct from the usual, typical disorder. In sum, the study of EOAD can reveal much about the clinical heterogeneity, predisposing factors, and neurobiology of this disease. Copyright © 2012 IMSS. Published by Elsevier Inc. All rights reserved.

  17. Canadian patient played key role in uncovering secrets about early-onset Alzheimer's disease.

    PubMed Central

    Lyttle, J

    1996-01-01

    Last June, the University of Toronto announced that Canadian scientists and a team of international researchers had discovered the gene responsible for most cases of early-onset Alzheimer's disease. One of the key players in that discovery had died just 3 months earlier. Frances Hodge, who participated in a battery of tests for the 20 years she lived with the disease, helped lead researchers to gene S182--and an ember of hope for future generations. Images p906-a PMID:8634971

  18. 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 ...

  19. [Utility of axial images in an early Alzheimer disease diagnosis support system (VSRAD)].

    PubMed

    Goto, Masami; Aoki, Shigeki; Abe, Osamu; Masumoto, Tomohiko; Watanabe, Yasushi; Satake, Yoshiroh; Nishida, Katsuji; Ino, Kenji; Yano, Keiichi; Iida, Kyohhito; Mima, Kazuo; Ohtomo, Kuni

    2006-09-20

    In recent years, voxel-based morphometry (VBM) has become a popular tool for the early diagnosis of Alzheimer disease. The Voxel-Based Specific Regional Analysis System for Alzheimer's Disease (VSRAD), a VBM system that uses MRI, has been reported to be clinically useful. The able-bodied person database (DB) of VSRAD, which employs sagittal plane imaging, is not suitable for analysis by axial plane imaging. However, axial plane imaging is useful for avoiding motion artifacts from the eyeball. Therefore, we created an able-bodied person DB by axial plane imaging and examined its utility. We also analyzed groups of able-bodied persons and persons with dementia by axial plane imaging and reviewed the validity. After using the DB of axial plane imaging, the Z-score of the intrahippocampal region improved by 8 in 13 instances. In all brains, the Z-score improved by 13 in all instances.

  20. A large early-onset Alzheimer`s disease pedigree linked to chromosome 14q24.3

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hannequin, D.; Campion, D.; Brice, A.

    1994-09-01

    A large French pedigree including 34 subjects with early-onset progressive dementia was identified. In patients, the mean age-at-onset was 46 {plus_minus} 3.5 (SD) years and the mean age at death 52.6 {plus_minus} 5.7 (SD) years. No evidence for anticipation or genetic imprinting was found. Twelve patients were clinically diagnosed as probable Alzheimer`s disease (AD) according to the NINCDS-ADRDA criteria. Myoclonus and extrapyramidal signs were common and seizures were found in all affected subjects. At autopsy, neuropathological changes typical of AD were present in two brains. A significant lod score of 5.38 was observed at a recombination fraction of {theta} =more » 0.0 with the genetic marker D14S43, thereby establishing that the responsible gene was located on chromosome 14q24.3. Furthermore, no obligate recombinant was observed with markers D14S77 and D14S71. Typing other genetic markers in this region will allow us to localize more precisely the pathological gene.« less

  1. Alzheimer's disease prevention: from risk factors to early intervention.

    PubMed

    Crous-Bou, Marta; Minguillón, Carolina; Gramunt, Nina; Molinuevo, José Luis

    2017-09-12

    Due to the progressive aging of the population, Alzheimer's disease (AD) is becoming a healthcare burden of epidemic proportions for which there is currently no cure. Disappointing results from clinical trials performed in mild-moderate AD dementia combined with clear epidemiological evidence on AD risk factors are contributing to the development of primary prevention initiatives. In addition, the characterization of the long asymptomatic stage of AD is allowing the development of intervention studies and secondary prevention programmes on asymptomatic at-risk individuals, before substantial irreversible neuronal dysfunction and loss have occurred, an approach that emerges as highly relevant.In this manuscript, we review current strategies for AD prevention, from primary prevention strategies based on identifying risk factors and risk reduction, to secondary prevention initiatives based on the early detection of the pathophysiological hallmarks and intervention at the preclinical stage of the disease. Firstly, we summarize the evidence on several AD risk factors, which are the rationale for the establishment of primary prevention programmes as well as revising current primary prevention strategies. Secondly, we review the development of public-private partnerships for disease prevention that aim to characterize the AD continuum as well as serving as platforms for secondary prevention trials. Finally, we summarize currently ongoing clinical trials recruiting participants with preclinical AD or a higher risk for the onset of AD-related cognitive impairment.The growing body of research on the risk factors for AD and its preclinical stage is favouring the development of AD prevention programmes that, by delaying the onset of Alzheimer's dementia for only a few years, would have a huge impact on public health.

  2. [Possibilities of modern imaging technologies in early diagnosis of Alzheimer disease].

    PubMed

    Unschuld, Paul G

    2015-04-01

    Recent advances in neuroimaging technology and image analysis algorithms have significantly contributed to a better understanding of spatial and temporal aspects of brain change associated with Alzheimer Disease. The current review will demonstrate how functional (fMRI) and structural magnetic resonance imaging (MRI) techniques may be used to identify distinct patterns of brain change associated with disease progression and also increased risk for Alzheimer Disease. Moreover, Positron Emission Tomography (PET) based measures of glucosemetabolism (Fluorodeoxyglucose, FDG) and Amyloid-beta plaque density (11-C-Pittsburgh Compound B, PiB and 18-F) will be reviewed regarding their diagnostic value for assessing the individual degree of Alzheimer -pathology and thus complement the information provided by MRI and other clinical measures.

  3. Public-private partnerships improve health outcomes in individuals with early stage Alzheimer's disease.

    PubMed

    Galvin, James E; Tolea, Magdalena I; George, Nika; Wingbermuehle, Cheryl

    2014-01-01

    In a collaborative effort between the Missouri Department of Health, Area Agencies on Aging (AAA), Alzheimer Association, and academic researchers, we tested whether early dementia detection and comprehensive care consultations would improve health outcomes in care receivers (CRs) and their family caregivers (FCGs), therefore addressing an important public health concern. A total of 244 community-dwelling older adults screened for early-stage dementia by the AAA field staff were referred to the Alzheimer Association and participated in Project Learn MORE (Missouri Outreach and Referral Expanded) (PLM) - a 2-year, nonrandomized multisite intervention consisting of comprehensive care consultations to improve coping skills. PLM participants were compared against 96 controls receiving the Alzheimer Association's "usual services" between January 2011 and December 2012. We examined CR and FCG outcomes, including burden, care confidence, and mood, as effects of PLM, on delaying transitions in level of care. CRs showed improved knowledge (P=0.002) and reduced depression (P=0.007), while FCGs demonstrated improved knowledge (P=0.003) and ability to identify sources of support for the CR (P=0.032) and for themselves (P=0.043). However, FCGs were more burdened after PLM (P=0.02), due to increased awareness of Alzheimer's disease. PLM delayed transitions in care (odds ratio [OR] 3.32, 95% confidence level [CI]: 1.25-8.83) with the number needed to treat =6.82. PLM was successful in improving detection of incident cases of dementia in the community and in connecting patients and their families with needed services. Our findings support the use of state agencies and community service partners to detect dementia. Early implementation of psychosocial interventions could have significant impact in improving patient- and family-centered outcomes, potentially providing a cost-efficient alternative to pharmacotherapy.

  4. Early Statin Use and the Progression of Alzheimer Disease: A Total Population-Based Case-Control Study.

    PubMed

    Lin, Feng-Cheng; Chuang, Yun-Shiuan; Hsieh, Hui-Min; Lee, Tzu-Chi; Chiu, Kuei-Fen; Liu, Ching-Kuan; Wu, Ming-Tsang

    2015-11-01

    The protective effect of statin on Alzheimer disease (AD) is still controversial, probably due to the debate about when to start the use of statin and the lack of any large-scale randomized evidence that actually supports the hypothesis. The purpose of this study was to examine the protective effect of early statin use on mild-to-moderate AD in the total Taiwanese population.This was a total population-based case-control study, using the total population of Taiwanese citizens seen in general medical practice; therefore, the findings can be applied to the general population. The study patients were those with newly diagnosed dementia (ICD-9 290.x) and prescribed any acetylcholinesterase inhibitors (AChEI) from the Taiwan National Health Insurance dataset in 1997 to 2008. The newly diagnosed eligible mild-to-moderate AD patients were traced from the dates of their index dates, which was defined as the first day to receive any AChEI treatment, back to 1 year (exposure period) to categorize them into AD with early statin use and without early statin use. Early statin use was defined as patients using statin before AChEI treatment. Alzheimer disease patients with early statin use were those receiving any statin treatment during the exposure period. Then, we used propensity-score-matched strategy to match these 2 groups as 1:1. The matched study patients were followed-up from their index dates. The primary outcome was the discontinuation of AChEI treatment, indicating AD progression.There were 719 mild-to-moderate AD-paired patients with early statin use and without early statin use for analyses. Alzheimer disease progression was statistically lower in AD patients with early statin use than those without (P = 0.00054). After adjusting for other covariates, mild-to-moderate AD patients with early stain use exhibited a 0.85-risk (95% CI = 0.76-0.95, P = 0.0066) to have AD progression than those without.Early statin use was significantly associated with a reduction in AD

  5. Daily Physical Activity Patterns During the Early Stage of Alzheimer's Disease.

    PubMed

    Varma, Vijay R; Watts, Amber

    2017-01-01

    Alzheimer's disease (AD) is a neurodegenerative disease that results in severe disability. Very few studies have explored changes in daily physical activity patterns during early stages of AD when components of physical function and mobility may be preserved. Our study explored differences in daily physical activity profiles, independent of the effects of non-cognitive factors including physical function and age, among individuals with mild AD compared to controls. Patients with mild AD and controls (n = 92) recruited from the University of Kansas Alzheimer's Disease Center Registry, wore the Actigraph GT3X+ for seven days, and provided objective physical function (VO2 max) and mobility data. Using multivariate linear regression, we explored whether individuals with mild AD had different daily average and diurnal physical activity patterns compared to controls independent of non-cognitive factors that may affect physical activity, including physical function and mobility. We found that mild AD was associated with less moderate-intensity physical activity (p < 0.05), lower peak activity (p < 0.01), and lower physical activity complexity (p < 0.05) particularly during the morning. Mild AD was not associated with greater sedentary activity or less lower-intensity physical activity across the day after adjusting for non-cognitive covariates. These findings suggest that factors independent of physical capacity and mobility may drive declines in moderate-intensity physical activity, and not lower-intensity or sedentary activity, during the early stage of AD. This underscores the importance of a better mechanistic understanding of how cognitive decline and AD pathology impact physical activity. Findings emphasize the potential value of designing and testing time-of-day specific physical activity interventions targeting individuals in the early stages of AD, prior to significant declines in mobility and physical function.

  6. Which medical and social decision topics are important after early diagnosis of Alzheimer's Disease from the perspectives of people with Alzheimer's Disease, spouses and professionals?

    PubMed

    Bronner, Katharina; Perneczky, Robert; McCabe, Rose; Kurz, Alexander; Hamann, Johannes

    2016-03-08

    The relevance of early decision making will rise with increasing availability of early detection of Alzheimer's disease (AD) using brain imaging or biomarkers. Five people with mild AD, six relatives and 13 healthcare professionals with experience in the management of AD were interviewed in a qualitative study regarding medical and social decision topics that emerge after early diagnosis of Alzheimer's disease. Medical treatment, assistance in everyday life and legal issues emerged as the main decision topics after an early diagnosis of AD. People with AD mostly got in contact with the health and social care system through the initiative of their spouses. They were usually aware of their illness and most received antidementia drugs and/or behavioural interventions. Following diagnosis people with AD received support by their spouses. Healthcare professionals were aware of the risk of excessive demand on relatives due to supporting their family member with AD. In the opinion of healthcare professionals legal issues should be arranged in time before patients lose their decisional capacity. In addition, people with AD and spouses reported various coping strategies, in particular "carry on as normal" after diagnosis but mostly are reluctant to actively plan for future stages of the disease. Due to the common desire to "carry on as usual" after a diagnosis of AD, many people with AD and spouses may miss the opportunity to discuss and decide on important medical and social topics. A structured approach e.g. a decision aid might support people with AD and spouses in their decision making process and thereby preserve persons' with AD autonomy before they lose the capacity in decision-making.

  7. Assessing disease-modifying effects of norepinephrine in Down syndrome and Alzheimer's disease.

    PubMed

    Ponnusamy, Ravikumar; McNerney, M Windy; Moghadam, Shahrzad; Salehi, Ahmad

    2017-11-08

    Building upon the knowledge that a number of important brain circuits undergo significant degeneration in Alzheimer's disease, numerous recent studies suggest that the norepinephrine-ergic system in the brainstem undergoes significant alterations early in the course of both Alzheimer's disease and Down syndrome. Massive projections from locus coeruleus neurons to almost the entire brain, extensive innervation of brain capillaries, and widespread distribution of noradrenergic receptors enable the norepinephrine-ergic system to play a crucial role in neural processes, including cognitive function. These anatomical and functional characteristics support the role of the norepinephrine-ergic system as an important target for developing new therapies for cognitive dysfunction. Careful neuropathological examinations using postmortem samples from individuals with Alzheimer's disease have implicated the role of the norepinephrine-ergic system in the etiopathogenesis of Alzheimer's disease. Furthermore, numerous studies have supported the existence of a strong interaction between norepinephrine-ergic and neuroimmune systems. We explore the interaction between the two systems that could play a role in the disease-modifying effects of norepinephrine in Alzheimer's disease and Down syndrome. Copyright © 2017. Published by Elsevier B.V.

  8. 'Making the best you can of it': living with early-stage Alzheimer's disease.

    PubMed

    Macrae, Hazel

    2008-04-01

    Drawing upon data from a qualitative study of persons who are in the early stage of the condition, this paper examines the meaning of Alzheimer's disease. It contrasts the meaning of the disease as portrayed in popular culture with its meaning as interpreted by persons living with it. Findings show that persons with the illness do not necessarily accept the negative cultural meaning of the disease, nor the helpless 'victim' role in which they are generally cast. With a determination to 'make the best of it', strategies such as humour, normalisation, present-time orientation, and life review are employed to create a meaningful life.

  9. Personality changes in patients with beginning Alzheimer disease.

    PubMed

    Pocnet, Cornelia; Rossier, Jérôme; Antonietti, Jean-Philippe; von Gunten, Armin

    2011-07-01

    To investigate personality traits in patients with Alzheimer disease, compared with mentally healthy control subjects. We compared both current personality characteristics using structured interviews as well as current and previous personality traits as assessed by proxies. Fifty-four patients with mild Alzheimer disease and 64 control subjects described their personality traits using the Structured Interview for the Five-Factor Model. Family members filled in the Revised NEO Personality Inventory, Form R, to evaluate their proxies' current personality traits, compared with 5 years before the estimated beginning of Alzheimer disease or 5 years before the control subjects. After controlling for age, the Alzheimer disease group presented significantly higher scores than normal control subjects on current neuroticism, and significantly lower scores on current extraversion, openness, and conscientiousness, while no significant difference was observed on agreeableness. A similar profile, though less accentuated, was observed when considering personality traits as the patients' proxies remembered them. Diachronic personality assessment showed again significant differences between the 2 groups for the same 4 domains, with important personality changes only for the Alzheimer disease group. Group comparison and retrospective personality evaluation are convergent. Significant personality changes follow a specific trend in patients with Alzheimer disease and contrast with the stability generally observed in mentally healthy people in their personality profile throughout their lives. Whether or not the personality assessment 5 years before the current status corresponds to an early sign of Alzheimer disease or real premorbid personality differences in people who later develop Alzheimer disease requires longitudinal studies.

  10. Knowledge of Alzheimer's disease among Vietnamese Americans and correlates of their knowledge about Alzheimer's disease.

    PubMed

    Lee, Sang E; Casado, Banghwa Lee

    2017-01-01

    The present study examined the knowledge of Alzheimer's disease and correlates of the disease knowledge among Vietnamese Americans. Cross-sectional survey interviews were conducted with 95 middle-aged and older Vietnamese Americans. Vietnamese Americans showed limited knowledge about Alzheimer's disease. Normalization of Alzheimer's disease in old age was prevalent. They lacked knowledge about treatment and cure of Alzheimer's disease. Those who reside longer in the U.S. and are more exposed to Alzheimer's disease are likely to have higher levels of Alzheimer's disease knowledge. Our study identified current Alzheimer's disease knowledge level and status, and areas of misconceptions and knowledge gaps among Vietnamese Americans, calling for urgent needs for educational outreach to improve knowledge about Alzheimer's disease among Vietnamese Americans. Information about who can be more or less knowledgeable about Alzheimer's disease can be used to strategize and tailor outreach efforts for different segments of the Vietnamese American population.

  11. Reversible Pisa Syndrome Induced by Rivastigmine in a Patient With Early-Onset Alzheimer Disease.

    PubMed

    Hsu, Chih-Wei; Lee, Yu; Lee, Chun-Yi; Lin, Pao-Yen

    Pisa syndrome (PS) is a state of dystonic muscle contraction with a marked truncal deviation to one side. It is an uncommon adverse effect of antipsychotic drugs, but is rarely reported in patients receiving acetylcholinesterase inhibitors, especially rivastigmine. We present a 57-year-old female patient with Alzheimer disease who began to develop symptoms of dementia at the age of 51 years. She was observed to have symptoms of PS after continuous use of rivastigmine (9 mg/d) for nearly 2 years. The PS symptoms improved after the dose of rivastigmine was reduced but recurred when the dose was added back to 9 mg/d. Finally, after we decreased the dose to 4.5 mg/d, her PS symptoms were remitted. This report reminds us that clinicians need to be cautious about the risk of PS when prescribing rivastigmine in a patient with early-onset Alzheimer disease.

  12. “Noncognitive” symptoms of early Alzheimer disease

    PubMed Central

    Masters, Mary Clare; Morris, John C.

    2015-01-01

    Objectives: To observe the natural time course of noncognitive symptoms before the onset of symptomatic Alzheimer disease dementia. Methods: Using the National Alzheimer's Coordinating Center Uniform Data Set from September 2005 to March 2013, data from cognitively normal individuals who were aged 50 years or older at first visit and had subsequent follow-up were analyzed. Survival analyses were used to examine the development of particular symptoms relative to each other on the Neuropsychiatric Inventory Questionnaire (NPI-Q), Functional Activities Questionnaire, and Geriatric Depression Scale, and to compare the development of individual symptoms for persons who did and did not receive a Clinical Dementia Rating (CDR) >0 (indicating abnormal cognition) during the follow-up period. Results: The order of symptom occurrence on the NPI-Q was similar for participants who remained at CDR 0 and for those who received a CDR >0 over the follow-up period, although the time to most NPI-Q symptoms was faster for participants who received a CDR >0 (p < 0.001). With the exception of memory, Geriatric Depression Scale symptoms reported by both CDR groups were similar. Conclusions: We found a significantly earlier presence of positive symptoms on the NPI-Q in cognitively normal patients who subsequently developed CDR >0. Among participants with no depression symptoms at baseline, results suggest that depressive symptoms may increase with aging regardless of incipient dementia. Such findings begin to delineate the noncognitive course of Alzheimer disease dementia in the preclinical stages. Future research must further elucidate the correlation between noncognitive changes and distinct dementia subtypes. PMID:25589671

  13. 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.

  14. 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. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Use of curcumin in diagnosis, prevention, and treatment of Alzheimer's disease

    PubMed Central

    Chen, Min; Du, Zhi-Yun; Zheng, Xi; Li, Dong-Li; Zhou, Ren-Ping; Zhang, Kun

    2018-01-01

    This review summarizes and describes the use of curcumin in diagnosis, prevention, and treatment of Alzheimer's disease. For diagnosis of Alzheimer's disease, amyloid-β and highly phosphorylated tau protein are the major biomarkers. Curcumin was developed as an early diagnostic probe based on its natural fluorescence and high binding affinity to amyloid-β. Because of its multi-target effects, curcumin has protective and preventive effects on many chronic diseases such as cerebrovascular disease, hypertension, and hyperlipidemia. For prevention and treatment of Alzheimer's disease, curcumin has been shown to effectively maintain the normal structure and function of cerebral vessels, mitochondria, and synapses, reduce risk factors for a variety of chronic diseases, and decrease the risk of Alzheimer's disease. The effect of curcumin on Alzheimer's disease involves multiple signaling pathways: anti-amyloid and metal iron chelating properties, antioxidation and anti-inflammatory activities. Indeed, there is a scientific basis for the rational application of curcumin in prevention and treatment of Alzheimer's disease. PMID:29722330

  16. Use of curcumin in diagnosis, prevention, and treatment of Alzheimer's disease.

    PubMed

    Chen, Min; Du, Zhi-Yun; Zheng, Xi; Li, Dong-Li; Zhou, Ren-Ping; Zhang, Kun

    2018-04-01

    This review summarizes and describes the use of curcumin in diagnosis, prevention, and treatment of Alzheimer's disease. For diagnosis of Alzheimer's disease, amyloid-β and highly phosphorylated tau protein are the major biomarkers. Curcumin was developed as an early diagnostic probe based on its natural fluorescence and high binding affinity to amyloid-β. Because of its multi-target effects, curcumin has protective and preventive effects on many chronic diseases such as cerebrovascular disease, hypertension, and hyperlipidemia. For prevention and treatment of Alzheimer's disease, curcumin has been shown to effectively maintain the normal structure and function of cerebral vessels, mitochondria, and synapses, reduce risk factors for a variety of chronic diseases, and decrease the risk of Alzheimer's disease. The effect of curcumin on Alzheimer's disease involves multiple signaling pathways: anti-amyloid and metal iron chelating properties, antioxidation and anti-inflammatory activities. Indeed, there is a scientific basis for the rational application of curcumin in prevention and treatment of Alzheimer's disease.

  17. A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease.

    PubMed

    Luedecke, Daniel; Becktepe, Jos S; Lehmbeck, Jan T; Finckh, Ulrich; Yamamoto, Raina; Jahn, Holger; Boelmans, Kai

    2014-04-30

    Mutations in the presenilin 1 (PS1) gene (PSEN1) are associated with familial Alzheimer disease (FAD). Here, we report on a 50-year-old patient presenting with progressive deterioration of his short-term memory and a family history of early-onset dementia. Diagnostic workup included a neuropsychological examination, structural magnetic resonance (MR) imaging, cerebrospinal fluid (CSF) biomarkers including total tau, phosphorylated tau, and Aβ42 levels, as well as sequencing relevant fragments of the genes PSEN1, PSEN2, and APP. Additionally, we were able to obtain archival paraffin-embedded cerebellar tissue from the patient's father for cosegregation analysis. Clinical, neuropsychological and MR imaging data were indicative of early-onset Alzheimer disease. Furthermore, CSF biomarkers showed a typical pattern for Alzheimer disease. DNA sequencing revealed a heterozygous nucleotide transition (c.824C>T) in exon 8 of PSEN1, leading to an amino acid change from alanine to valine at codon 275 (Ala275Val). The same mutation was found in an archival brain specimen of the patient's demented father, but not in a blood sample of the non-demented mother. This mutation alters a conserved residue in the large hydrophilic loop of PS1, suggesting pathogenic relevance. Cosegregegation analysis and the structural as well as the presumed functional role of the mutated and highly conserved residue suggest FAD causing characteristics of the novel PSEN1 mutation Ala275Val. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Metabolic brain networks in aging and preclinical Alzheimer's disease.

    PubMed

    Arnemann, Katelyn L; Stöber, Franziska; Narayan, Sharada; Rabinovici, Gil D; Jagust, William J

    2018-01-01

    Metabolic brain networks can provide insight into the network processes underlying progression from healthy aging to Alzheimer's disease. We explore the effect of two Alzheimer's disease risk factors, amyloid-β and ApoE ε4 genotype, on metabolic brain networks in cognitively normal older adults (N = 64, ages 69-89) compared to young adults (N = 17, ages 20-30) and patients with Alzheimer's disease (N = 22, ages 69-89). Subjects underwent MRI and PET imaging of metabolism (FDG) and amyloid-β (PIB). Normal older adults were divided into four subgroups based on amyloid-β and ApoE genotype. Metabolic brain networks were constructed cross-sectionally by computing pairwise correlations of metabolism across subjects within each group for 80 regions of interest. We found widespread elevated metabolic correlations and desegregation of metabolic brain networks in normal aging compared to youth and Alzheimer's disease, suggesting that normal aging leads to widespread loss of independent metabolic function across the brain. Amyloid-β and the combination of ApoE ε4 led to less extensive elevated metabolic correlations compared to other normal older adults, as well as a metabolic brain network more similar to youth and Alzheimer's disease. This could reflect early progression towards Alzheimer's disease in these individuals. Altered metabolic brain networks of older adults and those at the highest risk for progression to Alzheimer's disease open up novel lines of inquiry into the metabolic and network processes that underlie normal aging and Alzheimer's disease.

  19. 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. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  20. [Mutations of amyloid precursor protein in early-onset familial Alzheimer's disease].

    PubMed

    Naruse, S; Tsuji, S; Miyatake, T

    1992-09-01

    Genetic linkage studies of familial Alzheimer's disease (FAD) have suggested that some form of early-onset FAD is linked to proximal long arm of chromosome 21. It has been also suggested that some form of late-onset FAD is linked to long arm of chromosome 19. Goate et al have identified a mis-sense mutation (Val to Ile) in exon 17 of the amyloid precursor protein (APP) gene in 2 of 16 early-onset FAD families, and have shown that the FAD locus in an FAD family is tightly linked to the mis-sense mutation. To determine if the mis-sense mutation is observed in different ethnic origine, we have studied some early-onset FAD families. Two early-onset FAD families showed the existence of the mutation. As the mutation has been identified in different ethnic origine and the mutation has not been observed in normal individuals, it strengthen hypothesis that the mutation is pathogenic. Recently, Val to Phe and Val to Gly mutations have been also identified at the same codon (Codon 717) of the APP gene.

  1. Alzheimer's disease and other neurological disorders.

    PubMed

    Henderson, V W

    2007-10-01

    Menopausal status and estrogen-containing hormone therapy may influence several neurological disorders, including Alzheimer's disease, epilepsy, migraine headache, multiple sclerosis, Parkinson's disease, sleep disorders, and stroke. For most of these illnesses, evidence on hormone therapy is insufficient to guide practice decisions. For stroke, clinical trial evidence indicates that hormone therapy increases risk of cerebral infarction. For women with Alzheimer's disease, estrogen treatment trials have tended to be small and of short duration. Most suggest that estrogen started after the onset of dementia symptoms does not meaningfully improve cognition or slow disease progression. Hormone therapy initiated after age 64 increased all-cause dementia in the Women's Health Initiative Memory Study. Many observational studies, however, report protective associations between hormone use and Alzheimer risk. Apparent risk reduction may represent a bias toward hormone therapy, since hormones are more often prescribed to healthier women. However, when compared to the Women's Health Initiative Memory Study, estrogen exposures in many observational studies reflect hormone initiation at a younger age, closer to the time of menopause. One intriguing hypothesis is that hormone therapy initiated or used during an early critical window may reduce later Alzheimer incidence. Public health implications of this hypothesis are important, but current data are inadequate to decide the issue.

  2. P300 Amplitude in Alzheimer's Disease: A Meta-Analysis and Meta-Regression.

    PubMed

    Hedges, Dawson; Janis, Rebecca; Mickelson, Stephen; Keith, Cierra; Bennett, David; Brown, Bruce L

    2016-01-01

    Alzheimer's disease accounts for 60% of all dementia. Numerous biomarkers have been developed that can help in making an early diagnosis. The P300 is an event-related potential that may be abnormal in Alzheimer's disease. Given the possible association between P300 amplitude and Alzheimer's disease and the need for biomarkers in early Alzheimer's disease, the main purpose of this meta-analysis and meta-regression was to characterize P300 amplitude in probable Alzheimer's disease compared to healthy controls. Using online search engines, we identified peer-reviewed articles containing amplitude measures for the P300 in response to a visual or auditory oddball stimulus in subjects with Alzheimer's disease and in a healthy control group and pooled effect sizes for differences in P300 amplitude between Alzheimer's disease and control groups to obtain summary effect sizes. We also used meta-regression to determine whether age, sex, educational attainment, or dementia severity affected the association between P300 amplitude and Alzheimer's disease. Twenty articles containing a total of 646 subjects met inclusion and exclusion criteria. The overall effect size from all electrode locations was 1.079 (95% confidence interval=0.745-1.412, P<.001). The pooled effect sizes for the Cz, Fz, and Pz locations were 1.226 (P<.001), 0.724 (P=.0007), and 1.430 (P<.001), respectively. Meta-regression showed an association between amplitude and educational attainment, but no association between amplitude and age, sex, and dementia severity. In conclusion, P300 amplitude is smaller in subjects with Alzheimer's disease than in healthy controls. © EEG and Clinical Neuroscience Society (ECNS) 2014.

  3. 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…

  4. 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…

  5. Mental-orientation: A new approach to assessing patients across the Alzheimer's disease spectrum.

    PubMed

    Peters-Founshtein, Gregory; Peer, Michael; Rein, Yanai; Kahana Merhavi, Shlomzion; Meiner, Zeev; Arzy, Shahar

    2018-05-21

    This study aims to assess the role of mental-orientation in the diagnosis of mild cognitive impairment and Alzheimer's disease using a novel task. A behavioral study (Experiment 1) compared the mental-orientation task to standard neuropsychological tests in patients across the Alzheimer's disease spectrum. A functional MRI study (Experiment 2) in young adults compared activations evoked by the mental-orientation and standard-orientation tasks as well as their overlap with brain regions susceptible to Alzheimer's disease pathology. The mental-orientation task differentiated mild cognitively impaired and healthy controls at 95% accuracy, while the Addenbrooke's Cognitive Examination, Mini-Mental State Examination and standard-orientation achieved 74%, 70% and 50% accuracy, respectively. Functional MRI revealed the mental-orientation task to preferentially recruit brain regions exhibiting early Alzheimer's-related atrophy, unlike the standard-orientation test. Mental-orientation is suggested to play a key role in Alzheimer's disease, and consequently in early detection and follow-up of patients along the Alzheimer's disease spectrum. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  6. Early neurovascular dysfunction in a transgenic rat model of Alzheimer's disease.

    PubMed

    Joo, Illsung L; Lai, Aaron Y; Bazzigaluppi, Paolo; Koletar, Margaret M; Dorr, Adrienne; Brown, Mary E; Thomason, Lynsie A M; Sled, John G; McLaurin, JoAnne; Stefanovic, Bojana

    2017-04-12

    Alzheimer's disease (AD), pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aβ-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans.

  7. Lexical and semantic fluency discrepancy scores in aMCI and early Alzheimer's disease.

    PubMed

    Lonie, Jane A; Herrmann, Lucie L; Tierney, Kevin M; Donaghey, Claire; O'Carroll, Ronan; Lee, Andrew; Ebmeier, Klaus P

    2009-03-01

    Episodic memory is compromised in amnestic mild cognitive impairment (aMCI), but lesser deficits in other cognitive domains are also commonly observed and may be helpful in identifying this group. The relative difference in performance on lexical and semantic fluency tasks may be a sensitive and specific measure in aMCI and early Alzheimer's disease (AD). We compared four groups of participants, 35 early AD, 47 aMCI, 24 healthy controls, and 18 depressive out-patient controls, on semantic and lexical fluency as well as other neuropsychological tests. Early AD and aMCI patients showed a distinct pattern of semantic impairment in the two fluency measures compared with the healthy and depressive controls. The findings implicate early failure of the semantic memory system in aMCI and AD and suggest that consideration of the discrepancy in performance on semantic and lexical fluency measures may help in the early identification of AD.

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

    PubMed

    Claassen, Jurgen A H R

    2015-09-15

    The prevalence of dementia rises to between 20% and 40% with advancing age. The dominant cause of dementia in approximately 70% of these patients is Alzheimer disease. There is no effective disease-modifying pharmaceutical treatment for this neurodegenerative disease. A wide range of Alzheimer drugs that appeared effective in animal models have recently failed to show clinical benefit in patients. However, hopeful news has emerged from recent studies that suggest that therapeutic strategies aimed at reducing cardiovascular disease may also reduce the prevalence of dementia due to Alzheimer disease. This review summarizes the evidence for this link between cardiovascular disease and late onset Alzheimer dementia. Only evidence from human research is considered here. Longitudinal studies show an association between high blood pressure and pathological accumulation of the protein amyloid-beta42, and an even stronger association between vascular stiffness and amyloid accumulation, in elderly subjects. Amyloid-beta42 accumulation is considered to be an early marker of Alzheimer disease, and increases the risk of subsequent cognitive decline and development of dementia. These observations could provide an explanation for recent observations of reduced dementia prevalence associated with improved cardiovascular care. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Blood biomarkers in Alzheimer's disease.

    PubMed

    Altuna-Azkargorta, M; Mendioroz-Iriarte, M

    2018-05-08

    The early diagnosis of Alzheimer's disease (AD) via the use of biomarkers could facilitate the implementation and monitoring of early therapeutic interventions with the potential capacity to significantly modify the course of the disease. Classic cerebrospinal fluid biomarkers and approved structural and functional neuroimaging have a limited clinical application given their invasive nature and/or high cost. The identification of more accessible and less costly biomarkers, such as blood biomarkers, would facilitate application in clinical practice. We present a literature review of the main blood biochemical biomarkers with potential use for diagnosing Alzheimer's disease. Blood biomarkers are cost and time effective with regard to cerebrospinal fluid biomarkers. However, the immediate applicability of blood biochemical biomarkers in clinical practice is not very likely. The main limitations come from the difficulties in measuring and standardising thresholds between different laboratories and in failures to replicate results. Among all the molecules studied, apoptosis and neurodegeneration biomarkers and the biomarker panels obtained through omics approaches, such as isolated or combined metabolomics, offer the most promising results. Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  10. Early detection of Alzheimer disease: methods, markers, and misgivings.

    PubMed

    Green, R C; Clarke, V C; Thompson, N J; Woodard, J L; Letz, R

    1997-01-01

    There is at present no reliable predictive test for most forms of Alzheimer disease (AD). Although some information about future risk for disease is available in theory through ApoE genotyping, it is of limited accuracy and utility. Once neuroprotective treatments are available for AD, reliable early detection will become a key component of the treatment strategy. We recently conducted a pilot survey eliciting attitudes and beliefs toward an unspecified and hypothetical predictive test for AD. The survey was completed by a convenience sample of 176 individuals, aged 22-77, which was 75% female, 30% African-American, and of which 33% had a family member with AD. The survey revealed that 69% of this sample would elect to obtain predictive testing for AD if the test were 100% accurate. Individuals were more likely to desire predictive testing if they had an a priori belief that they would develop AD (p = 0.0001), had a lower educational level (p = 0.003), were worried that they would develop AD (p = 0.02), had a self-defined history of depression (p = 0.04), and had a family member with AD (p = 0.04). However, the desire for predictive testing was not significantly associated with age, gender, ethnicity, or income. The desire to obtain predictive testing for AD decreased as the assumed accuracy of the hypothetical test decreased. A better short-term strategy for early detection of AD may be computer-based neuropsychological screening of at-risk (older aged) individuals to identify very early cognitive impairment. Individuals identified in this manner could be referred for diagnostic evaluation and early cases of AD could be identified and treated. A new self-administered, touch-screen, computer-based, neuropsychological screening instrument called Neurobehavioral Evaluation System-3 is described, which may facilitate this type of screening.

  11. Errorless-based techniques can improve route finding in early Alzheimer's disease: a case study.

    PubMed

    Provencher, Véronique; Bier, Nathalie; Audet, Thérèse; Gagnon, Lise

    2008-01-01

    Topographical disorientation is a common and early manifestation of dementia of Alzheimer type, which threatens independence in activities of daily living. Errorless-based techniques appear to be effective in helping patients with amnesia to learn routes, but little is known about their effectiveness in early dementia of Alzheimer type. A 77-year-old woman with dementia of Alzheimer type had difficulty in finding her way around her seniors residence, which reduced her social activities. This study used an ABA design (A is the baseline and B is the intervention) with multiple baselines across routes for going to the rosary (target), laundry, and game rooms (controls). The errorless-based technique intervention was applied to 2 of the 3 routes. Analyses showed significant improvement only for the routes learned with errorless-based techniques. Following the study, the participant increased her topographical knowledge of her surroundings. Route learning interventions based on errorless-based techniques appear to be a promising approach for improving the independence in early dementia of Alzheimer type.

  12. Early diagnosis of mild cognitive impairment and Alzheimer's disease based on salivary lactoferrin.

    PubMed

    Carro, Eva; Bartolomé, Fernando; Bermejo-Pareja, Félix; Villarejo-Galende, Alberto; Molina, José Antonio; Ortiz, Pablo; Calero, Miguel; Rabano, Alberto; Cantero, José Luis; Orive, Gorka

    2017-01-01

    The Alzheimer's disease (AD) process is likely initiated many years before clinical onset. Biomarkers of preclinical disease are critical for the development of disease-modifying or even preventative therapies. Current biomarkers for early disease, including cerebrospinal fluid tau and amyloid β (Aβ) levels, structural and functional magnetic resonance imaging, and the use of brain amyloid imaging, are limited because they are very invasive or expensive. Noninvasive biomarkers may be a more accessible alternative, but none can currently detect preclinical AD with the required sensitivity and specificity. Here, we show a novel, straight-forward, and noninvasive approach for assessment of early stages of cognitive decline. Salivary samples from cases of amnestic mild cognitive impairment (aMCI) and AD, and neurology controls were analyzed. We have discovered and validated a new single saliva biomarker, lactoferrin, which in our cross-sectional investigation perfectly discriminates clinically diagnosed aMCI and AD patients from a cognitively healthy control group. The accuracy for AD diagnosis shown by salivary lactoferrin was greater than that obtained from core cerebrospinal fluid (CSF) biomarkers, including total tau and CSF Aβ 42 . Furthermore, salivary lactoferrin can be used for population screening and for identifying those underdiagnosed subjects with very early stages of mild cognitive impairment and AD. This biomarker may offer new insights in the early diagnostics for AD.

  13. The genetics of Alzheimer disease: current status and future prospects.

    PubMed

    Blacker, D; Tanzi, R E

    1998-03-01

    Four genes involved in the development of Alzheimer disease have been identified. Three fully penetrant (deterministic) genes lead to the development of Alzheimer disease in patients younger than 60 years: the amyloid beta-protein precursor on chromosome 21, presenilin 1 on chromosome 14, and presenilin 2 on chromosome 1. Together, they account for about half of this early-onset form of the disease. One genetic risk factor--apolipoprotein E-4--is associated with late-onset Alzheimer disease. It accounts for a substantial fraction of disease burden but seems to act primarily to lower the age of disease onset. In general, none of these genes can be easily adapted for use as a diagnostic or predictive test for Alzheimer disease. Research activity includes searching for additional genes, especially for late-onset disease, and elucidating the mechanism of action of all identified genes as part of a long-term effort to develop more effective therapeutic and preventive strategies.

  14. Tracking early decline in cognitive function in older individuals at risk for Alzheimer's disease dementia: the Alzheimer's Disease Cooperative Study Cognitive Function Instrument

    PubMed Central

    Amariglio, Rebecca E.; Donohue, Michael C.; Marshall, Gad A.; Rentz, Dorene M.; Salmon, David P.; Ferris, Steven H.; Karantzoulis, Stella; Aisen, Paul S.; Sperling, Reisa A.

    2015-01-01

    Importance Several large-scale Alzheimer's disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures that are sensitive to early clinical progression in individuals who are initially asymptomatic. Objective To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline. Design, Setting, and Participants Longitudinal study over the course of 48 months at participating Alzheimer's Disease Cooperative Study (ADCS) sites. The study included 468 healthy older individuals (Clinical Dementia Rating Scale [CDR] Global = 0, above cut-off on modified Mini-Mental State Exam and Free and Cued Selective Reminding Test) (mean age= 79.4 years ±3.6). All subjects and their study partners completed the Self and Partner CFI annually. Subjects also underwent concurrent annual neuropsychological assessment and apolipoprotein E (APOE) genotyping. Main outcomes and measures Comparison of CFI scores between clinical progressors (Clinical Dementia Rating Scale [CDR] ≥ 0.5) and non-progressors (CDR remained = 0), as well as between APOE ε4 carriers and non-carriers were performed. Correlations of change between the CFI and neuropsychological performance were assessed longitudinally. Results At 48 months, group differences between clinical progressors and non-progressors were significant for CFI Self, CFI Partner, and CFI Self+Partner total scores. At month 48, APOE ε4 carriers showed greater progression than non-carriers on CFI Partner and CFI Self+Partner scores. Both CFI Self and CFI Partner scores were associated with longitudinal cognitive decline, although findings suggest self report may be more accurate early in the process, whereas accuracy of partner report improves when there is progression to cognitive impairment. Conclusions and Relevance Demonstrating

  15. Caregiver burden and psychosocial services in patients with early and late onset Alzheimer's disease.

    PubMed

    Grønning, Helene; Kristiansen, Susanne; Dyre, Dorte; Rahmani, Abdul; Gyllenborg, Jesper; Høgh, Peter

    2013-07-01

    The purpose of the study was to analyse caregiver burden and consumption of psychosocial services in a consecutive group of patients with early onset Alzheimer's disease (EOAD) compared with a matching group with late onset Alzheimer's disease (LOAD). This was a case-control study with 42 patients who were matched according to disease severity at the time of diagnosis. Caregivers in both groups were interviewed using the Neuro Psychiatric Inventory (NPI), the Activities of Daily Living (ADL) scale and the Resource Utilization in Dementia scale. The quantitative outcomes were compared statistically. The EOAD group had a significantly higher ADL score than the LOAD group. There was a trend towards caregivers in the LOAD group spending more time helping the patients, and they needed more social services than the EOAD group. NPI scores were not significantly different, but a tendency towards a higher caregiver burden in the EOAD group was observed. The higher caregiver burden in patients with EOAD--despite a better ADL function than LOAD patients--suggests that the existing psychosocial services might be particularly insufficient for caregivers in EOAD. The study was funded by a three-month scholarship grant from the research fund at Roskilde Hospital. not relevant.

  16. Evaluation of Parkinson disease and Alzheimer disease with the use of neuromelanin MR imaging and (123)I-metaiodobenzylguanidine scintigraphy.

    PubMed

    Miyoshi, F; Ogawa, T; Kitao, S-i; Kitayama, M; Shinohara, Y; Takasugi, M; Fujii, S; Kaminou, T

    2013-01-01

    Progressive changes in the substantia nigra pars compacta and locus ceruleus of patients with Parkinson disease and Alzheimer disease visualized by neuromelanin MRI and cardiac postganglionic sympathetic nerve function on (123)I-metaiodobenzylguanidine scintigraphy have not been fully evaluated. We compared the diagnostic value of these modalities among patients with early Parkinson disease, late Parkinson disease, and Alzheimer disease. We compared contrast ratios of signal intensity in medial and lateral regions of the substantia nigra pars compacta and locus ceruleus with those of the tegmentum of the midbrain and the pons, respectively, by use of neuromelanin MRI in patients with early Parkinson disease (n = 13), late Parkinson disease (n = 31), Alzheimer disease (n = 6), and age-matched healthy control subjects (n = 20). We calculated heart-to-mediastinum ratios on (123)I-metaiodobenzylguanidine scintigrams after setting regions of interest on the left cardiac ventricle and upper mediastinum. The signal intensity of the lateral substantia nigra pars compacta on neuromelanin MRI was significantly reduced in early and late Parkinson disease, and that of the medial substantia nigra pars compacta was gradually and stage-dependently reduced in Parkinson disease. The signal intensity of the locus ceruleus was obviously reduced in late Parkinson disease. Signal reduction was not significant in the substantia nigra pars compacta and locus ceruleus of patients with Alzheimer disease. The heart-to-mediastinum ratio on (123)I-metaiodobenzylguanidine scintigrams was stage-dependently reduced in Parkinson disease and normal in Alzheimer disease. The signal intensity ratios in substantia nigra pars compacta and locus ceruleus on neuromelanin MRI positively correlated with the heart-to-mediastinum ratio on (123)I-metaiodobenzylguanidine scintigrams. Both neuromelanin MRI and (123)I-metaiodobenzylguanidine scintigraphy can help to evaluate disease progression in Parkinson

  17. Discourse changes in early Alzheimer disease, mild cognitive impairment, and normal aging.

    PubMed

    Chapman, Sandra Bond; Zientz, Jennifer; Weiner, Myron; Rosenberg, Roger; Frawley, William; Burns, Mary Hope

    2002-01-01

    The purpose of this study was to determine the sensitivity of discourse gist measures to the early cognitive-linguistic changes in Alzheimer disease (AD) and in the preclinical stages. Differences in discourse abilities were examined in 25 cognitively normal adults, 24 adults with mild probable AD, and 20 adults with mild cognitive impairment (MCI) at gist and detail levels of discourse processing. The authors found that gist and detail levels of discourse processing were significantly impaired in persons with AD and MCI as compared with normal control subjects. Gist-level discourse processing abilities showed minimal overlap between cognitively normal control subjects and those with mild AD. Moreover, the majority of the persons with MCI performed in the range of AD on gist measures. These findings indicate that discourse gist measures hold promise as a diagnostic complement to enhance early detection of AD. Further studies are needed to determine how early the discourse gist deficits arise in AD.

  18. Familial early-onset dementia with tau intron 10 + 16 mutation with clinical features similar to those of Alzheimer disease.

    PubMed

    Doran, Mark; du Plessis, Daniel G; Ghadiali, Eric J; Mann, David M A; Pickering-Brown, Stuart; Larner, Andrew J

    2007-10-01

    Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) owing to the tau intron 10 + 16 mutation usually occurs with a prototypical frontotemporal dementia phenotype with prominent disinhibition and affective disturbances. To report a new FTDP-17 pedigree with the tau intron 10 + 16 mutation demonstrating a clinical phenotype suggestive of Alzheimer disease. Case reports. Regional neuroscience centers in northwest England. Patients We examined 4 members of a kindred in which 8 individuals were affected in 3 generations. All 4 patients reported memory difficulty. Marked anomia was also present, but behavioral disturbances were conspicuously absent in the early stages of disease. All patients had an initial clinical diagnosis of Alzheimer disease. No mutations were found in the presenilin or amyloid precursor protein genes. Pathologic examination of the proband showed features typical of FTDP-17, and tau gene analysis showed the intron 10 + 16 mutation. This pedigree illustrates the phenotypic variability of tau intron 10 + 16 mutations. In pedigrees with a clinical diagnosis of Alzheimer disease but without presenilin or amyloid precursor protein gene mutations, tau gene mutations may be found.

  19. Over-representation of the APOE*4 allele in autopsy confirmed early- and late-onset sporadic Alzheimer`s disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kamboh, M.I.; DeKosky, S.T.; Ferrell, R.E.

    1994-09-01

    Apolipoprotein E binds to {beta}-amyloid peptide in senile plaques and neurofibrillary tangles in Alzheimer`s disease (AD). Recent studies have identified the APOE*4 allele as a major predisposing genetic factor for late-onset familial AD as well as in sporadic AD. Most of these association studies are based on clinically diagnosed AD cases with little data available on autopsy confirmed, definite AD. To characterize the distribution of APOE polymorphism in autopsy confirmed sporadic AD cases, we determined APOE genotypes in 111 DNA samples (aged 51-101 years) extracted from brain tissues which were available from the University of Pittsburgh Alzheimer`s Disease Research Center.more » The APOE data was compared between the AD group and 3 samples of population controls from Western Pennsylvania consisting of a young cohort (N=473, aged 18-48 years), middle cohort (N=473, aged 42-50 years) and an old cohort (N=870, aged 65-90 years). The frequency of the APOE*4 allele was similar in the young and middle cohorts (0.12) and slightly lower in the old cohort (0.10). However, the frequency of the APOE*4 allele was three times higher in both early-onset (<65 years; 0.36) and late-onset ({ge}65 years; 0.38) sporadic AD cases compared to the control groups (p<0.0001). In the AD cohort the frequency of the APOE*4 allele was similar across all age groups (<65, 65-75, 76-85, 86+) and so was in men and women (0.40 vs. 0.37). The E*4 homozygosity was observed in 18% of AD cases compared to 1% in each of the three control groups. The E*4 heterozygosity was present in 50% of AD cases compared to 17% in the control old cohort and 22% in both the young and middle control cohorts. These data confirm that the APOE*4 allele is a major risk factor for AD regardless of age-at-diagnosis or family history.« less

  20. Resting metabolic connectivity in prodromal Alzheimer's disease. A European Alzheimer Disease Consortium (EADC) project.

    PubMed

    Morbelli, Silvia; Drzezga, Alex; Perneczky, Robert; Frisoni, Giovanni B; Caroli, Anna; van Berckel, Bart N M; Ossenkoppele, Rik; Guedj, Eric; Didic, Mira; Brugnolo, Andrea; Sambuceti, Gianmario; Pagani, Marco; Salmon, Eric; Nobili, Flavio

    2012-11-01

    We explored resting-state metabolic connectivity in prodromal Alzheimer's disease (pAD) patients and in healthy controls (CTR), through a voxel-wise interregional correlation analysis of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) by means of statistical parametric mapping. Baseline 18F-fluorodeoxyglucose-positron emission tomography of 36 patients with amnestic mild cognitive impairment who converted to Alzheimer's disease (AD) dementia after an average time of 2 years (pAD) and of 105 CTR were processed. The area of hypometabolism in pAD showed less metabolic connectivity in patients than in CTR (autocorrelation and correlation with large temporal and frontal areas, respectively). pAD patients showed limited correlation even in selected nonhypometabolic areas, including the hippocampi and the dorsolateral prefrontal cortex (DLFC). On the contrary, in CTR group correlation was highlighted between hippocampi and precuneus/posterior cingulate and frontal cortex, and between dorsolateral prefrontal cortex and caudate nuclei and parietal cortex. The reduced metabolic connections both in hypometabolic and nonhypometabolic areas in pAD patients suggest that metabolic disconnection (reflecting early diaschisis) may antedate remote hypometabolism (early sign of synaptic degeneration). Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Selective Attention Deficits Associated with Mild Cognitive Impairment and Early Stage Alzheimer's Disease in Adults with Down Syndrome

    ERIC Educational Resources Information Center

    Krinsky-McHale, Sharon J.; Devenny, Darlynne A.; Kittler, Phyllis; Silverman, Wayne

    2008-01-01

    Adults with Down syndrome and early stage Alzheimer's disease showed decline in their ability to selectively attend to stimuli in a multitrial cancellation task. They also showed variability in their performance over the test trials, whereas healthy participants showed stability. These changes in performance were observed approximately 2 years…

  2. Longitudinal Study of the Transition From Healthy Aging to Alzheimer Disease

    PubMed Central

    Johnson, David K.; Storandt, Martha; Morris, John C.; Galvin, James E.

    2009-01-01

    Background Detection of the earliest cognitive changes signifying Alzheimer disease is difficult. Objective To model the cognitive decline in preclinical Alzheimer disease. Design Longitudinal archival study comparing individuals who became demented during follow-up and people who remained nondemented on each of 4 cognitive factors: global, verbal memory, visuospatial, and working memory. Setting Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri. Participants One hundred thirty-four individuals who became demented during follow-up and 310 who remained nondemented. Main Outcome Measures Inflection point in longitudinal cognitive performance. Results The best-fitting model for each of the 4 factors in the stable group was linear, with a very slight downward trend on all but the Visuospatial factor. In contrast, a piecewise model with accelerated slope after a sharp inflection point provided the best fit for the group that progressed. The optimal inflection point for all 4 factors was prior to diagnosis of dementia: Global, 2 years; Verbal and Working Memory, 1 year; and Visuospatial, 3 years. These results were also obtained when data were limited to the subset (n=44) with autopsy-confirmed Alzheimer disease. Conclusions There is a sharp inflection point followed by accelerating decline in multiple domains of cognition, not just memory, in the preclinical period in Alzheimer disease when there is insufficient cognitive decline to warrant clinical diagnosis using conventional criteria. Early change was seen in tests of visuospatial ability, most of which were speeded. Research into early detection of cognitive disorders using only episodic memory tasks may not be sensitive to all of the early manifestations of disease. PMID:19822781

  3. Treatment of Alzheimer disease.

    PubMed

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

    2011-06-15

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

  4. 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

  5. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome.

    PubMed

    Wiseman, Frances K; Al-Janabi, Tamara; Hardy, John; Karmiloff-Smith, Annette; Nizetic, Dean; Tybulewicz, Victor L J; Fisher, Elizabeth M C; Strydom, André

    2015-09-01

    Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP)--an Alzheimer disease risk factor--although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.

  6. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

    PubMed Central

    Wiseman, Frances K.; Al-Janabi, Tamara; Hardy, John; Karmiloff-Smith, Annette; Nizetic, Dean; Tybulewicz, Victor L. J.; Fisher, Elizabeth M. C.; Strydom, André

    2015-01-01

    Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) — an Alzheimer disease risk factor — although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population. PMID:26243569

  7. Early Alzheimer's Disease Neuropathology Detected by Proton MR Spectroscopy

    PubMed Central

    Murray, Melissa E.; Przybelski, Scott A.; Lesnick, Timothy G.; Liesinger, Amanda M.; Spychalla, Anthony; Zhang, Bing; Gunter, Jeffrey L.; Parisi, Joseph E.; Boeve, Bradley F.; Knopman, David S.; Petersen, Ronald C.; Jack, Clifford R.; Dickson, Dennis W.

    2014-01-01

    Proton magnetic resonance spectroscopy (1H-MRS) is sensitive to early neurodegenerative processes associated with Alzheimer's disease (AD). Although 1H-MRS metabolite ratios of N-acetyl aspartate (NAA)/creatine (Cr), NAA/myoinositol (mI), and mI/Cr measured in the posterior cingulate gyrus reveal evidence of disease progression in AD, pathologic underpinnings of the 1H-MRS metabolite changes in AD are unknown. Pathologically diagnosed human cases ranging from no likelihood to high likelihood AD (n = 41, 16 females and 25 males) who underwent antemortem 1H-MRS of the posterior cingulate gyrus at 3 tesla were included in this study. Immunohistochemical evaluation was performed on the posterior cingulate gyrus using antibodies to synaptic vesicles, hyperphosphorylated tau (pTau), neurofibrillary tangle conformational-epitope (cNFT), amyloid-β, astrocytes, and microglia. The slides were digitally analyzed using Aperio software, which allows neuropathologic quantification in the posterior cingulate gray matter. MRS and pathology associations were adjusted for time from scan to death. Significant associations across AD and control subjects were found between reduced synaptic immunoreactivity and both NAA/Cr and NAA/mI in the posterior cingulate gyrus. Higher pTau burden was associated with lower NAA/Cr and NAA/mI. Higher amyloid-β burden was associated with elevated mI/Cr and lower NAA/mI ratios, but not with NAA/Cr. 1H-MRS metabolite levels reveal early neurodegenerative changes associated with AD pathology. Our findings support the hypothesis that a decrease in NAA/Cr is associated with loss of synapses and early pTau pathology, but not with amyloid-β or later accumulation of cNFT pathology in the posterior cingulate gyrus. In addition, elevation of mI/Cr is associated with the occurrence of amyloid-β plaques in AD. PMID:25471565

  8. [Study on early intervention of compound nutrition for cognitive dysfunction in Alzheimer's disease].

    PubMed

    Wang, Chao; Xie, Wei; Zhu, Jinfeng; Dang, Rui; Wang, Decai

    2014-01-01

    To observe the early prevention effect of the compound nutrients recipe for cognitive dysfunction of Alzheimer' s disease model-APP-PSN transgenic mouse. 36 APP-PSN transgenic mice aged two months randomly were divided into the intervention group supplied with compound recipe in the diet and the control group fed based feed, the former had high dose and low dose, 12 APP-PSN transgenic negative mice aged two months as the negative control were fed based feed. After 3 months' intervention, four groups' cognitive functions were evaluated using the Morris water maze, active avoidance experiment and jumping stair experiment. There was not statistically different between all the four groups for the weight and food intake. Compared with the control group, Morris water maze's incubation period of the intervention group was lower obviously, and jumping stair experiment's incubation period of the intervention group was higher obviously. In the active avoidance experiment, the high and low dose intervention group' s conditioned response accounted about 46.67% and 45.00% respectively, and the control group's conditioned response accounted about 20.83%. The differences of the three behavioral experiments between control group and intervention group had the statistical significance (P < 0.05), so the same as between control group and negative control group (P < 0.05). And there was no difference between intervention group and negative control group for the three behavioral experiments. The early supplementation with compound nutrition could postpone the occurrence and development of Alzheimer' s disease mice model's cognitive dysfunction.

  9. SPECT in Alzheimer`s disease and the dementias

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    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 quitemore » 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.« less

  10. [Calcium hypothesis of Alzheimer disease].

    PubMed

    Riazantseva, M A; Mozhaeva, G N; Kaznacheeva, E V

    2012-01-01

    Alzheimer's disease is the most common neurodegenerative disorder characterized by progressive memory and cognitive abilities loss. The etiology of Alzheimer's disease is poorly understood. In this regard, there is no effective treatment for the disease. Various hypotheses to explain the nature of the pathology of Alzheimer's disease led to the development of appropriate therapeutics. Despite of decades of research and clinical trials available therapeutics, at best, can only slow down the progression of the disease, but cannot cure it. This review dedicated to the one of modern hypotheses of Alzheimer's disease pathogenesis implied the impairment of calcium homeostasis as a key event for the development of neurodegenerative processes.

  11. Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease

    PubMed Central

    Zetterberg, Henrik; Mattsson, Niklas; Johansson, Per; Minthon, Lennart; Blennow, Kaj; Olsson, Mattias

    2015-01-01

    Objective: To compare the diagnostic accuracy of CSF biomarkers and amyloid PET for diagnosing early-stage Alzheimer disease (AD). Methods: From the prospective, longitudinal BioFINDER study, we included 122 healthy elderly and 34 patients with mild cognitive impairment who developed AD dementia within 3 years (MCI-AD). β-Amyloid (Aβ) deposition in 9 brain regions was examined with [18F]-flutemetamol PET. CSF was analyzed with INNOTEST and EUROIMMUN ELISAs. The results were replicated in 146 controls and 64 patients with MCI-AD from the Alzheimer's Disease Neuroimaging Initiative study. Results: The best CSF measures for identifying MCI-AD were Aβ42/total tau (t-tau) and Aβ42/hyperphosphorylated tau (p-tau) (area under the curve [AUC] 0.93–0.94). The best PET measures performed similarly (AUC 0.92–0.93; anterior cingulate, posterior cingulate/precuneus, and global neocortical uptake). CSF Aβ42/t-tau and Aβ42/p-tau performed better than CSF Aβ42 and Aβ42/40 (AUC difference 0.03–0.12, p < 0.05). Using nonoptimized cutoffs, CSF Aβ42/t-tau had the highest accuracy of all CSF/PET biomarkers (sensitivity 97%, specificity 83%). The combination of CSF and PET was not better than using either biomarker separately. Conclusions: Amyloid PET and CSF biomarkers can identify early AD with high accuracy. There were no differences between the best CSF and PET measures and no improvement when combining them. Regional PET measures were not better than assessing the global Aβ deposition. The results were replicated in an independent cohort using another CSF assay and PET tracer. The choice between CSF and amyloid PET biomarkers for identifying early AD can be based on availability, costs, and doctor/patient preferences since both have equally high diagnostic accuracy. Classification of evidence: This study provides Class III evidence that amyloid PET and CSF biomarkers identify early-stage AD equally accurately. PMID:26354982

  12. 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. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For

  13. Subjective cognitive concerns and neuropsychiatric predictors of progression to the early clinical stages of Alzheimer disease.

    PubMed

    Donovan, Nancy J; Amariglio, Rebecca E; Zoller, Amy S; Rudel, Rebecca K; Gomez-Isla, Teresa; Blacker, Deborah; Hyman, Bradley T; Locascio, Joseph J; Johnson, Keith A; Sperling, Reisa A; Marshall, Gad A; Rentz, Dorene M

    2014-12-01

    To examine neuropsychiatric and neuropsychological predictors of progression from normal to early clinical stages of Alzheimer disease (AD). From a total sample of 559 older adults from the Massachusetts Alzheimer's Disease Research Center longitudinal cohort, 454 were included in the primary analysis: 283 with clinically normal cognition (CN), 115 with mild cognitive impairment (MCI), and 56 with subjective cognitive concerns (SCC) but no objective impairment, a proposed transitional group between CN and MCI. Two latent cognitive factors (memory-semantic, attention-executive) and two neuropsychiatric factors (affective, psychotic) were derived from the Alzheimer's Disease Centers' Uniform Data Set neuropsychological battery and Neuropsychiatric Inventory brief questionnaire. Factors were analyzed as predictors of time to progression to a worse diagnosis using a Cox proportional hazards regression model with backward elimination. Covariates included baseline diagnosis, gender, age, education, prior depression, antidepressant medication, symptom duration, and interaction terms. Higher/better memory-semantic factor score predicted lower hazard of progression (hazard ratio [HR] = 0.4 for 1 standard deviation [SD] increase, p <0.0001), and higher/worse affective factor score predicted higher hazard (HR = 1.3 for one SD increase, p = 0.01). No other predictors were significant in adjusted analyses. Using diagnosis as a sole predictor of transition to MCI, the SCC diagnosis carried a fourfold risk of progression compared with CN (HR = 4.1, p <0.0001). These results identify affective and memory-semantic factors as significant predictors of more rapid progression from normal to early stages of cognitive decline and highlight the subgroup of cognitively normal elderly with SCC as those with elevated risk of progression to MCI. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  14. Trends in brain oxygenation during mental and physical exercise measured using near-infrared spectroscopy (NIRS): potential for early detection of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Allen, Monica S.; Allen, Jeffery W.; Mikkilineni, Shweta; Liu, Hanli

    2005-04-01

    Motivation: Early diagnosis of Alzheimer's disease (AD) is crucial because symptoms respond best to available treatments in the initial stages of the disease. Recent studies have shown that marked changes in brain oxygenation during mental and physical tasks can be used for noninvasive functional brain imaging to detect Alzheimer"s disease. The goal of our study is to explore the possibility of using near infrared spectroscopy (NIRS) and mapping (NIRM) as a diagnostic tool for AD before the onset of significant morphological changes in the brain. Methods: A 16-channel NIRS brain imager was used to noninvasively measure spatial and temporal changes in cerebral hemodynamics induced during verbal fluency task and physical activity. The experiments involved healthy subjects (n = 10) in the age range of 25+/-5 years. The NIRS signals were taken from the subjects' prefrontal cortex during the activities. Results and Conclusion: Trends of oxygenated and deoxygenated hemoglobin in the prefrontal cortex of the brain were observed. During the mental stimulation, the subjects showed significant increase in oxygenated hemoglobin [HbO2] with a simultaneous decrease in deoxygenated hemoglobin [Hb]. However, physical exercise caused a rise in levels of HbO2 with small variations in Hb. This study basically demonstrates that NIRM taken from the prefrontal cortex of the human brain is sensitive to both mental and physical tasks and holds potential to serve as a diagnostic means for early detection of Alzheimer's disease.

  15. Explicit (semantic) memory for music in patients with mild cognitive impairment and early-stage Alzheimer's disease.

    PubMed

    Kerer, Manuela; Marksteiner, Josef; Hinterhuber, Hartmann; Mazzola, Guerino; Kemmler, Georg; Bliem, Harald R; Weiss, Elisabeth M

    2013-01-01

    BACKGROUND/STUDY CONTEXT: Explicit memory for music was investigated by using a new test with 24 existing and 3 newly composed pieces. Ten patients with mild cognitive impairment (MCI) and 10 patients with early stage of Alzheimer's disease (AD) were compared with 23 healthy subjects, in terms of verbal memory of music by the identification of familiar music excerpts and the discrimination of distortion and original timbre of musical excerpts. MCI and Alzheimer's patients showed significantly poorer performances in tasks requiring verbal memory of musical excerpts than the healthy participants. For discrimination of musical excerpts, MCI and AD patients surprisingly performed significantly better than the healthy comparison subjects. Our results support the notion of a specialized memory system for music.

  16. The Edinburgh Consensus: preparing for the advent of disease-modifying therapies for Alzheimer's disease.

    PubMed

    Ritchie, Craig W; Russ, Tom C; Banerjee, Sube; Barber, Bob; Boaden, Andrew; Fox, Nick C; Holmes, Clive; Isaacs, Jeremy D; Leroi, Ira; Lovestone, Simon; Norton, Matt; O'Brien, John; Pearson, Jim; Perry, Richard; Pickett, James; Waldman, Adam D; Wong, Wai Lup; Rossor, Martin N; Burns, Alistair

    2017-10-26

    This commentary discusses the implications of disease-modifying treatments for Alzheimer's disease which seem likely to appear in the next few years and results from a meeting of British experts in neurodegenerative diseases in Edinburgh. The availability of such treatments would help change public and professional attitudes and accelerate engagement with the prodromal and preclinical populations who might benefit from them. However, this would require an updated understanding of Alzheimer's disease, namely the important distinction between Alzheimer's disease and Alzheimer's dementia. Since treatments are likely to be most effective in the early stages, identification of clinically relevant brain changes (for example, amyloid burden using imaging or cerebrospinal fluid biomarkers) will be crucial. While current biomarkers could be useful in identifying eligibility for new therapies, trial data are not available to aid decisions about stopping or continuing treatment in clinical practice. Therefore, effective monitoring of safety and effectiveness when these treatments are introduced into clinical practice will be necessary to inform wide-scale use. Equity of access is key but there is a tension between universal access for everyone with a diagnosis of Alzheimer's disease and specifying an eligible population most likely to respond. We propose the resources necessary for an optimal care pathway as well as the necessary education and training for primary and secondary care. The majority of current services in the UK and elsewhere would not be able to accommodate the specialist investigations required to select patients and prescribe these therapies. Therefore, a stepped approach would be necessary: from innovating sentinel clinical-academic centres that already have capacity to deliver the necessary phase IV trials, through early adoption in a hub and spoke model, to nationwide adoption for true equity of access. The optimism generated by recent and anticipated

  17. [Biological markers in the diagnosis of dementia and Alzheimer's disease].

    PubMed

    Meiner, Zeev; Rosenmann, Hanna

    2012-05-01

    Alzheimer's disease is the leading cause of dementia in advanced age with a prevalence of above 40% among persons 80 years or older. In recent years, new studies have made some important discoveries regarding the pathogenesis of the diseases and potential therapeutic measures. These developments have led to the announcement of new guidelines for the diagnosis of the disease published by the National Institute on Aging and the ALzheimer's Association. These guidelines expand the definition of ALzheimer's disease to include 2 new phases of the disease: pre-symptomatic and mildly symptomatic but pre-dementia. For the first time, the guidelines also incorporated the usage of biological markers to assist in the diagnosis of the disease, although they are still only in the research agenda. These biomarkers include atrophy of the medial temporal lobe by MRI, reduction of glucose metabolism in specific brain areas by PET-FDG and presence of beta-amyloid staining in the brain by PET-amyloid scan. In addition, there are also cerebrospinal fluid ICSF) biomarkers characteristic of Alzheimer's disease, which consist of low levels of Abeta42 and elevated levels of total and phosphorylated TAU. These biomarkers may be used to diagnose the disease in the early pre-symptomatic phase, to differentiate Alzheimer's disease from other causes of dementia and may be helpful in the follow-up of newly developed specific treatments.

  18. A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials.

    PubMed

    Verma, Nishant; Beretvas, S Natasha; Pascual, Belen; Masdeu, Joseph C; Markey, Mia K

    2018-03-14

    Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Independent Deficits of Visual Word and Motion Processing in Aging and Early Alzheimer's Disease

    PubMed Central

    Velarde, Carla; Perelstein, Elizabeth; Ressmann, Wendy; Duffy, Charles J.

    2013-01-01

    We tested whether visual processing impairments in aging and Alzheimer's disease (AD) reflect uniform posterior cortical decline, or independent disorders of visual processing for reading and navigation. Young and older normal controls were compared to early AD patients using psychophysical measures of visual word and motion processing. We find elevated perceptual thresholds for letters and word discrimination from young normal controls, to older normal controls, to early AD patients. Across subject groups, visual motion processing showed a similar pattern of increasing thresholds, with the greatest impact on radial pattern motion perception. Combined analyses show that letter, word, and motion processing impairments are independent of each other. Aging and AD may be accompanied by independent impairments of visual processing for reading and navigation. This suggests separate underlying disorders and highlights the need for comprehensive evaluations to detect early deficits. PMID:22647256

  20. Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport.

    PubMed

    Kunkle, Brian W; Vardarajan, Badri N; Naj, Adam C; Whitehead, Patrice L; Rolati, Sophie; Slifer, Susan; Carney, Regina M; Cuccaro, Michael L; Vance, Jeffery M; Gilbert, John R; Wang, Li-San; Farrer, Lindsay A; Reitz, Christiane; Haines, Jonathan L; Beecham, Gary W; Martin, Eden R; Schellenberg, Gerard D; Mayeux, Richard P; Pericak-Vance, Margaret A

    2017-09-01

    Mutations in APP, PSEN1, and PSEN2 lead to early-onset Alzheimer disease (EOAD) but account for only approximately 11% of EOAD overall, leaving most of the genetic risk for the most severe form of Alzheimer disease unexplained. This extreme phenotype likely harbors highly penetrant risk variants, making it primed for discovery of novel risk genes and pathways for AD. To search for rare variants contributing to the risk for EOAD. In this case-control study, whole-exome sequencing (WES) was performed in 51 non-Hispanic white (NHW) patients with EOAD (age at onset <65 years) and 19 Caribbean Hispanic families previously screened as negative for established APP, PSEN1, and PSEN2 causal variants. Participants were recruited from John P. Hussman Institute for Human Genomics, Case Western Reserve University, and Columbia University. Rare, deleterious, nonsynonymous, or loss-of-function variants were filtered to identify variants in known and suspected AD genes, variants in multiple unrelated NHW patients, variants present in 19 Hispanic EOAD WES families, and genes with variants in multiple unrelated NHW patients. These variants/genes were tested for association in an independent cohort of 1524 patients with EOAD, 7046 patients with late-onset AD (LOAD), and 7001 cognitively intact controls (age at examination, >65 years) from the Alzheimer's Disease Genetics Consortium. The study was conducted from January 21, 2013, to October 13, 2016. Alzheimer disease diagnosed according to standard National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria. Association between Alzheimer disease and genetic variants and genes was measured using logistic regression and sequence kernel association test-optimal gene tests, respectively. Of the 1524 NHW patients with EOAD, 765 (50.2%) were women and mean (SD) age was 60.0 (4.9) years; of the 7046 NHW patients with LOAD, 4171 (59.2%) were women and mean

  1. Sex differences in cognitive impairment and Alzheimer's disease.

    PubMed

    Li, Rena; Singh, Meharvan

    2014-08-01

    Studies have shown differences in specific cognitive ability domains and risk of Alzheimer's disease between the men and women at later age. However it is important to know that sex differences in cognitive function during adulthood may have their basis in both organizational effects, i.e., occurring as early as during the neuronal development period, as well as in activational effects, where the influence of the sex steroids influence brain function in adulthood. Further, the rate of cognitive decline with aging is also different between the sexes. Understanding the biology of sex differences in cognitive function will not only provide insight into Alzheimer's disease prevention, but also is integral to the development of personalized, gender-specific medicine. This review draws on epidemiological, translational, clinical, and basic science studies to assess the impact of sex differences in cognitive function from young to old, and examines the effects of sex hormone treatments on Alzheimer's disease in men and women. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Rethinking the Food and Drug Administration's 2013 guidance on developing drugs for early-stage Alzheimer's disease.

    PubMed

    Schneider, Lon S

    2014-03-01

    The February 2013 Food and Drug Administration (FDA) draft guidance for developing drugs for early-stage Alzheimer's disease (AD) creates certain challenges as they guide toward the use of one cognitive outcome to gain accelerated marketing approval for preclinical AD drugs, and a composite clinical scale - the Clinical Dementia Rating Scale in particular - for the primary outcome for prodromal AD clinical trials. In light of the developing knowledge regarding early stage diagnoses and clinical trials outcomes, we recommend that FDA describe its requirements for validating preclinical AD diagnoses for drug development purposes, maintain the principle for requiring coprimary outcomes, and encourage the advancement of outcomes for early stage AD trials. The principles for drug development for early stage AD should not differ from those for clinical AD, especially as the diagnoses of prodromal and early AD impinge on each other. The FDA should not recommend that a composite scale be used as a sole primary efficacy outcome to support a marketing claim unless it requires that the cognitive and functional components of such a scale are demonstrated to be individually meaningful. The current draft guidelines may inadvertently constrain efforts to better assess the clinical effects of new drugs and inhibit innovation in an area where evidence-based clinical research practices are still evolving. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  3. CSF N-glycoproteomics for early diagnosis in Alzheimer's disease.

    PubMed

    Palmigiano, Angelo; Barone, Rita; Sturiale, Luisa; Sanfilippo, Cristina; Bua, Rosaria Ornella; Romeo, Donata Agata; Messina, Angela; Capuana, Maria Luisa; Maci, Tiziana; Le Pira, Francesco; Zappia, Mario; Garozzo, Domenico

    2016-01-10

    This work aims at exploring the human CSF (Cerebrospinal fluid) N-glycome by MALDI MS techniques, in order to assess specific glycosylation pattern(s) in patients with Alzheimer's disease (n:24) and in subjects with mild cognitive impairment (MCI) (n:11), these last as potential AD patients at a pre-dementia stage. For comparison, 21 healthy controls were studied. We identified a group of AD and MCI subjects (about 40-50% of the studied sample) showing significant alteration of CSF N-glycome profiling, consisting of a decrease in the overall sialylation degree and an increase in species bearing bisecting GlcNAc. Noteworthy, all the MCI patients that converted to AD within the clinical follow-up, had an abnormal CSF glycosylation profile. Based on the studied cohort, CSF glycosylation changes may occur before an AD clinical onset. Previous studies specifically focused on the key role of glycosyltransferase GnT-III on AD-pathogenesis, addressing the patho-mechanism to specific sugar modification of BACE-1 glycoprotein with bisecting GlcNAc. Our patients addressed protein N-glycosylation changes at an early phase of the whole biomolecular misregulation on AD, pointing to CSF N-glycome analyses as promising tool to enhance early detection of AD and also suggesting alternative therapeutics target molecules, such as specific glyco-enzymes. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Level of understanding of Alzheimer disease among caregivers and the general population.

    PubMed

    Jorge, C; Cetó, M; Arias, A; Blasco, E; Gil, M P; López, R; Dakterzada, F; Purroy, F; Piñol-Ripoll, G

    2018-05-11

    Understanding of Alzheimer disease is fundamental for early diagnosis and to reduce caregiver burden. The objective of this study is to evaluate the degree of understanding of Alzheimer disease among informal caregivers and different segments of the general population through the Alzheimer's Disease Knowledge Scale. We assessed the knowledge of caregivers in different follow-up periods (less than one year, between 1 and 5 years, and over 5 years since diagnosis) and individuals from the general population. Alzheimer's Disease Knowledge Scale scores were grouped into different items: life impact, risk factors, symptoms, diagnosis, treatment, disease progression, and caregiving. A total of 419 people (215 caregivers and 204 individuals from the general population) were included in the study. No significant differences were found between groups for overall Alzheimer's Disease Knowledge Scale score (19.1 vs. 18.8, P = .9). There is a scarce knowledge of disease risk factors (49.3%) or the care needed (51.2%), while symptoms (78.6%) and course of the disease (77.2%) were the best understood aspects. Older caregiver age was correlated with worse Alzheimer's Disease Knowledge Scale scores overall and for life impact, symptoms, treatment, and disease progression (P < .05). Time since diagnosis improved caregivers' knowledge of Alzheimer disease symptoms (P = .00) and diagnosis (P = .05). Assessing the degree of understanding of Alzheimer disease is essential to the development of health education strategies both in the general population and among caregivers. Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. Power analysis to detect treatment effects in longitudinal clinical trials for Alzheimer's disease.

    PubMed

    Huang, Zhiyue; Muniz-Terrera, Graciela; Tom, Brian D M

    2017-09-01

    Assessing cognitive and functional changes at the early stage of Alzheimer's disease (AD) and detecting treatment effects in clinical trials for early AD are challenging. Under the assumption that transformed versions of the Mini-Mental State Examination, the Clinical Dementia Rating Scale-Sum of Boxes, and the Alzheimer's Disease Assessment Scale-Cognitive Subscale tests'/components' scores are from a multivariate linear mixed-effects model, we calculated the sample sizes required to detect treatment effects on the annual rates of change in these three components in clinical trials for participants with mild cognitive impairment. Our results suggest that a large number of participants would be required to detect a clinically meaningful treatment effect in a population with preclinical or prodromal Alzheimer's disease. We found that the transformed Mini-Mental State Examination is more sensitive for detecting treatment effects in early AD than the transformed Clinical Dementia Rating Scale-Sum of Boxes and Alzheimer's Disease Assessment Scale-Cognitive Subscale. The use of optimal weights to construct powerful test statistics or sensitive composite scores/endpoints can reduce the required sample sizes needed for clinical trials. Consideration of the multivariate/joint distribution of components' scores rather than the distribution of a single composite score when designing clinical trials can lead to an increase in power and reduced sample sizes for detecting treatment effects in clinical trials for early AD.

  6. Neurovascular unit impairment in early Alzheimer's disease measured with magnetic resonance imaging.

    PubMed

    van de Haar, Harm J; Jansen, Jacobus F A; van Osch, Matthias J P; van Buchem, Mark A; Muller, Majon; Wong, Sau May; Hofman, Paul A M; Burgmans, Saartje; Verhey, Frans R J; Backes, Walter H

    2016-09-01

    The neurovascular unit, which protects neuronal cells and supplies them with essential molecules, plays an important role in the pathophysiology of Alzheimer's Disease (AD). The aim of this study was to noninvasively investigate 2 linked functional elements of the neurovascular unit, blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), in patients with early AD and healthy controls. Therefore, both dynamic contrast-enhanced magnetic resonance imaging and arterial spin labeling magnetic resonance imaging were applied to measure BBB permeability and CBF, respectively. The patients with early AD showed significantly lower CBF and local blood volume in the gray matter, compared with controls. In the patients, we also found that a reduction in CBF is correlated with an increase in leakage rate. This finding supports the hypothesis that neurovascular damage, and in particular impairment of the neurovascular unit constitutes the pathophysiological link between CBF reduction and BBB impairment in AD. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Wayfinding in ageing and Alzheimer's disease within a virtual senior residence: study protocol.

    PubMed

    Davis, Rebecca; Ohman, Jennifer

    2016-07-01

    To report a study protocol that examines the impact of adding salient cues in a virtual reality simulation of a senior residential building on wayfinding for older adults with and without Alzheimer's disease. An early symptom of Alzheimer's disease is the inability to find one's way (wayfinding). Senior residential environments are especially difficult for wayfinding. Salient cues may be able to help persons with Alzheimer's disease find their way more effectively so they can maintain independence. A repeated measures, within and between subjects design. This study was funded by the National Institutes of Health (August 2012). Older adults (N = 40) with normal cognition and older adults with early stage Alzheimer's disease/mild cognitive impairment (N = 40) will try to find their way to a location repeatedly in a virtual reality simulation of senior residence. There are two environments: standard (no cues) and salient (multiple cues). Outcome measures include how often and how quickly participants find the target location in each cue condition. The results of this study have the potential to provide evidence for ways to make the environment more supportive for wayfinding for older adults with Alzheimer's disease. This study is registered at Trialmatch.alz.org (Identifier 260425-5). © 2016 John Wiley & Sons Ltd.

  8. Perceptions of stigma among people affected by early- and late-onset Alzheimer's disease.

    PubMed

    Ashworth, Rosalie

    2017-07-01

    The aim of this research was to explore perceptions of stigma among people with early- and late-onset Alzheimer's disease and those who support them, using questionnaires ( n = 44) and semi-structured interviews ( n = 14). Perceived stigma reporting was low in the questionnaires, whereas interviews revealed higher levels of perceived stigma in the form of unpredictable reactions to diagnosis, feeling stupid and ignorance of the condition among the public. Perceived stigma was managed in similar ways across age groups, focusing on 'being the lucky ones'. Results support the need to further tackle stigma and challenge expectations, particularly given the drive to diagnose people and thereby expose them to stigma.

  9. Brain MRI analysis for Alzheimer's disease diagnosis using an ensemble system of deep convolutional neural networks.

    PubMed

    Islam, Jyoti; Zhang, Yanqing

    2018-05-31

    Alzheimer's disease is an incurable, progressive neurological brain disorder. Earlier detection of Alzheimer's disease can help with proper treatment and prevent brain tissue damage. Several statistical and machine learning models have been exploited by researchers for Alzheimer's disease diagnosis. Analyzing magnetic resonance imaging (MRI) is a common practice for Alzheimer's disease diagnosis in clinical research. Detection of Alzheimer's disease is exacting due to the similarity in Alzheimer's disease MRI data and standard healthy MRI data of older people. Recently, advanced deep learning techniques have successfully demonstrated human-level performance in numerous fields including medical image analysis. We propose a deep convolutional neural network for Alzheimer's disease diagnosis using brain MRI data analysis. While most of the existing approaches perform binary classification, our model can identify different stages of Alzheimer's disease and obtains superior performance for early-stage diagnosis. We conducted ample experiments to demonstrate that our proposed model outperformed comparative baselines on the Open Access Series of Imaging Studies dataset.

  10. 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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Potential Role of Aminoprocalcitonin in the Pathogenesis of Alzheimer Disease.

    PubMed

    Tavares, Eva; Antequera, Desiree; López-González, Irene; Ferrer, Isidro; Miñano, Francisco J; Carro, Eva

    2016-10-01

    Increasing evidence suggests that inflammatory responses cause brain atrophy and play a prominent and early role in the progression of Alzheimer disease. Recent findings show that the neuroendocrine peptide aminoprocalcitonin (NPCT) plays a critical role in the development of systemic inflammatory response; however, the presence, possible function, regulation, and mechanisms by which NPCT may be involved in Alzheimer disease neuropathology remain unknown. We explored the expression of NPCT and its interaction with amyloid-β (Aβ), and proinflammatory and neurogenic effects. By using brain samples of Alzheimer disease patients and APP/PS1 transgenic mice, we evaluated the potential role of NPCT on Aβ-related pathology. We found that NPCT is expressed in hippocampal and cortical neurons and Aβ-induced up-regulation of NPCT expression. Peripherally administered antibodies against NPCT decreased microglial activation, decreased circulating levels of proinflammatory cytokines, and prevented Aβ-induced neurotoxicity in experimental models of Alzheimer disease. Remarkably, anti-NPTC therapy resulted in a significant improvement in the behavioral status of APP/PS1 mice. Our results indicate a central role of NPCT in Alzheimer disease pathogenesis and suggest NPCT as a potential biomarker and therapeutic target. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  12. 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

  13. Contribution of early Alzheimer's Disease-related Pathophysiology to the Development of Acquired epilepsy.

    PubMed

    Gschwind, Tilo; Lafourcade, Carlos; Gfeller, Tim; Zaichuk, Mariana; Rambousek, Lukas; Knuesel, Irene; Fritschy, Jean-Marc

    2018-06-04

    Aberrant epileptic activity is detectable at early disease stages in Alzheimer's disease (AD) patients and in AD mouse models. Here, we investigated in young ArcticAβ mice whether AD-like pathology renders neuronal networks more susceptible to development of acquired epilepsy induced by unilateral intrahippocampal injection of kainic acid (IHK). In this temporal lobe epilepsy model, IHK induces a status epilepticus followed after two weeks by spontaneous recurrent seizures (SRS). ArcticAβ mice exhibited more severe status epilepticus and early onset of SRS. This hyperexcitable phenotype was characterized in CA1 neurons by decreased synaptic strength, increased kainic acid-induced LTP, and reduced frequency of spontaneous inhibitory currents. However, no difference in neurodegeneration, neuroinflammation, axonal reorganization or adult neurogenesis was observed in ArcticAβ mice compared to wildtype littermates following IHK-induced epileptogenesis. Neuropeptide Y (NPY) expression was reduced at baseline and its IHK-induced elevation in mossy fibers and granule cells was attenuated. However, although this alteration might underlie premature seizure onset, neutralization of soluble Aβ species by intracerebroventricular Aβ-specific antibody application mitigated the hyperexcitable phenotype of ArcticAβ mice and prevented early SRS onset. Therefore, development of seizures at early stages of AD is mediated primarily by Aβ species causing widespread changes in synaptic function. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  14. Alzheimer disease: focus on computed tomography.

    PubMed

    Reynolds, April

    2013-01-01

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

  15. 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.

  16. Early-stage reduction of the dendritic complexity in basolateral amygdala of a transgenic mouse model of Alzheimer's disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Guo, Congdi; Long, Ben; Hu, Yarong

    Alzheimer's disease is a representative age-related neurodegenerative disease that could result in loss of memory and cognitive deficiency. However, the precise onset time of Alzheimer's disease affecting neuronal circuits and the mechanisms underlying the changes are not clearly known. To address the neuroanatomical changes during the early pathologic developing process, we acquired the neuronal morphological characterization of AD in APP/PS1 double-transgenic mice using the Micro-Optical Sectioning Tomography system. We reconstructed the neurons in 3D datasets with a resolution of 0.32 × 0.32 × 1 μm and used the Sholl method to analyze the anatomical characterization of the dendritic branches. The results showed that, similar tomore » the progressive change in amyloid plaques, the number of dendritic branches were significantly decreased in 9-month-old mice. In addition, a distinct reduction of dendritic complexity occurred in third and fourth-order dendritic branches of 9-month-old mice, while no significant changes were identified in these parameters in 6-month-old mice. At the branch-level, the density distribution of dendritic arbors in the radial direction decreased in the range of 40–90 μm from the neuron soma in 6-month-old mice. These changes in the dendritic complexity suggest that these reductions contribute to the progressive cognitive impairment seen in APP/PS1 mice. This work may yield insights into the early changes in dendritic abnormality and its relevance to dysfunctional mechanisms of learning, memory and emotion in Alzheimer's disease. - Highlights: • Neuron-level, reduction of dendritic complexity in BLA of 9-month-old AD mice. • Specific range of branch decrease in density of 6-month-old AD mice. • 3D imaging with high resolution will provide insights into brain aging.« less

  17. A conceptual framework and ethics analysis for prevention trials of Alzheimer Disease.

    PubMed

    Peters, Kevin R; Lynn Beattie, B; Feldman, Howard H; Illes, Judy

    2013-11-01

    As our understanding of the neurobiology of Alzheimer Disease deepens, it has become evident that early intervention is critical to achieving successful therapeutic impact. The availability of diagnostic criteria for preclinical Alzheimer Disease adds momentum to research directed at this goal and even to prevention. The landscape of therapeutic research is thus poised to undergo a dramatic shift in the next 5-10 years, with clinical trials involving subjects at risk for Alzheimer Disease who have few or no symptoms. These trials will also likely rely heavily on genetics, biomarkers, and or risk factor stratification to identify individuals at risk for Alzheimer Disease. Here, we propose a conceptual framework to guide this next generation of pharmacological and non-pharmacological clinical pursuit, and discuss some of the foreseeable ethical considerations that may accompany them. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Genetic heterogeneity and Alzheimer`s disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    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 descendantsmore » 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.« less

  19. 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

  20. Inflammatory signaling in Alzheimer disease and depression.

    PubMed

    Barber, Robert

    2011-08-01

    To help define the relationships among inflammation, Alzheimer disease, and depression, the Texas Alzheimer's Research Consortium analyzed an array of inflammatory biomarkers in a cohort of patients with Alzheimer disease and in controls. Inflammation severity was highly correlated with earlier age at onset of Alzheimer disease and was also associated with cognitive decline. The relationship between inflammation and depression was not as clear, and it varied with aspects of depression, gender, and the presence of Alzheimer disease.

  1. Driving in Early-Stage Alzheimer's Disease: An Integrative Review of the Literature.

    PubMed

    Davis, Rebecca L; Ohman, Jennifer M

    2017-03-01

    One of the most difficult decisions for individuals with Alzheimer's disease (AD) is when to stop driving. Because driving is a fundamental activity linked to socialization, independent functioning, and well-being, making the decision to stop driving is not easy. Cognitive decline in older adults can lead to getting lost while driving, difficulty detecting and avoiding hazards, as well as increased errors while driving due to compromised judgment and difficulty in making decisions. The purpose of the current literature review was to synthesize evidence regarding how individuals with early-stage AD, their families, and providers make determinations about driving safety, interventions to increase driving safety, and methods to assist cessation and coping for individuals with early-stage AD. The evidence shows that changes in driving ability start early and progress throughout the trajectory of AD. Some individuals with mild cognitive impairment or early-stage AD may be safe to drive for a period of time. Support groups aimed at helping with the transition have been shown to be helpful for individuals who stop driving. Research and practice must support interventions to help individuals maintain safety while driving, as well as cope with driving cessation. [Res Gerontol Nurs. 2017; 10(2):86-100.]. Copyright 2016, SLACK Incorporated.

  2. Tracking early decline in cognitive function in older individuals at risk for Alzheimer disease dementia: the Alzheimer's Disease Cooperative Study Cognitive Function Instrument.

    PubMed

    Amariglio, Rebecca E; Donohue, Michael C; Marshall, Gad A; Rentz, Dorene M; Salmon, David P; Ferris, Steven H; Karantzoulis, Stella; Aisen, Paul S; Sperling, Reisa A

    2015-04-01

    Several large-scale Alzheimer disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures that are sensitive to early clinical progression in individuals who are initially asymptomatic. To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline. Longitudinal study from February 2002 through February 2007 at participating Alzheimer's Disease Cooperative Study sites. Individuals were followed up annually for 48 months after the baseline visit. The study included 468 healthy older individuals (Clinical Dementia Rating scale [CDR] global scores of 0, above cutoff on the modified Mini-Mental State Examination and Free and Cued Selective Reminding Test) (mean [SD] age, 79.4 [3.6] years; age range, 75.0-93.8 years). All study participants and their study partners completed the self and partner CFIs annually. Individuals also underwent concurrent annual neuropsychological assessment and APOE genotyping. The CFI scores between clinical progressors (CDR score, ≥0.5) and nonprogressors (CDR score, 0) and between APOE ε4 carriers and noncarriers were compared. Correlations of change between the CFI scores and neuropsychological performance were assessed longitudinally. At 48 months, group differences between clinical progressors and non-progressors were significant for self (2.13, SE=0.45, P<.001), partner (5.08, SE=0.59, P<.001), and self plus partner (7.04, SE=0.83, P<.001) CFI total scores. At month 48, APOE ε4 carriers had greater progression than noncarriers on the partner (1.10, SE=0.44, P<.012) and self plus partner (1.56, SE=0.63, P<.014) CFI scores. Both self and partner CFI change were associated with longitudinal cognitive decline (self, ρ=0.32, 95% CI, 0.13 to 0.46; partner, ρ=0.56, 95% CI, 0.42 to 0.68), although findings suggest self

  3. Subjective cognitive impairment: Towards early identification of Alzheimer disease.

    PubMed

    Garcia-Ptacek, S; Eriksdotter, M; Jelic, V; Porta-Etessam, J; Kåreholt, I; Manzano Palomo, S

    2016-10-01

    Neurodegeneration in Alzheimer disease (AD) begins decades before dementia and patients with mild cognitive impairment (MCI) already demonstrate significant lesion loads. Lack of information about the early pathophysiology in AD complicates the search for therapeutic strategies.Subjective cognitive impairment is the description given to subjects who have memory-related complaints without pathological results on neuropsychological tests. There is no consensus regarding this heterogeneous syndrome, but at least some of these patients may represent the earliest stage in AD. We reviewed available literature in order to summarise current knowledge on subjective cognitive impairment. Although they may not present detectable signs of disease, SCI patients as a group score lower on neuropsychological tests than the general population does, and they also have a higher incidence of future cognitive decline. Depression and psychiatric co-morbidity play a role but cannot account for all cognitive complaints. Magnetic resonance imaging studies in these patients reveal a pattern of hippocampal atrophy similar to that of amnestic mild cognitive impairment and functional MRI shows increased activation during cognitive tasks which might indicate compensation for loss of function. Prevalence of an AD-like pattern of beta-amyloid (Aβ42) and tau proteins in cerebrospinal fluid is higher in SCI patients than in the general population. Memory complaints are relevant symptoms and may predict AD. Interpatient variability and methodological differences between clinical studies make it difficult to assign a definition to this syndrome. In the future, having a standard definition and longitudinal studies with sufficient follow-up times and an emphasis on quantifiable variables may clarify aspects of early AD. Copyright © 2012 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  4. Proverb and idiom comprehension in Alzheimer disease.

    PubMed

    Kempler, D; Van Lancker, D; Read, S

    1988-01-01

    Twenty-nine patients diagnosed with Probable Alzheimer Disease were administered tests of word, familiar phrases (idioms and proverbs), and novel phrase comprehension. From the early stage of the disease, patients performed worse at understanding familiar phrases than single words or novel phrases. The results uphold common observations that AD patients have difficulty interpreting abstract meanings. Cognitive variables responsible for poor idiom/proverb comprehension and the clinical implications of this new protocol are discussed.

  5. New Alzheimer's disease locus on chromosome 8.

    PubMed

    Giedraitis, V; Hedlund, M; Skoglund, L; Blom, E; Ingvast, S; Brundin, R; Lannfelt, L; Glaser, A

    2006-12-01

    Family history is one of the most consistent risk factors for dementia. Therefore, analysis of families with a distinct inheritance pattern of disease can be a powerful approach for the identification of previously unknown disease genes. To map susceptibility regions for Alzheimer's disease. A complete genome scan with 369 microsatellite markers was carried out in 12 extended families collected in Sweden. Age at disease onset ranged from 53 to 78 years, but in 10 of the families there was at least one member with age at onset of < or =65 years. Mutations in known early-onset Alzheimer's disease susceptibility genes have been excluded. All people were genotyped for APOE, but no clear linkage with the epsilon4 allele was observed. Although no common disease locus could be found in all families, in two families an extended haplotype was identified on chromosome 8q shared by all affected members. In one of the families, a non-parametric multimarker logarithm of the odds (LOD) score of 4.2 (p = 0.004) was obtained and analysis based on a dominant model showed a parametric LOD score of 2.4 for this region. All six affected members of this family shared a haplotype of 10 markers spanning about 40 cM. Three affected members in another family also shared a haplotype in the same region. On the basis of our data, we propose the existence of a dominantly acting Alzheimer's disease susceptibility locus on chromosome 8.

  6. Molecular imaging of Alzheimer disease pathology.

    PubMed

    Kantarci, K

    2014-06-01

    Development of molecular imaging agents for fibrillar β-amyloid positron-emission tomography during the past decade has brought molecular imaging of Alzheimer disease pathology into the spotlight. Large cohort studies with longitudinal follow-up in cognitively normal individuals and patients with mild cognitive impairment and Alzheimer disease indicate that β-amyloid deposition can be detected many years before the onset of symptoms with molecular imaging, and its progression can be followed longitudinally. The utility of β-amyloid PET in the differential diagnosis of Alzheimer disease is greatest when there is no pathologic overlap between 2 dementia syndromes, such as in frontotemporal lobar degeneration and Alzheimer disease. However β-amyloid PET alone may be insufficient in distinguishing dementia syndromes that commonly have overlapping β-amyloid pathology, such as dementia with Lewy bodies and vascular dementia, which represent the 2 most common dementia pathologies after Alzheimer disease. The role of molecular imaging in Alzheimer disease clinical trials is growing rapidly, especially in an era when preventive interventions are designed to eradicate the pathology targeted by molecular imaging agents. © 2014 by American Journal of Neuroradiology.

  7. [Late life depression or prodromal Alzheimer's disease: Which tools for the differential diagnosis?

    PubMed

    Gasser, A-I; Salamin, V; Zumbach, S

    2018-02-01

    Depression and Alzheimer's disease are both very frequent in elderly people. Cognitive deficits are the hallmark of Alzheimer's disease, but they are also common in depressed elderly people who often present cognitive deficits such as memory, attention and executive function problems. On the other hand, people with early Alzheimer's disease demonstrate emotional and behavioral disorders generally encountered in depression such as loss of energy, apathy, mood disorder, and irritability. Thus, in older adults with depression, the presence of cognitive deficits can make it difficult to distinguish cognitive decline that is associated with a depressive illness and the decline encountered in Alzheimer's disease because the clinical picture of the two disorders are similar. However, early distinction between the two disorders is very important from a prognostic and therapeutical point of view. After a brief description of the relationship between depression and early Alzheimer's disease in elderly people, this paper aims to present an updated literature review of data on differential diagnoses between these disorders. We performed a non-systematical, yet as exhaustive as possible, literature search with Pubmed electronic database, screening studies from 2000 to 2016. The majority of the studies concerned cognitive aspects, but only a few studies investigated others markers such as cerebral imaging, electroencephalography, cerebrospinal fluid markers. At the neuropsychological examination, a detailed analysis of the mnesic profile revealed a better benefit of semantic cueing in patients with late life depression in comparison to those with prodromal Alzheimer's disease and better performances in recognition memory. Moreover, longitudinal follow-up of patients with depression indicated that deficits in delayed recall memory, but not in executive functions, were associated with the subsequent development of Alzheimer's disease. Several studies showed that tests of

  8. Future targeted disease modifying drugs for Alzheimer's disease.

    PubMed

    Dash, Sandip K

    2011-01-01

    Alzheimer's disease is the most common form of dementia. Alzheimer's disease will be responsible for an enormous burden on the individual and the society, as with the aging of the population, the incidence and the prevalence will grow. Presently, the drugs used in Alzheimer's disease are only effective symptomatically and improve functioning. They do not halt the progression of the disease. With the recent advances in our understanding of the pathogenesis of this disease, there have been tremendous advances in the clinical trials of compounds that can modify the disease process. Numerous therapeutic interventions and neuroprotective approaches are also in trial phase. It seems that in near future some of these compounds may be found effective and safe for use in this disease there by reducing the incidence of this disease in years to come, thereby lessen the burden due to it. In this article various compounds that can modify the course of the disease are discussed. Some recent patents and inventions for the treatment of Alzheimer's disease have also been discussed.

  9. [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.

  10. Epoch-based Entropy for Early Screening of Alzheimer's Disease.

    PubMed

    Houmani, N; Dreyfus, G; Vialatte, F B

    2015-12-01

    In this paper, we introduce a novel entropy measure, termed epoch-based entropy. This measure quantifies disorder of EEG signals both at the time level and spatial level, using local density estimation by a Hidden Markov Model on inter-channel stationary epochs. The investigation is led on a multi-centric EEG database recorded from patients at an early stage of Alzheimer's disease (AD) and age-matched healthy subjects. We investigate the classification performances of this method, its robustness to noise, and its sensitivity to sampling frequency and to variations of hyperparameters. The measure is compared to two alternative complexity measures, Shannon's entropy and correlation dimension. The classification accuracies for the discrimination of AD patients from healthy subjects were estimated using a linear classifier designed on a development dataset, and subsequently tested on an independent test set. Epoch-based entropy reached a classification accuracy of 83% on the test dataset (specificity = 83.3%, sensitivity = 82.3%), outperforming the two other complexity measures. Furthermore, it was shown to be more stable to hyperparameter variations, and less sensitive to noise and sampling frequency disturbances than the other two complexity measures.

  11. Frontotemporal dementia and Alzheimer's disease: retrospective differentiation using information from informants.

    PubMed Central

    Barber, R; Snowden, J S; Craufurd, D

    1995-01-01

    The study examined the feasibility of differentiating frontotemporal dementia from Alzheimer's disease on the basis of retrospective historical information obtained from relatives of patients. A structured questionnaire was devised of patients' symptoms, with emphasis on those cognitive and neuropsychiatric features found in earlier prospective clinical studies to distinguish the two conditions. The questionnaire was given to close relatives of deceased patients in whom the diagnosis of non-Alzheimer's frontotemporal degeneration of Alzheimer's disease had been verified at necropsy. The interviewer had no previous contact or knowledge of those patients, nor clinical experience of patients with frontotemporal dementia. The questionnaire elicited a distinct profile of responses for the two diagnostic groups with emphasis on early personality change, unconcern, and socially inappropriate behaviour in frontotemporal dementia and disturbance in memory and topographical orientation prominent in patients with Alzheimer's disease. A scoring system separated out individual patients with frontotemporal dementia from those with Alzheimer's disease. It is concluded that it is possible to obtain useful information about the precise pattern of dementia from informants even many years after the patient's death. The questionnaire provides the foundation of a diagnostic instrument for use in family history studies of dementia. PMID:7608712

  12. Epidemiology of Alzheimer disease.

    PubMed

    Mayeux, Richard; Stern, Yaakov

    2012-08-01

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

  13. The pre-synaptic vesicle protein synaptotagmin is a novel biomarker for Alzheimer's disease.

    PubMed

    Öhrfelt, Annika; Brinkmalm, Ann; Dumurgier, Julien; Brinkmalm, Gunnar; Hansson, Oskar; Zetterberg, Henrik; Bouaziz-Amar, Elodie; Hugon, Jacques; Paquet, Claire; Blennow, Kaj

    2016-10-03

    Synaptic degeneration is a central pathogenic event in Alzheimer's disease that occurs early during the course of disease and correlates with cognitive symptoms. The pre-synaptic vesicle protein synaptotagmin-1 appears to be essential for the maintenance of an intact synaptic transmission and cognitive function. Synaptotagmin-1 in cerebrospinal fluid is a candidate Alzheimer biomarker for synaptic dysfunction that also may correlate with cognitive decline. In this study, a novel mass spectrometry-based assay for measurement of cerebrospinal fluid synaptotagmin-1 was developed, and was evaluated in two independent sample sets of patients and controls. Sample set I included cerebrospinal fluid samples from patients with dementia due to Alzheimer's disease (N = 17, age 52-86 years), patients with mild cognitive impairment due to Alzheimer's disease (N = 5, age 62-88 years), and controls (N = 17, age 41-82 years). Sample set II included cerebrospinal fluid samples from patients with dementia due to Alzheimer's disease (N = 24, age 52-84 years), patients with mild cognitive impairment due to Alzheimer's disease (N = 18, age 58-83 years), and controls (N = 36, age 43-80 years). The reproducibility of the novel method showed coefficients of variation of the measured synaptotagmin-1 peptide 215-223 (VPYSELGGK) and peptide 238-245 (HDIIGEFK) of 14 % or below. In both investigated sample sets, the CSF levels of synaptotagmin-1 were significantly increased in patients with dementia due to Alzheimer's disease (P ≤ 0.0001) and in patients with mild cognitive impairment due to Alzheimer's disease (P < 0.001). In addition, in sample set I the synaptotagmin-1 level was significantly higher in patients with mild cognitive impairment due to Alzheimer's disease compared with patients with dementia due to Alzheimer's disease (P ≤ 0.05). Cerebrospinal fluid synaptotagmin-1 is a promising biomarker to monitor synaptic dysfunction and degeneration

  14. From here to epilepsy: the risk of seizure in patients with Alzheimer's disease.

    PubMed

    Nicastro, Nicolas; Assal, Frédéric; Seeck, Margitta

    2016-03-01

    To describe the association between Alzheimer's disease and seizures by reviewing epidemiological data from available literature and to assess the putative pathophysiological links between neurodegeneration and altered cortical excitability. We also discuss specific antiepileptic treatment strategies in patients with Alzheimer's disease, as well as transient epileptic amnesia as a possible crossroads between degeneration and epilepsy. Regarding epidemiology, we searched publications in Pubmed, Medline, Scopus and Web of Science (until September 2015) using the keywords "incidence", "prevalence" and "frequency", as well as "Alzheimer's disease" and "seizures". In addition, therapeutic aspects for seizures in Alzheimer's disease were searched using the key words "antiepileptic drugs", "seizure treatment" and "Alzheimer". The prevalence and incidence rates of seizures were found to be increased 2 to 6-fold in patients with Alzheimer's disease compared to age-adjusted control patients. Treatment strategies have mainly been extrapolated from elderly patients without dementia, except for one single randomised trial, in which levetiracetam, lamotrigine and phenobarbital efficacy and tolerance were investigated in patients with Alzheimer's disease. Mouse models appear to show a major role of amyloid precursor protein and its cleavage products in the generation of cortical hyperexcitability. A link between Alzheimer's disease and epilepsy has long been described and recent cohort studies have more clearly delineated risk factors associated with the genesis of seizures, such as early onset and possibly severity of dementia. As genetic forms of Alzheimer's disease and experimental mouse models suggest, beta-amyloid may play a prominent role in the propagation of synchronised abnormal discharges, perhaps more via an excitatory mode than a direct neurodegenerative effect.

  15. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease.

    PubMed

    Rodriguez-Vieitez, Elena; Saint-Aubert, Laure; Carter, Stephen F; Almkvist, Ove; Farid, Karim; Schöll, Michael; Chiotis, Konstantinos; Thordardottir, Steinunn; Graff, Caroline; Wall, Anders; Långström, Bengt; Nordberg, Agneta

    2016-03-01

    Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-β, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer (11)C-deuterium-L-deprenyl), fibrillar amyloid-β plaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 ± 0.6 years. By using linear

  16. [Working memory for music in patients with mild cognitive impairment and early stage Alzheimer's disease].

    PubMed

    Kerer, Manuela; Marksteiner, Josef; Hinterhuber, Hartmann; Mazzola, Guerino; Kemmler, Georg; Bliem, Harald R; Weiss, Elisabeth M

    2013-01-01

    A variety of studies demonstrated that some forms of memory for music are spared in dementia, but only few studies have investigated patients with early stages of dementia. In this pilot-study we tested working memory for music in patients with mild cognitive impairment (MCI) and early stage Alzheimer's disease (AD) with a newly created test. The test probed working memory using 7 gradually elongated tone-lines and 6 chords which were each followed by 3 similar items and 1 identical item. The participants of the study, namely 10 patients with MCI, 10 patients with early stage AD and 23 healthy subjects were instructed to select the identical tone-line or chord. Subjects with MCI and early AD showed significantly reduced performance than controls in most of the presented tasks. In recognizing chords MCI- participants surprisingly showed an unimpaired performance. The gradual increase of the impairment during the preclinical phase of AD seems to spare this special ability in MCI.

  17. Early diagnosis of Alzheimer's disease and Parkinson's disease associated with dementia using cerebral perfusion SPECT.

    PubMed

    Song, In-Uk; Chung, Yong-An; Chung, Sung-Woo; Jeong, Jaeseung

    2014-01-01

    Since patterns of cognitive dysfunction in mild Parkinson's disease associated with dementia (PDD) are similar to those in mild Alzheimer's disease (AD), it is difficult to accurately differentiate between these two types of dementia in their early phases using neuropsychological tests. The purpose of the current study was to investigate differences in cerebral perfusion patterns of patients with AD and PDD at the earliest stages using single photon emission computed tomography (SPECT). We consecutively recruited 31 patients with mild PDD, 32 patients with mild probable AD and 33 age-matched healthy subjects. All subjects underwent (99m)Tc-hexamethylpropyleneamine oxime perfusion SPECT and completed general neuropsychological tests. We found that both mild PDD and AD patients showed distinct hypoperfusion in frontal, parietal and temporal regions, compared with healthy subjects. More importantly, hypoperfusion in occipital and cerebellar regions was observed only in mild PDD. The observation of a significant decrease in cerebral perfusion in occipital and cerebellar regions in patients with mild PDD is likely useful to differentiate between PDD and AD at the earliest stages. © 2013 S. Karger AG, Basel.

  18. 7T T₂*-weighted magnetic resonance imaging reveals cortical phase differences between early- and late-onset Alzheimer's disease.

    PubMed

    van Rooden, Sanneke; Doan, Nhat Trung; Versluis, Maarten J; Goos, Jeroen D C; Webb, Andrew G; Oleksik, Ania M; van der Flier, Wiesje M; Scheltens, Philip; Barkhof, Frederik; Weverling-Rynsburger, Annelies W E; Blauw, Gerard Jan; Reiber, Johan H C; van Buchem, Mark A; Milles, Julien; van der Grond, Jeroen

    2015-01-01

    The aim of this study is to explore regional iron-related differences in the cerebral cortex, indicative of Alzheimer's disease pathology, between early- and late-onset Alzheimer's disease (EOAD, LOAD, respectively) patients using 7T magnetic resonance phase images. High-resolution T2(∗)-weighted scans were acquired in 12 EOAD patients and 17 LOAD patients with mild to moderate disease and 27 healthy elderly control subjects. Lobar peak-to-peak phase shifts and regional mean phase contrasts were computed. An increased peak-to-peak phase shift was found for all lobar regions in EOAD patients compared with LOAD patients (p < 0.05). Regional mean phase contrast in EOAD patients was higher than in LOAD patients in the superior medial and middle frontal gyrus, anterior and middle cingulate gyrus, postcentral gyrus, superior and inferior parietal gyrus, and precuneus (p ≤ 0.042). These data suggest that EOAD patients have an increased iron accumulation, possibly related to an increased amyloid deposition, in specific cortical regions as compared with LOAD patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Serum neurofilament light in familial Alzheimer disease: A marker of early neurodegeneration.

    PubMed

    Weston, Philip S J; Poole, Teresa; Ryan, Natalie S; Nair, Akshay; Liang, Yuying; Macpherson, Kirsty; Druyeh, Ronald; Malone, Ian B; Ahsan, R Laila; Pemberton, Hugh; Klimova, Jana; Mead, Simon; Blennow, Kaj; Rossor, Martin N; Schott, Jonathan M; Zetterberg, Henrik; Fox, Nick C

    2017-11-21

    To investigate whether serum neurofilament light (NfL) concentration is increased in familial Alzheimer disease (FAD), both pre and post symptom onset, and whether it is associated with markers of disease stage and severity. We recruited 48 individuals from families with PSEN1 or APP mutations to a cross-sectional study: 18 had symptomatic Alzheimer disease (AD) and 30 were asymptomatic but at 50% risk of carrying a mutation. Serum NfL was measured using an ultrasensitive immunoassay on the single molecule array (Simoa) platform. Cognitive testing and MRI were performed; 33 participants had serial MRI, allowing calculation of atrophy rates. Genetic testing established mutation status. A generalized least squares regression model was used to compare serum NfL among symptomatic mutation carriers, presymptomatic carriers, and noncarriers, adjusting for age and sex. Spearman coefficients assessed associations between serum NfL and (1) estimated years to/from symptom onset (EYO), (2) cognitive measures, and (3) MRI measures of atrophy. Nineteen of the asymptomatic participants were mutation carriers (mean EYO -9.6); 11 were noncarriers. Compared with noncarriers, serum NfL concentration was higher in both symptomatic ( p < 0.0001) and presymptomatic mutation carriers ( p = 0.007). Across all mutation carriers, serum NfL correlated with EYO (ρ = 0.81, p < 0.0001) and multiple cognitive and imaging measures, including Mini-Mental State Examination (ρ = -0.62, p = 0.0001), Clinical Dementia Rating Scale sum of boxes (ρ = 0.79, p < 0.0001), baseline brain volume (ρ = -0.62, p = 0.0002), and whole-brain atrophy rate (ρ = 0.53, p = 0.01). Serum NfL concentration is increased in FAD prior to symptom onset and correlates with measures of disease stage and severity. Serum NfL may thus be a feasible biomarker of early AD-related neurodegeneration. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

  20. Epidemiology of Alzheimer Disease

    PubMed Central

    Mayeux, Richard; Stern, Yaakov

    2012-01-01

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

  1. Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives.

    PubMed

    Hampel, Harald; Frank, Richard; Broich, Karl; Teipel, Stefan J; Katz, Russell G; Hardy, John; Herholz, Karl; Bokde, Arun L W; Jessen, Frank; Hoessler, Yvonne C; Sanhai, Wendy R; Zetterberg, Henrik; Woodcock, Janet; Blennow, Kaj

    2010-07-01

    Advances in therapeutic strategies for Alzheimer's disease that lead to even small delays in onset and progression of the condition would significantly reduce the global burden of the disease. To effectively test compounds for Alzheimer's disease and bring therapy to individuals as early as possible there is an urgent need for collaboration between academic institutions, industry and regulatory organizations for the establishment of standards and networks for the identification and qualification of biological marker candidates. Biomarkers are needed to monitor drug safety, to identify individuals who are most likely to respond to specific treatments, to stratify presymptomatic patients and to quantify the benefits of treatments. Biomarkers that achieve these characteristics should enable objective business decisions in portfolio management and facilitate regulatory approval of new therapies.

  2. Emerging ocular biomarkers of Alzheimer disease.

    PubMed

    van Wijngaarden, Peter; Hadoux, Xavier; Alwan, Mostafa; Keel, Stuart; Dirani, Mohamed

    2017-01-01

    Interest in reliable biomarkers of Alzheimer disease, the leading cause of dementia, has been fuelled by challenges in diagnosing the disease and monitoring disease progression as well as the response to therapy. A range of ocular manifestations of Alzheimer disease, including retinal and lens amyloid-beta accumulation, retinal nerve fiber layer loss, and retinal vascular changes, have been proposed as potential biomarkers of the disease. Herein, we examine the evidence regarding the potential value of these ocular biomarkers of Alzheimer disease. © 2016 Royal Australian and New Zealand College of Ophthalmologists.

  3. Self-transcendence in Alzheimer's disease: the application of theory to practice.

    PubMed

    Vitale, Susan Ann; Shaffer, Cheryl M; Acosta Fenton, Holly R

    2014-12-01

    The middle-range nursing theory of self-transcendence may be applicable to individuals in the early stages of Alzheimer's disease. Full cognitive ability may not be necessary for the essential principles of this theory to be implemented. The theory can offer guidance to families and health care providers in attempting to facilitate a meaningful aging process. A case scenario of an elderly woman with Alzheimer's disease demonstrates how family and caregivers can initiate interventions based on the theoretical concepts. © The Author(s) 2014.

  4. Neuroinflammation in Alzheimer's Disease

    PubMed Central

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

    2018-01-01

    Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment but strongly interacts with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on micro- and astroglia and trigger an innate immune response, characterized by the release of inflammatory mediators, which contribute to disease progression and severity. Genome wide analysis suggests that several genes, which increase the risk for sporadic Alzheimer's disease en-code for factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity are likely to interfere with the immunological processes of the brain and further promote disease progression. This re-view provides an overview on the current knowledge and focuses on the most recent and exciting findings. Modulation of risk factors and intervention with the described immune mechanisms are likely to lead to future preventive or therapeutic strategies for Alzheimer's disease. PMID:25792098

  5. Tau PET binding distinguishes patients with early-stage posterior cortical atrophy from amnestic Alzheimer disease dementia

    PubMed Central

    Day, Gregory S.; Gordon, Brian A.; Jackson, Kelley; Christensen, Jon J.; Ponisio, Maria Rosana; Su, Yi; Ances, Beau M; Benzinger, Tammie L.S.; Morris, John C.

    2017-01-01

    Background Flortaucipir (tau) PET binding distinguishes individuals with clinically well-established posterior cortical atrophy (PCA) due to Alzheimer disease (AD) from cognitively normal (CN) controls. However, it is not known whether tau PET binding patterns differentiate individuals with PCA from those with amnestic AD, particularly early in the symptomatic stages of disease. Methods Flortaucipir and florbetapir (β-amyloid) PET-imaging were performed in individuals with early-stage PCA (N=5), amnestic AD dementia (N=22), and CN controls (N=47). Average tau and β-amyloid deposition were quantified using standard uptake value ratios and compared at a voxel-wise level, controlling for age. Results PCA patients (median age-at-onset, 59 [51–61] years) were younger at symptom-onset than similarly-staged individuals with amnestic AD (75 [60–85] years) or CN controls (73 [61–90] years; p=0.002). Flortaucipir uptake was higher in individuals with early-stage symptomatic PCA versus those with early-stage amnestic AD or CN controls, and greatest in posterior regions. Regional elevations in florbetapir were observed in areas of greatest tau deposition in PCA patients. Conclusions and Relevance Flortaucipir uptake distinguished individuals with PCA and amnestic AD dementia early in the symptomatic course. The posterior brain regions appear to be uniquely vulnerable to tau deposition in PCA, aligning with clinical deficits that define this disease subtype. PMID:28394771

  6. Tau-PET Binding Distinguishes Patients With Early-stage Posterior Cortical Atrophy From Amnestic Alzheimer Disease Dementia.

    PubMed

    Day, Gregory S; Gordon, Brian A; Jackson, Kelley; Christensen, Jon J; Rosana Ponisio, Maria; Su, Yi; Ances, Beau M; Benzinger, Tammie L S; Morris, John C

    2017-01-01

    Flortaucipir (tau) positron emission tomography (PET) binding distinguishes individuals with clinically well-established posterior cortical atrophy (PCA) due to Alzheimer disease (AD) from cognitively normal (CN) controls. However, it is not known whether tau-PET binding patterns differentiate individuals with PCA from those with amnestic AD, particularly early in the symptomatic stages of disease. Flortaucipir and florbetapir (β-amyloid) PET imaging were performed in individuals with early-stage PCA (N=5), amnestic AD dementia (N=22), and CN controls (N=47). Average tau and β-amyloid deposition were quantified using standard uptake value ratios and compared at a voxelwise level, controlling for age. PCA patients [median age-at-onset, 59 (51 to 61) years] were younger at symptom onset than similarly staged individuals with amnestic AD [75 (60 to 85) years] or CN controls [73 (61 to 90) years; P=0.002]. Flortaucipir uptake was higher in individuals with early-stage symptomatic PCA versus those with early-stage amnestic AD or CN controls, and greatest in posterior regions. Regional elevations in florbetapir were observed in areas of greatest tau deposition in PCA patients. Flortaucipir uptake distinguished individuals with PCA and amnestic AD dementia early in the symptomatic course. The posterior brain regions appear to be uniquely vulnerable to tau deposition in PCA, aligning with clinical deficits that define this disease subtype.

  7. Comprehension of metaphors and idioms in patients with Alzheimer's disease: a longitudinal study.

    PubMed

    Papagno, C

    2001-07-01

    Language in patients with Alzheimer's disease has been extensively studied, with the exception of non-literal language comprehension. However, in our speech, we often make use of expressions, which are not necessarily interpreted on a literal ground. Comprehension of metaphors and idioms was examined in 39 patients with probable early Alzheimer's disease. The results showed that the decline of figurative language is not an early symptom of dementia and can occur independently from the impairment of propositional language. It was also found that metaphors and idioms differ as far as the predominant kind of error is concerned.

  8. Design of the NL-ENIGMA study: Exploring the effect of Souvenaid on cerebral glucose metabolism in early Alzheimer's disease.

    PubMed

    Scheltens, Nienke M E; Kuyper, Ingrid S; Boellaard, Ronald; Barkhof, Frederik; Teunissen, Charlotte E; Broersen, Laus M; Lansbergen, Marieke M; van der Flier, Wiesje M; van Berckel, Bart N M; Scheltens, Philip

    2016-11-01

    Alzheimer's disease is associated with early synaptic loss. Specific nutrients are known to be rate limiting for synapse formation. Studies have shown that administering specific nutrients may improve memory function, possibly by increasing synapse formation. This Dutch study explores the Effect of a specific Nutritional Intervention on cerebral Glucose Metabolism in early Alzheimer's disease (NL-ENIGMA, Dutch Trial Register NTR4718, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4718). The NL-ENIGMA study is designed to test whether the specific multinutrient combination Fortasyn Connect present in the medical food Souvenaid influences cerebral glucose metabolism as a marker for improved synapse function. This study is a double-blind, randomized controlled parallel-group single-center trial. Forty drug-naive patients with mild cognitive impairment or mild dementia with evidence of amyloid deposition are 1:1 randomized to receive either the multinutrient combination or placebo once daily. Main exploratory outcome parameters include absolute quantitative positron emission tomography with 18 F-fluorodeoxyglucose (including arterial sampling) and standard uptake value ratios normalized for the cerebellum or pons after 24 weeks. We expect the NL-ENIGMA study to provide further insight in the potential of this multinutrient combination to improve synapse function.

  9. Influence of cerebrovascular disease on brain networks in prodromal and clinical Alzheimer's disease.

    PubMed

    Chong, Joanna Su Xian; Liu, Siwei; Loke, Yng Miin; Hilal, Saima; Ikram, Mohammad Kamran; Xu, Xin; Tan, Boon Yeow; Venketasubramanian, Narayanaswamy; Chen, Christopher Li-Hsian; Zhou, Juan

    2017-11-01

    Network-sensitive neuroimaging methods have been used to characterize large-scale brain network degeneration in Alzheimer's disease and its prodrome. However, few studies have investigated the combined effect of Alzheimer's disease and cerebrovascular disease on brain network degeneration. Our study sought to examine the intrinsic functional connectivity and structural covariance network changes in 235 prodromal and clinical Alzheimer's disease patients with and without cerebrovascular disease. We focused particularly on two higher-order cognitive networks-the default mode network and the executive control network. We found divergent functional connectivity and structural covariance patterns in Alzheimer's disease patients with and without cerebrovascular disease. Alzheimer's disease patients without cerebrovascular disease, but not Alzheimer's disease patients with cerebrovascular disease, showed reductions in posterior default mode network functional connectivity. By comparison, while both groups exhibited parietal reductions in executive control network functional connectivity, only Alzheimer's disease patients with cerebrovascular disease showed increases in frontal executive control network connectivity. Importantly, these distinct executive control network changes were recapitulated in prodromal Alzheimer's disease patients with and without cerebrovascular disease. Across Alzheimer's disease patients with and without cerebrovascular disease, higher default mode network functional connectivity z-scores correlated with greater hippocampal volumes while higher executive control network functional connectivity z-scores correlated with greater white matter changes. In parallel, only Alzheimer's disease patients without cerebrovascular disease showed increased default mode network structural covariance, while only Alzheimer's disease patients with cerebrovascular disease showed increased executive control network structural covariance compared to controls. Our

  10. SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer's disease.

    PubMed

    Brinkmalm, Ann; Brinkmalm, Gunnar; Honer, William G; Frölich, Lutz; Hausner, Lucrezia; Minthon, Lennart; Hansson, Oskar; Wallin, Anders; Zetterberg, Henrik; Blennow, Kaj; Öhrfelt, Annika

    2014-11-23

    Synaptic degeneration is an early pathogenic event in Alzheimer's disease, associated with cognitive impairment and disease progression. Cerebrospinal fluid biomarkers reflecting synaptic integrity would be highly valuable tools to monitor synaptic degeneration directly in patients. We previously showed that synaptic proteins such as synaptotagmin and synaptosomal-associated protein 25 (SNAP-25) could be detected in pooled samples of cerebrospinal fluid, however these assays were not sensitive enough for individual samples. We report a new strategy to study synaptic pathology by using affinity purification and mass spectrometry to measure the levels of the presynaptic protein SNAP-25 in cerebrospinal fluid. By applying this novel affinity mass spectrometry strategy on three separate cohorts of patients, the value of SNAP-25 as a cerebrospinal fluid biomarker for synaptic integrity in Alzheimer's disease was assessed for the first time. We found significantly higher levels of cerebrospinal fluid SNAP-25 fragments in Alzheimer's disease, even in the very early stages, in three separate cohorts. Cerebrospinal fluid SNAP-25 differentiated Alzheimer's disease from controls with area under the curve of 0.901 (P < 0.0001). We developed a sensitive method to analyze SNAP-25 levels in individual CSF samples that to our knowledge was not possible previously. Our results support the notion that synaptic biomarkers may be important tools for early diagnosis, assessment of disease progression, and to monitor drug effects in treatment trials.

  11. Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer's disease.

    PubMed

    Portelius, Erik; Zetterberg, Henrik; Skillbäck, Tobias; Törnqvist, Ulrika; Andreasson, Ulf; Trojanowski, John Q; Weiner, Michael W; Shaw, Leslie M; Mattsson, Niklas; Blennow, Kaj

    2015-11-01

    cerebrospinal fluid neurogranin levels in the mild cognitive impairment group correlated with longitudinal reductions in cortical glucose metabolism (P < 0.001) and hippocampal volume (P < 0.001) at clinical follow-up. Furthermore, within the progressive mild cognitive impairment group, elevated cerebrospinal fluid neurogranin levels were associated with accelerated deterioration in Alzheimer's Disease Assessment Scale-cognitive subscale (β = 0.0017, P = 0.01). These data demonstrate that cerebrospinal fluid neurogranin is increased already at the early clinical stage of Alzheimer's disease and predicts cognitive deterioration and disease-associated changes in metabolic and structural biomarkers over time. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  12. Diagnostic and prognostic role of semantic processing in preclinical Alzheimer's disease.

    PubMed

    Venneri, Annalena; Jahn-Carta, Caroline; Marco, Matteo De; Quaranta, Davide; Marra, Camillo

    2018-06-13

    Relatively spared during most of the timeline of normal aging, semantic memory shows a subtle yet measurable decline even during the pre-clinical stage of Alzheimer's disease. This decline is thought to reflect early neurofibrillary changes and impairment is detectable using tests of language relying on lexical-semantic abilities. A promising approach is the characterization of semantic parameters such as typicality and age of acquisition of words, and propositional density from verbal output. Seminal research like the Nun Study or the analysis of the linguistic decline of famous writers and politicians later diagnosed with Alzheimer's disease supports the early diagnostic value of semantic processing and semantic memory. Moreover, measures of these skills may play an important role for the prognosis of patients with mild cognitive impairment.

  13. Phospholipase A2 activation as a therapeutic approach for cognitive enhancement in early-stage Alzheimer disease.

    PubMed

    Schaeffer, Evelin L; Forlenza, Orestes V; Gattaz, Wagner F

    2009-01-01

    Alzheimer disease (AD) is the leading cause of dementia in the elderly and has no known cure. Evidence suggests that reduced activity of specific subtypes of intracellular phospholipases A2 (cPLA2 and iPLA2) is an early event in AD and may contribute to memory impairment and neuropathology in the disease. The objective of this study was to review the literature focusing on the therapeutic role of PLA2 stimulation by cognitive training and positive modulators, or of supplementation with arachidonic acid (PLA2 product) in facilitating memory function and synaptic transmission and plasticity in either research animals or human subjects. MEDLINE database was searched (no date restrictions) for published articles using the keywords Alzheimer disease (mild, moderate, severe), mild cognitive impairment, healthy elderly, rats, mice, phospholipase A(2), phospholipid metabolism, phosphatidylcholine, arachidonic acid, cognitive training, learning, memory, long-term potentiation, protein kinases, dietary lipid compounds, cell proliferation, neurogenesis, and neuritogenesis. Reference lists of the identified articles were checked to select additional studies of interest. Overall, the data suggest that PLA2 activation is induced in the healthy brain during learning and memory. Furthermore, learning seems to regulate endogenous neurogenesis, which has been observed in AD brains. Finally, PLA2 appears to be implicated in homeostatic processes related to neurite outgrowth and differentiation in both neurodevelopmental processes and response to neuronal injury. The use of positive modulators of PLA2 (especially of cPLA2 and iPLA2) or supplementation with dietary lipid compounds (e.g., arachidonic acid) in combination with cognitive training could be a valuable therapeutic strategy for cognitive enhancement in early-stage AD.

  14. Subjective experiences of an art museum engagement activity for persons with early-stage Alzheimer's disease and their family caregivers.

    PubMed

    Flatt, Jason D; Liptak, Amy; Oakley, Mary Ann; Gogan, Jessica; Varner, Tresa; Lingler, Jennifer H

    2015-06-01

    To describe the subjective experiences of older adults with early-stage Alzheimer's disease or related cognitive disorders (ADRDs) and their family caregivers who participated in an art museum engagement activity. Four focus groups were conducted with 10 persons with ADRD and 10 family caregivers following the completion of a 1-time, 3-hour engagement activity. Participants also completed a brief satisfaction survey, and associations were examined using nonparametric statistics. Three key themes were identified: cognitive stimulation, social connections, and self-esteem. In addition, we identified programmatic issues such as activity-specific concerns and program logistics that could help improve future art program offerings. Past experience with art and perceived social cohesion were correlated with participants' overall satisfaction with the program. Efforts aimed at improving the quality of life of those with Alzheimer's disease and their family caregivers should consider the potential role of art museums. © The Author(s) 2014.

  15. Grey matter atrophy in mild cognitive impairment / early Alzheimer disease associated with delusions: a voxel-based morphometry study.

    PubMed

    Ting, Windsor Kwan-Chun; Fischer, Corinne E; Millikin, Colleen P; Ismail, Zahinoor; Chow, Tiffany W; Schweizer, Tom A

    2015-01-01

    Grey matter atrophy in the right hemisphere has been shown to be more severe in dementia patients with delusions, suggesting a neuroanatomical localization that may be pertinent to impending neurodegeneration. Delusional symptoms may arise when atrophy in these areas reduces the regulatory functions of the right hemisphere, in tandem with asymmetric neuropathology in the left hemisphere. We hypothesized that delusional patients with either amnestic mild cognitive impairment (MCI) or early Alzheimer Disease (AD) would experience more pronounced grey matter atrophy in the right frontal lobe compared with matched patients without delusions. We used neuroimaging and clinical data obtained from the Alzheimer's Disease Neuroimaging Initiative. A comparison group of twenty-nine nondelusional MCI/early AD participants were compared with twenty-nine delusional participants using voxel-based morphometry, matched at baseline by age, sex, education, and Mini-Mental State Exam score. All included participants were diagnosed with amnestic MCI at study baseline. Fifteen voxel clusters of decreased grey matter in participants with delusions were detected. Prominent grey matter decrease was observed in the right precentral gyrus, right inferior frontal gyrus, right insula, and left middle occipital gyrus, areas that may be involved in control of thought and emotions. Greater right fronto-temporal grey matter atrophy was observed in MCI or early AD participants with delusions compared to matched patients without delusions. Consistent with our predictions, asymmetric grey matter atrophy in the right hemisphere may contribute to development of delusions through loss of executive inhibition.

  16. 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

  17. Early Detection of Amyloid Plaque in Alzheimer’s Disease Via X-ray Phase CT

    DTIC Science & Technology

    2015-06-01

    medical imaging, and eight (8) papers published in leading international conferences. 15. SUBJECT TERMS Alzheimer disease, Amyloid plaque, X-ray phase...11 4 Introduction A. Overall: As the elderly population increases, dementia caused by Alzheimer’s disease (AD) has become a major...with an emphasis on improving the performance of G1 and G2, and the development of algorithmic solutions to deal with the issue caused by the

  18. Impact of DNA testing for early-onset familial Alzheimer disease and frontotemporal dementia.

    PubMed

    Steinbart, E J; Smith, C O; Poorkaj, P; Bird, T D

    2001-11-01

    DNA testing of persons at risk for hereditary, degenerative neurologic diseases is relatively new. Only anecdotal reports of such testing in familial Alzheimer disease (FAD) exist, and little is know about the personal and social impact of such testing. In a descriptive, observational study, individuals at 50% risk for autosomal dominant, early-onset FAD or frontotemporal dementia with parkinsonism linked to chromosome 17 underwent DNA testing for the genetic mutations previously identified in affected family members. Individuals were followed up for (1/2) to 3 years and were interviewed regarding attitudes toward the testing process and the impact of the results. Twenty-one (8.4%) of 251 persons at risk for FAD or frontotemporal dementia requested genetic testing. The most common reasons for requesting testing were concern about early symptoms of dementia, financial or family planning, and relief from anxiety. Twelve individuals had positive DNA test results, and 6 of these had early symptoms of dementia; 8 had negative results; and 1 has not yet received results. Of 14 asymptomatic individuals completing testing, 13 believed the testing was beneficial. Two persons reported moderate anxiety and 1 reported moderate depression. As expected, persons with negative test results had happier experiences overall, but even they had to deal with ongoing anxiety and depression. Thus far, there have been no psychiatric hospitalizations, suicide attempts, or denials of insurance. Genetic testing in early-onset FAD and frontotemporal dementia can be completed successfully. Most individuals demonstrate effective coping skills and find the testing to be beneficial, but long-term effects remain unknown.

  19. Recall and recognition of verbal paired associates in early Alzheimer's disease.

    PubMed

    Lowndes, G J; Saling, M M; Ames, D; Chiu, E; Gonzalez, L M; Savage, G R

    2008-07-01

    The primary impairment in early Alzheimer's disease (AD) is encoding/consolidation, resulting from medial temporal lobe (MTL) pathology. AD patients perform poorly on cued-recall paired associate learning (PAL) tasks, which assess the ability of the MTLs to encode relational memory. Since encoding and retrieval processes are confounded within performance indexes on cued-recall PAL, its specificity for AD is limited. Recognition paradigms tend to show good specificity for AD, and are well tolerated, but are typically less sensitive than recall tasks. Associate-recognition is a novel PAL task requiring a combination of recall and recognition processes. We administered a verbal associate-recognition test and cued-recall analogue to 22 early AD patients and 55 elderly controls to compare their ability to discriminate these groups. Both paradigms used eight arbitrarily related word pairs (e.g., pool-teeth) with varying degrees of imageability. Associate-recognition was equally effective as the cued-recall analogue in discriminating the groups, and logistic regression demonstrated classification rates by both tasks were equivalent. These preliminary findings provide support for the clinical value of this recognition tool. Conceptually it has potential for greater specificity in informing neuropsychological diagnosis of AD in clinical samples but this requires further empirical support.

  20. 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…

  1. Active Vaccines for Alzheimer Disease Treatment.

    PubMed

    Sterner, Rosalie M; Takahashi, Paul Y; Yu Ballard, Aimee C

    2016-09-01

    Vaccination against peptides specific to Alzheimer disease may generate an immune response that could help inhibit disease and symptom progression. PubMed and Scopus were searched for clinical trial articles, review articles, and preclinical studies relevant to the field of active Alzheimer disease vaccines and raw searches yielded articles ranging from 2016 to 1973. ClinicalTrials.gov was searched for active Alzheimer disease vaccine trials. Manual research and cross-referencing from reviews and original articles was performed. First generation Aβ42 phase 2a trial in patients with mild to moderate Alzheimer disease resulted in cases of meningoencephalitis in 6% of patients, so next generation vaccines are working to target more specific epitopes to induce a more controlled immune response. Difficulty in developing these vaccines resides in striking a balance between providing a vaccine that induces enough of an immune response to actually clear protein sustainably but not so much of a response that results in excess immune activation and possibly adverse effects such as meningoencephalitis. Although much work still needs to be done in the field to make this a practical possibility, the enticing allure of being able to treat or even prevent the extraordinarily impactful disease that is Alzheimer disease makes the idea of active vaccination for Alzheimer disease very appealing and something worth striving toward. Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

  2. Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease.

    PubMed

    Mattsson, Niklas; Insel, Philip S; Donohue, Michael; Landau, Susan; Jagust, William J; Shaw, Leslie M; Trojanowski, John Q; Zetterberg, Henrik; Blennow, Kaj; Weiner, Michael W

    2015-03-01

    cerebrospinal fluid and positron emission tomography amyloid-β provide partially independent information about a wide range of Alzheimer's measures supports the theory that these modalities represent partly different aspects of Alzheimer's pathology. The fact that mismatch, with positive cerebrospinal fluid amyloid-β but normal positron emission tomography amyloid-β, is relatively common in cognitively healthy people may be considered when using these biomarkers to identify early stage Alzheimer's disease. Reduced cerebrospinal fluid amyloid-β may be more strongly related to early stage Alzheimer's disease, whereas increased positron emission tomography amyloid-β may be more strongly related to disease progression. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Rare Variants in PLD3 Do Not Affect Risk for Early-Onset Alzheimer Disease in a European Consortium Cohort.

    PubMed

    Cacace, Rita; Van den Bossche, Tobi; Engelborghs, Sebastiaan; Geerts, Nathalie; Laureys, Annelies; Dillen, Lubina; Graff, Caroline; Thonberg, Håkan; Chiang, Huei-Hsin; Pastor, Pau; Ortega-Cubero, Sara; Pastor, Maria A; Diehl-Schmid, Janine; Alexopoulos, Panagiotis; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Nacmias, Benedetta; Sorbi, Sandro; Sanchez-Valle, Raquel; Lladó, Albert; Gelpi, Ellen; Almeida, Maria Rosário; Santana, Isabel; Tsolaki, Magda; Koutroumani, Maria; Clarimon, Jordi; Lleó, Alberto; Fortea, Juan; de Mendonça, Alexandre; Martins, Madalena; Borroni, Barbara; Padovani, Alessandro; Matej, Radoslav; Rohan, Zdenek; Vandenbulcke, Mathieu; Vandenberghe, Rik; De Deyn, Peter P; Cras, Patrick; van der Zee, Julie; Sleegers, Kristel; Van Broeckhoven, Christine

    2015-12-01

    Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole-genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and two splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta-analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (P = 0.43; OR = 1.53, 95% CI 0.60-3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated. © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

  4. The Harvard Automated Phone Task: new performance-based activities of daily living tests for early Alzheimer's disease.

    PubMed

    Marshall, Gad A; Dekhtyar, Maria; Bruno, Jonathan M; Jethwani, Kamal; Amariglio, Rebecca E; Johnson, Keith A; Sperling, Reisa A; Rentz, Dorene M

    2015-12-01

    Impairment in activities of daily living is a major burden for Alzheimer's disease dementia patients and caregivers. Multiple subjective scales and a few performance-based instruments have been validated and proven to be reliable in measuring instrumental activities of daily living in Alzheimer's disease dementia but less so in amnestic mild cognitive impairment and preclinical Alzheimer's disease. To validate the Harvard Automated Phone Task, a new performance-based activities of daily living test for early Alzheimer's disease, which assesses high level tasks that challenge seniors in daily life. In a cross-sectional study, the Harvard Automated Phone Task was associated with demographics and cognitive measures through univariate and multivariate analyses; ability to discriminate across diagnostic groups was assessed; test-retest reliability with the same and alternate versions was assessed in a subset of participants; and the relationship with regional cortical thickness was assessed in a subset of participants. Academic clinical research center. One hundred and eighty two participants were recruited from the community (127 clinically normal elderly and 45 young normal participants) and memory disorders clinics at Brigham and Women's Hospital and Massachusetts General Hospital (10 participants with mild cognitive impairment). As part of the Harvard Automated Phone Task, participants navigated an interactive voice response system to refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and make a bank account transfer and payment (APT-Bank). The 3 tasks were scored based on time, errors, and repetitions from which composite z-scores were derived, as well as a separate report of correct completion of the task. We found that the Harvard Automated Phone Task discriminated well between diagnostic groups (APT-Script: p=0.002; APT-PCP: p<0.001; APT-Bank: p=0.02), had an incremental level of difficulty, and had excellent test

  5. Vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of white matter lesions on MRI: the evaluation of vascular care in Alzheimer's disease (EVA) study.

    PubMed

    Richard, Edo; Gouw, Alida A; Scheltens, Philip; van Gool, Willem A

    2010-03-01

    White matter lesions (WMLs) and cerebral infarcts are common findings in Alzheimer disease and may contribute to dementia severity. WMLs and lacunar infarcts may provide a potential target for intervention strategies. This study assessed whether multicomponent vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of WMLs and prevents occurrence of new infarcts. A randomized controlled clinical trial, including 123 subjects, compared vascular care with standard care in patients with Alzheimer disease with cerebrovascular lesions on MRI. Progression of WMLs, lacunes, medial temporal lobe atrophy, and global cortical atrophy were semiquantitatively scored after 2-year follow-up. Sixty-five subjects (36 vascular care, 29 standard care) had a baseline and a follow-up MRI and in 58 subjects, a follow-up scan could not be obtained due to advanced dementia or death. Subjects in the vascular care group had less progression of WMLs as measured with the WML change score (1.4 versus 2.3, P=0.03). There was no difference in the number of new lacunes or change in global cortical atrophy or medial temporal lobe atrophy between the 2 groups. Vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of WMLs. Treatment aimed at vascular risk factors in patients with early Alzheimer disease may be beneficial, possibly in an even earlier stage of the disease.

  6. Reduced limbic and hypothalamic volumes correlate with bone density in early Alzheimer's disease.

    PubMed

    Loskutova, Natalia; Honea, Robyn A; Brooks, William M; Burns, Jeffrey M

    2010-01-01

    Accelerated bone loss is associated with Alzheimer's disease (AD). Although the central nervous system plays a direct role in regulating bone mass, primarily through the actions of the hypothalamus, there is little work investigating the possible role of neurodegeneration in bone loss. In this cross-sectional study, we examined the association between bone mineral density (BMD) and neuroimaging markers of neurodegeneration (i.e., global and regional measures of brain volume) in early AD and non-demented aging. Fifty-five non-demented and 63 early AD participants underwent standard neurological and neuropsychological assessment, structural MRI scanning, and dual energy x-ray absorptiometry. In early AD, voxel-based morphometry analyses demonstrated that low BMD was associated with low volume in limbic grey matter (GM) including the hypothalamus, cingulate, and parahippocampal gyri and in the left superior temporal gyrus and left inferior parietal cortex. No relationship between BMD and regional GM volume was found in non-demented controls. The hypothesis-driven region of interest analysis further isolating the hypothalamus demonstrated a positive relationship between BMD and hypothalamic volume after controlling for age and gender in the early AD group but not in non-demented controls. These results demonstrate that lower BMD is associated with lower hypothalamic volume in early AD, suggesting that central mechanisms of bone remodeling may be disrupted by neurodegeneration.

  7. miRNAs Expressions and Interaction with Biological Systems in Patients with Alzheimer`s Disease. Using miRNAs as a Diagnosis and Prognosis Biomarker.

    PubMed

    Negoita, Silvius I; Sandesc, Dorel; Rogobete, Alexandru F; Dutu, Madalina; Bedreag, Ovidiu H; Papurica, Marius; Ercisli, Muhammed F; Popovici, Sonia E; Dumache, Raluca; Sandesc, Mihai; Dinu, Anca; Sas, Adriana M; Serban, Denis; Corneci, Dan

    2017-09-01

    A high percentage of patients develop Alzheimer`s disease (AD). The main signs are loss of memory and cognitive functions which have a significant impact on lifestyle. Numerous studies have been conducted to identify new biomarkers for early diagnosis of patients with AD. An ideal biomarker is represented by the expression of miRNAs. In this paper, we want to summarize expressions miRNAs in AD. We also want to present the pathophysiological and genetic interactions of miRNAs with protein systems in these patients. For the study, we examined available studies in scientific databases, such as PubMed and Scopus. The studies were searched using the keywords "miRNAs expression", "Alzheimer`s disease", "genetic polymorphisms", and "genetic biomarkers". For the assessment and monitoring of patients with AD, the expression of miRNAs can be used successfully due to increased specificity and selectivity. Moreover, the expression of miRNAs can provide important answers regarding possible genetic interactions and genetic therapeutic regimens. For the evaluation and non-invasive monitoring of patients with Alzheimer`s disease the expression of miRNAs can be successfully used.

  8. 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

  9. Mitochondrial genes are altered in blood early in Alzheimer's disease.

    PubMed

    Lunnon, Katie; Keohane, Aoife; Pidsley, Ruth; Newhouse, Stephen; Riddoch-Contreras, Joanna; Thubron, Elisabeth B; Devall, Matthew; Soininen, Hikka; Kłoszewska, Iwona; Mecocci, Patrizia; Tsolaki, Magda; Vellas, Bruno; Schalkwyk, Leonard; Dobson, Richard; Malik, Afshan N; Powell, John; Lovestone, Simon; Hodges, Angela

    2017-05-01

    Although mitochondrial dysfunction is a consistent feature of Alzheimer's disease in the brain and blood, the molecular mechanisms behind these phenomena are unknown. Here we have replicated our previous findings demonstrating reduced expression of nuclear-encoded oxidative phosphorylation (OXPHOS) subunits and subunits required for the translation of mitochondrial-encoded OXPHOS genes in blood from people with Alzheimer's disease and mild cognitive impairment. Interestingly this was accompanied by increased expression of some mitochondrial-encoded OXPHOS genes, namely those residing closest to the transcription start site of the polycistronic heavy chain mitochondrial transcript (MT-ND1, MT-ND2, MT-ATP6, MT-CO1, MT-CO2, MT-C03) and MT-ND6 transcribed from the light chain. Further we show that mitochondrial DNA copy number was unchanged suggesting no change in steady-state numbers of mitochondria. We suggest that an imbalance in nuclear and mitochondrial genome-encoded OXPHOS transcripts may drive a negative feedback loop reducing mitochondrial translation and compromising OXPHOS efficiency, which is likely to generate damaging reactive oxygen species. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. Selective alterations of neurons and circuits related to early memory loss in Alzheimer's disease.

    PubMed

    Llorens-Martín, Maria; Blazquez-Llorca, Lidia; Benavides-Piccione, Ruth; Rabano, Alberto; Hernandez, Felix; Avila, Jesus; DeFelipe, Javier

    2014-01-01

    A progressive loss of episodic memory is a well-known clinical symptom that characterizes Alzheimer's disease (AD). The beginning of this loss of memory has been associated with the very early, pathological accumulation of tau and neuronal degeneration observed in the entorhinal cortex (EC). Tau-related pathology is thought to then spread progressively to the hippocampal formation and other brain areas as the disease progresses. The major cortical afferent source of the hippocampus and dentate gyrus is the EC through the perforant pathway. At least two main circuits participate in the connection between EC and the hippocampus; one originating in layer II and the other in layer III of the EC giving rise to the classical trisynaptic (ECII → dentate gyrus → CA3 → CA1) and monosynaptic (ECIII → CA1) circuits. Thus, the study of the early pathological changes in these circuits is of great interest. In this review, we will discuss mainly the alterations of the granule cell neurons of the dentate gyrus and the atrophy of CA1 pyramidal neurons that occur in AD in relation to the possible differential alterations of these two main circuits.

  11. Reliability study of the Behavioral Assessment of the Dysexecutive Syndrome adapted for a Brazilian sample of older-adult controls and probable early Alzheimer's disease patients.

    PubMed

    Canali, Fabíola; Brucki, Sonia M D; Bertolucci, Paulo H F; Bueno, Orlando F A

    2011-12-01

    Ecological tests are useful in assessing executive function deficits and may be of value in appraising response to treatment in Alzheimer's disease patients. Our aims were to examine executive function using the Behavioral Assessment of the Dysexecutive Syndrome for a Brazilian sample of older-adult controls and probable early Alzheimer's disease patients, and verify the applicability of this test battery. Forty-one older-adult controls were matched with mild Alzheimer's disease patients by age, education, and gender. There significant inter-group differences in overall profile and almost all subtests except temporal judgment, time spent on planning the first and second Zoo Map visit, number of errors when copying drawings, naming pictures and Six Modified Elements arithmetic, and dysexecutive questionnaire self-rating. The Behavioral Assessment of the Dysexecutive Syndrome item that best discriminated controls from patients was the Modified Six Elements - adapted (general index), with a sensitivity of 80% and specificity of 90%, (AUC = 0.91, p < 0.001). Behavioral Assessment of the Dysexecutive Syndrome was effective in detecting executive function deficits in mild Alzheimer's disease patients, particularly the task switching, time monitoring, and rule-shift subtests.

  12. [Anesthesia and Alzheimer disease - Current perceptions].

    PubMed

    Marques, Ana Filipa Vieira da Silva Ferreira; Lapa, Teresa Alexandra Santos Carvalho

    It has been speculated that the use of anesthetic agents may be a risk factor for the development of Alzheimer disease. The objective of this review is to describe and discuss pre-clinical and clinical data related to anesthesia and this disease. Alzheimer disease affects about 5% of the population over 65 years old, with age being the main risk factor and being associated with a high morbidity. Current evidence questions a possible association between anesthesia, surgery, and long-term cognitive effects, including Alzheimer disease. Although data from some animal studies suggest an association between anesthesia and neurotoxicity, this link remains inconclusive in humans. We performed a review of the literature in which we selected scientific articles in the PubMed database, published between 2005 and 2016 (one article from 1998 due to its historical relevance), in English, which address the possible relationship between anesthesia and Alzheimer disease. 49 articles were selected. The possible relationship between anesthetic agents, cognitive dysfunction, and Alzheimer disease remains to be clarified. Prospective cohort studies or randomized clinical trials for a better understanding of this association will be required. Copyright © 2017 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  13. Survival after initial diagnosis of Alzheimer disease.

    PubMed

    Larson, Eric B; Shadlen, Marie-Florence; Wang, Li; McCormick, Wayne C; Bowen, James D; Teri, Linda; Kukull, Walter A

    2004-04-06

    Alzheimer disease is an increasingly common condition in older people. Knowledge of life expectancy after the diagnosis of Alzheimer disease and of associations of patient characteristics with survival may help planning for future care. To investigate the course of Alzheimer disease after initial diagnosis and examine associations hypothesized to correlate with survival among community-dwelling patients with Alzheimer disease. Prospective observational study. An Alzheimer disease patient registry from a base population of 23 000 persons age 60 years and older in the Group Health Cooperative, Seattle, Washington. 521 newly recognized persons with Alzheimer disease enrolled from 1987 to 1996 in an Alzheimer disease patient registry. Baseline measurements included patient demographic features, Mini-Mental State Examination score, Blessed Dementia Rating Scale score, duration since reported onset of symptoms, associated symptoms, comorbid conditions, and selected signs. Survival was the outcome of interest. The median survival from initial diagnosis was 4.2 years for men and 5.7 years for women with Alzheimer disease. Men had poorer survival across all age groups compared with females. Survival was decreased in all age groups compared with the life expectancy of the U.S. population. Predictors of mortality based on proportional hazards models included a baseline Mini-Mental State Examination score of 17 or less, baseline Blessed Dementia Rating Scale score of 5.0 or greater, presence of frontal lobe release signs, presence of extrapyramidal signs, gait disturbance, history of falls, congestive heart failure, ischemic heart disease, and diabetes at baseline. The base population, although typical of the surrounding Seattle community, may not be representative of other, more diverse populations. In this sample of community-dwelling elderly persons who received a diagnosis of Alzheimer disease, survival duration was shorter than predicted on the basis of U.S. population

  14. Advanced Glycation End-Products Are Associated With the Presence and Severity of Paratonia in Early Stage Alzheimer Disease.

    PubMed

    Drenth, Hans; Zuidema, Sytse U; Krijnen, Wim P; Bautmans, Ivan; van der Schans, Cees; Hobbelen, Hans

    2017-07-01

    Paratonia, a distinctive form of hypertonia in patients with dementia, causes loss of functional mobility in early stage dementia to severe contractures and pain in the late stages. The pathogenesis of paratonia is not well understood. Patients in early stage dementia with diabetes mellitus showed a significantly higher risk for the development of paratonia. Both Alzheimer disease and diabetes mellitus are related to higher concentrations of advanced glycation end-products (AGEs). The purpose of this study is to explore the association of AGEs with the prevalence and severity of paratonia in patients with Alzheimer disease. Observational longitudinal, 1-year follow-up cohort study with 3 assessments. Day care centers for patients with dementia. A total of 144 community-dwelling patients with early stage Alzheimer or Alzheimer/vascular disease were recruited from 24 dementia day care centers in The Netherlands. The presence of paratonia (Paratonia Assessment Instrument), the severity of paratonia (Modified Ashworth Scale for paratonia), and AGE levels (AGE-reader). From the 144 participants (56.3% female and 43.7% male, with a mean [standard deviation] age of 80.7 [7.7] years), 118 participants were available for final follow-up. A significant association between AGE levels and the presence of paratonia (odds ratio 3.47, 95% confidence interval [CI] 1.87-6.44, P < .001) and paratonia severity (β = 0.17, 95% CI 0.11-0.23, P < .001) was determined. In participants who developed paratonia and those with persistent paratonia throughout the study the AGE levels (95% CI -0.38 to -0.13, P < .001 and 95% CI -0.46 to -0.06, P = .012, respectively) and the severity of paratonia (95% CI -0.60 to -0.35, P < .001 and 95% CI -0.38 to -0.12, P < .001, respectively) significantly increased, whereas the AGE levels remained stable in those participants without paratonia. Notwithstanding, change in AGE levels was not significantly (P = .062) related to change

  15. The ALFA project: A research platform to identify early pathophysiological features of Alzheimer's disease.

    PubMed

    Molinuevo, José Luis; Gramunt, Nina; Gispert, Juan Domingo; Fauria, Karine; Esteller, Manel; Minguillon, Carolina; Sánchez-Benavides, Gonzalo; Huesa, Gema; Morán, Sebastián; Dal-Ré, Rafael; Camí, Jordi

    2016-06-01

    The preclinical phase of Alzheimer's disease (AD) is optimal for identifying early pathophysiological events and developing prevention programs, which are shared aims of the ALFA project, including the ALFA registry and parent cohort and the nested ALFA+ cohort study. The ALFA parent cohort baseline visit included full cognitive evaluation, lifestyle habits questionnaires, DNA extraction, and MRI. The nested ALFA+ study adds wet and imaging biomarkers for deeper phenotyping. A total of 2743 participants aged 45 to 74 years were included in the ALFA parent cohort. We show that this cohort, mostly composed of cognitively normal offspring of AD patients, is enriched for AD genetic risk factors. The ALFA project represents a valuable infrastructure that will leverage with different studies and trials to prevent AD. The longitudinal ALFA+ cohort will serve to untangle the natural history of the disease and to model the preclinical stages to develop successful trials.

  16. Somatotype in Alzheimer's disease.

    PubMed

    Buffa, Roberto; Lodde, Marco; Floris, Giovanni; Zaru, Cristina; Putzu, Paolo F; Marini, Elisabetta

    2007-01-01

    The clinical picture of Alzheimer's disease includes anthropometric and body composition variations. Somatotyping is a practical non-invasive method to assess body type. The objective of this study was to describe the somatotype of a sample of Alzheimer's patients. The sample consisted of 55 Alzheimer disease individuals in the mild-moderate stage (17 men, mean age = 76.9 +/- 7.2 years; 38 women, mean age = 79.6 +/- 6.4 years). The pathological subjects were compared with a control group consisting of 280 healthy individuals (134 men, mean age = 74.2 +/- 7.3 years; 146 women, mean age = 74.9 +/- 7.4 years). The Heath-Carter somatotype was applied. The Alzheimer patients (mean somatotype: 6.1-5.5-0.8 in men, 7.0-5.3-0.7 in women) are less mesomorphic and more ectomorphic than the controls (mean somatotype: 6.1-6.3-0.6 in men, 7.7-6.3-0.4 in women), the differences being significant in women (mesomorphy, p = 0.000; ectomorphy, p = 0.012). Alzheimer patients show peculiar somatometric characteristics. The somatotype technique could represent a suitable tool for the study and monitoring of physical variations. Copyright 2007 S. Karger AG, Basel.

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    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 havemore » 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.« less

  18. Serum pentosidine as an indicator of Alzheimer's disease.

    PubMed

    Meli, M; Perier, C; Ferron, C; Parssegny, F; Denis, C; Gonthier, R; Laurent, B; Reynaud, E; Frey, J; Chamson, A

    2002-04-01

    Pentosidine, an advanced glycation end product (AGE), was assayed by HPLC in serum proteins from patients with Alzheimer type dementia (AD), patients with diabetes mellitus (D), and healthy (C) age-matched old subjects (mean age from each group = 84 years). Serum pentosidine was significantly different between the three groups despite similar renal function (serum creatinine < 160 micromol/L). In all groups of patients, pentosidine was independent of glycated hemoglobin (HbA1C) and the early glycation marker fructosamine and appeared to be an independent marker, mainly bound to serum albumin. Pentosidine could be an important factor useful for the diagnosis of Alzheimer's disease.

  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. Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  20. Impairment of memory generalization in preclinical autosomal dominant Alzheimer's disease mutation carriers.

    PubMed

    Petok, Jessica R; Myers, Catherine E; Pa, Judy; Hobel, Zachary; Wharton, David M; Medina, Luis D; Casado, Maria; Coppola, Giovanni; Gluck, Mark A; Ringman, John M

    2018-05-01

    Fast, inexpensive, and noninvasive identification of Alzheimer's disease (AD) before clinical symptoms emerge would augment our ability to intervene early in the disease. Individuals with fully penetrant genetic mutations causing autosomal dominant Alzheimer's disease (ADAD) are essentially certain to develop the disease, providing a unique opportunity to examine biomarkers during the preclinical stage. Using a generalization task that has previously shown to be sensitive to medial temporal lobe pathology, we compared preclinical individuals carrying ADAD mutations to noncarrying kin to determine whether generalization (the ability to transfer previous learning to novel but familiar recombinations) is vulnerable early, before overt cognitive decline. As predicted, results revealed that preclinical ADAD mutation carriers made significantly more errors during generalization than noncarrying kin, despite no differences between groups during learning or retention. This impairment correlated with the left hippocampal volume, particularly in mutation carriers. Such identification of generalization deficits in early ADAD may provide an easily implementable and potentially linguistically and culturally neutral way to identify and track cognition in ADAD. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog): Normative Data for the Portuguese Population.

    PubMed

    Nogueira, Joana; Freitas, Sandra; Duro, Diana; Tábuas-Pereira, Miguel; Guerreiro, Manuela; Almeida, Jorge; Santana, Isabel

    2018-02-28

    The Alzheimer's Disease Assessment Scale - Cognitive Subscale is a brief battery developed to assess cognitive functioning in Alzheimer's disease that encompasses the core characteristics of cognitive decline (e.g. memory, language, praxis, constructive ability and orientation). The early detection, as well as the monitoring of cognitive decline along disease progression, is extremely important in clinical care and interventional research. The main goals of the present study were to analyze the psychometric properties of the Portuguese version of the Alzheimer's Disease Assessment Scale - Cognitive Subscale, and to establish normative values for the Portuguese population. The Portuguese version of Alzheimer's Disease Assessment Scale - Cognitive Subscale was administered to 223 cognitively healthy participants according to a standard assessment protocol consisting of the Mini-Mental State Examination, the Montreal Cognitive Assessment and the Adults and Older Adults Functional Assessment Inventory. Normal performance on the assessment protocol was the inclusion criteria for the study. The Alzheimer's Disease Assessment Scale - Cognitive Subscale revealed good psychometric properties when used in the Portuguese population. Age was the main predictor of the Alzheimer's Disease Assessment Scale - Cognitive Subscale total score (R2 = 0.123), whereas the influence of education level was lower (R2 = 0.027). These two variables explained 14.4% of the variance on the Alzheimer's Disease Assessment Scale - Cognitive Subscale scores and were used to stratify the normative values for the Portuguese population presented here. On the total sample, the average total score in the Alzheimer's Disease Assessment Scale - Cognitive Subscale was 6 points. The normative data were determined according to age and educational level as these were the sociodemographic variables that significantly contributed to the prediction of the Alzheimer's Disease Assessment Scale - Cognitive Subscale

  2. The cognitive and neural expression of semantic memory impairment in mild cognitive impairment and early Alzheimer's disease.

    PubMed

    Joubert, Sven; Brambati, Simona M; Ansado, Jennyfer; Barbeau, Emmanuel J; Felician, Olivier; Didic, Mira; Lacombe, Jacinthe; Goldstein, Rachel; Chayer, Céline; Kergoat, Marie-Jeanne

    2010-03-01

    Semantic deficits in Alzheimer's disease have been widely documented, but little is known about the integrity of semantic memory in the prodromal stage of the illness. The aims of the present study were to: (i) investigate naming abilities and semantic memory in amnestic mild cognitive impairment (aMCI), early Alzheimer's disease (AD) compared to healthy older subjects; (ii) investigate the association between naming and semantic knowledge in aMCI and AD; (iii) examine if the semantic impairment was present in different modalities; and (iv) study the relationship between semantic performance and grey matter volume using voxel-based morphometry. Results indicate that both naming and semantic knowledge of objects and famous people were impaired in aMCI and early AD groups, when compared to healthy age- and education-matched controls. Item-by-item analyses showed that anomia in aMCI and early AD was significantly associated with underlying semantic knowledge of famous people but not with semantic knowledge of objects. Moreover, semantic knowledge of the same concepts was impaired in both the visual and the verbal modalities. Finally, voxel-based morphometry analyses revealed that semantic impairment in aMCI and AD was associated with cortical atrophy in the anterior temporal lobe (ATL) region as well as in the inferior prefrontal cortex (IPC), some of the key regions of the semantic cognition network. These findings suggest that the semantic impairment in aMCI may result from a breakdown of semantic knowledge of famous people and objects, combined with difficulties in the selection, manipulation and retrieval of this knowledge. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

  3. Balance and mobility dysfunction and falls risk in older people with mild to moderate Alzheimer disease.

    PubMed

    Suttanon, Plaiwan; Hill, Keith D; Said, Catherine M; Logiudice, Dina; Lautenschlager, Nicola T; Dodd, Karen J

    2012-01-01

    This study aimed to identify the magnitude and type of balance and mobility impairments in people with Alzheimer disease by comparing their performance with that of older people without cognitive impairment. Twenty-five community-dwelling people with mild to moderate Alzheimer disease and a comparison group of 25 cognitively intact age- and sex-matched people completed a comprehensive balance and mobility assessment. This included computerized posturography measures of static and dynamic balance under various conditions, clinical balance, and mobility measures, and measures of falls and falls risk. The level of falls risk was higher in people with Alzheimer disease. Standing balance in people with Alzheimer disease was significantly impaired across a range of static and dynamic balance conditions. Activity level, gait, and mobility measures were also impaired, particularly turning and dual tasks. The findings of the study highlight the value of including balance screening as a routine component of early dementia assessment. This would allow for the early detection of balance dysfunction and the introduction of balance retraining before impairments progress to more advanced levels.

  4. Genetic Aspects of Alzheimer Disease

    PubMed Central

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

    2011-01-01

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

  5. 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…

  6. Recruitment of subjects into clinical trials for Alzheimer disease.

    PubMed

    Knebl, Janice A; Patki, Deepti

    2010-09-01

    Alzheimer disease is a devastating neurodegenerative disorder affecting millions of Americans. It reduces the ability of the individual to remain independent, places a burden on caregivers, and substantially increases healthcare costs. New treatments are being tested in numerous clinical trials with the goal of preventing or delaying the onset of Alzheimer disease, slowing or modifying the disease's course, or finding a cure for patients with the disease. Alzheimer disease research can successfully proceed only if individuals who have this illness are willing to participate in clinical trials. However, recruitment and retention of subjects in clinical trials for Alzheimer disease is a challenging task. Furthermore, because of reductions in decision-making capacities of individuals with Alzheimer disease, clinical trials also need to involve caregivers. The present article delineates unique hurdles encountered in the recruitment process for Alzheimer disease clinical trials. The article also identifies strategies for effective recruitment of subjects in Alzheimer disease clinical trials, including guidelines to help principal investigators and clinical research coordinators reach recruitment goals.

  7. Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease.

    PubMed

    Roy, Dheeraj S; Arons, Autumn; Mitchell, Teryn I; Pignatelli, Michele; Ryan, Tomás J; Tonegawa, Susumu

    2016-03-24

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD.

  8. The neuropsychological profile of Alzheimer disease.

    PubMed

    Weintraub, Sandra; Wicklund, Alissa H; Salmon, David P

    2012-04-01

    Neuropsychological assessment has featured prominently over the past 30 years in the characterization of dementia associated with Alzheimer disease (AD). Clinical neuropsychological methods have identified the earliest, most definitive cognitive and behavioral symptoms of illness, contributing to the identification, staging, and tracking of disease. With increasing public awareness of dementia, disease detection has moved to earlier stages of illness, at a time when deficits are both behaviorally and pathologically selective. For reasons that are not well understood, early AD pathology frequently targets large-scale neuroanatomical networks for episodic memory before other networks that subserve language, attention, executive functions, and visuospatial abilities. This chapter reviews the pathognomonic neuropsychological features of AD dementia and how these differ from "normal," age-related cognitive decline and from other neurodegenerative diseases that cause dementia, including cortical Lewy body disease, frontotemporal lobar degeneration, and cerebrovascular disease.

  9. 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.

  10. 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 ...

  11. Evolution in the conceptualization of dementia and Alzheimer's disease: Greco-Roman period to the 1960s.

    PubMed

    Berchtold, N C; Cotman, C W

    1998-01-01

    Most histories of senile dementia commence with Alois Alzheimer's description in 1906 of the first case of Alzheimer's disease, yet the history of senile dementia before 1906 is quite rich, dating back to the ancient Greek and Roman philosophers and physicians. Over the 2500 years since ancient times, the concept of senile dementia has evolved from a rather vague notion that mental decline occurred inevitably in old age, to become defined today by a distinct set of clinical and pathological features with the potential for treatment and prevention within grasp. Throughout history, many elderly individuals with unpredictable behavior were sequestered in institutions, and the line between mental disorders and senile dementia was hazy at best. The identification of Alzheimer's disease at the onset of the 20th century was a turning point for the understanding of senile dementia, and the concepts and histological findings presented by the early researchers of Alzheimer's disease remain relevant still today. Indeed, these early findings are proving to be a continuing source of insight, as many of the issues debated at the turn of the century remain unresolved still today. This paper thus traces the history of the evolution of our current conceptualization of Alzheimer's disease from the amorphous Greco-Roman concept of age-associated dementia.

  12. Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial.

    PubMed

    Lin, Chieh-Hsin; Chen, Ping-Kun; Chang, Yue-Cune; Chuo, Liang-Jen; Chen, Yan-Syun; Tsai, Guochuan E; Lane, Hsien-Yuan

    2014-05-01

    N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission is vital for learning and memory. Hypofunction of NMDAR has been reported to play a role in the pathophysiology of Alzheimer disease (AD), particularly in the early phase. Enhancing NMDAR activation might be a novel treatment approach. One of the methods to enhance NMDAR activity is to raise the levels of NMDA coagonists by blocking their metabolism. This study examined the efficacy and safety of sodium benzoate, a D-amino acid oxidase inhibitor, for the treatment of amnestic mild cognitive impairment and mild AD. We conducted a randomized, double-blind, placebo-controlled trial in four major medical centers in Taiwan. Sixty patients with amnestic mild cognitive impairment or mild AD were treated with 250-750 mg/day of sodium benzoate or placebo for 24 weeks. Alzheimer's Disease Assessment Scale-cognitive subscale (the primary outcome) and global function (assessed by Clinician Interview Based Impression of Change plus Caregiver Input) were measured every 8 weeks. Additional cognition composite was measured at baseline and endpoint. Sodium benzoate produced a better improvement than placebo in Alzheimer's Disease Assessment Scale-cognitive subscale (p = .0021, .0116, and .0031 at week 16, week 24, and endpoint, respectively), additional cognition composite (p = .007 at endpoint) and Clinician Interview Based Impression of Change plus Caregiver Input (p = .015, .016, and .012 at week 16, week 24, and endpoint, respectively). Sodium benzoate was well-tolerated without evident side-effects. Sodium benzoate substantially improved cognitive and overall functions in patients with early-phase AD. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for early dementing processes. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  13. Gender's Effects to the Early Symptoms of Alzheimer's Disease in 5 Asian Countries.

    PubMed

    Yang, Yuan-Han; Meguro, Kenichi; Dominguez, Jacqueline; Chen, Christopher Li-Hsian; Wang, Huali; Ong, Paulus Anam

    2017-06-01

    Asia has the greatest population and more patients with dementia in the world. Early recognition of clinical symptoms of Alzheimer's disease (AD) is crucial for dementia care. In order to foster collaboration in AD care, a uniformed manner to report the early clinical symptoms of AD is necessary. We have recruited clinically diagnosed patients with AD at their very mild stage with Clinical Dementia Rating (CDR) 0.5 in Taiwan, Japan, China, Philippines, and Singapore. Demographic characteristics and psychometrics including Ascertain of Dementia-8 (AD8) questionnaire were administrated to collect and report the clinical presentation in these countries. In total, 713 clinically diagnosed patients with AD at very mild stage, CDR 0.5, have been recruited from these 5 countries. "Repeats questions, stories, or statements" were consistently the frequently reported symptom across these countries. Taiwan, China, and Singapore have the higher AD8 total score compared to that in Japan and Philippines. Japan and Philippines have the gender-related differences in clinical presentation of early AD. Difficulties in using small trouble appliance and in handling complicated financial affairs were frequently reported in Japan female, compared to male, patients with AD. Identifying the clinical symptom of AD and the gender-related issues would be crucial in the dementia care in Asia.

  14. Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer's disease.

    PubMed

    Franzmeier, Nicolai; Düzel, Emrah; Jessen, Frank; Buerger, Katharina; Levin, Johannes; Duering, Marco; Dichgans, Martin; Haass, Christian; Suárez-Calvet, Marc; Fagan, Anne M; Paumier, Katrina; Benzinger, Tammie; Masters, Colin L; Morris, John C; Perneczky, Robert; Janowitz, Daniel; Catak, Cihan; Wolfsgruber, Steffen; Wagner, Michael; Teipel, Stefan; Kilimann, Ingo; Ramirez, Alfredo; Rossor, Martin; Jucker, Mathias; Chhatwal, Jasmeer; Spottke, Annika; Boecker, Henning; Brosseron, Frederic; Falkai, Peter; Fliessbach, Klaus; Heneka, Michael T; Laske, Christoph; Nestor, Peter; Peters, Oliver; Fuentes, Manuel; Menne, Felix; Priller, Josef; Spruth, Eike J; Franke, Christiana; Schneider, Anja; Kofler, Barbara; Westerteicher, Christine; Speck, Oliver; Wiltfang, Jens; Bartels, Claudia; Araque Caballero, Miguel Ángel; Metzger, Coraline; Bittner, Daniel; Weiner, Michael; Lee, Jae-Hong; Salloway, Stephen; Danek, Adrian; Goate, Alison; Schofield, Peter R; Bateman, Randall J; Ewers, Michael

    2018-04-01

    interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    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 maymore » 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

  16. Data-Driven Sequence of Changes to Anatomical Brain Connectivity in Sporadic Alzheimer's Disease.

    PubMed

    Oxtoby, Neil P; Garbarino, Sara; Firth, Nicholas C; Warren, Jason D; Schott, Jonathan M; Alexander, Daniel C

    2017-01-01

    Model-based investigations of transneuronal spreading mechanisms in neurodegenerative diseases relate the pattern of pathology severity to the brain's connectivity matrix, which reveals information about how pathology propagates through the connectivity network. Such network models typically use networks based on functional or structural connectivity in young and healthy individuals, and only end-stage patterns of pathology, thereby ignoring/excluding the effects of normal aging and disease progression. Here, we examine the sequence of changes in the elderly brain's anatomical connectivity over the course of a neurodegenerative disease. We do this in a data-driven manner that is not dependent upon clinical disease stage, by using event-based disease progression modeling. Using data from the Alzheimer's Disease Neuroimaging Initiative dataset, we sequence the progressive decline of anatomical connectivity, as quantified by graph-theory metrics, in the Alzheimer's disease brain. Ours is the first single model to contribute to understanding all three of the nature, the location, and the sequence of changes to anatomical connectivity in the human brain due to Alzheimer's disease. Our experimental results reveal new insights into Alzheimer's disease: that degeneration of anatomical connectivity in the brain may be a viable, even early, biomarker and should be considered when studying such neurodegenerative diseases.

  17. Perception of Alzheimer Disease in Iranian Traditional Medicine.

    PubMed

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

    2016-03-01

    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. 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. 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. 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.

  18. Seizures and epileptiform activity in the early stages of Alzheimer disease.

    PubMed

    Vossel, Keith A; Beagle, Alexander J; Rabinovici, Gil D; Shu, Huidy; Lee, Suzee E; Naasan, Georges; Hegde, Manu; Cornes, Susannah B; Henry, Maya L; Nelson, Alexandra B; Seeley, William W; Geschwind, Michael D; Gorno-Tempini, Maria L; Shih, Tina; Kirsch, Heidi E; Garcia, Paul A; Miller, Bruce L; Mucke, Lennart

    2013-09-01

    Epileptic activity associated with Alzheimer disease (AD) deserves increased attention because it has a harmful impact on these patients, can easily go unrecognized and untreated, and may reflect pathogenic processes that also contribute to other aspects of the illness. We report key features of AD-related seizures and epileptiform activity that are instructive for clinical practice and highlight similarities between AD and transgenic animal models of the disease. To describe common clinical characteristics and treatment outcomes of patients with amnestic mild cognitive impairment (aMCI) or early AD who also have epilepsy or subclinical epileptiform activity. Retrospective observational study from 2007 to 2012. SETTING Memory and Aging Center, University of California, San Francisco. We studied 54 patients with a diagnosis of aMCI plus epilepsy (n = 12), AD plus epilepsy (n = 35), and AD plus subclinical epileptiform activity (n = 7). Clinical and demographic data, electroencephalogram (EEG) readings, and treatment responses to antiepileptic medications. Patients with aMCI who had epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy (64.3 vs 71.1 years; P = .02). Patients with AD who had epilepsy presented with cognitive decline 5.5 years earlier than patients with AD who did not have epilepsy (64.8 vs 70.3 years; P = .001). Patients with AD who had subclinical epileptiform activity also had an early onset of cognitive decline (58.9 years). The timing of seizure onset in patients with aMCI and AD was nonuniform (P < .001), clustering near the onset of cognitive decline. Epilepsies were most often complex partial seizures (47%) and more than half were nonconvulsive (55%). Serial or extended EEG monitoring appeared to be more effective than routine EEG at detecting interictal and subclinical epileptiform activity. Epileptic foci were predominantly unilateral and temporal. Of the

  19. 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. Copyright © 2014. Published by Elsevier Inc.

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Piert, M.; Koeppe, R.A.; Giordani, B.

    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 agemore » = 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.« less

  1. Imaging Alzheimer's disease pathophysiology with PET

    PubMed Central

    Schilling, Lucas Porcello; Zimmer, Eduardo R.; Shin, Monica; Leuzy, Antoine; Pascoal, Tharick A.; Benedet, Andréa L.; Borelli, Wyllians Vendramini; Palmini, André; Gauthier, Serge; Rosa-Neto, Pedro

    2016-01-01

    ABSTRACT Alzheimer's disease (AD) has been reconceptualised as a dynamic pathophysiological process characterized by preclinical, mild cognitive impairment (MCI), and dementia stages. Positron emission tomography (PET) associated with various molecular imaging agents reveals numerous aspects of dementia pathophysiology, such as brain amyloidosis, tau accumulation, neuroreceptor changes, metabolism abnormalities and neuroinflammation in dementia patients. In the context of a growing shift toward presymptomatic early diagnosis and disease-modifying interventions, PET molecular imaging agents provide an unprecedented means of quantifying the AD pathophysiological process, monitoring disease progression, ascertaining whether therapies engage their respective brain molecular targets, as well as quantifying pharmacological responses. In the present study, we highlight the most important contributions of PET in describing brain molecular abnormalities in AD. PMID:29213438

  2. Alzheimer's Disease Assessment Scale-Cognitive subscale variants in mild cognitive impairment and mild Alzheimer's disease: change over time and the effect of enrichment strategies.

    PubMed

    Podhorna, Jana; Krahnke, Tillmann; Shear, Michael; Harrison, John E

    2016-02-12

    Development of new treatments for Alzheimer's disease (AD) has broadened into early interventions in individuals with modest cognitive impairment and a slow decline. The 11-item version of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) was originally developed to measure cognition in patients with mild to moderate AD. Attempts to improve its properties for early AD by removing items prone to ceiling and/or by adding cognitive measures known to be impaired early have yielded a number of ADAS-Cog variants. Using Alzheimer's Disease Neuroimaging Initiative data, we compared the performance of the 3-, 5-, 11- and 13-item ADAS-Cog variants in subjects with early AD. Given the interest in enrichment strategies, we also examined this aspect with a focus on cerebrospinal fluid (CSF) markers. Subjects with mild cognitive impairment (MCI) and mild AD with available ADAS-Cog 13 and CSF data were analysed. The decline over time was defined by change from baseline. Direct cross-comparison of the ADAS-Cog variants was performed using the signal-to-noise ratio (SNR), with higher values reflecting increased sensitivity to detect change over time. The decline over time on any of the ADAS-Cog variants was minimal in subjects with MCI. Approximately half of subjects with MCI fulfilled enrichment criteria for positive AD pathology. The impact of enrichment was detectable but subtle in MCI. The annual decline in mild AD was more pronounced but still modest. More than 90 % of subjects with mild AD had positive AD pathology. SNRs were low in MCI but greater in mild AD. The numerically largest SNRs were seen for the ADAS-Cog 5 in MCI and for both the 5- and 13-item ADAS-Cog variants in mild AD, although associated confidence intervals were large. The possible value of ADAS-Cog expansion or reduction is less than compelling, particularly in MCI. In mild AD, adding items known to be impaired at early stages seems to provide more benefit than removing items on which

  3. Early brain connectivity alterations and cognitive impairment in a rat model of Alzheimer's disease.

    PubMed

    Muñoz-Moreno, Emma; Tudela, Raúl; López-Gil, Xavier; Soria, Guadalupe

    2018-02-07

    Animal models of Alzheimer's disease (AD) are essential to understanding the disease progression and to development of early biomarkers. Because AD has been described as a disconnection syndrome, magnetic resonance imaging (MRI)-based connectomics provides a highly translational approach to characterizing the disruption in connectivity associated with the disease. In this study, a transgenic rat model of AD (TgF344-AD) was analyzed to describe both cognitive performance and brain connectivity at an early stage (5 months of age) before a significant concentration of β-amyloid plaques is present. Cognitive abilities were assessed by a delayed nonmatch-to-sample (DNMS) task preceded by a training phase where the animals learned the task. The number of training sessions required to achieve a learning criterion was recorded and evaluated. After DNMS, MRI acquisition was performed, including diffusion-weighted MRI and resting-state functional MRI, which were processed to obtain the structural and functional connectomes, respectively. Global and regional graph metrics were computed to evaluate network organization in both transgenic and control rats. The results pointed to a delay in learning the working memory-related task in the AD rats, which also completed a lower number of trials in the DNMS task. Regarding connectivity properties, less efficient organization of the structural brain networks of the transgenic rats with respect to controls was observed. Specific regional differences in connectivity were identified in both structural and functional networks. In addition, a strong correlation was observed between cognitive performance and brain networks, including whole-brain structural connectivity as well as functional and structural network metrics of regions related to memory and reward processes. In this study, connectivity and neurocognitive impairments were identified in TgF344-AD rats at a very early stage of the disease when most of the pathological hallmarks

  4. Gait variability in community dwelling adults with Alzheimer disease.

    PubMed

    Webster, Kate E; Merory, John R; Wittwer, Joanne E

    2006-01-01

    Studies have shown that measures of gait variability are associated with falling in older adults. However, few studies have measured gait variability in people with Alzheimer disease, despite the high incidence of falls in Alzheimer disease. The purpose of this study was to compare gait variability of community-dwelling older adults with Alzheimer disease and control subjects at various walking speeds. Ten subjects with mild-moderate Alzheimer disease and ten matched control subjects underwent gait analysis using an electronic walkway. Participants were required to walk at self-selected slow, preferred, and fast speeds. Stride length and step width variability were determined using the coefficient of variation. Results showed that stride length variability was significantly greater in the Alzheimer disease group compared with the control group at all speeds. In both groups, increases in walking speed were significantly correlated with decreases in stride length variability. Step width variability was significantly reduced in the Alzheimer disease group compared with the control group at slow speed only. In conclusion, there is an increase in stride length variability in Alzheimer disease at all walking speeds that may contribute to the increased incidence of falls in Alzheimer disease.

  5. Temporal order memory assessed during spatiotemporal navigation as a behavioral cognitive marker for differential Alzheimer's disease diagnosis.

    PubMed

    Bellassen, Virginie; Iglói, Kinga; de Souza, Leonardo Cruz; Dubois, Bruno; Rondi-Reig, Laure

    2012-02-08

    Episodic memory impairment is a hallmark for early diagnosis of Alzheimer's disease. Most actual tests used to diagnose Alzheimer's disease do not assess the spatiotemporal properties of episodic memory and lead to false-positive or -negative diagnosis. We used a newly developed, nonverbal navigation test for Human, based on the objective experimental testing of a spatiotemporal experience, to differentially Alzheimer's disease at the mild stage (N = 16 patients) from frontotemporal lobar degeneration (N = 11 patients) and normal aging (N = 24 subjects). Comparing navigation parameters and standard neuropsychological tests, temporal order memory appeared to have the highest predictive power for mild Alzheimer's disease diagnosis versus frontotemporal lobar degeneration and normal aging. This test was also nonredundant with classical neuropsychological tests. As a conclusion, our results suggest that temporal order memory tested in a spatial navigation task may provide a selective behavioral marker of Alzheimer's disease.

  6. Aspartic proteases involved in Alzheimer's disease.

    PubMed

    Schmidt, Boris

    2003-05-09

    Alzheimer's disease afflicts every tenth human aged over 65. Despite the dramatic progress that has been made in understanding the disease, the exact cause of Alzheimer's disease is still unknown. Most gene mutations associated with Alzheimer's disease point at the same culprits: amyloid precursor protein and ultimately amyloid beta. The enigmatic proteases alpha-,beta-, and gamma-secretase are the three executioners of amyloid precursor protein processing, and disruption of their delicate balance is suspected to result in Alzheimer's disease. Significant progress has been made in the selective control of these proteases, regardless of the availability of structural information. Not even the absence of a robust cell-free assay for gamma-secretase could hamper the identification of nonpeptidic inhibitors of this enzyme for long. Within five years, four distinctly different structural moieties were developed and the first drug candidates are in clinical trials. Unfortunately, selective inhibition of amyloid beta formation remains a crucial issue because fundamental fragments of the gamma-secretase complex are important for other signaling events. This problem makes beta-secretase inhibition and alpha-secretase induction even more appealing.

  7. [Nutritional approaches to modulate oxidative stress that induce Alzheimer's disease. Nutritional approaches to prevent Alzheimer's disease].

    PubMed

    Lara, Humberto Herman; Alanís-Garza, Eduardo Javier; Estrada Puente, María Fernanda; Mureyko, Lucía Liliana; Alarcón Torres, David Alejandro; Ixtepan Turrent, Liliana

    2015-01-01

    Alzheimer's disease is the most common cause of dementia in the world; symptoms first appear after age 65 and have a progressive evolution. Expecting an increase on its incidence and knowing there is currently no cure for Alzheimer's disease, it is a necessity to prevent progression. The change in diet due to globalization may explain the growth of the incidence in places such as Japan and Mediterranean countries, which used to have fewer incidences. There is a direct correlation between disease progression and the increased intake of alcohol, saturated fats, and red meat. Therefore, we find obesity and higher serum levels in cholesterol due to saturated fat as a result. A way to decrease the progression of Alzheimer's is through a diet rich in polipheno/es (potent antioxidants), unsaturated fats (monounsaturated and polyunsaturated), fish, vegetable fa t, fruits with low glycemic index, and a moderate consumption of red wine. Through this potent antioxidant diet we accomplish the prevention of dementia and the progression of Alzheimer's disease. This article emphasizes the food and other components that have been demonstrated to decrease the oxidative stress related to these progressive diseases.

  8. 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.

  9. The Neuropsychological Profile of Alzheimer Disease

    PubMed Central

    Weintraub, Sandra; Wicklund, Alissa H.; Salmon, David P.

    2012-01-01

    Neuropsychological assessment has featured prominently over the past 30 years in the characterization of dementia associated with Alzheimer disease (AD). Clinical neuropsychological methods have identified the earliest, most definitive cognitive and behavioral symptoms of illness, contributing to the identification, staging, and tracking of disease. With increasing public awareness of dementia, disease detection has moved to earlier stages of illness, at a time when deficits are both behaviorally and pathologically selective. For reasons that are not well understood, early AD pathology frequently targets large-scale neuroanatomical networks for episodic memory before other networks that subserve language, attention, executive functions, and visuospatial abilities. This chapter reviews the pathognomonic neuropsychological features of AD dementia and how these differ from “normal,” age-related cognitive decline and from other neurodegenerative diseases that cause dementia, including cortical Lewy body disease, frontotemporal lobar degeneration, and cerebrovascular disease. PMID:22474609

  10. Memory loss in Alzheimer's disease

    PubMed Central

    Jahn, Holger

    2013-01-01

    Loss of memory is among the first symptoms reported by patients suffering from Alzheimer's disease (AD) and by their caretakers. Working memory and long-term declarative memory are affected early during the course of the disease. The individual pattern of impaired memory functions correlates with parameters of structural or functional brain integrity. AD pathology interferes with the formation of memories from the molecular level to the framework of neural networks. The investigation of AD memory loss helps to identify the involved neural structures, such as the default mode network, the influence of epigenetic and genetic factors, such as ApoE4 status, and evolutionary aspects of human cognition. Clinically, the analysis of memory assists the definition of AD subtypes, disease grading, and prognostic predictions. Despite new AD criteria that allow the earlier diagnosis of the disease by inclusion of biomarkers derived from cerebrospinal fluid or hippocampal volume analysis, neuropsychological testing remains at the core of AD diagnosis. PMID:24459411

  11. The Alzheimer's Prevention Initiative Generation Program: Evaluating CNP520 Efficacy in the Prevention of Alzheimer's Disease.

    PubMed

    Lopez Lopez, C; Caputo, A; Liu, F; Riviere, M E; Rouzade-Dominguez, M-L; Thomas, R G; Langbaum, J B; Lenz, R; Reiman, E M; Graf, A; Tariot, P N

    2017-01-01

    Alzheimer's disease pathology begins decades before the onset of clinical symptoms. This provides an opportunity for interventional clinical trials to potentially delay or prevent the onset of cognitive impairment or dementia. CNP520 (a beta-site-amyloid precursor protein-cleaving enzyme inhibitor) is in clinical development for the treatment of preclinical Alzheimer's disease under the Alzheimer's Prevention Initiative Generation Program. The Alzheimer's Prevention Initiative is a public-private partnership intended to accelerate the evaluation of Alzheimer's disease prevention therapies. The Generation Program comprises two pivotal phase II/III studies with similar designs to assess the efficacy and safety of investigational treatments in a cognitively unimpaired population at increased risk for developing Alzheimer's disease based on age and apolipoprotein E (APOE) genotype (i.e., presence of the APOE ε4 allele). The program has been designed to maximize benefit to Alzheimer's disease research. Generation Study 1 (NCT02565511) and Generation Study 2 (NCT03131453) are currently enrolling; their key features are presented here.

  12. Nanotechnology for Alzheimer Disease.

    PubMed

    Leszek, Jerzy; Md Ashraf, Ghulam; Tse, Wai Hei; Zhang, Jin; Gasiorowski, Kazimierz; Avila-Rodriguez, Marco Fidel; Tarasov, Vadim V; Barreto, George E; Klochkov, Sergey G; Bachurin, Sergey O; Aliev, Gjumrakch

    2017-01-01

    Alzheimer disease (AD) typically affects behavior, memory and thinking. The change in brain have been reported to begin approx. 10-20 years before the appearance of actual symptoms and diagnosis of AD. An early stage diagnosis and treatment of this lethal disease is the prime challenge, which is mainly halted by the lack of validated biomarkers. Recent nanotechnological advancements have the potential to offer large scale effective diagnostic and therapeutic options. Targeted drug (e.g. Rivastigmine) delivery with the help of nanoparticles (NPs) in the range of 1-100 nm diameters can effectively cross the blood brain barrier with minimized side effects. Moreover, biocompatible nanomaterials with increased magnetic and optical properties can act as excellent alternative agents for an early diagnosis. With the high volume of research coming in support of the effective usage of NP based drug delivery in critical environment of CNS, it is quite likely that this approach can end up providing remarkable breakthroughs in early stage diagnosis and therapy of AD. In the current review, we have presented a comprehensive outlook on the current challenges in diagnosis and therapy of AD, with an emphasis on the effective options provided by biocompatible NPs as imaging contrast agents and drug carriers. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. The first case series of Chinese patients in Hong Kong with familial Alzheimer's disease compared with those with biomarker-confirmed sporadic late-onset Alzheimer's disease.

    PubMed

    Shea, Y F; Chu, L W; Lee, S C; Chan, A Ok

    2017-12-01

    Patients with familial Alzheimer's disease are being increasingly reported in Hong Kong. The objectives of this study were to report the clinical features of these patients, and to compare them with those with biomarker-confirmed sporadic late-onset Alzheimer's disease. All symptomatic Chinese patients with familial Alzheimer's disease who attended Queen Mary Hospital, Memory Clinic between January 1998 and December 2016 were included. Information about clinical features, baseline Mini-Mental State Examination score, and presenting cognitive symptoms or atypical clinical features were collected. Their clinical features were compared with those of 12 patients with sporadic late-onset Alzheimer's disease with cerebrospinal fluid biomarker evidence of Alzheimer's disease and 14 patients with late-onset Alzheimer's disease and positive amyloid loading on Pittsburgh compound B imaging. There were three families with familial Alzheimer's disease among whom eight family members were affected. The mean (± standard deviation) age of onset and the Mini-Mental State Examination score were 48.4 ± 7.7 years and 7.9 ± 9.2, respectively. Compared with the sporadic late-onset Alzheimer's disease patients, those with familial Alzheimer's disease had an earlier age of onset and presentation (both P<0.001) and received the correct diagnosis later (median [interquartile range], 7.5 [5.3-14.5] vs 2 [1.0-3.3] years; P<0.001). Patients with familial disease had a lower Mini-Mental State Examination score at presentation than those having late-onset Alzheimer's disease (mean, 7.9 ± 9.2 vs 17.6 ± 7.2; P=0.01). They also had fewer delusions, and less dysphoria and irritability (0% vs 41.7%, 0% vs 50% and 0% vs 54.2%; P=0.04, 0.01 and 0.01, respectively). There was a trend of less frequent amnesia among patients with familial Alzheimer's disease compared with those having late-onset Alzheimer's disease (75% vs 100%; P=0.05). Clinical features differ for patients with familial Alzheimer

  14. 76 FR 68615 - National Alzheimer's Disease Awareness Month, 2011

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-04

    ... National Alzheimer's Disease Awareness Month, 2011 By the President of the United States of America A... disease is a pain they know all too well. Alzheimer's disease burdens an increasing number of our Nation's... health. During National Alzheimer's Disease Awareness Month, we stand united in our commitment to improve...

  15. Linear Combinations of Multiple Outcome Measures to Improve the Power of Efficacy Analysis ---Application to Clinical Trials on Early Stage Alzheimer Disease

    PubMed Central

    Xiong, Chengjie; Luo, Jingqin; Morris, John C; Bateman, Randall

    2018-01-01

    Modern clinical trials on Alzheimer disease (AD) focus on the early symptomatic stage or even the preclinical stage. Subtle disease progression at the early stages, however, poses a major challenge in designing such clinical trials. We propose a multivariate mixed model on repeated measures to model the disease progression over time on multiple efficacy outcomes, and derive the optimum weights to combine multiple outcome measures by minimizing the sample sizes to adequately power the clinical trials. A cross-validation simulation study is conducted to assess the accuracy for the estimated weights as well as the improvement in reducing the sample sizes for such trials. The proposed methodology is applied to the multiple cognitive tests from the ongoing observational study of the Dominantly Inherited Alzheimer Network (DIAN) to power future clinical trials in the DIAN with a cognitive endpoint. Our results show that the optimum weights to combine multiple outcome measures can be accurately estimated, and that compared to the individual outcomes, the combined efficacy outcome with these weights significantly reduces the sample size required to adequately power clinical trials. When applied to the clinical trial in the DIAN, the estimated linear combination of six cognitive tests can adequately power the clinical trial. PMID:29546251

  16. 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…

  17. The NACP/synuclein gene: chromosomal assignment and screening for alterations in Alzheimer disease.

    PubMed

    Campion, D; Martin, C; Heilig, R; Charbonnier, F; Moreau, V; Flaman, J M; Petit, J L; Hannequin, D; Brice, A; Frebourg, T

    1995-03-20

    The major component of the vascular and plaque amyloid deposits in Alzheimer disease is the amyloid beta peptide (A beta). A second intrinsic component of amyloid, the NAC (non-A beta component of amyloid) peptide, has recently been identified, and its precursor protein was named NACP. A computer homology search allowed us to establish that the human NACP gene was homologous to the rat synuclein gene. We mapped the NACP/synuclein gene to chromosome 4 and cloned three alternatively spliced transcripts in lymphocytes derived from a normal subject. We analyzed by RT-PCR and direct sequencing the entire coding region of the NACP/synuclein gene in a group of patients with familial early onset Alzheimer disease. No mutation was found in 26 unrelated patients. Further studies are required to investigate the implication of the NACP/synuclein gene in Alzheimer disease.

  18. The European Medicines Agency's strategies to meet the challenges of Alzheimer disease.

    PubMed

    Haas, Manuel; Mantua, Valentina; Haberkamp, Marion; Pani, Luca; Isaac, Maria; Butlen-Ducuing, Florence; Vamvakas, Spiros; Broich, Karl

    2015-04-01

    Regulatory agencies have a key role in facilitating the development of new drugs for Alzheimer disease, particularly given the challenges associated with early intervention. Here, we highlight the strategies of the European Medicines Agency to help address such challenges.

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

    PubMed

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

    2014-08-01

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

  20. Cuba's Strategy for Alzheimer Disease and Dementia Syndromes.

    PubMed

    Bosch-Bayard, Rodolfo I; Llibre-Rodríguez, Juan J; Fernández-Seco, Alberto; Borrego-Calzadilla, Carmen; Carrasco-García, Mayra R; Zayas-Llerena, Tania; Moreno-Carbonell, Carmen R; Reymond-Vasconcelos, Ana G

    2016-10-01

    Dementia is a great challenge to public health in Cuba due to its impact on society and families. Cuba's National Intervention Strategy for Alzheimer Disease and Dementia Syndromes is designed to address this challenge. The Strategy includes working guidelines for primary and secondary care, education about rights of people with cognitive impairment, professional development, research, and health promotion and dementia prevention. An associated action plan, focused on primary care, includes proposals for creation of memory clinics, day centers and comprehensive rehabilitation services for cognitive stimulation. Short-term measures proposed include increasing early detection; creating a dementia morbidity and mortality registry; promoting professional training; providing support for families; and promoting basic and clinical research on dementia. Medium-term proposals aim to reduce dementia incidence and mortality by controlling risk factors and promoting healthy lifestyles, offering new treatment options and optimizing early detection. A set of indicators has been developed to evaluate strategy implementation. With this strategy, Cuba joins the small number of developing countries that have responded to WHO's call to improve care for patients with dementia and alleviate its impact on society and families. KEYWORDS Dementia, Alzheimer disease, aging, national health programs, social stigma, primary prevention, health promotion, civil rights, Cuba.

  1. Regional 18F-Fluorodeoxyglucose Hypometabolism is Associated with Higher Apathy Scores Over Time in Early Alzheimer Disease.

    PubMed

    Gatchel, Jennifer R; Donovan, Nancy J; Locascio, Joseph J; Becker, J Alex; Rentz, Dorene M; Sperling, Reisa A; Johnson, Keith A; Marshall, Gad A

    2017-07-01

    Apathy is among the earliest and most pervasive neuropsychiatric symptoms in prodromal and mild Alzheimer disease (AD) dementia that correlates with functional impairment and disease progression. We investigated the association of apathy with regional 18F-fluorodeoxyglucose (FDG) metabolism in cognitively normal, mild cognitive impairment, and AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative database. Cross-sectional and longitudinal studies. 57 North American research sites. 402 community dwelling elders. Apathy was assessed using the Neuropsychiatric Inventory Questionnaire. Baseline FDG metabolism in five regions implicated in the neurobiology of apathy and AD was investigated in relationship to apathy at baseline (cross-sectional general linear model) and longitudinally (mixed random/fixed effect model). Covariates included age, sex, diagnosis, apolipoprotein E genotype, premorbid intelligence, cognition, and antidepressant use. Cross-sectional analysis revealed that posterior cingulate hypometabolism, diagnosis, male sex, and antidepressant use were associated with higher apathy scores. Longitudinal analysis revealed that the interaction of supramarginal hypometabolism and time, posterior cingulate hypometabolism, and antidepressant use were associated with higher apathy scores across time; only supramarginal hypometabolism was positively related to rate of increase of apathy. Results support an association of apathy with hypometabolism in parietal regions commonly affected in early stages of AD, rather than medial frontal regions implicated in the neurobiology of apathy in later stages. Further work is needed to substantiate whether this localization is specific to apathy rather than to disease stage, and to investigate the potential role of AD proteinopathies in the pathogenesis of apathy. Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  2. 77 FR 66519 - National Alzheimer's Disease Awareness Month, 2012

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-06

    ... National Alzheimer's Disease Awareness Month, 2012 By the President of the United States of America A Proclamation Every day, families across our country confront the tragic realities of Alzheimer's disease--an.... As the number of older Americans grows in the coming years, Alzheimer's disease will continue to pose...

  3. Anosognosia and Its Relation to Psychiatric Symptoms in Early-Onset Alzheimer Disease.

    PubMed

    Yoon, Bora; Shim, Yong S; Hong, Yun Jeong; Choi, Seong Hye; Park, Hee Kyung; Park, Sun Ah; Jeong, Jee Hyang; Yoon, Soo Jin; Yang, Dong-Won

    2017-05-01

    We investigated differences in the prevalence of anosognosia and neuropsychiatric symptoms (NPSs) characteristics according to disease severity in patients with early-onset Alzheimer disease (EOAD). We recruited 616 patients with EOAD. We subdivided participants into 2 groups based on the presence or absence of anosognosia and then again by Clinical Dementia Rating (CDR) scale. We compared the differences in the Neuropsychiatric Inventory (NPI) scores according to anosognosia and disease severity. The percentage of patients with anosognosia in each CDR group steadily increased as the CDR rating increased (CDR 0.5 8.6% vs CDR 1 13.6% vs CDR 2 26.2%). The NPI total score was significantly higher in patients with anosognosia in the CDR 0.5 and 1 groups; by contrast, it had no association in the CDR 2 group. Frontal lobe functions were associated with anosognosia only in the CDR 0.5 and 1 groups. After stratification by CDR, in the CDR 0.5 group, the prevalence of agitation ( P = .040) and appetite ( P = .013) was significantly higher in patients with anosognosia. In the CDR 1 group, patients with anosognosia had a significantly higher prevalence of delusions ( P = .032), hallucinations ( P = .048), and sleep disturbances ( P = .047). In the CDR 2 group, we found no statistical difference in the frequency of symptoms between patients with and without anosognosia. These results confirm that the prevalence of anosognosia as well as the individual NPS and cognitive functions associated with it differ according to EOAD severity.

  4. The Missing Link between Faces and Names: Evidence from Alzheimer's Disease Patients

    ERIC Educational Resources Information Center

    Calabria, Marco; Sabio, Alicia; Martin, Clara; Hernandez, Mireia; Juncadella, Montserrat; Gascon-Bayarri, Jordi; Rene, Ramon; Ortiz-Gil, Jordi; Ugas, Lidia; Costa, Albert

    2012-01-01

    Retrieval of proper names is a cause of concern and complaint among elderly adults and it is an early symptom of patients suffering from neurodegenerative diseases such as Alzheimer's disease (AD). While it is well established that AD patients have deficits of proper name retrieval, the nature of such impairment is not yet fully understood.…

  5. The NACP/synuclein gene: Chromosomal assignment and screening for alterations in Alzheimer disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Campion, D.; Martin, C.; Charbonnier, F.

    1995-03-20

    The major component of the vascular and plaque amyloid deposits in Alzheimer disease is the amyloid {beta} peptide (A{beta}). A second intrinsic component of amyloid, the NAC (non-A{beta} component of amyloid) peptide, has recently been identified, and its precursor protein was named NACP. A computer homology search allowed us to establish that the human NACP gene was homologous to the rat synuclein gene. We mapped the NACP/synuclein gene to chromosome 4 and cloned three alternatively spliced transcripts in lymphocytes derived from a normal subject. We analyzed by RT-PCR and direct sequencing the entire coding region of the NACP/synuclein gene inmore » a group of patients with familial early onset Alzheimer disease. No mutation was found in 26 unrelated patients. Further studies are required to investigate the implication of the NACP/synuclein gene in Alzheimer disease. 21 refs., 3 tabs.« less

  6. Targeting Aβ and tau in Alzheimer's disease, an early interim report

    PubMed Central

    Golde, Todd E.; Petrucelli, Leonard; Lewis, Jada

    2009-01-01

    The amyloid β (Aβ) and tau proteins, which misfold, aggregate, and accumulate in the Alzheimer's disease (AD) brain, are implicated as central factors in a complex neurodegenerative cascade. Studies of mutations that cause early onset AD and promote Aβ accumulation in the brain strongly support the notion that inhibiting Aβ aggregation will prevent AD. Similarly, genetic studies of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17 MAPT) showing that mutations in the MAPT gene encoding tau lead to abnormal tau accumulation and neurodegeneration. Such genetic studies clearly show that tau dysfunction and aggregation can be central to neurodegeneration, however, most likely in a secondary fashion in relation to AD. Additional pathologic, biochemical and modeling studies further support the concept that Aβ and tau are prime targets for disease modifying therapies in AD. Treatment strategies aimed at preventing the aggregation and accumulation of Aβ, tau, or both proteins should therefore be theoretically possible, assuming that treatment can be initiated before either irreversible damage is present or downstream, self-sustaining, pathological cascades have been initiated. Herein, we will review recent advances and also potential setbacks with respect to the myriad of therapeutic strategies that are designed to slow down, prevent, or clear the accumulation of either “pathological” Aβ or tau. We will also discuss the need for thoughtful prioritization with respect to clinical development of the pre-clinically validated modifiers of Aβ and tau pathology. The current number of candidate therapies targeting Aβ is becoming so large that a triage process is clearly needed to insure that resources are invested in a way such that the best candidates for disease modifying therapy are rapidly moved toward clinical trials. Finally, we will discuss the challenges for an appropriate “triage” after potential disease modifying therapies

  7. S182 and STM2 gene missense mutations in sporadic alzheimer disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Higuchi, Susumu; Matsushita, Sachio; Hasegawa, Yoshio

    1996-07-26

    The linkage of genes S182 and STM2 to early-onset or late-onset sporadic Alzheimer disease (AD) was not found in a group of 97 clinically-diagnosed AD patients and 46 autopsy-confirmed AD cases, using PCR-RFLP methods. 7 refs.

  8. Alzheimer and his disease: a brief history.

    PubMed

    Cipriani, Gabriele; Dolciotti, Cristina; Picchi, Lucia; Bonuccelli, Ubaldo

    2011-04-01

    More than 100 years ago, Alois Alzheimer first described the clinical and pathological features of an unusual brain disease during the meeting of the Society of Southwest German Psychiatrists in Tübingen: the patient, Auguste Deter, suffered memory loss, disorientation, hallucinations and delusions and died at the age of 55. In 1910, Emil Kraepelin named the condition with the eponym of "Alzheimer's disease" (AD) that is, now, the most common neurodegenerative disease with more than 25 million cases worldwide and a major medical problem nearing catastrophic levels. The present article discusses Alzheimer's work in the context of his life and time.

  9. Reduced hippocampal functional connectivity in Alzheimer disease.

    PubMed

    Allen, Greg; Barnard, Holly; McColl, Roderick; Hester, Andrea L; Fields, Julie A; Weiner, Myron F; Ringe, Wendy K; Lipton, Anne M; Brooker, Matthew; McDonald, Elizabeth; Rubin, Craig D; Cullum, C Munro

    2007-10-01

    To determine if functional connectivity of the hippocampus is reduced in patients with Alzheimer disease. Functional connectivity magnetic resonance imaging was used to investigate coherence in the magnetic resonance signal between the hippocampus and all other regions of the brain. Eight patients with probable Alzheimer disease and 8 healthy volunteers. Control subjects showed hippocampal functional connectivity with diffuse cortical, subcortical, and cerebellar sites, while patients demonstrated markedly reduced functional connectivity, including an absence of connectivity with the frontal lobes. These findings suggest a functional disconnection between the hippocampus and other brain regions in patients with Alzheimer disease.

  10. 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.

  11. Connected speech as a marker of disease progression in autopsy-proven Alzheimer's disease.

    PubMed

    Ahmed, Samrah; Haigh, Anne-Marie F; de Jager, Celeste A; Garrard, Peter

    2013-12-01

    Although an insidious history of episodic memory difficulty is a typical presenting symptom of Alzheimer's disease, detailed neuropsychological profiling frequently demonstrates deficits in other cognitive domains, including language. Previous studies from our group have shown that language changes may be reflected in connected speech production in the earliest stages of typical Alzheimer's disease. The aim of the present study was to identify features of connected speech that could be used to examine longitudinal profiles of impairment in Alzheimer's disease. Samples of connected speech were obtained from 15 former participants in a longitudinal cohort study of ageing and dementia, in whom Alzheimer's disease was diagnosed during life and confirmed at post-mortem. All patients met clinical and neuropsychological criteria for mild cognitive impairment between 6 and 18 months before converting to a status of probable Alzheimer's disease. In a subset of these patients neuropsychological data were available, both at the point of conversion to Alzheimer's disease, and after disease severity had progressed from the mild to moderate stage. Connected speech samples from these patients were examined at later disease stages. Spoken language samples were obtained using the Cookie Theft picture description task. Samples were analysed using measures of syntactic complexity, lexical content, speech production, fluency and semantic content. Individual case analysis revealed that subtle changes in language were evident during the prodromal stages of Alzheimer's disease, with two-thirds of patients with mild cognitive impairment showing significant but heterogeneous changes in connected speech. However, impairments at the mild cognitive impairment stage did not necessarily entail deficits at mild or moderate stages of disease, suggesting non-language influences on some aspects of performance. Subsequent examination of these measures revealed significant linear trends over the

  12. Genomics of Alzheimer Disease: A Review.

    PubMed

    Rosenberg, Roger N; Lambracht-Washington, Doris; Yu, Gang; Xia, Weiming

    2016-07-01

    To provide a comprehensive review of knowledge of the genomics of Alzheimer disease (AD) and DNA amyloid β 42 (Aβ42) vaccination as a potential therapy. Genotype-phenotype correlations of AD are presented to provide a comprehensive appreciation of the spectrum of disease causation. Alzheimer disease is caused in part by the overproduction and lack of clearance of Aβ protein. Oligomer Aβ, the most toxic species of Aβ, causes direct injury to neurons, accompanied by enhanced neuroinflammation, astrocytosis and gliosis, and eventually neuronal loss. The strongest genetic evidence supporting this hypothesis derives from mutations in the amyloid precursor protein (APP) gene. A detrimental APP mutation at the β-secretase cleavage site linked to early-onset AD found in a Swedish pedigree enhances Aβ production, in contrast to a beneficial mutation 2 residues away in APP that reduces Aβ production and protects against the onset of sporadic AD. A number of common variants associated with late-onset AD have been identified including apolipoprotein E, BIN1, ABC7, PICALM, MS4A4E/MS4A6A, CD2Ap, CD33, EPHA1, CLU, CR1, and SORL1. One or 2 copies of the apolipoprotein E ε4 allele are a major risk factor for late-onset AD. With DNA Aβ42 vaccination, a Th2-type noninflammatory immune response was achieved with a downregulation of Aβ42-specific effector (Th1, Th17, and Th2) cell responses at later immunization times. DNA Aβ42 vaccination upregulated T regulator cells (CD4+, CD25+, and FoxP3+) and its cytokine interleukin 10, resulting in downregulation of T effectors. Mutations in APP and PS-1 and PS-2 genes that are associated with early-onset, autosomal, dominantly inherited AD, in addition to the at-risk gene polymorphisms responsible for late-onset AD, all indicate a direct and early role of Aβ in the pathogenesis of AD. A translational result of genomic research has been Aβ-reducing therapies including DNA Aβ42 vaccination as a promising approach to delay or

  13. A Critical Assessment of Research on Neurotransmitters in Alzheimer's Disease.

    PubMed

    Reddy, P Hemachandra

    2017-01-01

    The purpose of this mini-forum, "Neurotransmitters and Alzheimer's Disease", is to critically assess the current status of neurotransmitters in Alzheimer's disease. Neurotransmitters are essential neurochemicals that maintain synaptic and cognitive functions in mammals, including humans, by sending signals across pre- to post-synaptic neurons. Authorities in the fields of synapses and neurotransmitters of Alzheimer's disease summarize the current status of basic biology of synapses and neurotransmitters, and also update the current status of clinical trials of neurotransmitters in Alzheimer's disease. This article discusses the prevalence, economic impact, and stages of Alzheimer's dementia in humans.

  14. Promising developments in neuropsychological approaches for the detection of preclinical Alzheimer's disease: a selective review.

    PubMed

    Rentz, Dorene M; Parra Rodriguez, Mario A; Amariglio, Rebecca; Stern, Yaakov; Sperling, Reisa; Ferris, Steven

    2013-01-01

    Recently published guidelines suggest that the most opportune time to treat individuals with Alzheimer's disease is during the preclinical phase of the disease. This is a phase when individuals are defined as clinically normal but exhibit evidence of amyloidosis, neurodegeneration and subtle cognitive/behavioral decline. While our standard cognitive tests are useful for detecting cognitive decline at the stage of mild cognitive impairment, they were not designed for detecting the subtle cognitive variations associated with this biomarker stage of preclinical Alzheimer's disease. However, neuropsychologists are attempting to meet this challenge by designing newer cognitive measures and questionnaires derived from translational efforts in neuroimaging, cognitive neuroscience and clinical/experimental neuropsychology. This review is a selective summary of several novel, potentially promising, approaches that are being explored for detecting early cognitive evidence of preclinical Alzheimer's disease in presymptomatic individuals.

  15. Progressive biparietal atrophy: an atypical presentation of Alzheimer's disease.

    PubMed Central

    Ross, S J; Graham, N; Stuart-Green, L; Prins, M; Xuereb, J; Patterson, K; Hodges, J R

    1996-01-01

    OBJECTIVES: To define the clinical, neuropsychological, and radiological features of bilateral parietal lobe atrophy. METHODS: Four patients underwent a comprehensive longitudinal neuropsychological assessment, as well as MRI and HMPAO-SPECT. RESULTS: The consistent findings in the patients were early visuospatial problems, agraphia of a predominantly peripheral (or apraxic) type, and difficulty with bimanual tasks, all of which outweighted deficits in memory and language until later in the course of the illness. As the disease progressed, impairments in the phonological aspects of language and in auditory-verbal short term memory were often striking, perhaps reflecting spread from the parietal lobe to perisylvian language areas. Three patients went on to develop a global dementia and fulfilled the criteria for a clinical diagnosis of probable Alzheimer's disease; the fourth patient has only recently been identified. Neuroimaging disclosed bilateral parietal lobe atrophy (MRI) and hypoperfusion (SPECT), which was out of proportion to that seen elsewhere in the brain. One patient has died and had pathologically confirmed Alzheimer's disease with particular concentration in both superior parietal lobes. CONCLUSIONS: Bilateral biparietal atrophy is a recognisable clinical syndrome which can be the presenting feature of Alzheimer's disease. Although the label "posterior cortical atrophy" has been applied to such cases, review of the medical literature suggests that this broad rubric actually consists of two main clinical syndromes with features reflecting involvement of the occipitotemporal (ventral) and biparietal (dorsal) cortical areas respectively. Images PMID:8890778

  16. Developing injectable immunoglobulins to treat cognitive impairment in Alzheimer's disease.

    PubMed

    Steinitz, Michael

    2008-05-01

    Alzheimer's disease is a devastating disorder, clinically characterized by a comprehensive cognitive decline. The novel strategy of anti-amyloid-beta immunotherapy has been suggested following encouraging results obtained in murine models of Alzheimer's disease, in non-human primates, and in small-scale clinical trials. To examine the choice between active or passive anti-amyloid-beta immunization and the choice of the molecule to which the immune machinery should be targeted, which are central issues in future immune therapy of Alzheimer's disease. Research into the new area of Alzheimer's disease immune therapy is primarily based on in vivo and in vitro studies of murine models of Alzheimer's disease. The studies are hence limited to defined genetic deficiencies. In humans, infusion of anti-amyloid-beta antibodies is considered a safer approach than active anti-amyloid-beta vaccination. Alzheimer's-disease-protective anti-amyloid-beta monoclonal antibodies should target specific epitopes within the amyloid beta(1 42) peptide, avoiding possibly harmful binding to the ubiquitous normal amyloid precursor protein. Since Alzheimer's disease immunotherapy requires repeated infusion of antibodies over a prolonged period of time, Alzheimer's disease patients will tolerate such antibodies provided the latter are exclusively of human origin. Human monoclonal antibodies that correspond to ubiquitous anti-amyloid-beta, present in all healthy humans, might bear important protective characteristics.

  17. Apolipoprotein E alleles in Alzheimer`s and Parkinson`s patients

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Poduslo, S.E.; Schwankhaus, J.D.

    1994-09-01

    A number of investigators have found an association between the apolipoprotein E4 allele and Alzheimer`s disease. The E4 allele appears at a higher frequency in late onset familial Alzheimer`s patients. In our studies we obtained blood samples from early and late onset familial and sporadic Alzheimer`s patients and spouses, as well as from Parkinson`s patients. The patients were diagnosed as probable Alzheimer`s patients after a neurological examination, extensive blood work, and a CAT scan. The diagnosis was made according to the NINCDS-ADRDA criteria. The apolipoprotein E4 polymorphism was detected after PCR amplification of genomic DNA, restriction enzyme digestion with Hhal,more » and polyacrylamide gel electrophoresis. Ethidium bromide-stained bands at 91 bp were designated as allele 3, at 83 bp as allele 2, and at 72 bp as allele 4. Of the 84 probable Alzheimer`s patients (all of whom were Caucasian), 47 were heterozygous and 13 were homozygous for the E4 allele. There were 26 early onset patients; 13 were heterozygous and 7 homozygous for the E4 allele. The frequencies for the E4 allele for late onset familial patients was 0.45 and for sporadic patients was 0.37. We analyzed 77 spouses with an average age of 71.9 {plus_minus} 7.4 years as controls, and 15 were heterozygous for the E4 allele for an E4 frequency of 0.097. Of the 53 Parkinson`s patients, 11 had the E4 allele for a frequency of 0.113. Thus our findings support the association of the ApoE4 allele with Alzheimer`s disease.« less

  18. 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

  19. Mutation screening of patients with Alzheimer disease identifies APP locus duplication in a Swedish patient

    PubMed Central

    2011-01-01

    Background Missense mutations in three different genes encoding amyloid-β precursor protein, presenilin 1 and presenilin 2 are recognized to cause familial early-onset Alzheimer disease. Also duplications of the amyloid precursor protein gene have been shown to cause the disease. At the Dept. of Geriatric Medicine, Karolinska University Hospital, Sweden, patients are referred for mutation screening for the identification of nucleotide variations and for determining copy-number of the APP locus. Methods We combined the method of microsatellite marker genotyping with a quantitative real-time PCR analysis to detect duplications in patients with Alzheimer disease. Results In 22 DNA samples from individuals diagnosed with clinical Alzheimer disease, we identified one patient carrying a duplication on chromosome 21 which included the APP locus. Further mapping of the chromosomal region by array-comparative genome hybridization showed that the duplication spanned a maximal region of 1.09 Mb. Conclusions This is the first report of an APP duplication in a Swedish Alzheimer patient and describes the use of quantitative real-time PCR as a tool for determining copy-number of the APP locus. PMID:22044463

  20. Mutation screening of patients with Alzheimer disease identifies APP locus duplication in a Swedish patient.

    PubMed

    Thonberg, Håkan; Fallström, Marie; Björkström, Jenny; Schoumans, Jacqueline; Nennesmo, Inger; Graff, Caroline

    2011-11-01

    Missense mutations in three different genes encoding amyloid-β precursor protein, presenilin 1 and presenilin 2 are recognized to cause familial early-onset Alzheimer disease. Also duplications of the amyloid precursor protein gene have been shown to cause the disease. At the Dept. of Geriatric Medicine, Karolinska University Hospital, Sweden, patients are referred for mutation screening for the identification of nucleotide variations and for determining copy-number of the APP locus. We combined the method of microsatellite marker genotyping with a quantitative real-time PCR analysis to detect duplications in patients with Alzheimer disease. In 22 DNA samples from individuals diagnosed with clinical Alzheimer disease, we identified one patient carrying a duplication on chromosome 21 which included the APP locus. Further mapping of the chromosomal region by array-comparative genome hybridization showed that the duplication spanned a maximal region of 1.09 Mb. This is the first report of an APP duplication in a Swedish Alzheimer patient and describes the use of quantitative real-time PCR as a tool for determining copy-number of the APP locus.

  1. SORL1 variants across Alzheimer's disease European American cohorts.

    PubMed

    Fernández, Maria Victoria; Black, Kathleen; Carrell, David; Saef, Ben; Budde, John; Deming, Yuetiva; Howells, Bill; Del-Aguila, Jorge L; Ma, Shengmei; Bi, Catherine; Norton, Joanne; Chasse, Rachel; Morris, John; Goate, Alison; Cruchaga, Carlos

    2016-12-01

    The accumulation of the toxic Aβ peptide in Alzheimer's disease (AD) largely relies upon an efficient recycling of amyloid precursor protein (APP). Recent genetic association studies have described rare variants in SORL1 with putative pathogenic consequences in the recycling of APP. In this work, we examine the presence of rare coding variants in SORL1 in three different European American cohorts: early-onset, late-onset AD (LOAD) and familial LOAD.

  2. Head-to-Head Visual Comparison between Brain Perfusion SPECT and Arterial Spin-Labeling MRI with Different Postlabeling Delays in Alzheimer Disease.

    PubMed

    Kaneta, T; Katsuse, O; Hirano, T; Ogawa, M; Yoshida, K; Odawara, T; Hirayasu, Y; Inoue, T

    2017-08-01

    Arterial spin-labeling MR imaging has been recently developed as a noninvasive technique with magnetically labeled arterial blood water as an endogenous contrast medium for the evaluation of CBF. Our aim was to compare arterial spin-labeling MR imaging and SPECT in the visual assessment of CBF in patients with Alzheimer disease. In 33 patients with Alzheimer disease or mild cognitive impairment due to Alzheimer disease, CBF images were obtained by using both arterial spin-labeling-MR imaging with a postlabeling delay of 1.5 seconds and 2.5 seconds (PLD 1.5 and PLD 2.5 , respectively) and brain perfusion SPECT. Twenty-two brain regions were visually assessed, and the diagnostic confidence of Alzheimer disease was recorded. Among all arterial spin-labeling images, 84.9% of PLD 1.5 and 9% of PLD 2.5 images showed the typical pattern of advanced Alzheimer disease (ie, decreased CBF in the bilateral parietal, temporal, and frontal lobes). PLD 1.5 , PLD 2.5 , and SPECT imaging resulted in obviously different visual assessments. PLD 1.5 showed a broad decrease in CBF, which could have been due to an early perfusion. In contrast, PLD 2.5 did not appear to be influenced by an early perfusion but showed fewer pathologic findings than SPECT. The distinctions observed by us should be carefully considered in the visual assessments of Alzheimer disease. Further studies are required to define the patterns of change in arterial spin-labeling-MR imaging associated with Alzheimer disease. © 2017 by American Journal of Neuroradiology.

  3. 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 ...

  4. Plasma tau in Alzheimer disease.

    PubMed

    Mattsson, Niklas; Zetterberg, Henrik; Janelidze, Shorena; Insel, Philip S; Andreasson, Ulf; Stomrud, Erik; Palmqvist, Sebastian; Baker, David; Tan Hehir, Cristina A; Jeromin, Andreas; Hanlon, David; Song, Linan; Shaw, Leslie M; Trojanowski, John Q; Weiner, Michael W; Hansson, Oskar; Blennow, Kaj

    2016-10-25

    To test whether plasma tau is altered in Alzheimer disease (AD) and whether it is related to changes in cognition, CSF biomarkers of AD pathology (including β-amyloid [Aβ] and tau), brain atrophy, and brain metabolism. This was a study of plasma tau in prospectively followed patients with AD (n = 179), patients with mild cognitive impairment (n = 195), and cognitive healthy controls (n = 189) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and cross-sectionally studied patients with AD (n = 61), mild cognitive impairment (n = 212), and subjective cognitive decline (n = 174) and controls (n = 274) from the Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study at Lund University, Sweden. A total of 1284 participants were studied. Associations were tested between plasma tau and diagnosis, CSF biomarkers, MRI measures, 18 fluorodeoxyglucose-PET, and cognition. Higher plasma tau was associated with AD dementia, higher CSF tau, and lower CSF Aβ 42 , but the correlations were weak and differed between ADNI and BioFINDER. Longitudinal analysis in ADNI showed significant associations between plasma tau and worse cognition, more atrophy, and more hypometabolism during follow-up. Plasma tau partly reflects AD pathology, but the overlap between normal aging and AD is large, especially in patients without dementia. Despite group-level differences, these results do not support plasma tau as an AD biomarker in individual people. Future studies may test longitudinal plasma tau measurements in AD. © 2016 American Academy of Neurology.

  5. [Tauopathy and Alzheimer disease: a full degenerating process].

    PubMed

    Buée, Luc; Delacourte, André

    2006-12-01

    Neurofibrillary degeneration is well correlated to the clinical signs of Alzheimer disease. However, the amyloid cascade is so well established in the scientific and medical community that the role of neurofibrillary degeneration in Alzheimer's disease etiopathogenesis is often underestimated. However, neuronal vulnerability is clearly a key factor for facilitating the amyloid pathology which allows the propagation of the degenerating process. In the present work, the role of tau pathology as both diagnostic marker and therapeutic target is highlighted in Alzheimer disease and related disorders.

  6. Alzheimer's Disease-Related Dementias Summit 2016: National research priorities.

    PubMed

    Corriveau, Roderick A; Koroshetz, Walter J; Gladman, Jordan T; Jeon, Sophia; Babcock, Debra; Bennett, David A; Carmichael, S Thomas; Dickinson, Susan L-J; Dickson, Dennis W; Emr, Marian; Fillit, Howard; Greenberg, Steven M; Hutton, Michael L; Knopman, David S; Manly, Jennifer J; Marder, Karen S; Moy, Claudia S; Phelps, Creighton H; Scott, Paul A; Seeley, William W; Sieber, Beth-Anne; Silverberg, Nina B; Sutherland, Margaret L; Taylor, Angela; Torborg, Christine L; Waddy, Salina P; Gubitz, Amelie K; Holtzman, David M

    2017-12-05

    Goal 1 of the National Plan to Address Alzheimer's Disease is to prevent and effectively treat Alzheimer disease and Alzheimer disease-related dementias by 2025. To help inform the research agenda toward achieving this goal, the NIH hosts periodic summits that set and refine relevant research priorities for the subsequent 5 to 10 years. This proceedings article summarizes the 2016 Alzheimer's Disease-Related Dementias Summit, including discussion of scientific progress, challenges, and opportunities in major areas of dementia research, including mixed-etiology dementias, Lewy body dementia, frontotemporal degeneration, vascular contributions to cognitive impairment and dementia, dementia disparities, and dementia nomenclature. © 2017 American Academy of Neurology.

  7. Alzheimer's and Dementia Testing for Earlier Diagnosis

    MedlinePlus

    ... focused on early detection of Alzheimer's disease. Imaging technologies used in Alzheimer's research Structural imaging provides information ... chemical changes linked to specific diseases. Molecular imaging technologies include PET, fMRI and single photon emission computed ...

  8. The role of novel chitin-like polysaccharides in Alzheimer disease.

    PubMed

    Castellani, Rudy J; Perry, George; Smith, Mark A

    2007-12-01

    While controversy over the role of carbohydrates in amyloidosis has existed since the initial recognition of amyloid, current understanding of the role of polysaccharides in the pathogenesis of amyloid deposition of Alzheimer disease and other amyloidoses is limited to studies of glyco-conjugates such as heparin sulfate proteoglycan. We hypothesized that polysaccharides may play a broader role in light of 1) the impaired glucose utilization in Alzheimer disease; 2) the demonstration of amylose in the Alzheimer disease brain; 3) the role of amyloid in Alzheimer disease pathogenesis. Specifically, as with glucose polymers (amyloid), we wanted to explore whether glucosamine polymers such as chitin were being synthesized and deposited as a result of impaired glucose utilization and aberrant hexosamine pathway activation. To this end, using calcofluor histochemistry, we recently demonstrated that amyloid plaques and blood vessels affected by amyloid angiopathy in subjects with sporadic and familial Alzheimer disease elicit chitin-type characteristics. Since chitin is a highly insoluble molecule and a substrate for glycan-protein interactions, chitin-like polysaccharides within the Alzheimer disease brain could provide a scaffolding for amyloid-beta deposition. As such, glucosamine may facilitate the process of amyloidosis, and /or provide neuroprotection in the Alzheimer disease brain.

  9. Glaucoma and Alzheimer Disease: A Single Age-Related Neurodegenerative Disease of the Brain.

    PubMed

    Mancino, Raffaele; Martucci, Alessio; Cesareo, Massimo; Giannini, Clarissa; Corasaniti, Maria Tiziana; Bagetta, Giacinto; Nucci, Carlo

    2017-12-06

    Open Angle Glaucoma is one of the leading causes of irreversible blindness worldwide. Elevated intraocular pressure is considered an important risk factor for glaucoma, however a subset of patients experience disease progression even in presence of normal intraocular pressure values. This implies that risk factors other than intraocular pressure are involved in the pathogenesis of glaucoma. A possible relationship between glaucoma and neurodegenerative diseases such as Alzheimer Disease has been suggested. In this regard, we have recently described a high prevalence of alterations typical of glaucoma, using Heidelberg Retinal Tomograph-3 (HRT-3), in a group of patients with Alzheimer Disease. Interestingly, these alterations were not associated with elevated intraocular pressure or abnormal Central Corneal Thickness values. Alzheimer Disease is the most common form of dementia associated with progressive deterioration of memory and cognition. Complaints related to vision are common among Alzheimer Disease patients. Features common to both diseases, including risk factors and pathophysiological mechanisms, gleaned from the recent literature do suggest that Alzheimer Disease and glaucoma can be considered age-related neurodegenerative diseases that may co-exist in the elderly. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Use of multimodality imaging and artificial intelligence for diagnosis and prognosis of early stages of Alzheimer's disease.

    PubMed

    Liu, Xiaonan; Chen, Kewei; Wu, Teresa; Weidman, David; Lure, Fleming; Li, Jing

    2018-04-01

    Alzheimer's disease (AD) is a major neurodegenerative disease and the most common cause of dementia. Currently, no treatment exists to slow down or stop the progression of AD. There is converging belief that disease-modifying treatments should focus on early stages of the disease, that is, the mild cognitive impairment (MCI) and preclinical stages. Making a diagnosis of AD and offering a prognosis (likelihood of converting to AD) at these early stages are challenging tasks but possible with the help of multimodality imaging, such as magnetic resonance imaging (MRI), fluorodeoxyglucose (FDG)-positron emission topography (PET), amyloid-PET, and recently introduced tau-PET, which provides different but complementary information. This article is a focused review of existing research in the recent decade that used statistical machine learning and artificial intelligence methods to perform quantitative analysis of multimodality image data for diagnosis and prognosis of AD at the MCI or preclinical stages. We review the existing work in 3 subareas: diagnosis, prognosis, and methods for handling modality-wise missing data-a commonly encountered problem when using multimodality imaging for prediction or classification. Factors contributing to missing data include lack of imaging equipment, cost, difficulty of obtaining patient consent, and patient drop-off (in longitudinal studies). Finally, we summarize our major findings and provide some recommendations for potential future research directions. Copyright © 2018 Elsevier Inc. All rights reserved.

  11. 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

  12. Alzheimer's Disease Phenotypes and Genotypes Associated with Mutations in Presenilin 2

    ERIC Educational Resources Information Center

    Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D.

    2010-01-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11…

  13. Genetic dissection of Alzheimer disease, a heterogeneous disorder.

    PubMed

    Schellenberg, G D

    1995-09-12

    The genetics of Alzheimer disease (AD) are complex and not completely understood. Mutations in the amyloid precursor protein gene (APP) can cause early-onset autosomal dominant AD. In vitro studies indicate that cells expressing mutant APPs overproduce pathogenic forms of the A beta peptide, the major component of AD amyloid. However, mutations in the APP gene are responsible for 5% or less of all early-onset familial AD. A locus on chromosome 14 is responsible for AD in other early-onset AD families and represents the most severe form of the disease in terms of age of onset and rate of decline. Attempts to identify the AD3 gene by positional cloning methods are underway. At least one additional early-onset AD locus remains to be located. In late-onset AD, the apolipoprotein E gene allele epsilon 4 is a risk factor for AD. This allele appears to act as a dose-dependent age-of-onset modifier. The epsilon 2 allele of this gene may be protective. Other late-onset susceptibility factors remain to be identified.

  14. Effectiveness of self-generated cues in early Alzheimer's disease.

    PubMed

    Lipinska, B; Bäckman, L; Mäntylä, T; Viitanen, M

    1994-12-01

    The ability to utilize cognitive support in the form of self-generated cues in mild Alzheimer's disease (AD), and the factors promoting efficient cue utilization in this group of patients, were examined in two experiments on memory for words. Results from both experiments showed that normal old adults as well as AD patients performed better with self-generated cues than with experimenter-provided cues, although the latter type of cues resulted in gains relative to free recall. The findings indicate no qualitative differences in patterns of performance between the normal old and the AD patients. For both groups of subjects, cue effectiveness was optimized when (a) there was self-generation activity at encoding, and (b) encoding and retrieval conditions were compatible.

  15. Alzheimer's Disease Facts and Figures

    MedlinePlus Videos and Cool Tools

    ... disease is the only top 10 cause of death in the United States that cannot be prevented, ... Alzheimer's disease is the sixth-leading cause of death in the United States, and the fifth-leading ...

  16. The Effects of Alzheimer's Disease on Close Relationships between Patients and Caregivers.

    ERIC Educational Resources Information Center

    Blieszner, Rosemary; Shifflett, Peggy A.

    1990-01-01

    Interviewed 11 caregivers for early-stage Alzheimer's patients to investigate changes in relationships concurrently with onset and progress of disease. Over 18 months, intimacy declined in both spouse and parent-child relationships. Caregivers were saddened at loss of reciprocal aspects of relationship and had difficulty coping with uncertain…

  17. Textural content in 3T MR: an image-based marker for Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Bharath Kumar, S. V.; Mullick, Rakesh; Patil, Uday

    2005-04-01

    In this paper, we propose a study, which investigates the first-order and second-order distributions of T2 images from a magnetic resonance (MR) scan for an age-matched data set of 24 Alzheimer's disease and 17 normal patients. The study is motivated by the desire to analyze the brain iron uptake in the hippocampus of Alzheimer's patients, which is captured by low T2 values. Since, excess iron deposition occurs locally in certain regions of the brain, we are motivated to investigate the spatial distribution of T2, which is captured by higher-order statistics. Based on the first-order and second-order distributions (involving gray level co-occurrence matrix) of T2, we show that the second-order statistics provide features with sensitivity >90% (at 80% specificity), which in turn capture the textural content in T2 data. Hence, we argue that different texture characteristics of T2 in the hippocampus for Alzheimer's and normal patients could be used as an early indicator of Alzheimer's disease.

  18. 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.

  19. Chronic Mild Stress Assay Leading to Early Onset and Propagation of Alzheimer's Disease Phenotype in Mouse Models.

    PubMed

    Cuadrado-Tejedor, Mar; García-Osta, Ana

    2016-01-01

    A comprehensive chronic mild stress (CMS) procedure is presented, which consists in the application of unpredictable mild stressors to animal models in a random order for several weeks. This assay can be applied to Alzheimer's disease (AD) mouse models, leading to accelerated onset and increased severity of AD phenotypes and signs, including memory deficits and the accumulation of amyloid-β and phospho-tau. These assays open the way towards advanced studies on the influence of sustained mild stress, stress responses and pathways on the onset and propagation of Alzheimer's disease.

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

    PubMed

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

    2017-03-01

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

  1. Linkage of familial Alzheimer disease to chromosome 14 in two large early-onset pedigrees: effects of marker allele frequencies on lod scores.

    PubMed

    Nechiporuk, A; Fain, P; Kort, E; Nee, L E; Frommelt, E; Polinsky, R J; Korenberg, J R; Pulst, S M

    1993-05-01

    Alzheimer disease (AD) is a devastating neurodegenerative disease leading to global dementia. In addition to sporadic forms of AD, familial forms (FAD) have been recognized. Mutations in the amyloid precursor protein (APP) gene on chromosome (CHR) 21 have been shown to cause early-onset AD in a small number of pedigrees. Recently, linkage to markers on CHR 14 has been established in several early-onset FAD pedigrees. We now report lod scores for CHR 14 markers in two large early-onset FAD pedigrees. Pairwise linkage analysis suggested that in these pedigrees the mutation is tightly linked to the loci D14S43 and D14S53. However, assumptions regarding marker allele frequencies had a major and often unpredictable effect on calculated lod scores. Therefore, caution needs to be exercised when single pedigrees are analyzed with marker allele frequencies determined from the literature or from a pool of spouses.

  2. Drug delivery strategies for Alzheimer's disease treatment.

    PubMed

    Di Stefano, Antonio; Iannitelli, Antonio; Laserra, Sara; Sozio, Piera

    2011-05-01

    Current Alzheimer's disease (AD) therapy is based on the administration of the drugs donepezil, galantamine, rivastigmine and memantine. Until disease-modifying therapies become available, further research is needed to develop new drug delivery strategies to ensure ease of administration and treatment persistence. In addition to the conventional oral formulations, a variety of drug delivery strategies applied to the treatment of AD are reviewed in this paper, with a focus on strategies leading to simplified dosage regimens and to providing new pharmacological tools. Alternatives include extended release, orally disintegrating or sublingual formulations, intranasal or short- and long-acting intramuscular or transdermal forms, and nanotechnology-based delivery systems. The advent of new research on molecular mechanisms of AD pathogenesis has outlined new strategies for therapeutic intervention; these include the stimulation of α-secretase cleavage, the inhibition of γ-secretase activity, the use of non-steroidal anti-inflammatory drugs, neuroprotection based on antioxidant therapy, the use of estrogens, NO synthetase inhibitors, and natural agents such as polyphenols. Unfortunately, these compounds might not help patients with end stage AD, but might hopefully slow or stop the disease process in its early stage. Nanotechnologies may prove to be a promising contribution in future AD drug delivery strategies, in particular drug carrier nano- or microsystems, which can limit the side effects of anti-Alzheimer drugs.

  3. Alzheimer's disease is associated with prostate cancer: a population-based study.

    PubMed

    Lin, Herng-Ching; Kao, Li-Ting; Chung, Shiu-Dong; Huang, Chung-Chien; Shia, Ben-Chang; Huang, Chao-Yuan

    2018-01-26

    Alzheimer's disease and cancer are increasingly prevalent with advancing age. However, the association between Alzheimer's disease and prostate cancer remains unclear. The aim of this study was to examine the relationship between prior Alzheimer's disease and subsequent prostate cancer using a population-based dataset in Taiwan. Data for this study were sourced from the Taiwan Longitudinal Health Insurance Database 2005. This case-control study included 2101 prostate cancer patients as cases and 6303 matched controls. We used conditional logistic regression analyses to calculate the odds ratio (OR) and corresponding 95% confidence interval (CI) for Alzheimer's disease between prostate cancer patients and controls. We found that of the 8404 sampled patients, 128 (1.5%) had been diagnosed with Alzheimer's disease prior to the index date. A Chi-squared test showed that there was a significant difference in the prevalences of prior Alzheimer's disease between prostate cancer patients and controls (2.1% vs. 1.3%, p < 0.001). The conditional logistic regression analysis showed that the OR of prior Alzheimer's disease for prostate cancer patients was 1.53 (95% CI: 1.06∼2.21) compared to controls. Furthermore, the OR of prior Alzheimer's disease for prostate cancer patients was 1.52 (95% CI: 1.04∼2.22) compared to controls after adjusting for hypertension, diabetes, coronary heart disease, hyperlipidemia, obesity, prostatitis, gonorrhea or chlamydia infection, testitis or epididymitis, and alcohol abuse/alcohol dependency syndrome. This study revealed an association between prior Alzheimer's disease and prostate cancer. We suggest that clinicians be alert to the increased risk of prostate cancer when caring for elderly individuals with Alzheimer's disease.

  4. Is cerebral microbleed prevalence relevant as a biomarker in amnestic mild cognitive impairment and mild Alzheimer's disease?

    PubMed

    Rabelo, Ana Gb; Teixeira, Camila Vl; Magalhães, Thamires Nc; Carletti-Cassani, Ana Flávia Mk; Amato Filho, Augusto Cs; Joaquim, Helena Pg; Talib, Leda L; Forlenza, Orestes; Ribeiro, Patrícia Ao; Secolin, Rodrigo; Lopes-Cendes, Iscia; Cendes, Fernando; Balthazar, Marcio Lf

    2017-10-01

    Alzheimer's disease process, their presence is not a good candidate for a neuroimaging biomarker of the disease, especially in its early phases.

  5. The Alzheimer's disease transcriptome mimics the neuroprotective signature of IGF-1 receptor-deficient neurons.

    PubMed

    George, Caroline; Gontier, Géraldine; Lacube, Philippe; François, Jean-Christophe; Holzenberger, Martin; Aïd, Saba

    2017-07-01

    Seminal studies using post-mortem brains of patients with Alzheimer's disease evidenced aberrant insulin-like growth factor 1 receptor (IGF1R) signalling. Addressing causality, work in animal models recently demonstrated that long-term suppression of IGF1R signalling alleviates Alzheimer's disease progression and promotes neuroprotection. However, the underlying mechanisms remain largely elusive. Here, we showed that genetically ablating IGF1R in neurons of the ageing brain efficiently protects from neuroinflammation, anxiety and memory impairments induced by intracerebroventricular injection of amyloid-β oligomers. In our mutant mice, the suppression of IGF1R signalling also invariably led to small neuronal soma size, indicative of profound changes in cellular homeodynamics. To gain insight into transcriptional signatures leading to Alzheimer's disease-relevant neuronal defence, we performed genome-wide microarray analysis on laser-dissected hippocampal CA1 after neuronal IGF1R knockout, in the presence or absence of APP/PS1 transgenes. Functional analysis comparing neurons in early-stage Alzheimer's disease with IGF1R knockout neurons revealed strongly convergent transcriptomic signatures, notably involving neurite growth, cytoskeleton organization, cellular stress response and neurotransmission. Moreover, in Alzheimer's disease neurons, a high proportion of genes responding to Alzheimer's disease showed a reversed differential expression when IGF1R was deleted. One of the genes consistently highlighted in genome-wide comparison was the neurofilament medium polypeptide Nefm. We found that NEFM accumulated in hippocampus in the presence of amyloid pathology, and decreased to control levels under IGF1R deletion, suggesting that reorganized cytoskeleton likely plays a role in neuroprotection. These findings demonstrated that significant resistance of the brain to amyloid-β can be achieved lifelong by suppressing neuronal IGF1R and identified IGF

  6. Heterogeneity of neuroanatomical patterns in prodromal Alzheimer's disease: links to cognition, progression and biomarkers.

    PubMed

    Dong, Aoyan; Toledo, Jon B; Honnorat, Nicolas; Doshi, Jimit; Varol, Erdem; Sotiras, Aristeidis; Wolk, David; Trojanowski, John Q; Davatzikos, Christos

    2017-03-01

    executive impairment; and (iv) individuals with notably focal involvement of the medial temporal lobe and a slow steady progression, likely representing in early Alzheimer's disease stages. These four atrophy patterns effectively define a 4-dimensional categorization of neuroanatomical alterations in mild cognitive impairment and Alzheimer's disease that can complement existing dimensional approaches for staging Alzheimer's disease using a variety of biomarkers, which offer the potential for enabling precision diagnostics and prognostics, as well as targeted patient recruitment of relatively homogeneous subgroups of subjects for clinical trials. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. [Nicotinic Receptor, galantamine and Alzheimer disease].

    PubMed

    Arroyo, G; Aldea, M; Fuentealba, J; García, A G

    Population aging has increased and will drastically increase the prevalence of Alzheimer disease. The disease develops inexorably towards a syndrome of marked cognitive impairment, accompanied of emotional alterations and profound changes of personality. The patient loses its autonomy, and requires special attention of caregivers; this leads to a decrease of the quality of life, not only of the patient but also of its caregivers and family. The reduction of the number of functional nicotinic receptors in brain keeps pace with neurological symptoms and the severity of the disease (cholinergic theory of Alzheimer disease). There is a pleyade of data and observations reinforcing the idea that improving cholinergic neurotransmission is an investment in memory. Up to now, although with limited success, this improvement has been achieved only with the reversible inhibitors of acetylcholinesterase tacrine, rivastigmine and donepezil, available in the clinic since a few years. The last approved has been galantamine that in spite of being a modest inhibitor of acetylcholinesterase, improves memory (ADAS cog test) and slows down cognitive impairment of Alzheimer patients. To explain this therapeutic effect, a second mechanism of action for galantamine has been suggested, the positive allosteric modulation of presynaptic nicotinic receptors, that will favour the release of acetylcholine and other neurotransmitters involved in memory formation. Furthermore, galantamine possesses neuroprotectant antiapoptotic effects, according to recent data from our laboratory. These effects provide new ideas and therapeutic targets that might help to find novel and efficacious treatments for patients suffering Alzheimer disease.

  8. Alzheimer's or Depression: Could It Be Both?

    MedlinePlus

    Alzheimer's or depression: Could it be both? Alzheimer's and depression have some similar symptoms. Proper treatment improves quality of life. By Mayo Clinic Staff Early Alzheimer's disease and depression share many symptoms, so it can be hard — ...

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

    PubMed

    Giaccone, Giorgio

    2015-01-01

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

  10. Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    van Duinen, S.G.; Castano, E.M.; Prelli, F.

    1987-08-01

    Hereditary cerebral hemorrhage with amyloidosis in Dutch patients is an autosomal dominant form of vascular amyloidosis restricted to the leptomeninges and cerebral cortex. Clinically the disease is characterized by cerebral hemorrhages leading to an early death. Immunohistochemical studies of five patients revealed that the vascular amyloid deposits reacted intensely with an antiserum raised against a synthetic peptide homologous to the Alzheimer disease-related ..beta..-protein. Silver stain-positive, senile plaque-like structures were also labeled by the antiserum, yet these lesions lacked the dense amyloid cores present in typical plaques of Alzheimer disease. No neurofibrillary tangles were present. Amyloid fibrils were purified from themore » leptomeningeal vessels of one patient who clinically had no signs of dementia. The protein had a molecular weight of approx. 4000 and its partial amino acid sequence to position 21 showed homology to the ..beta..-protein of Alzheimer disease and Down syndrome. These results suggest that hereditary cerebral hemorrhage with amyloidosis of Dutch origin is pathogenetically related to Alzheimer disease and support the concept that the initial amyloid deposition in this disorder occurs in the vessel walls before damaging the brain parenchyma. Thus, deposition of ..beta..-protein in brain tissue seems to be related to a spectrum of diseases involving vascular syndromes, progressive dementia, or both.« less

  11. Augmentation of sensory-evoked hemodynamic response in an early Alzheimer's disease mouse model.

    PubMed

    Kim, Jinho; Jeong, Yong

    2013-01-01

    Based on enlarged blood oxygen level-dependent (BOLD) responses in cognitively normal subjects at risk for Alzheimer's disease (AD), compensatory neuronal hyperactivation has been proposed as an early marker for diagnosis of AD. The BOLD response results from neurovascular coupling, i.e., hemodynamic response induced by neuronal activity. However, there has been no evidence of task-induced increases in hemodynamic response in animal models of AD. Here, we observed an augmented hemodynamic response pattern in a transgenic AβPP(SWE)/PS1ΔE9 mouse model of AD using three in vivo imaging methods: intrinsic optical signal imaging, multi-photon laser scanning microscopy, and laser Doppler flowmetry. Sensory stimulation resulted in augmented and prolonged hemodynamic responses in transgenic mice evidenced by changes in total, oxygenated, and deoxygenated hemoglobin concentration. This difference between transgenic and wild-type mice was significant at 7 months of age when amyloid plaques and cerebral amyloid angiopathy had developed but not at younger or older ages. Correspondingly, sensory stimulation-induced pial arteriole diameter was also augmented and prolonged in transgenic mice at 7 months of age. Cerebral blood flow response in transgenic mice was augmented but not prolonged. These results are consistent with the existence of BOLD signal hyperactivation in non-demented AD-risk human subjects, supporting its potential use as an early diagnostic marker of AD.

  12. Cognitive Impairment and Structural Abnormalities in Late Life Depression with Olfactory Identification Impairment: an Alzheimer's Disease-Like Pattern.

    PubMed

    Chen, Ben; Zhong, Xiaomei; Mai, Naikeng; Peng, Qi; Wu, Zhangying; Ouyang, Cong; Zhang, Weiru; Liang, Wanyuan; Wu, Yujie; Liu, Sha; Chen, Lijian; Ning, Yuping

    2018-03-15

    Late-life depression patients are at a high risk of developing Alzheimer's disease, and diminished olfactory identification is an indicator in early screening for Alzheimer's disease in the elderly. However, whether diminished olfactory identification is associated with risk of developing Alzheimer's disease in late-life depression patients remains unclear. One hundred and twenty-five late-life depression patients, 50 Alzheimer's disease patients, and 60 normal controls were continuously recruited. The participants underwent a clinical evaluation, olfactory test, neuropsychological assessment, and neuroimaging assessment. The olfactory identification impairment in late-life depression patients was milder than that in Alzheimer's disease patients. Diminished olfactory identification was significantly correlated with worse cognitive performance (global function, memory language, executive function, and attention) and reduced grey matter volume (olfactory bulb and hippocampus) in the late-life depression patients. According to a multiple linear regression analysis, olfactory identification was significantly associated with the memory scores in late-life depression group (B=1.623, P<.001). The late-life depression with olfactory identification impairment group had worse cognitive performance (global, memory, language, and executive function) and more structural abnormalities in Alzheimer's disease-related regions than the late-life depression without olfactory identification impairment group, and global cognitive function and logical memory in the late-life depression without olfactory identification impairment group was intact. Reduced volume observed in many areas (hippocampus, precuneus, etc.) in the Alzheimer's disease group was also observed in late-life depression with olfactory identification impairment group but not in the late-life depression without olfactory identification impairment group. The patterns of cognitive impairment and structural abnormalities in

  13. The use of errorless learning strategies for patients with Alzheimer's disease: a literature review.

    PubMed

    Li, Ruijie; Liu, Karen P Y

    2012-12-01

    The aim of this article was to review the evidence of errorless learning on learning outcomes in patients with early-stage Alzheimer's disease. A computer-aided literature search from 1999 to 2011 was carried out using MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and PsycArticles. Keywords included 'errorless learning or practice' and 'Alzheimer's disease'. Four studies that fulfilled the inclusion criteria were selected and reviewed. Two of the studies were clinical controlled trials: one was a single-group pretest-post-test trial and the other was a multiple single-participant study. Demographic variables, design, treatment and outcome measures were summarized. Recall trials were used as the primary outcome measure. Results indicate that the use of errorless learning promotes better retention of specific types of information. Errorless learning is effective in memory rehabilitation of older adults with Alzheimer's disease. However, it would require more studies with unified outcome measures to allow for the formulation of standardized clinical protocol and recommendations.

  14. How Should Clinicians Counsel a Woman with a Strong Family History of Early-Onset Alzheimer's Disease about Her Pregnancy?

    PubMed

    Mapes, Marianna V; O'Brien, Barbara M; King, Louise P

    2017-07-01

    Counseling patients regarding the benefits, harms, and dilemmas of genetic testing is one of the greatest ethical challenges facing reproductive medicine today. With or without test results, clinicians grapple with how to communicate potential genetic risks as patients weigh their reproductive options. Here, we consider a case of a woman with a strong family history of early-onset Alzheimer's disease (EOAD). She is early in her pregnancy and unsure about learning her own genetic status. We address the ethical ramifications of each of her options, which include genetic testing, genetic counseling, and termination versus continuation of the pregnancy. Our analysis foregrounds clinicians' role in helping to ensure autonomous decision making as the patient reflects on these clinical options in light of her goals and values. © 2017 American Medical Association. All Rights Reserved.

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

    PubMed

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

    2018-02-01

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

  16. Analysis of recent failures of disease modifying therapies in Alzheimer's disease suggesting a new methodology for future studies.

    PubMed

    Amanatkar, Hamid Reza; Papagiannopoulos, Bill; Grossberg, George Thomas

    2017-01-01

    Pharmaceutical companies and the NIH have invested heavily in a variety of potential disease-modifying therapies for Alzheimer's disease (AD) but unfortunately all double-blind placebo-controlled Phase III studies of these drugs have failed to show statistically significant results supporting their clinical efficacy on cognitive measures. These negative results are surprising as most of these medications have the capability to impact the biomarkers which are associated with progression of Alzheimer's disease. Areas covered: This contradiction prompted us to review all study phases of Intravenous Immunoglobulin (IVIG), Bapineuzumab, Solanezumab, Avagacestat and Dimebolin to shed more light on these recent failures. We critically analyzed these studies, recommending seven lessons from these failures which should not be overlooked. Expert commentary: We suggest a new methodology for future treatment research in Alzheimer's disease considering early intervention with more focus on cognitive decline as a screening tool, more sophisticated exclusion criteria with more reliance on biomarkers, stratification of subjects based on the rate of cognitive decline aiming less heterogeneity, and a longer study duration with periodic assessment of cognition and activities of daily living during the study and also after a washout period.

  17. Modifiable pathways in Alzheimer's disease: Mendelian randomisation analysis.

    PubMed

    Larsson, Susanna C; Traylor, Matthew; Malik, Rainer; Dichgans, Martin; Burgess, Stephen; Markus, Hugh S

    2017-12-06

    To determine which potentially modifiable risk factors, including socioeconomic, lifestyle/dietary, cardiometabolic, and inflammatory factors, are associated with Alzheimer's disease. Mendelian randomisation study using genetic variants associated with the modifiable risk factors as instrumental variables. International Genomics of Alzheimer's Project. 17 008 cases of Alzheimer's disease and 37 154 controls. Odds ratio of Alzheimer's per genetically predicted increase in each modifiable risk factor estimated with Mendelian randomisation analysis. This study included analyses of 24 potentially modifiable risk factors. A Bonferroni corrected threshold of P=0.002 was considered to be significant, and P<0.05 was considered suggestive of evidence for a potential association. Genetically predicted educational attainment was significantly associated with Alzheimer's. The odds ratios were 0.89 (95% confidence interval 0.84 to 0.93; P=2.4×10 -6 ) per year of education completed and 0.74 (0.63 to 0.86; P=8.0×10 -5 ) per unit increase in log odds of having completed college/university. The correlated trait intelligence had a suggestive association with Alzheimer's (per genetically predicted 1 SD higher intelligence: 0.73, 0.57 to 0.93; P=0.01). There was suggestive evidence for potential associations between genetically predicted higher quantity of smoking (per 10 cigarettes a day: 0.69, 0.49 to 0.99; P=0.04) and 25-hydroxyvitamin D concentrations (per 20% higher levels: 0.92, 0.85 to 0.98; P=0.01) and lower odds of Alzheimer's and between higher coffee consumption (per one cup a day: 1.26, 1.05 to 1.51; P=0.01) and higher odds of Alzheimer's. Genetically predicted alcohol consumption, serum folate, serum vitamin B 12 , homocysteine, cardiometabolic factors, and C reactive protein were not associated with Alzheimer's disease. These results provide support that higher educational attainment is associated with a reduced risk of Alzheimer's disease. Published by the BMJ

  18. Molecular Insights into the Pathogenesis of Alzheimer's Disease and Its Relationship to Normal Aging

    PubMed Central

    Podtelezhnikov, Alexei A.; Tanis, Keith Q.; Nebozhyn, Michael; Ray, William J.

    2011-01-01

    Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression. PMID:22216330

  19. [Effects of the association of sulbutiamine with an acetylcholinesterase inhibitor in early stage and moderate Alzheimer disease].

    PubMed

    Ollat, H; Laurent, B; Bakchine, S; Michel, B-F; Touchon, J; Dubois, B

    2007-01-01

    The efficacy of the inhibitors of acetylcholinesterase in Alzheimer's Disease (AD) is moderated and some patients do not respond to these treatments. Sulbutiamine potentializes cholinergic and glutamatergic transmissions, mainly in hippocampus and prefrontal cortex. This multicentric, randomized and double-blind trial evaluates the effects of the association of sulbutiamine to an anticholinesterasic drug in cognitive functions in patients with AD at an early stage (episodic memory, working memory, executive functions, attention). Patients had first donepezil (D) or sulbutiamine (S) during three months. During this period, only attention improved in both groups. During the three following months, a placebo (P) in patients D and donepezil in patients S were added. Compared to entry results, episodic memory decreased in group D + P but improved in group S + D. At the same time the improvement of attention persisted in both groups. Daylife activities only improved in group S + D. In conclusion sulbutiamine can be an adjuvant to treatment in early stage and moderate AD by anticholinesterasic drugs.

  20. A selective egocentric topographical working memory deficit in the early stages of Alzheimer's disease: a preliminary study.

    PubMed

    Bianchini, F; Di Vita, A; Palermo, L; Piccardi, L; Blundo, C; Guariglia, C

    2014-12-01

    The aim of this study was to determine whether an egocentric topographical working memory (WM) deficit is present in the early stages of Alzheimer's disease (AD) with respect to other forms of visuospatial WM. Further, we would investigate whether this deficit could be present in patients having AD without topographical disorientation (TD) signs in everyday life assessed through an informal interview to caregivers. Seven patients with AD and 20 healthy participants performed the Walking Corsi Test and the Corsi Block-Tapping Test. The former test requires memorizing a sequence of places by following a path and the latter is a well-known visuospatial memory task. Patients with AD also performed a verbal WM test to exclude the presence of general WM impairments. Preliminary results suggest that egocentric topographical WM is selectively impaired, with respect to visuospatial and verbal WM, even without TD suggesting an important role of this memory in the early stages of AD. © The Author(s) 2014.

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

    PubMed

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

    2017-03-01

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

  2. [The Application of Magnetic Resonance Imaging in Alzheimer's Disease].

    PubMed

    Matsuda, Hiroshi

    2017-07-01

    In Alzheimer's disease (AD), magnetic resonance imaging (MRI) is essential for early diagnosis, differential diagnosis, and evaluation of disease progression. In structural MRI, the automatic diagnosis of atrophy by computers, even when it is not visually noticeable, is possible in daily clinical practice. Furthermore, subfield volumetric measurements of the medial temporal structures, as well as longitudinal volume measurements with high accuracy, have been developed and are useful for calculating the needed sample size in clinical trials. In addition to detecting local atrophy, graph theory has been applied to structural MRI for evaluation of alterations of the brain networks potentially affected in AD.

  3. Naturalistic Driving Study Investigating Self-Regulation Behavior in Early Alzheimer's Disease: A Pilot Study.

    PubMed

    Paire-Ficout, Laurence; Lafont, Sylviane; Conte, Fanny; Coquillat, Amandine; Fabrigoule, Colette; Ankri, Joël; Blanc, Frédéric; Gabel, Cécilia; Novella, Jean-Luc; Morrone, Isabella; Mahmoudi, Rachid

    2018-05-16

    Because cognitive processes decline in the earliest stages of Alzheimer's disease (AD), the driving abilities are often affected. The naturalistic driving approach is relevant to study the driving habits and behaviors in normal or critical situations in a familiar environment of participants. This pilot study analyzed in-car video recordings of naturalistic driving in patients with early-stage AD and in healthy controls, with a special focus on tactical self-regulation behavior. Twenty patients with early-stage AD (Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria), and 21 healthy older adults were included in the study. Data collection equipment was installed in their personal vehicles. Two expert psychologists assessed driving performance using a specially designed Naturalistic Driving Assessment Scale (NaDAS), paying particular attention to tactical self-regulation behavior, and they recorded all critical safety events. Poorer driving performance was observed among AD drivers: their tactical self-regulation behavior was of lower quality. AD patients had also twice as many critical events as healthy drivers and three times more "unaware" critical events. This pilot study using a naturalistic approach to accurately show that AD drivers have poorer tactical self-regulation behavior than healthy older drivers. Future deployment of assistance systems in vehicles should specifically target tactical self-regulation components.

  4. A light therapy for treating Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Wang, Xue; Han, Mengmeng; Wang, Qiyan; Zeng, Yuhui; Meng, Qingqiang; Zhang, Jun; Wei, Xunbin

    2017-02-01

    It is generally believed that there are some connections between Alzheimer's disease and amyloid protein plaques in the brain. The typical symptoms of Alzheimer's disease are memory loss, language disorders, mood swings, loss of motivation and behavioral issues. Currently, the main therapeutic method is pharmacotherapy, which may temporarily reduce symptoms, but has many side effects. Infrared 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 studied the effect of infrared light on Alzheimer's disease through transgenic mouse model. We designed an experimental apparatus for treating mice, which primarily included a therapeutic box and a LED array, which emitted infrared light. After the treatment, we assessed the effects of infrared light by performing two tests: cognitive performance of mice in Morris water maze, and plaque load by immunofluorescence analysis. Immunofluorescence analysis was based on measuring the quantity of plaques in mouse brain slices. Our results show that infrared therapy is able to improve cognitive performance in the mouse model. It might provide a novel and safe way to treat Alzheimer's disease.

  5. Evidence for apolipoprotein E {epsilon}4 association in early-onset Alzheimer`s patients with late-onset relatives

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Perez-Tur, J.; Delacourte, A.; Chartier-Harlin, M.C.

    1995-12-18

    Recently several reports have extended the apolipoprotein E (APOE) {epsilon}4 association found in late-onset Alzheimer`s disease (LOAD) patients to early-onset (EO) AD patients. We have studied this question in a large population of 119 EOAD patients (onset {<=}60 years) in which family history was carefully assessed and in 109 controls. We show that the APOE {epsilon}A allele frequency is increased only in the subset of patients who belong to families where LOAD secondary cases are present. Our sampling scheme permits us to demonstrate that, for an individual, bearing at least one {epsilon}4 allele increases both the risk of AD beforemore » age 60 and the probability of belonging to a family with late-onset affected subjects. Our results suggest that a subset of EOAD cases shares a common determinism with LOAD cases. 19 refs., 3 tabs.« less

  6. Diagnostic Value of a Tablet-Based Drawing Task for Discrimination of Patients in the Early Course of Alzheimer's Disease from Healthy Individuals.

    PubMed

    Müller, Stephan; Preische, Oliver; Heymann, Petra; Elbing, Ulrich; Laske, Christoph

    2017-01-01

    There is a considerable delay in the diagnosis of dementia, which may reduce the effectiveness of available treatments. Thus, it is of great interest to develop fast and easy to perform, non-invasive and non-expensive diagnostic measures for the early detection of cognitive impairment and dementia. Here we investigate movement kinematics between 20 patients with early dementia due to Alzheimer's disease (eDAT), 30 patients with amnestic mild cognitive impairment (aMCI), and 20 cognitively healthy control (HC) individuals while copying a three-dimensional house using a digitizing tablet. Receiver-operating characteristic (ROC) curves and logistic regression analyzes have been conducted to explore whether alterations in movement kinematics could be used to discriminate patients with aMCI and eDAT from healthy individuals. Time-in-air (i.e., transitioning from one stroke to the next without touching the surface) differed significantly between patients with aMCI, eDAT, and HCs demonstrating an excellent sensitivity and a moderate specificity to discriminate aMCI subjects from normal elderly and an excellent sensitivity and specificity to discriminate patients affected by mild Alzheimer's disease from healthy individuals. Time-on-surface (i.e., time while stylus is touching the surface) differed only between HCs and patients with eDAT but not between HCs and patients with aMCI. Furthermore, total-time (i.e., time-in-air plus time-on-surface) did not differ between patients with aMCI and early dementia due to AD. Modern digitizing devices offer the opportunity to measure a broad range of visuoconstructive abilities that may be used as a fast and easy to perform screening instrument for the early detection of cognitive impairment and dementia in primary care.

  7. Whole Exome Analysis of Early Onset Alzheimer’s Disease

    DTIC Science & Technology

    2015-04-01

    autosomal recessive early-onset Parkinson’s disease and juvenile Parkinson disease , Parkin has been shown to promote intracellular Abeta1–42 clearance [15... Parkinsonism . Conclusions Mutations were found in 6/50 families. The presence of an APOE-4 allele may account for disease status in one affected non...AD_________________ Award Number: W81XWH-12-1-0013 TITLE: Whole Exome Analysis of Early Onset Alzheimer’s Disease PRINCIPAL INVESTIGATOR

  8. Altered cell-matrix associated ADAM proteins in Alzheimer disease.

    PubMed

    Gerst, J L; Raina, A K; Pirim, I; McShea, A; Harris, P L; Siedlak, S L; Takeda, A; Petersen, R B; Smith, M A

    2000-03-01

    Alterations in cell-matrix 'contact' are often related to a disruption of cell cycle regulation and, as such, occur variously in neoplasia. Given the recent findings showing cell cycle alterations in Alzheimer disease, we undertook a study of ADAM-1 and 2 (A Disintegrin And Metalloprotease), developmentally-regulated, integrin-binding, membrane-bound metalloproteases. Our results show that whereas ADAM-1 and 2 are found in susceptible hippocampal neurons in Alzheimer disease, these proteins were not generally increased in similar neuronal populations in younger or age-matched controls except in association with age-related neurofibrillary alterations. This increase in both ADAM-1 and 2 in cases of Alzheimer disease was verified by immunoblot analysis (P < 0.05). An ADAM-induced loss of matrix integration would effectively "reset" the mitotic clock and thereby stimulate re-entry into the cell cycle in neurons in Alzheimer disease. Furthermore, given the importance of integrins in maintaining short-term memory, alterations in ADAM proteins or their proteolytic activity could also play a proximal role in the clinico-pathological manifestations of Alzheimer disease. Copyright 2000 Wiley-Liss, Inc.

  9. Impairment in proverb interpretation as an executive function deficit in patients with amnestic mild cognitive impairment and early Alzheimer's disease.

    PubMed

    Leyhe, Thomas; Saur, Ralf; Eschweiler, Gerhard W; Milian, Monika

    2011-01-01

    Proverb interpretation is assumed to reflect executive functions. We hypothesized that proverb interpretation is impaired in patients with amnestic mild cognitive impairment (aMCI) diagnosed as single-domain impairment by common neuropsychological testing. We compared performance in a proverb interpretation test in single-domain aMCI patients and patients with early Alzheimer's disease (EAD). The groups with aMCI and EAD performed significantly worse than healthy controls. Both patient groups gave concrete answers with a similar frequency. However, patients with EAD tended to give senseless answers more frequently. Our data suggest that in patients diagnosed as single-domain aMCI, deterioration of executive functions is detectable with subtle and appropriate neuropsychological testing. Implementation of these procedures may improve the early prediction of AD.

  10. Olfactory dysfunction correlates with amyloid-beta burden in an Alzheimer's disease mouse model.

    PubMed

    Wesson, Daniel W; Levy, Efrat; Nixon, Ralph A; Wilson, Donald A

    2010-01-13

    Alzheimer's disease often results in impaired olfactory perceptual acuity-a potential biomarker of the disorder. However, the usefulness of olfactory screens to serve as informative indicators of Alzheimer's is precluded by a lack of knowledge regarding why the disease impacts olfaction. We addressed this question by assaying olfactory perception and amyloid-beta (Abeta) deposition throughout the olfactory system in mice that overexpress a mutated form of the human amyloid-beta precursor protein. Such mice displayed progressive olfactory deficits that mimic those observed clinically-some evident at 3 months of age. Also, at 3 months of age, we observed nonfibrillar Abeta deposition within the olfactory bulb-earlier than deposition within any other brain region. There was also a correlation between olfactory deficits and the spatial-temporal pattern of Abeta deposition. Therefore, nonfibrillar, versus fibrillar, Abeta-related mechanisms likely contribute to early olfactory perceptual loss in Alzheimer's disease. Furthermore, these results present the odor cross-habituation test as a powerful behavioral assay, which reflects Abeta deposition and thus may serve to monitor the efficacy of therapies aimed at reducing Abeta.

  11. Reversal of metabolic deficits by lipoic acid in a triple transgenic mouse model of Alzheimer's disease: a 13C NMR study

    PubMed Central

    Sancheti, Harsh; Kanamori, Keiko; Patil, Ishan; Díaz Brinton, Roberta; Ross, Brian D; Cadenas, Enrique

    2014-01-01

    Alzheimer's disease is an age-related neurodegenerative disease characterized by deterioration of cognition and loss of memory. Several clinical studies have shown Alzheimer's disease to be associated with disturbances in glucose metabolism and the subsequent tricarboxylic acid (TCA) cycle-related metabolites like glutamate (Glu), glutamine (Gln), and N-acetylaspartate (NAA). These metabolites have been viewed as biomarkers by (a) assisting early diagnosis of Alzheimer's disease and (b) evaluating the efficacy of a treatment regimen. In this study, 13-month-old triple transgenic mice (a mouse model of Alzheimer's disease (3xTg-AD)) were given intravenous infusion of [1-13C]glucose followed by an ex vivo 13C NMR to determine the concentrations of 13C-labeled isotopomers of Glu, Gln, aspartate (Asp), GABA, myo-inositol, and NAA. Total (12C+13C) Glu, Gln, and Asp were quantified by high-performance liquid chromatography to calculate enrichment. Furthermore, we examined the effects of lipoic acid in modulating these metabolites, based on its previously established insulin mimetic effects. Total 13C labeling and percent enrichment decreased by ∼50% in the 3xTg-AD mice. This hypometabolism was partially or completely restored by lipoic acid feeding. The ability of lipoic acid to restore glucose metabolism and subsequent TCA cycle-related metabolites further substantiates its role in overcoming the hypometabolic state inherent in early stages of Alzheimer's disease. PMID:24220168

  12. Impaired Word Recognition in Alzheimer's Disease: The Role of Age of Acquisition

    ERIC Educational Resources Information Center

    Cuetos, Fernando; Herrera, Elena; Ellis, Andrew W.

    2010-01-01

    Studies of word production in patients with Alzheimer's disease have identified the age of acquisition of words as an important predictor of retention or loss, with early acquired words remaining accessible for longer than later acquired words. If, as proposed by current theories, effects of age of acquisition reflect the involvement of semantic…

  13. Galantamine for Alzheimer's disease.

    PubMed

    Olin, J; Schneider, L

    2001-01-01

    Galantamine (also called galanthamine, marketed as Reminyl (Janssen)) can be isolated from several plants, including daffodil bulbs, and now synthesized. Galantamine is a specific, competitive, and reversible acetylcholinesterase inhibitor. It is also an allosteric modulator at nicotinic cholinergic receptor sites potentiating cholinergic nicotinic neurotransmission. A small number of early studies showed mild cognitive and global benefits for patients with Alzheimer's disease, and recently several multicentre clinical trials have been published with positive findings. Galantamine has received regulatory approval in Sweden, is available in Austria, and awaits marketing approval in the United States, Europe, and other countries. The objective of this review is to assess the clinical effects of galantamine in patients with probable Alzheimer's disease, and to investigate potential moderators of an effect. The Cochrane Dementia Group specialized register of clinical trials was searched using the terms 'galantamine,' and 'galanthamine' (15 February 2000) as was the Cochrane Controlled Trials Register (2000, Issue 2). These terms were also used to search the following databases: EMBASE, MEDLINE, PsychLit; Combined Health Information Database, NRR (National Research Register), ADEAR (Alzheimer's Disease Education and Referral Centre clinical database, BIOMED (Biomedicine and Health), Glaxo-Wellcome Clinical Trials Register, National Institutes of Health Clinical Trials Databases, Current Controlled Trials, Dissertation Abstracts (mainly North American dissertations) 1961-1994, Index to UK Theses (British dissertations) 1970-1994. Published reviews were inspected for further sources. Additional information was collected from an unpublished investigational brochure for galantamine. Trials selected were randomized, double-blind, parallel-group, and unconfounded comparisons of galantamine with placebo for a treatment duration of greater than 4 weeks in people with Alzheimer

  14. Oxidant/Antioxidant Imbalance in Alzheimer's Disease: Therapeutic and Diagnostic Prospects

    PubMed Central

    2018-01-01

    Alzheimer's disease (AD) is the most common cause of dementia and a great socioeconomic burden in the aging society. Compelling evidence demonstrates that molecular change characteristics for AD, such as oxidative stress and amyloid β (Aβ) oligomerization, precede by decades the onset of clinical dementia and that the disease represents a biological and clinical continuum of stages, from asymptomatic to severely impaired. Nevertheless, the sequence of the early molecular alterations and the interplay between them are incompletely understood. This review presents current knowledge about the oxidative stress-induced impairments and compromised oxidative stress defense mechanisms in AD brain and the cross-talk between various pathophysiological insults, with the focus on excessive reactive oxygen species (ROS) generation and Aβ overproduction at the early stages of the disease. Prospects for AD therapies targeting oxidant/antioxidant imbalance are being discussed, as well as for the development of novel oxidative stress-related, blood-based biomarkers for early, noninvasive AD diagnostics. PMID:29636850

  15. Early etiology of Alzheimer's disease: tipping the balance toward autophagy or endosomal dysfunction?

    PubMed

    Peric, Aleksandar; Annaert, Wim

    2015-03-01

    Alzheimer's disease (AD) is the most common form of dementia in the elderly. This brain neuropathology is characterized by a progressive synaptic dysfunction and neuronal loss, which lead to decline in memory and other cognitive functions. Histopathologically, AD manifests via synaptic abnormalities, neuronal degeneration as well as the deposition of extracellular amyloid plaques and intraneuronal neurofibrillary tangles. While the exact pathogenic contribution of these two AD hallmarks and their abundant constituents [aggregation-prone amyloid β (Aβ) peptide species and hyperphosphorylated tau protein, respectively] remain debated, a growing body of evidence suggests that their development may be paralleled or even preceded by the alterations/dysfunctions in the endolysosomal and the autophagic system. In AD-affected neurons, abnormalities in these cellular pathways are readily observed already at early stages of disease development, and even though many studies agree that defective lysosomal degradation may relate to or even underlie some of these deficits, specific upstream molecular defects are still deliberated. In this review we summarize various pathogenic events that may lead to these cellular abnormalities, in light of our current understanding of molecular mechanisms that govern AD progression. In addition, we also highlight the increasing evidence supporting mutual functional dependence of the endolysosomal trafficking and autophagy, in particular focusing on those molecules and processes which may be of significance to AD.

  16. Differentiation of neuropsychological features between posterior cortical atrophy and early onset Alzheimer's disease.

    PubMed

    Li, Jieying; Wu, Liyong; Tang, Yi; Zhou, Aihong; Wang, Fen; Xing, Yi; Jia, Jianping

    2018-05-10

    Posterior cortical atrophy (PCA) is a group of clinical syndromes characterized by visuospatial and visuoperceptual impairment, with memory relatively preserved. Although PCA is pathologically almost identical to Alzheimer's disease (AD), they have different cognitive features. Those differences have only rarely been reported in any Chinese population. The purpose of the study is to establish neuropsychological tests that distinguish the clinical features of PCA from early onset AD (EOAD). Twenty-one PCA patients, 20 EOAD patients, and 20 healthy controls participated in this study. Patients had disease duration of ≤4 years. All participants completed a series of neuropsychological tests to evaluate their visuospatial, visuoperceptual, visuo-constructive, language, executive function, memory, calculation, writing, and reading abilities. The cognitive features of PCA and EOAD were compared. All the neuropsychological test scores showed that both the PCA and EOAD patients were significantly more impaired than people in the control group. However, PCA patients were significantly more impaired than EOAD patients in visuospatial, visuoperceptual, and visuo-constructive function, as well as in handwriting, and reading Chinese characters. The profile of neuropsychological test results highlights cognitive features that differ between PCA and EOAD. One surprising result is that the two syndromes could be distinguished by patients' ability to read and write Chinese characters. Tests based on these characteristics could therefore form a brief PCA neuropsychological examination that would improve the diagnosis of PCA.

  17. Is α‐T catenin (VR22) an Alzheimer's disease risk gene?

    PubMed Central

    Bertram, Lars; Mullin, Kristina; Parkinson, Michele; Hsiao, Monica; Moscarillo, Thomas J; Wagner, Steven L; Becker, K David; Velicelebi, Gonul; Blacker, Deborah; Tanzi, Rudolph E

    2007-01-01

    Background Recently, conflicting reports have been published on the potential role of genetic variants in the α‐T catenin gene (VR22; CTNNA3) on the risk for Alzheimer's disease. In these papers, evidence for association is mostly observed in multiplex families with Alzheimer's disease, whereas case–control samples of sporadic Alzheimer's disease are predominantly negative. Methods After sequencing VR22 in multiplex families with Alzheimer's disease linked to chromosome 10q21, we identified a novel non‐synonymous (Ser596Asn; rs4548513) single nucleotide polymorphism (SNP). This and four non‐coding SNPs were assessed in two independent samples of families with Alzheimer's disease, one with 1439 subjects from 437 multiplex families with Alzheimer's disease and the other with 489 subjects from 217 discordant sibships. Results A weak association with the Ser596Asn SNP in the multiplex sample, predominantly in families with late‐onset Alzheimer's disease (p = 0.02), was observed. However, this association does not seem to contribute substantially to the chromosome 10 Alzheimer's disease linkage signal that we and others have reported previously. No evidence was found of association with any of the four additional SNPs tested in the multiplex families with Alzheimer's disease. Finally, the Ser596Asn change was not associated with the risk for Alzheimer's disease in the independent discordant sibship sample. Conclusions This is the first study to report evidence of an association between a potentially functional, non‐synonymous SNP in VR22 and the risk for Alzheimer's disease. As the underlying effects are probably small, and are only seen in families with multiple affected members, the population‐wide significance of this finding remains to be determined. PMID:17209133

  18. Inverse relationship between Alzheimer's disease and cancer, and other factors contributing to Alzheimer's disease: a systematic review.

    PubMed

    Shafi, Ovais

    2016-11-22

    The AD etiology is yet not properly known. Interactions among environmental factors, multiple susceptibility genes and aging, contribute to AD. This study investigates the factors that play role in causing AD and how changes in cellular pathways contribute to AD. PUBMED database, MEDLINE database and Google Scholar were searched with no date restrictions for published articles involving cellular pathways with roles in cancers, cell survival, growth, proliferation, development, aging, and also contributing to Alzheimer's disease. This research explores inverse relationship between AD and cancer, also investigates other factors behind AD using several already published research literature to find the etiology of AD. Cancer and Alzheimer's disease have inverse relationship in many aspects such as P53, estrogen, neurotrophins and growth factors, growth and proliferation, cAMP, EGFR, Bcl-2, apoptosis pathways, IGF-1, HSV, TDP-43, APOE variants, notch signals and presenilins, NCAM, TNF alpha, PI3K/AKT/MTOR pathway, telomerase, ROS, ACE levels. AD occurs when brain neurons have weakened growth, cell survival responses, maintenance mechanisms, weakened anti-stress responses such as Vimentin, Carbonic anhydrases, HSPs, SAPK. In cancer, these responses are upregulated and maintained. Evolutionarily conserved responses and maintenance mechanisms such as FOXO are impaired in AD. Countermeasures or compensatory mechanisms by AD affected neurons such as Tau, Beta Amyloid, S100, are last attempts for survival which may be protective for certain time, or can speed up AD in Alzheimer's microenvironment via C-ABL activation, GSK3, neuro-inflammation. Alzheimer's disease and Cancer have inverse relationship; many factors that are upregulated in any cancer to sustain growth and survival are downregulated in Alzheimer's disease contributing to neuro-degeneration. When aged neurons or genetically susceptible neurons have weakened growth, cell survival and anti-stress responses, age

  19. Screening of Early and Late Onset Alzheimer's Disease Genetic Risk Factors in a Cohort of Dementia Patients from Liguria, Italy.

    PubMed

    Ferrari, Raffaele; Ferrara, Michela; Alinani, Anwar; Sutton, Roger Brian; Famà, Francesco; Picco, Agnese; Rodriguez, Guido; Nobili, Flavio; Momeni, Parastoo

    2015-01-01

    Cohorts from a defined geographical area enable ad hoc genotype-phenotype correlation studies providing novel and unique insight into disease. We analysed genetic risk factors associated with early and late onset Alzheimer's disease (EOAD and LOAD) in a population from Liguria (northern Italy), as part of an ongoing longitudinal study. We screened 37 AD, 8 mild cognitive impairment (MCI), 3 AD and CVD (cerebrovascular disease), 3 MCI and CVD, 8 frontotemporal dementia (FTD) and 2 progressive supranuclear palsy (PSP) patients, and 28 normal controls (NCs).We sequenced PSEN1, PSEN2 and APP (EOAD risk factors), as well as MAPT, GRN and TARDBP for all cases and NCs, and analysed the APOE, CLU, CR1 and PICALM genotypes as well as the MAPT and ACE haplotypes (LOAD risk factors) for the AD (n = 37) and AD + MCI (n = 45) cases and NCs (n = 28).We identified variants in PSEN1, PSEN2 and TARDBP across a range of phenotypes (AD, AD and CVD, FTD and PSP), suggesting that screening of all known candidate genes of Alzheimer's and non-Alzheimer's forms of dementias in all dementia cases might be warranted. The analysis of the LOAD risk factors revealed no association with AD or AD + MCI status after Bonferroni correction. Lack of association with APOE is supported by previous studies in the Italian population. Our data also evidenced: 1) a potentially protective haplotype at the PSEN2 locus; 2) a nominal association with the GWAS-risk allele A for rs3818361 in CR1 and; 3) a threefold prevalence of AD in the female population compared to men.Our results will need to be further assessed and confirmed in larger cohorts from this area. 

  20. Detecting navigational deficits in cognitive aging and Alzheimer disease using virtual reality

    PubMed Central

    Cushman, Laura A.; Stein, Karen; Duffy, Charles J.

    2008-01-01

    Background: Older adults get lost, in many cases because of recognized or incipient Alzheimer disease (AD). In either case, getting lost can be a threat to individual and public safety, as well as to personal autonomy and quality of life. Here we compare our previously described real-world navigation test with a virtual reality (VR) version simulating the same navigational environment. Methods: Quantifying real-world navigational performance is difficult and time-consuming. VR testing is a promising alternative, but it has not been compared with closely corresponding real-world testing in aging and AD. We have studied navigation using both real-world and virtual environments in the same subjects: young normal controls (YNCs, n = 35), older normal controls (ONCs, n = 26), patients with mild cognitive impairment (MCI, n = 12), and patients with early AD (EAD, n = 14). Results: We found close correlations between real-world and virtual navigational deficits that increased across groups from YNC to ONC, to MCI, and to EAD. Analyses of subtest performance showed similar profiles of impairment in real-world and virtual testing in all four subject groups. The ONC, MCI, and EAD subjects all showed greatest difficulty in self-orientation and scene localization tests. MCI and EAD patients also showed impaired verbal recall about both test environments. Conclusions: Virtual environment testing provides a valid assessment of navigational skills. Aging and Alzheimer disease (AD) share the same patterns of difficulty in associating visual scenes and locations, which is complicated in AD by the accompanying loss of verbally mediated navigational capacities. We conclude that virtual navigation testing reveals deficits in aging and AD that are associated with potentially grave risks to our patients and the community. GLOSSARY AD = Alzheimer disease; EAD = early Alzheimer disease; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; ONC = older normal control; std

  1. Ocular biomarkers of Alzheimer's disease.

    PubMed

    Heaton, George R; Davis, Benjamin M; Turner, Lisa A; Cordeiro, Maria F

    2015-01-01

    Alzheimer's disease (AD) is a devastating neurodegenerative disease characterised clinically by a progressive decline in executive functions, memory and cognition. Classic neuropathological hallmarks of AD include intracellular hyper-phosphorylated tau protein which forms neurofibrillary tangles (NFT), and extracellular deposits of amyloid β (Aβ) protein, the primary constituent of senile plaques (SP). The gradual process of pathogenic amyloid accumulation is thought to occur 10-20 years prior to symptomatic manifestation. Advance detection of these deposits therefore offers a highly promising avenue for prodromal AD diagnosis. Currently, the most sophisticated method of 'probable AD' diagnosis is via neuroimaging or cerebral spinal fluid (CSF) biomarker analysis. Whilst these methods have reported a high degree of diagnostic specificity and accuracy, they fall significantly short in terms of practicality; they are often highly invasive, expensive or unsuitable for large-scale population screening. In recent years, ocular screening has received substantial attention from the scientific community due to its potential for non-invasive and inexpensive central nervous system (CNS) imaging. In this appraisal we build upon our previous reviews detailing ocular structural and functional changes in AD (Retinal manifestations of Alzheimer's disease, Alzheimer's disease and Retinal Neurodegeneration) and consider their use as biomarkers. In addition, we present an overview of current advances in the use of fluorescent reporters to detect AD pathology through non-invasive retinal imaging.

  2. Cognitive Assessment of Patients With Alzheimer's Disease by Telemedicine: Pilot Study.

    PubMed

    Carotenuto, Anna; Rea, Raffaele; Traini, Enea; Ricci, Giovanna; Fasanaro, Angiola Maria; Amenta, Francesco

    2018-05-11

    Approximately 46.8 million people are living with dementia worldwide and their number will grow in the next years. Any potential treatment should be administered as early as possible because it is important to provide an early cognitive assessment and to regularly monitor the mental function of patients. Information and communication technologies can be helpful to reach and follow patients without displacing them, but there may be doubts about the reliability of cognitive tests performed by telemedicine. The purpose of this study was to evaluate the reliability of the Mini Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) tests administered in hospital by videoconference to patients with mild to moderate Alzheimer's disease. The tests were administered to 28 Alzheimer's disease outpatients (8 male, mean age 73.88, SD 7.45 years; 20 female mean age 76.00, SD 5.40 years) recruited and followed in the Alzheimer's Unit of the A Cardarelli National Hospital (Naples, Italy) at baseline and after 6, 12, 18, and 24 months of observation. Patients were evaluated first face-to-face by a psychologist and then, after 2 weeks, by another psychologist via videoconference in hospital. This study showed no differences in the MMSE and ADAS-cog scores when the tests were administered face-to-face or by videoconference, except in patients with more pronounced cognitive deficits (MMSE<17), in which the assessment via videoconference overestimated the cognitive impairment (face to face, MMSE mean 13.9, SD 4.9 and ADAS-cog mean 9.0, SD 3.8; videoconference, MMSE mean 42.8, SD 12.5 and ADAS-cog mean 56.9, SD 5.5). We found that videoconferencing is a reliable approach to document cognitive stability or decline, and to measure treatment effects in patients with mild to moderate dementia. A more extended study is needed to confirm these results. ©Anna Carotenuto, Raffaele Rea, Enea Traini, Giovanna Ricci, Angiola Maria Fasanaro

  3. The ROSAS Cohort: A Prospective, Longitudinal Study of Biomarkers for Alzheimer's Disease. Strategy, Methods and Initial Results.

    PubMed

    de Mauléon, A; Soto, M; Kiyasova, V; Delrieu, J; Guignot, I; Galtier, S; Lilamand, M; Cantet, C; Lala, F; Sastre, N; Andrieu, S; Pueyo, M; Ousset, P J; Vellas, B

    2017-01-01

    The aims of the Research Of biomarkers in Alzheimer's diseaSe (ROSAS) study were to determine the biofluid and imaging biomarkers permitting an early diagnosis of Alzheimer's disease and better characterisation of cognitive and behavioural course of the pathology. This paper outlines the overall strategy, methodology of the study, baseline characteristics of the population and first longitudinal results from the ROSAS cohort. Longitudinal prospective monocentric observational study performed at the Alzheimer's disease Research centre in Toulouse. A total of 387 patients were studied and analyzed in 3 groups: 184 patients with dementia of Alzheimer's type, 96 patients with memory disorders without dementia (Mild Cognitive Impairment) and 107 patients without abnormal memory tests (control group), and were followed up during 4 years. Patient's sociodemographic characteristics, risk factors, medical conditions, previous and current medications, neuropsychological assessment and overall cognitive status were recorded. Blood and urine samples were collected at every year, Magnetic Resonance Imaging were performed at inclusion, after one year of follow-up and at the end of the study. At baseline, three different groups of the cohort differed interestingly in age, level of education, and in percentage of ApoEε4 carriers whereas the history of cardiovascular and endocrine pathologies were similar among the groups. During the follow-up period (3-4 years) 42 mild cognitive impairment patients (43.8%) progressed to dementia, 7 controls progressed into mild cognitive impairment and 1 patient in the control group converted from mild cognitive impairment group to dementia of Alzheimer's type group. During the first year of follow up, the incidence of progression from mild cognitive impairment to dementia of Alzheimer's type was 12.7 per 100, during the second year 33.9 per 100 and 46.7 per 100 for the third year. This paper presents the baseline characteristics of the unique

  4. Polygenic risk of Alzheimer disease is associated with early- and late-life processes.

    PubMed

    Mormino, Elizabeth C; Sperling, Reisa A; Holmes, Avram J; Buckner, Randy L; De Jager, Philip L; Smoller, Jordan W; Sabuncu, Mert R

    2016-08-02

    To examine associations between aggregate genetic risk and Alzheimer disease (AD) markers in stages preceding the clinical symptoms of dementia using data from 2 large observational cohort studies. We computed polygenic risk scores (PGRS) using summary statistics from the International Genomics of Alzheimer's Project genome-wide association study of AD. Associations between PGRS and AD markers (cognitive decline, clinical progression, hippocampus volume, and β-amyloid) were assessed within older participants with dementia. Associations between PGRS and hippocampus volume were additionally examined within healthy younger participants (age 18-35 years). Within participants without dementia, elevated PGRS was associated with worse memory (p = 0.002) and smaller hippocampus (p = 0.002) at baseline, as well as greater longitudinal cognitive decline (memory: p = 0.0005, executive function: p = 0.01) and clinical progression (p < 0.00001). High PGRS was associated with AD-like levels of β-amyloid burden as measured with florbetapir PET (p = 0.03) but did not reach statistical significance for CSF β-amyloid (p = 0.11). Within the younger group, higher PGRS was associated with smaller hippocampus volume (p = 0.05). This pattern was evident when examining a PGRS that included many loci below the genome-wide association study (GWAS)-level significance threshold (16,123 single nucleotide polymorphisms), but not when PGRS was restricted to GWAS-level significant loci (18 single nucleotide polymorphisms). Effects related to common genetic risk loci distributed throughout the genome are detectable among individuals without dementia. The influence of this genetic risk may begin in early life and make an individual more susceptible to cognitive impairment in late life. Future refinement of polygenic risk scores may help identify individuals at risk for AD dementia. © 2016 American Academy of Neurology.

  5. Polygenic risk of Alzheimer disease is associated with early- and late-life processes

    PubMed Central

    Sperling, Reisa A.; Holmes, Avram J.; Buckner, Randy L.; De Jager, Philip L.; Smoller, Jordan W.; Sabuncu, Mert R.

    2016-01-01

    Objective: To examine associations between aggregate genetic risk and Alzheimer disease (AD) markers in stages preceding the clinical symptoms of dementia using data from 2 large observational cohort studies. Methods: We computed polygenic risk scores (PGRS) using summary statistics from the International Genomics of Alzheimer's Project genome-wide association study of AD. Associations between PGRS and AD markers (cognitive decline, clinical progression, hippocampus volume, and β-amyloid) were assessed within older participants with dementia. Associations between PGRS and hippocampus volume were additionally examined within healthy younger participants (age 18–35 years). Results: Within participants without dementia, elevated PGRS was associated with worse memory (p = 0.002) and smaller hippocampus (p = 0.002) at baseline, as well as greater longitudinal cognitive decline (memory: p = 0.0005, executive function: p = 0.01) and clinical progression (p < 0.00001). High PGRS was associated with AD-like levels of β-amyloid burden as measured with florbetapir PET (p = 0.03) but did not reach statistical significance for CSF β-amyloid (p = 0.11). Within the younger group, higher PGRS was associated with smaller hippocampus volume (p = 0.05). This pattern was evident when examining a PGRS that included many loci below the genome-wide association study (GWAS)–level significance threshold (16,123 single nucleotide polymorphisms), but not when PGRS was restricted to GWAS-level significant loci (18 single nucleotide polymorphisms). Conclusions: Effects related to common genetic risk loci distributed throughout the genome are detectable among individuals without dementia. The influence of this genetic risk may begin in early life and make an individual more susceptible to cognitive impairment in late life. Future refinement of polygenic risk scores may help identify individuals at risk for AD dementia. PMID:27385740

  6. 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 ...

  7. Exploring the nexus of Alzheimer's disease and related dementias with cancer and cancer therapies: A convening of the Alzheimer's Association & Alzheimer's Drug Discovery Foundation.

    PubMed

    Snyder, Heather M; Ahles, Tim; Calderwood, Stuart; Carrillo, Maria C; Chen, Honglei; Chang, Chung-Chou H; Craft, Suzanne; De Jager, Philip; Driver, Jane A; Fillit, Howard; Knopman, David; Lotze, Michael; Tierney, Mary C; Petanceska, Suzana; Saykin, Andrew; Seshadri, Sudha; Shineman, Diana; Ganguli, Mary

    2017-03-01

    Recent population studies suggest an intriguing inverse relationship between several types of cancer and neurodegenerative diseases, including Alzheimer's disease. Understanding the intersection of the underlying biology for these two distinct families of diseases with one another may offer novel approaches to identify new therapeutic approaches and possible opportunities to repurpose existing drug candidates. The Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened a one-day workshop to delve into this discussion. Workshop participants outlined research focus areas, potential collaborations, and partnerships for future action. Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  8. Alzheimer Disease: Pharmacologic and Nonpharmacologic Therapies for Cognitive and Functional Symptoms.

    PubMed

    Epperly, Ted; Dunay, Megan A; Boice, Jack L

    2017-06-15

    Alzheimer disease comprises a syndrome of progressive cognitive and functional decline. Treatments should target cognitive and functional symptoms. Cholinesterase inhibitors, memantine, and a combination of a cholinesterase inhibitor and memantine have produced statistically significant but clinically small delays in various domains of cognitive and functional decline in select patients with Alzheimer disease. Vitamin E has been shown to delay functional decline in patients with mild to moderate Alzheimer disease, especially when taken in combination with a cholinesterase inhibitor. Structured programs of physical exercise improve physical function and reduce rates of neuropsychiatric symptoms in patients with mild to severe Alzheimer disease. Cognitive stimulation programs show benefit in maintenance of cognitive function and improved self-reported quality of life in patients with mild to moderate Alzheimer disease.

  9. Early classification of Alzheimer's disease using hippocampal texture from structural MRI

    NASA Astrophysics Data System (ADS)

    Zhao, Kun; Ding, Yanhui; Wang, Pan; Dou, Xuejiao; Zhou, Bo; Yao, Hongxiang; An, Ningyu; Zhang, Yongxin; Zhang, Xi; Liu, Yong

    2017-03-01

    Convergent evidence has been collected to support that Alzheimer's disease (AD) is associated with reduction in hippocampal volume based on anatomical magnetic resonance imaging (MRI) and impaired functional connectivity based on functional MRI. Radiomics texture analysis has been previously successfully used to identify MRI biomarkers of several diseases, including AD, mild cognitive impairment and multiple sclerosis. In this study, our goal was to determine if MRI hippocampal textures, including the intensity, shape, texture and wavelet features, could be served as an MRI biomarker of AD. For this purpose, the texture marker was trained and evaluated from MRI data of 48 AD and 39 normal samples. The result highlights the presence of hippocampal texture abnormalities in AD, and the possibility that texture may serve as a neuroimaging biomarker for AD.

  10. Theory of mind in Alzheimer disease: Evidence of authentic impairment during social interaction.

    PubMed

    Moreau, Noémie; Rauzy, Stéphane; Viallet, François; Champagne-Lavau, Maud

    2016-03-01

    The present study aimed to investigate theory of mind (the ability to infer others' mental states) deficit in 20 patients with mild Alzheimer's disease and 20 healthy controls, with 2 theory of mind tasks, 1 of them being a real interactive task. Previous results concerning preserved or altered theory of mind abilities in Alzheimer's disease have been inconsistent and relationships with other cognitive dysfunctions (notably episodic memory and executive functions) are still unclear. The first task we used was a false belief paradigm as frequently used in literature whereas the second task, a referential communication task, assessed theory of mind in a real situation of interaction. Participants also underwent neuropsychological evaluation to investigate potential relationships between theory of mind and memory deficits. The results showed that Alzheimer patients presented a genuine and significant theory of mind deficit compared to control participants characterized notably by difficulties to attribute knowledge to an interlocutor in a real social interaction. These results further confirm that theory of mind is altered in early stages of Alzheimer dementia which is consistent with previous works. More specifically, this study is the first to objectivize this impairment in social interaction. (c) 2016 APA, all rights reserved).

  11. Improvement of memory recall by quercetin in rodent contextual fear conditioning and human early-stage Alzheimer's disease patients.

    PubMed

    Nakagawa, Toshiyuki; Itoh, Masanori; Ohta, Kazunori; Hayashi, Yuichi; Hayakawa, Miki; Yamada, Yasushi; Akanabe, Hiroshi; Chikaishi, Tokio; Nakagawa, Kiyomi; Itoh, Yoshinori; Muro, Takato; Yanagida, Daisuke; Nakabayashi, Ryo; Mori, Tetsuya; Saito, Kazuki; Ohzawa, Kaori; Suzuki, Chihiro; Li, Shimo; Ueda, Masashi; Wang, Miao-Xing; Nishida, Emika; Islam, Saiful; Tana; Kobori, Masuko; Inuzuka, Takashi

    2016-06-15

    Patients with Alzheimer's disease (AD) experience a wide array of cognitive deficits, which typically include the impairment of explicit memory. In previous studies, the authors reported that a flavonoid, quercetin, reduces the expression of ATF4 and delays memory deterioration in an early-stage AD mouse model. In the present study, the effects of long-term quercetin intake on memory recall were assessed using contextual fear conditioning in aged wild-type mice. In addition, the present study examined whether memory recall was affected by the intake of quercetin-rich onion (a new cultivar of hybrid onion 'Quergold') powder in early-stage AD patients. In-vivo analysis indicated that memory recall was enhanced in aged mice fed a quercetin-containing diet. Memory recall in early-stage AD patients, determined using the Revised Hasegawa Dementia Scale, was significantly improved by the intake of quercetin-rich onion (Quergold) powder for 4 weeks compared with the intake of control onion ('Mashiro' white onion) powder. These results indicate that quercetin might influence memory recall.

  12. Angiotensin II, hypertension and angiotensin II receptor antagonism: Roles in the behavioural and brain pathology of a mouse model of Alzheimer's disease.

    PubMed

    Wiesmann, Maximilian; Roelofs, Monica; van der Lugt, Robert; Heerschap, Arend; Kiliaan, Amanda J; Claassen, Jurgen Ahr

    2017-07-01

    Elevated angiotensin II causes hypertension and contributes to Alzheimer's disease by affecting cerebral blood flow. Angiotensin II receptor blockers may provide candidates to reduce (vascular) risk factors for Alzheimer's disease. We studied effects of two months of angiotensin II-induced hypertension on systolic blood pressure, and treatment with the angiotensin II receptor blockers, eprosartan mesylate, after one month of induced hypertension in wild-type C57bl/6j and AβPPswe/PS1ΔE9 (AβPP/PS1/Alzheimer's disease) mice. AβPP/PS1 showed higher systolic blood pressure than wild-type. Subsequent eprosartan mesylate treatment restored this elevated systolic blood pressure in all mice. Functional connectivity was decreased in angiotensin II-infused Alzheimer's disease and wild-type mice, and only 12 months of Alzheimer's disease mice showed impaired cerebral blood flow. Only angiotensin II-infused Alzheimer's disease mice exhibited decreased spatial learning in the Morris water maze. Altogether, angiotensin II-induced hypertension not only exacerbated Alzheimer's disease-like pathological changes such as impairment of cerebral blood flow, functional connectivity, and cognition only in Alzheimer's disease model mice, but it also induced decreased functional connectivity in wild-type mice. However, we could not detect hypertension-induced overexpression of Aβ nor increased neuroinflammation. Our findings suggest a link between midlife hypertension, decreased cerebral hemodynamics and connectivity in an Alzheimer's disease mouse model. Eprosartan mesylate treatment restored and beneficially affected cerebral blood flow and connectivity. This model could be used to investigate prevention/treatment strategies in early Alzheimer's disease.

  13. Comparison of CSF Distribution between Idiopathic Normal Pressure Hydrocephalus and Alzheimer Disease.

    PubMed

    Yamada, S; Ishikawa, M; Yamamoto, K

    2016-07-01

    CSF volumes in the basal cistern and Sylvian fissure are increased in both idiopathic normal pressure hydrocephalus and Alzheimer disease, though the differences in these volumes in idiopathic normal pressure hydrocephalus and Alzheimer disease have not been well-described. Using CSF segmentation and volume quantification, we compared the distribution of CSF in idiopathic normal pressure hydrocephalus and Alzheimer disease. CSF volumes were extracted from T2-weighted 3D spin-echo sequences on 3T MR imaging and quantified semi-automatically. We compared the volumes and ratios of the ventricles and subarachnoid spaces after classification in 30 patients diagnosed with idiopathic normal pressure hydrocephalus, 10 with concurrent idiopathic normal pressure hydrocephalus and Alzheimer disease, 18 with Alzheimer disease, and 26 control subjects 60 years of age or older. Brain to ventricle ratios at the anterior and posterior commissure levels and 3D volumetric convexity cistern to ventricle ratios were useful indices for the differential diagnosis of idiopathic normal pressure hydrocephalus or idiopathic normal pressure hydrocephalus with Alzheimer disease from Alzheimer disease, similar to the z-Evans index and callosal angle. The most distinctive characteristics of the CSF distribution in idiopathic normal pressure hydrocephalus were small convexity subarachnoid spaces and the large volume of the basal cistern and Sylvian fissure. The distribution of the subarachnoid spaces in the idiopathic normal pressure hydrocephalus with Alzheimer disease group was the most deformed among these 3 groups, though the mean ventricular volume of the idiopathic normal pressure hydrocephalus with Alzheimer disease group was intermediate between that of the idiopathic normal pressure hydrocephalus and Alzheimer disease groups. The z-axial expansion of the lateral ventricle and compression of the brain just above the ventricle were the common findings in the parameters for differentiating

  14. 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

  15. Ron Hays: A Story of Art as Self Treatment for Alzheimer's Disease

    ERIC Educational Resources Information Center

    Jones, Robin M. N.; Hays, Nancy Scheller

    2016-01-01

    Ronald E. Hays is the former Director of the Hahnemann Creative Arts in Therapy Department at Drexel University in Philadelphia, Pennsylvania, and the cofounder of the graduate art therapy program at Eastern Virginia Medical School in Norfolk, Virginia. At the age of 62 he was diagnosed with early onset Alzheimer's disease, a form of dementia. In…

  16. Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer's disease.

    PubMed

    Lin, Ai-Ling; Jahrling, Jordan B; Zhang, Wei; DeRosa, Nicholas; Bakshi, Vikas; Romero, Peter; Galvan, Veronica; Richardson, Arlan

    2017-01-01

    Apolipoprotein E ɛ4 allele is a common susceptibility gene for late-onset Alzheimer's disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E ɛ4 carriers decades before the onset of Alzheimer's disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer's disease-like symptoms in pre-symptomatic Apolipoprotein E ɛ4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E ɛ4 mice treated with rapamycin had restored cerebral blood flow, blood-brain barrier integrity and glucose metabolism, compared to age- and gender-matched wild-type controls. The preserved vasculature and metabolism were associated with amelioration of incipient learning deficits. We also found that rapamycin restored the levels of the proinflammatory cyclophilin A in vasculature, which may contribute to the preservation of cerebrovascular function in the apolipoprotein E ɛ4 transgenics. Our results show that rapamycin improves functional outcomes in this mouse model and may have potential as an effective intervention to block progression of vascular, metabolic and early cognitive deficits in human Apolipoprotein E ɛ4 carriers. As rapamycin is FDA-approved and neuroimaging is readily used in humans, the results of the present study may provide the basis for future Alzheimer's disease intervention studies in human subjects. © The Author(s) 2015.

  17. Memory self-awareness in the preclinical and prodromal stages of Alzheimer's disease.

    PubMed

    Vannini, Patrizia; Amariglio, Rebecca; Hanseeuw, Bernard; Johnson, Keith A; McLaren, Donald G; Chhatwal, Jasmeer; Pascual-Leone, Alvaro; Rentz, Dorene; Sperling, Reisa A

    2017-05-01

    While loss of insight of cognitive deficits, anosognosia, is a common symptom in Alzheimer's disease dementia, there is a lack of consensus regarding the presence of altered awareness of memory function in the preclinical and prodromal stages of the disease. Paradoxically, very early in the Alzheimer's disease process, individuals may experience heightened awareness of memory changes before any objective cognitive deficits can be detected, here referred to as hypernosognosia. In contrast, awareness of memory dysfunction shown by individuals with mild cognitive impairment (MCI) is very variable, ranging from marked concern to severe lack of insight. This study aims at improving our mechanistic understanding of how alterations in memory self-awareness are related to pathological changes in clinically normal (CN) adults and MCI patients. 297 CN and MCI patients underwent PiB-PET (Positron Emission Tomography using Pittsburgh Compound B) in vivo amyloid imaging. Amyloid burden was estimated from Alzheimer's disease vulnerable regions, including the frontal, lateral parietal and lateral temporal, and retrosplenial cortex. Memory self-awareness was assessed using discrepancy scores between subjective and objective measures of memory function. A set of univariate analysis of variance were performed to assess the relationship between self-awareness of memory and amyloid pathology. Whereas CN individuals harboring amyloid pathology demonstrated hypernosognosia, MCI patients with increased amyloid pathology demonstrated anosognosia. In contrast, MCI patients with low amounts of amyloid were observed to have normal insight into their memory functions. Altered self-awareness of memory tracks with amyloid pathology. The findings of variability of awareness may have important implications for the reliability of self-report of dysfunction across the spectrum of preclinical and prodromal Alzheimer's disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Molecular insights into the pathogenesis of Alzheimer's disease and its relationship to normal aging.

    PubMed

    Podtelezhnikov, Alexei A; Tanis, Keith Q; Nebozhyn, Michael; Ray, William J; Stone, David J; Loboda, Andrey P

    2011-01-01

    Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression. © 2011 Podtelezhnikov et al.

  19. Impairment in Proverb Interpretation as an Executive Function Deficit in Patients with Amnestic Mild Cognitive Impairment and Early Alzheimer's Disease

    PubMed Central

    Leyhe, Thomas; Saur, Ralf; Eschweiler, Gerhard W.; Milian, Monika

    2011-01-01

    Background/Aims Proverb interpretation is assumed to reflect executive functions. We hypothesized that proverb interpretation is impaired in patients with amnestic mild cognitive impairment (aMCI) diagnosed as single-domain impairment by common neuropsychological testing. Methods We compared performance in a proverb interpretation test in single-domain aMCI patients and patients with early Alzheimer's disease (EAD). Results The groups with aMCI and EAD performed significantly worse than healthy controls. Both patient groups gave concrete answers with a similar frequency. However, patients with EAD tended to give senseless answers more frequently. Conclusions Our data suggest that in patients diagnosed as single-domain aMCI, deterioration of executive functions is detectable with subtle and appropriate neuropsychological testing. Implementation of these procedures may improve the early prediction of AD. PMID:22163233

  20. The effect of red grape juice on Alzheimer's disease in rats.

    PubMed

    Siahmard, Zahra; Alaei, Hojjatollah; Reisi, Parham; Pilehvarian, Ali Asghar

    2012-01-01

    Alzheimer's disease is a neurodegenerative disease appearing as a result of free radicals and oxidative stress. Antioxidants agents boost memory and control Alzheimer's disease. Since red grape juice contains antioxidant agents, its effects on speed of learning and improvement of memory was studied in Alzheimer's rats. Alzheimer's model was induced by bilateral infusion of streptozocine into lateral ventricles of brain of male rats. Rats drank 10% red grape juice for 21 days. Passive avoidance learning test was used for measuring memory and learning in rats. Our results showed that learning and memory in STZ-group decreased significantly compared to Sham group. However, intake of red grape juice increased speed of learning and improvement of memory in Alzheimer's rats. Our results suggest that there are active ingredients in red grape juice, which probably have therapeutic and preventive effects on cognitive impairments in Alzheimer's disease.

  1. False-Positive Error Rates for Reliable Digit Span and Auditory Verbal Learning Test Performance Validity Measures in Amnestic Mild Cognitive Impairment and Early Alzheimer Disease.

    PubMed

    Loring, David W; Goldstein, Felicia C; Chen, Chuqing; Drane, Daniel L; Lah, James J; Zhao, Liping; Larrabee, Glenn J

    2016-06-01

    The objective is to examine failure on three embedded performance validity tests [Reliable Digit Span (RDS), Auditory Verbal Learning Test (AVLT) logistic regression, and AVLT recognition memory] in early Alzheimer disease (AD; n = 178), amnestic mild cognitive impairment (MCI; n = 365), and cognitively intact age-matched controls (n = 206). Neuropsychological tests scores were obtained from subjects participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI). RDS failure using a ≤7 RDS threshold was 60/178 (34%) for early AD, 52/365 (14%) for MCI, and 17/206 (8%) for controls. A ≤6 RDS criterion reduced this rate to 24/178 (13%) for early AD, 15/365 (4%) for MCI, and 7/206 (3%) for controls. AVLT logistic regression probability of ≥.76 yielded unacceptably high false-positive rates in both clinical groups [early AD = 149/178 (79%); MCI = 159/365 (44%)] but not cognitively intact controls (13/206, 6%). AVLT recognition criterion of ≤9/15 classified 125/178 (70%) of early AD, 155/365 (42%) of MCI, and 18/206 (9%) of control scores as invalid, which decreased to 66/178 (37%) for early AD, 46/365 (13%) for MCI, and 10/206 (5%) for controls when applying a ≤5/15 criterion. Despite high false-positive rates across individual measures and thresholds, combining RDS ≤ 6 and AVLT recognition ≤9/15 classified only 9/178 (5%) of early AD and 4/365 (1%) of MCI patients as invalid performers. Embedded validity cutoffs derived from mixed clinical groups produce unacceptably high false-positive rates in MCI and early AD. Combining embedded PVT indicators lowers the false-positive rate. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  2. Language background in early life may be related to neuropsychiatry symptoms in patients with Alzheimer disease.

    PubMed

    Liu, Yi-Chien; Hsu, Jung-Lung; Wang, Shuu-Jin; Yip, Ping-Keung; Meguro, Kenichi; Fuh, Jong-Ling

    2017-02-10

    The relationship between early life experience and the occurrence of neuropsychiatry symptoms (NPSs) in patients with Alzheimer disease (AD) is unclear. From 2012 to 2014, we prospectively recruited 250 patients with probable AD from the memory clinic of Taipei Veterans General Hospital. All patients underwent standard assessments, including brain magnetic resonance imaging or computed tomography, neuropsychological tests, neuropsychiatry inventory (NPI-Q) and related blood tests. A linear regression analysis was performed to investigate the relationship between NPSs and age, gender, disease severity, depression, language background (with or without Japanese education). Among the 250 participants, 113 (45.2%) were women. Their average age was 82.6 years. Of all the participants, 93 (37.2%) had received formal Japanese education, whereas 157 (62.8%) did not receive Japanese education. The participants with Japanese education were slightly younger (83.1 ± 3.6 vs. 81.4 ± 3.4, P = 0.006), with a higher proportion of them were women (30.5% vs. 69.8%, P < 0.001) and fewer years of total education (10.8 ± 4.5 vs. 7.7 ± 3.2, P < 0.001), compared to the participants without Japanese education. NPI-Q scores significantly differed between the two groups (15.8 vs. 24.1, P = 0.024). Both disease severity and language background predicted NPI-Q scores. Language background in early life may be related to NPSs in patients with AD, and this effect is more significant in patients with a lower education level than in those with a higher education level. More NPSs may be the result of negative effects on dominant language or early life experiences.

  3. Meta-analysis of the rs2075650 polymorphism and risk of Alzheimer disease.

    PubMed

    He, Ya; Li, Chen; Yang, Ying; Li, Yizhou; Wang, Yuan; Yang, Hua; Jin, Tianbo; Chen, Songsheng

    2016-10-01

    Several researchers have suggested that the rs2075650 polymorphism is significantly associated with an increased risk of developing Alzheimer disease (AD) in European. However, some others found inconsistent results in Asian (Chinese and Korean). We addressed the controversy through performing a meta-analysis of the relationship between rs2075650 in TOMM40 (translocase of outer mitochondrial membrane 40 homologue) and Alzheimer disease. We selected eight case-control studies involving 4290 cases of Alzheimer disease and 5556 healthy individuals. The association between the TOMM40 rs2075650 polymorphism and Alzheimer disease was examined by overall odds ratio (OR) with a 95 % confidence interval (CI). We used different genetic model analysis, sensitivity analysis, and assessments of bias in our meta-analysis. The pooled analysis showed the inconsistent results that TOMM40 rs2075650 polymorphism was associated with Alzheimer disease in European and Korean population in all genetic models, but there was no significant association between the TOMM40 rs2075650 polymorphism and Alzheimer disease risk in Chinese population. We conclude that rs2075650 in TOMM40 gene may increase the risk of Alzheimer disease.

  4. Changes in sleep theta rhythm are related to episodic memory impairment in early Alzheimer's disease.

    PubMed

    Hot, Pascal; Rauchs, Géraldine; Bertran, Françoise; Denise, Pierre; Desgranges, Béatrice; Clochon, Patrice; Eustache, Francis

    2011-07-01

    Impairments have been reported both in sleep structure and episodic memory in Alzheimer's disease [AD]. Our objective was to investigate the relationships between episodic memory deficits and electro-encephalography [EEG] abnormalities occurring during sleep in patients with early AD. Postlearning sleep was recorded in 14 patients with mild to moderate AD, and 14 healthy elderly controls after they performed an episodic memory task derived from the Grober and Buschke's procedure. For each sleep stage, the relative power and mean frequency in each band were analyzed. Relative to agematched controls, AD patients presented faster mean theta frequency in both REM sleep and slow wave sleep [SWS]. In AD patients, a correlative analysis revealed that faster theta frequency during SWS was associated with better delayed episodic recall. We assume that increased theta activity reflects changes in neuronal activity to maintain memory performance, indicating that compensatory mechanisms already described at the waking state could also be engaged during SWS. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. An evaluation of volume-based morphometry for prediction of mild cognitive impairment and Alzheimer's disease

    PubMed Central

    Schmitter, Daniel; Roche, Alexis; Maréchal, Bénédicte; Ribes, Delphine; Abdulkadir, Ahmed; Bach-Cuadra, Meritxell; Daducci, Alessandro; Granziera, Cristina; Klöppel, Stefan; Maeder, Philippe; Meuli, Reto; Krueger, Gunnar

    2014-01-01

    Voxel-based morphometry from conventional T1-weighted images has proved effective to quantify Alzheimer's disease (AD) related brain atrophy and to enable fairly accurate automated classification of AD patients, mild cognitive impaired patients (MCI) and elderly controls. Little is known, however, about the classification power of volume-based morphometry, where features of interest consist of a few brain structure volumes (e.g. hippocampi, lobes, ventricles) as opposed to hundreds of thousands of voxel-wise gray matter concentrations. In this work, we experimentally evaluate two distinct volume-based morphometry algorithms (FreeSurfer and an in-house algorithm called MorphoBox) for automatic disease classification on a standardized data set from the Alzheimer's Disease Neuroimaging Initiative. Results indicate that both algorithms achieve classification accuracy comparable to the conventional whole-brain voxel-based morphometry pipeline using SPM for AD vs elderly controls and MCI vs controls, and higher accuracy for classification of AD vs MCI and early vs late AD converters, thereby demonstrating the potential of volume-based morphometry to assist diagnosis of mild cognitive impairment and Alzheimer's disease. PMID:25429357

  6. Survival in Alzheimer disease

    PubMed Central

    Helzner, E P.; Scarmeas, N; Cosentino, S; Tang, M X.; Schupf, N; Stern, Y

    2008-01-01

    Objective: To describe factors associated with survival in Alzheimer disease (AD) in a multiethnic, population-based longitudinal study. Methods: AD cases were identified in the Washington Heights Inwood Columbia Aging Project, a longitudinal, community-based study of cognitive aging in Northern Manhattan. The sample comprised 323 participants who were initially dementia-free but developed AD during study follow-up (incident cases). Participants were followed for an average of 4.1 (up to 12.6) years. Possible factors associated with shorter lifespan were assessed using Cox proportional hazards models with attained age as the time to event (time from birth to death or last follow-up). In subanalyses, median postdiagnosis survival durations were estimated using postdiagnosis study follow-up as the timescale. Results: The mortality rate was 10.7 per 100 person-years. Mortality rates were higher among those diagnosed at older ages, and among Hispanics compared to non-Hispanic whites. The median lifespan of the entire sample was 92.2 years (95% CI: 90.3, 94.1). In a multivariable-adjusted Cox model, history of diabetes and history of hypertension were independently associated with a shorter lifespan. No differences in lifespan were seen by race/ethnicity after multivariable adjustment. The median postdiagnosis survival duration was 3.7 years among non-Hispanic whites, 4.8 years among African Americans, and 7.6 years among Hispanics. Conclusion: Factors influencing survival in Alzheimer disease include race/ethnicity and comorbid diabetes and hypertension. GLOSSARY AD = Alzheimer disease; NDI = National Death Index; WHICAP = Washington Heights Inwood Columbia Aging Project. PMID:18981370

  7. Practical treatment strategies for patients with Alzheimer's disease.

    PubMed

    Christensen, Daniel D; Lin, Peter

    2007-12-01

    With the "baby boomers" entering retirement and beyond and the life expectancy of the entire population increasing, the burden of Alzheimer's Disease (AD) grows alarmingly greater. Over 5 million people in the United States currently have AD, and that number could triple by 2050. The financial impact of caring for these patients is substantial. Estimates of direct and indirect costs are as high as $148 billion per year. In addition to its substantial economic impact, AD has devastating effects on patients and their families. Alzheimer's disease begins with gradual memory loss and progresses to personality change, behavioral disturbance, loss of executive function, and loss of the ability to perform basic activities of daily living, including eating, walking, dressing, and grooming. These impairments strain families and caregivers and create challenges to the care and safety of the patient as well as threaten the health and well-being of the caregiver. As the number of patients diagnosed with AD increases, there is an ever-growing need for early diagnosis, which often is first observed in the primary care setting. While AD cannot be reversed or stopped, disease progression can be delayed and quality of life enhanced with early diagnosis and treatment. Early and accurate diagnosis has become increasingly important and will become even more so with the anticipated new generation of medications. Though several consensus statements on diagnosis and treatment of AD have been developed, few primary care physicians routinely follow evidence-based guidelines in their clinical practices. A 2006 survey conducted by the American Academy of Family Physicians identified a moderate to high level of need for education on AD in a majority of respondents. This article illustrates the primary care management of AD beginning with diagnosis and concluding with autopsy. Enhancing diagnostic and treatment skills in primary care will promote earlier diagnosis, improved patient management

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

    PubMed

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

    2013-01-01

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

  9. Random Forest Algorithm for the Classification of Neuroimaging Data in Alzheimer's Disease: A Systematic Review.

    PubMed

    Sarica, Alessia; Cerasa, Antonio; Quattrone, Aldo

    2017-01-01

    Objective: Machine learning classification has been the most important computational development in the last years to satisfy the primary need of clinicians for automatic early diagnosis and prognosis. Nowadays, Random Forest (RF) algorithm has been successfully applied for reducing high dimensional and multi-source data in many scientific realms. Our aim was to explore the state of the art of the application of RF on single and multi-modal neuroimaging data for the prediction of Alzheimer's disease. Methods: A systematic review following PRISMA guidelines was conducted on this field of study. In particular, we constructed an advanced query using boolean operators as follows: ("random forest" OR "random forests") AND neuroimaging AND ("alzheimer's disease" OR alzheimer's OR alzheimer) AND (prediction OR classification) . The query was then searched in four well-known scientific databases: Pubmed, Scopus, Google Scholar and Web of Science. Results: Twelve articles-published between the 2007 and 2017-have been included in this systematic review after a quantitative and qualitative selection. The lesson learnt from these works suggest that when RF was applied on multi-modal data for prediction of Alzheimer's disease (AD) conversion from the Mild Cognitive Impairment (MCI), it produces one of the best accuracies to date. Moreover, the RF has important advantages in terms of robustness to overfitting, ability to handle highly non-linear data, stability in the presence of outliers and opportunity for efficient parallel processing mainly when applied on multi-modality neuroimaging data, such as, MRI morphometric, diffusion tensor imaging, and PET images. Conclusions: We discussed the strengths of RF, considering also possible limitations and by encouraging further studies on the comparisons of this algorithm with other commonly used classification approaches, particularly in the early prediction of the progression from MCI to AD.

  10. The primary care of Alzheimer disease.

    PubMed

    Rubin, Craig D

    2006-12-01

    Alzheimer disease is the most common cause of progressive irreversible intellectual loss in aging humans. The number of individuals and families affected by this disorder will continue to grow as society ages worldwide. Our understanding of the biology, underlying pathophysiology, and diagnosis of Alzheimer disease has greatly expanded over the past few years and much has been published in these areas. This review focuses on the primary care of this disorder and addresses the "now what" question. Topics examined include limiting excess disability, responding to commonly raised questions of family members, pharmacologic and nonpharmacologic therapeutic options, long-term planning, and caregiver issues.

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

    PubMed

    Gao, F; Barker, P B

    2014-06-01

    MR spectroscopy is a noninvasive technique that allows the detection of several naturally occurring compounds (metabolites) from well-defined regions of interest within the human brain. Alzheimer disease, a progressive neurodegenerative disorder, is the most common cause of dementia in the elderly. During the past 20 years, multiple studies have been performed on MR spectroscopy in patients with both mild cognitive impairment and Alzheimer disease. Generally, MR spectroscopy studies have found decreased N-acetylaspartate and increased myo-inositol in both patients with mild cognitive impairment and Alzheimer disease, with greater changes in Alzheimer disease than in mild cognitive impairment. This review summarizes the information content of proton brain MR spectroscopy and its related technical aspects, as well as applications of MR spectroscopy to mild cognitive impairment and Alzheimer disease. While MR spectroscopy may have some value in the differential diagnosis of dementias and assessing prognosis, more likely its role in the near future will be predominantly as a tool for monitoring disease response or progression in treatment trials. More work is needed to evaluate the role of MR spectroscopy as a biomarker in Alzheimer disease and its relationship to other imaging modalities. © 2014 by American Journal of Neuroradiology.

  12. The effect of red grape juice on Alzheimer's disease in rats

    PubMed Central

    Siahmard, Zahra; Alaei, Hojjatollah; Reisi, Parham; Pilehvarian, Ali Asghar

    2012-01-01

    Background: Alzheimer's disease is a neurodegenerative disease appearing as a result of free radicals and oxidative stress. Antioxidants agents boost memory and control Alzheimer's disease. Since red grape juice contains antioxidant agents, its effects on speed of learning and improvement of memory was studied in Alzheimer's rats. Materials and Methods: Alzheimer's model was induced by bilateral infusion of streptozocine into lateral ventricles of brain of male rats. Rats drank 10% red grape juice for 21 days. Passive avoidance learning test was used for measuring memory and learning in rats. Results: Our results showed that learning and memory in STZ-group decreased significantly compared to Sham group. However, intake of red grape juice increased speed of learning and improvement of memory in Alzheimer's rats. Conclusions: Our results suggest that there are active ingredients in red grape juice, which probably have therapeutic and preventive effects on cognitive impairments in Alzheimer's disease. PMID:23326794

  13. A diagnostic approach in Alzheimer`s disease using three-dimensional stereotactic surface projections of Fluorine-18-FDG PET

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    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 bymore » 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.« less

  14. Science Signaling Podcast for 10 May 2016: PKCα in Alzheimer's disease.

    PubMed

    Newton, Alexandra C; Tanzi, Rudolph E; VanHook, Annalisa M

    2016-05-10

    This Podcast features an interview with Alexandra Newton and Rudolph Tanzi, authors of a Research Article that appears in the 10 May 2016 issue of Science Signaling, about activating mutations in protein kinase Cα that may promote the type of neural defects that characterize Alzheimer's disease. Alzheimer's disease is a progressive neurodegenerative disorder that causes cognitive loss and, eventually, death. Alzheimer's disease is characterized by the accumulation of amyloid-β (Aβ), synaptic depression, and synaptic degeneration. Alfonso et al found activating mutations in the gene encoding protein kinase Cα (PKCα) in some families with inherited Alzheimer's disease. Loss of PKCα function prevented Aβ-induced synaptic depression in brain tissue from mice, suggesting that activated forms of PKCα may contribute to Alzheimer's disease in some patients.Listen to Podcast. Copyright © 2016, American Association for the Advancement of Science.

  15. Controversies in Alzheimer's disease drug development.

    PubMed

    Cummings, Jeffrey L

    2008-08-01

    Understanding of the pathophysiological basis of Alzheimer's disease (AD) is increasing rapidly and a variety of potential treatment modalities have emerged based on these improved mechanistic insights. The optimal way of proceeding with disease-modifying drug development remains to be clarified and controversies have emerged regarding the definition of Alzheimer's disease, the participation of mild cognitive impairment patients in clinical trials, the definition of disease modification, the potential impediments to satisfaction from patients receiving disease-modifying therapy, the importance of add-on therapy with symptomatic agents, the optimal clinical trial design to demonstrate disease modification, the best means of minimizing time spent in Phase II of drug development, the potential role of adaptive designs in clinical trials, the use of enrichment designs in clinical trials, the role of biomarkers in clinical trials, the treatment of advanced patients with disease-modifying agents, and distinctions between disease modification and disease prevention. The questions surrounding these issues must be resolved as disease-modifying therapies for AD are advanced. These controversies are framed and potential directions towards resolution described.

  16. [Connections between sleep and Alzheimer's disease : Insomnia, amnesia and amyloid].

    PubMed

    Busche, M A; Kekuš, M; Förstl, H

    2017-03-01

    Sleep plays an essential role in memory consolidation. Although sleep problems are common in Alzheimer's disease, they are not usually thought to be key features of the disease; however, new experimental research has shown that sleep disturbances not only occur before the onset of typical cognitive deficits but are also associated with the pathogenesis of Alzheimer's disease and may have a decisive influence on the symptoms and course. Thus, sleep disturbances may be potentially modifiable risk factors for Alzheimer's disease that deserve more attention in research, diagnostics and treatment.

  17. Polygenic hazard scores in preclinical Alzheimer disease.

    PubMed

    Tan, Chin Hong; Hyman, Bradley T; Tan, Jacinth J X; Hess, Christopher P; Dillon, William P; Schellenberg, Gerard D; Besser, Lilah M; Kukull, Walter A; Kauppi, Karolina; McEvoy, Linda K; Andreassen, Ole A; Dale, Anders M; Fan, Chun Chieh; Desikan, Rahul S

    2017-09-01

    Identifying asymptomatic older individuals at elevated risk for developing Alzheimer disease (AD) is of clinical importance. Among 1,081 asymptomatic older adults, a recently validated polygenic hazard score (PHS) significantly predicted time to AD dementia and steeper longitudinal cognitive decline, even after controlling for APOE ɛ4 carrier status. Older individuals in the highest PHS percentiles showed the highest AD incidence rates. PHS predicted longitudinal clinical decline among older individuals with moderate to high Consortium to Establish a Registry for Alzheimer's Disease (amyloid) and Braak (tau) scores at autopsy, even among APOE ɛ4 noncarriers. Beyond APOE, PHS may help identify asymptomatic individuals at highest risk for developing Alzheimer neurodegeneration. Ann Neurol 2017;82:484-488. © 2017 American Neurological Association.

  18. Global issues in drug development for Alzheimer's disease.

    PubMed

    Doody, Rachelle S; Cole, Patricia E; Miller, David S; Siemers, Eric; Black, Ronald; Feldman, Howard; Schindler, Rachel; Graham, Stephen; Heath, Theresa; Khachaturian, Ara S; Evans, Rebecca; Carrillo, Maria C

    2011-03-01

    The number of clinical trials for Alzheimer's disease conducted outside the United States in a broad array of countries is increasing. As the number of compounds ready for clinical testing increases, and as trials become longer and more complex, this trend is expected to grow. The cultural and ethical context of global clinical trials, potential benefits for those involved, and practical approaches to obstacles generated by these global trials were discussed at a meeting of the Alzheimer's Association Research Roundtable. Regulatory issues, including regional differences in study registration procedures, rules for collecting and reporting serious adverse events, requirements for national identity of study populations, and regulatory audits were also discussed by individuals who are knowledgeable about global clinical trials for Alzheimer's disease. Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

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

    PubMed

    delEtoile, Jon; Adeli, Hojjat

    2017-04-01

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

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

    PubMed

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

    2015-12-01

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

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

    PubMed Central

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

    2015-01-01

    White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer's. Age remains the greatest risk factor for Alzheimer's and the prevalence of age-related late onset Alzheimer's is greatest in females. We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer's risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A2 sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its chronologically phased activation, links mitochondrial dysfunction early in aging with later age development of white matter degeneration. The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. Elucidation of the initiating factors and the mechanistic pathway leading to white matter catabolism in the aging female brain provides potential therapeutic targets to prevent and treat demyelinating diseases such as Alzheimer's and multiple sclerosis. Targeting stages of disease and associated mechanisms will be critical. PMID:26844268

  2. Multimodal and Multiscale Deep Neural Networks for the Early Diagnosis of Alzheimer's Disease using structural MR and FDG-PET images.

    PubMed

    Lu, Donghuan; Popuri, Karteek; Ding, Gavin Weiguang; Balachandar, Rakesh; Beg, Mirza Faisal

    2018-04-09

    Alzheimer's Disease (AD) is a progressive neurodegenerative disease where biomarkers for disease based on pathophysiology may be able to provide objective measures for disease diagnosis and staging. Neuroimaging scans acquired from MRI and metabolism images obtained by FDG-PET provide in-vivo measurements of structure and function (glucose metabolism) in a living brain. It is hypothesized that combining multiple different image modalities providing complementary information could help improve early diagnosis of AD. In this paper, we propose a novel deep-learning-based framework to discriminate individuals with AD utilizing a multimodal and multiscale deep neural network. Our method delivers 82.4% accuracy in identifying the individuals with mild cognitive impairment (MCI) who will convert to AD at 3 years prior to conversion (86.4% combined accuracy for conversion within 1-3 years), a 94.23% sensitivity in classifying individuals with clinical diagnosis of probable AD, and a 86.3% specificity in classifying non-demented controls improving upon results in published literature.

  3. Visual and Visuospatial Short-Term Memory in Mild Cognitive Impairment and Alzheimer Disease: Role of Attention

    ERIC Educational Resources Information Center

    Alescio-Lautier, B.; Michel, B. F.; Herrera, C.; Elahmadi, A.; Chambon, C.; Touzet, C.; Paban, V.

    2007-01-01

    It has been proposed that visual recognition memory and certain attentional mechanisms are impaired early in Alzheimer disease (AD). Little is known about visuospatial recognition memory in AD. The crucial role of the hippocampus on spatial memory and its damage in AD suggest that visuospatial recognition memory may also be impaired early. The aim…

  4. Aging With Down Syndrome: The Dual Diagnosis: Alzheimer's Disease and Down Syndrome.

    PubMed

    Cipriani, Gabriele; Danti, Sabrina; Carlesi, Cecilia; Di Fiorino, Mario

    2018-06-01

    People with Down syndrome (DS) enjoy a longer life expectancy now than they ever have before and are therefore at greater risk of developing conditions associated with aging, including dementia. To explore the phenomenon of dementia in DS. Medline and Google Scholar searches were conducted for relevant articles, chapters, and books published until 2017. Search terms included Alzheimer's disease, cognitive impairment, dementia, DS, and trisomy 21. Publications found through this indexed search were reviewed for further references. Virtually, all subject aged 35 to 40 show key neuropathologic changes characteristic of Alzheimer's disease, but only a part of them show clinical signs of dementia, usually around the age of 50 years. Early signs of dementia in people with DS may be different from those experienced by the general population. Failure to recognize this can delay diagnosis and subsequent interventions.

  5. Phenotypic similarities between late-onset autosomal dominant and sporadic Alzheimer disease: A single-family case-control study

    PubMed Central

    Day, Gregory S; Musiek, Erik S; Roe, Catherine M; Norton, Joanne; Goate, Alison M; Cruchaga, Carlos; Cairns, Nigel J; Morris, John C

    2016-01-01

    Importance The “amyloid hypothesis” posits that disrupted amyloid-beta (Aβ) homeostasis initiates the pathological process resulting in Alzheimer disease (AD). Autosomal dominant Alzheimer disease (ADAD) has an early symptomatic onset and is caused by single gene mutations that result in overproduction of Aβ42. To the extent that “sporadic” late-onset Alzheimer disease (LOAD) also results from dysregulated Aβ42, the clinical phenotypes of ADAD and LOAD should be similar when controlling for the effects of age. Objective To use a family with late-onset ADAD caused by a presenilin 1 (PSEN1) mutation to mitigate the potential confound of age when comparing ADAD and LOAD. Design Case-control study of a family with late-onset ADAD and individuals with histopathologically-proven LOAD. Setting The Knight Alzheimer Disease Research Center, Washington University, St Louis, and other National Institutes of Aging-funded Alzheimer Disease Centers in the United States. Participants Ten PSEN1 A79V mutation carriers from multiple generations of a family with late-onset ADAD (median age-at-onset, 75.0 [63–77] years) and 12 noncarrier family members, followed at the Knight Alzheimer Disease Research Center (1985–2015); and 1115 individuals with neuropathologically confirmed LOAD (median age-at-onset, 74.0 [60–101] years) from the National Alzheimer Coordinating Center database (09/2005-12/14). Main Outcome and Measure Planned comparison of clinical characteristics between cohorts, including age at symptomatic onset, associated symptoms and signs, rates of progression, and disease duration. Results Seven (70%) mutation carriers developed AD dementia, while three are yet asymptomatic in their 7th and 8th decades of life. No differences were observed between mutation carriers and individuals with LOAD concerning age at symptomatic onset, presenting symptoms and duration, and rate of progression of dementia. Early emergence of comorbid hallucinations and delusions were

  6. Effects of medicinal plants on Alzheimer's disease and memory deficits

    PubMed Central

    Akram, Muhammad; Nawaz, Allah

    2017-01-01

    Alzheimer's disease is an age-related neurodegenerative disorder characterized by memory deficits. Various studies have been carried out to find therapeutic approaches for Alzheimer's disease. However, the proper treatment option is still not available. There is no cure for Alzheimer's disease, but symptomatic treatment may improve the memory and other dementia related problems. Traditional medicine is practiced worldwide as memory enhancer since ancient times. Natural therapy including herbs and medicinal plants has been used in the treatment of memory deficits such as dementia, amnesia, as well as Alzheimer's disease since a long time. Medicinal plants have been used in different systems of medicine, particularly Unani system of medicines and exhibited their powerful roles in the management and cure of memory disorders. Most of herbs and plants have been chemically evaluated and their efficacy has also been proven in clinical trials. However, the underlying mechanisms of actions are still on the way. In this paper, we have reviewed the role of different medicinal plants that play an important role in the treatment of Alzheimer's disease and memory deficits using conventional herbal therapy. PMID:28553349

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

    NASA Astrophysics Data System (ADS)

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

    2014-02-01

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

  8. Comparison of clinical characteristics between familial and non-familial early onset Alzheimer's disease.

    PubMed

    Joshi, Aditi; Ringman, John M; Lee, Albert S; Juarez, Kevin O; Mendez, Mario F

    2012-10-01

    Although familial Alzheimer's disease (FAD) is an early onset AD (EAD), most patients with EAD do not have a familial disorder. Recent guidelines recommend testing for genes causing FAD only in those EAD patients with two first-degree relatives. However, some patients with FAD may lack a known family history or other indications for suspecting FAD but might nonetheless be carriers of FAD mutations. The study was aimed to identify clinical features that distinguish FAD from non-familial EAD (NF-EAD). A retrospective review of a university-based cohort of 32 FAD patients with PSEN1-related AD and 81 with NF-EAD was conducted. The PSEN1 patients, compared to the NF-EAD patients, had an earlier age of disease onset (41.8 ± 5.2 vs. 55.9 ± 4.8 years) and, at initial assessment, a longer disease duration (5.1 ± 3.4 vs. 3.3 ± 2.6 years) and lower MMSE scores (10.74 ± 8.0 vs. 20.95 ± 5.8). Patients with NF-EAD were more likely to present with non-memory deficits, particularly visuospatial symptoms, than were FAD patients. When age, disease duration, and MMSE scores were controlled in a logistical regression model, FAD patients were more likely to have significant headaches, myoclonus, gait abnormality, and pseudobulbar affect than those with NF-EAD. In addition to a much younger age of onset, FAD patients with PSEN1 mutations differed from those with NF-EAD by a history of headaches and pseudobulbar affect, as well as myoclonus and gait abnormality on examination. These may represent differences in pathophysiology between FAD and NF-EAD and in some contexts such findings should lead to genetic counseling and appropriate recommendations for genetic testing for FAD.

  9. Biomarkers for Early Diagnosis of Alzheimer's Disease in the Oldest Old: Yes or No?

    PubMed

    Paolacci, Lucia; Giannandrea, David; Mecocci, Patrizia; Parnetti, Lucilla

    2017-01-01

    In recent years, many efforts have been spent to identify sensitive biomarkers able to improve the accuracy of Alzheimer's disease (AD) diagnosis. Two different workgroups (NIA-AA and IWG) included cerebrospinal fluid (CSF) and neuroimaging findings in their sets of criteria in order to improve diagnostic accuracy as well as early diagnosis. The number of subjects with cognitive impairment increases with aging but the oldest old (≥85 years of age), the fastest growing age group, is still the most unknown from a biological point of view. For this reason, the aim of our narrative mini-review is to evaluate the pertinence of the new criteria for AD diagnosis in the oldest old. Moreover, since different subgroups of oldest old have been described in scientific literature (escapers, delayers, survivors), we want to outline the clinical profile of the oldest old who could really benefit from the use of biomarkers for early diagnosis. Reviewing the literature on biomarkers included in the diagnostic criteria, we did not find a high degree of evidence for their use in the oldest old, although CSF biomarkers seem to be still the most useful for excluding AD diagnosis in the "fit" subgroup of oldest old subjects, due to the high negative predictive value maintained in this age group.

  10. The amyloid precursor protein locus and very-late-onset Alzheimer disease.

    PubMed

    Olson, J M; Goddard, K A; Dudek, D M

    2001-10-01

    Although mutations in the amyloid-beta precursor protein (APP) gene are known to confer high risk of Alzheimer disease (AD) to a small percentage of families in which it has early onset, convincing evidence of a major role for the APP locus in late-onset AD has not been forthcoming. In this report, we have used a covariate-based affected-sib-pair linkage method to analyze the chromosome 21 clinical and genetic data obtained on affected sibships by the National Institute of Mental Health Alzheimer Disease Genetics Initiative. The baseline model (without covariates) gave a LOD score of 0.02, which increases to 1.43 when covariates representing the additive effects of E2 and E4 are added. Larger increases in LOD scores were found when age at last examination/death (LOD score 5.54; P=.000002) or age at onset plus disease duration (LOD score 5.63; P=.000006) were included in the linkage model. We conclude that the APP locus may predispose to AD in the very elderly.

  11. 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…

  12. Alzheimer's disease public-private partnerships: update 2014.

    PubMed

    Snyder, Heather M; Kim, Hye; Bain, Lisa J; Egge, Robert; Carrillo, Maria C

    2014-11-01

    The National Plan to Address Alzheimer's Disease highlights the need for coordinated public-private partnerships. In recent years, the number of collaborations and consortia have expanded and grown in Alzheimer's research. The Alzheimer's Association compiles this annually updated compendium to centralize this inventory of partnerships in an effort to synergize these activities. This manuscript reflects the 2014 landscape of non-profit organizations who engage in public-private partnerships to promote and support dementia research. Copyright © 2014. Published by Elsevier Inc.

  13. Everyday Decision Making in Individuals with Early-Stage Alzheimer's Disease: An Integrative Review of the Literature.

    PubMed

    Davis, Rebecca; Ziomkowski, Mary K; Veltkamp, Amy

    2017-09-01

    Individuals with Alzheimer's disease (AD) demonstrate fluctuation in cognitive abilities that can affect their ability to make decisions. Everyday decision making encompasses the types of decisions about typical daily activities, such as what to eat, what to do, and what to wear. Everyday decisions are encountered many times per day by individuals with AD/dementia and their caregivers. However, not much is known about the ability of individuals with AD/dementia to make these types of decisions. The purpose of the current literature review was to synthesize the evidence regarding everyday decision making in individuals with early-stage AD/dementia. Findings from the review indicate there is beginning evidence that individuals with early to moderate stages of AD/dementia desire to have input in daily decisions, have the ability to state their wishes consistently at times, and having input in decision making is important to their selfhood. The literature revealed few interventions to assist individuals with AD/dementia in everyday decision making. Findings from the review are discussed with implications for nursing practice and research. [Res Gerontol Nurs. 2017; 10(5):240-247.]. Copyright 2017, SLACK Incorporated.

  14. 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

  15. Metabolomic profiling of serum in the progression of Alzheimer's disease by capillary electrophoresis-mass spectrometry.

    PubMed

    González-Domínguez, Raúl; García, Antonia; García-Barrera, Tamara; Barbas, Coral; Gómez-Ariza, José Luis

    2014-12-01

    There is high interest in the discovery of early diagnostic biomarkers of Alzheimer's disease, for which metabolomics exhibits a great potential. In this work, a metabolomic approach based on ultrafiltration and analysis by CE-MS has been used to obtain representative fingerprints of polar metabolites from serum samples in order to distinguish between patients with Alzheimer's disease, mild cognitive impairment, and healthy controls. By the use of partial least squares discriminant analysis it was possible to classify patients according to the disease stage and then identify potential markers. Significant increase was observed with progression of disease in levels of choline, creatinine, asymmetric dimethyl-arginine, homocysteine-cysteine disulfide, phenylalanyl-phenylalanine, and different medium chain acylcarnitines. On the other hand, asparagine, methionine, histidine, carnitine, acetyl-spermidine, and C5-carnitine were reduced in these serum samples. In this way, multiple essential pathways were found implicated in the underlying pathology, such as oxidative stress or defects in energy metabolism. However, the most interesting results are related to the association of several vascular risk factors with Alzheimer's disease. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Matrix metalloproteinase 14 modulates diabetes and Alzheimer's disease cross-talk: a meta-analysis.

    PubMed

    Cheng, Jack; Liu, Hsin-Ping; Lee, Cheng-Chun; Chen, Mei-Ying; Lin, Wei-Yong; Tsai, Fuu-Jen

    2018-02-01

    Diabetes mellitus is associated with dementia, but whether diabetes is associated with Alzheimer's disease remains controversial. Alzheimer's disease is characterized by amyloid beta aggregation. We hypothesized that genes, involved in amyloid beta degradation, may be altered due to diabetes and thus participate in progression of Alzheimer's disease. Expression profiling of amyloid beta-degrading enzymes in streptozotocin-induced diabetic mice and their correlation with expression of amyloid precursor protein in hippocampus of Alzheimer's disease patients were accessed. We found that matrix metalloproteinase 14 decreased in brain but not in other tissues of streptozotocin-induced diabetic mice, and was negatively correlated with expression of amyloid precursor protein in hippocampus of Alzheimer's disease patients. These findings suggested matrix metalloproteinase 14 may link insulin-deficient diabetes to Alzheimer's disease.

  17. Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study.

    PubMed

    Driver, Jane A; Beiser, Alexa; Au, Rhoda; Kreger, Bernard E; Splansky, Greta Lee; Kurth, Tobias; Kiel, Douglas P; Lu, Kun Ping; Seshadri, Sudha; Wolf, Phillip A

    2012-03-12

    To relate cancer since entry into the Framingham Heart Study with the risk of incident Alzheimer's disease and to estimate the risk of incident cancer among participants with and without Alzheimer's disease. Community based prospective cohort study; nested age and sex matched case-control study. Framingham Heart Study, USA. 1278 participants with and without a history of cancer who were aged 65 or more and free of dementia at baseline (1986-90). Hazard ratios and 95% confidence intervals for the risks of Alzheimer's disease and cancer. Over a mean follow-up of 10 years, 221 cases of probable Alzheimer's disease were diagnosed. Cancer survivors had a lower risk of probable Alzheimer's disease (hazard ratio 0.67, 95% confidence interval 0.47 to 0.97), adjusted for age, sex, and smoking. The risk was lower among survivors of smoking related cancers (0.26, 0.08 to 0.82) than among survivors of non-smoking related cancers (0.82, 0.57 to 1.19). In contrast with their decreased risk of Alzheimer's disease, survivors of smoking related cancer had a substantially increased risk of stroke (2.18, 1.29 to 3.68). In the nested case-control analysis, participants with probable Alzheimer's disease had a lower risk of subsequent cancer (0.39, 0.26 to 0.58) than reference participants, as did participants with any Alzheimer's disease (0.38) and any dementia (0.44). Cancer survivors had a lower risk of Alzheimer's disease than those without cancer, and patients with Alzheimer's disease had a lower risk of incident cancer. The risk of Alzheimer's disease was lowest in survivors of smoking related cancers, and was not primarily explained by survival bias. This pattern for cancer is similar to that seen in Parkinson's disease and suggests an inverse association between cancer and neurodegeneration.

  18. The Benefits of Exercise and Metabolic Interventions for the Prevention and Early Treatment of Alzheimer's Disease.

    PubMed

    Maliszewska-Cyna, Ewelina; Lynch, Madelaine; Oore, Jonathan Jordan; Nagy, Paul Michael; Aubert, Isabelle

    2017-01-01

    Alzheimer's disease (AD) is characterized by neuronal degeneration, vascular pathology and cognitive decline. Furthermore, deficits in cerebral glucose metabolism and insulin resistance are being increasingly recognized in AD. Many lifestyle-modifying approaches, including diet and exercise, have yielded promising results in modulating brain morphology and function for the prevention and early treatment of AD. This review focuses on the effects of physical exercise on rescuing cognition and limiting the progression of AD pathology. Specifically, the impact of exercise, in human and animal models of AD, on the stimulation and preservation of cognition, neurotransmission, neurogenesis, vasculature, glucose metabolism and insulin signaling is discussed. Studies have highlighted the potential of physical activity to improve overall brain health, which could delay or lessen AD-related cognitive deficits and pathology. Physical activity influences cognitive function, vascular health and brain metabolism, which taken together offers benefits for the aging population, including AD patients.

  19. Caregiving for Alzheimer's Disease or Other Dementia

    MedlinePlus

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

  20. Neural Correlates of Self-Reference Effect in Early Alzheimer's Disease.

    PubMed

    Gaubert, Malo; Villain, Nicolas; Landeau, Brigitte; Mézenge, Florence; Egret, Stéphanie; Perrotin, Audrey; Belliard, Serge; de La Sayette, Vincent; Eustache, Francis; Desgranges, Béatrice; Chételat, Gaël; Rauchs, Géraldine

    2017-01-01

    Information that is processed with reference to the self (i.e., self-referential processing, SRP) is generally associated with better remembering than information processed in a semantic condition. This benefit of self on memory performance is called self-reference effect (SRE). In the present study, we assessed changes in the SRE and SRP-related brain activity in patients diagnosed with mild cognitive impairment or early Alzheimer's disease (MCI/AD). Fifteen patients with confirmed amyloid-β deposits (positive florbetapir-PET scan) and 28 healthy controls (negative florbetapir-PET scan) were included. Participants either had to judge personality trait adjectives with reference to themselves (self condition) or to a celebrity (other condition), or determine whether these adjectives were positive or not (semantic condition). These adjectives were then presented with distractors in a surprise recognition task. Functional MRI data were acquired during both the judgment and recognition tasks. The SRE was observed in controls, but reduced in patients. Both controls and patients activated cortical midline structures when judging items with reference to themselves, but patients exhibited reduced activity in the angular gyrus. In patients, activity at encoding in the angular gyrus positively correlated with subsequent recognition accuracy in the self condition (self accuracy). This region also exhibited significant hypometabolism and Aβ burden, both related to self accuracy. By contrast, there were no differences in brain activity during recognition, either between the self and semantic conditions, or between groups. These results highlight SRE impairment in patients with MCI/AD, despite intact activity in cortical midline structures, and suggest that dysfunction of the angular gyrus is related to this impairment.

  1. Vitamin D and the risk of dementia and Alzheimer disease.

    PubMed

    Littlejohns, Thomas J; Henley, William E; Lang, Iain A; Annweiler, Cedric; Beauchet, Olivier; Chaves, Paulo H M; Fried, Linda; Kestenbaum, Bryan R; Kuller, Lewis H; Langa, Kenneth M; Lopez, Oscar L; Kos, Katarina; Soni, Maya; Llewellyn, David J

    2014-09-02

    To determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease. One thousand six hundred fifty-eight elderly ambulatory adults free from dementia, cardiovascular disease, and stroke who participated in the US population-based Cardiovascular Health Study between 1992-1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992-1993. Incident all-cause dementia and Alzheimer disease status were assessed during follow-up using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria. During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease. Using Cox proportional hazards models, the multivariate adjusted hazard ratios (95% confidence interval [CI]) for incident all-cause dementia in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (≥25 to <50 nmol/L) were 2.25 (95% CI: 1.23-4.13) and 1.53 (95% CI: 1.06-2.21) compared to participants with sufficient concentrations (≥50 nmol/L). The multivariate adjusted hazard ratios for incident Alzheimer disease in participants who were severely 25(OH)D deficient and deficient compared to participants with sufficient concentrations were 2.22 (95% CI: 1.02-4.83) and 1.69 (95% CI: 1.06-2.69). In multivariate adjusted penalized smoothing spline plots, the risk of all-cause dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L. Our results confirm that vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease. This adds to the ongoing debate about the role of vitamin D in nonskeletal conditions. © 2014 American Academy of Neurology.

  2. Mild cognitive impairment (MCI) - the novel trend of targeting Alzheimer's disease in its early stages - methodological considerations.

    PubMed

    Pater, C

    2011-11-01

    While much uncertainty exists in the estimates of the global burden of Alzheimer's disease and about the potential impact of various interventions, there is a widespread acceptance of the fact that the steady increase in the incidence and prevalence of the condition worldwide is becoming a massive public health problem as well as a huge economic burden for all healthcare systems and societies. These heavy demands are further compounded by the poor quality of life of the affected individuals, of their families and of their caregivers. The epidemic proportion of Alzheimer's disease has triggered relentless attempts for development of treatment approaches during the past two decades by a multitude of pharmaceuticals and biotech companies. Commercial development of the acetylcholinesterase inhibitors has, until recently, virtually dominated the field and, although efficacy has been demonstrated for five different products, the longterm clinical results suggested that alternate approaches were warranted. Disease modifying strategies targeting the β- amyloid plaques (e.g., decreasing β-amyloid formation through β- and γ-secretase inhibition, diminishing β-amyloid aggregation through anti-aggregants or enhancement of β-amyloid clearance through active/passive immunization), targeting the neurofibrillary tangles through inhibition of tau protein hyperphosphorilation or, more recently, by increasing mitochondrial permeability, all these potential treatment modalities are facing major methodological challenges during the conduct of a myriad of clinical trials meant to bring the novel therapies to the market. Failure of more than 400 products tested in more than 800 clinical trials to date, with many of these failures occurring in late stage development (phase III) have triggered a paradigm shift toward targeting of the early stages of cognitive deficiencies (mild cognitive impairment- MCI) and a refinement of the investigative methodologies. The great heterogeneity of

  3. The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers.

    PubMed

    Ayutyanont, Napatkamon; Langbaum, Jessica B S; Hendrix, Suzanne B; Chen, Kewei; Fleisher, Adam S; Friesenhahn, Michel; Ward, Michael; Aguirre, Camilo; Acosta-Baena, Natalia; Madrigal, Lucìa; Muñoz, Claudia; Tirado, Victoria; Moreno, Sonia; Tariot, Pierre N; Lopera, Francisco; Reiman, Eric M

    2014-06-01

    To identify a cognitive composite that is sensitive to tracking preclinical Alzheimer's disease decline to be used as a primary end point in treatment trials. We capitalized on longitudinal data collected from 1995 to 2010 from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world's largest known early-onset autosomal dominant Alzheimer's disease kindred to identify a composite cognitive test with the greatest statistical power to track preclinical Alzheimer's disease decline and estimate the number of carriers age 30 years and older needed to detect a treatment effect in the Alzheimer's Prevention Initiative's (API) preclinical Alzheimer's disease treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of 1 to 7 cognitive tests/subtests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a 2- and 5-year follow-up period (n = 78 and 57), using data from noncarriers (n = 31 and 56) during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top-performing combinations, and representation of relevant cognitive domains. The optimal test combination included Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Recall, CERAD Boston Naming Test (high frequency items), Mini-Mental State Examination (MMSE) Orientation to Time, CERAD Constructional Praxis, and Raven's Progressive Matrices (Set A), with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR = 0.38) or the entire CERAD-Col battery (MSDR = 0.76). A sample size of 75 cognitively normal PSEN1 E280A mutation carriers aged 30 years and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, P = .05). We

  4. Regulation of gamma-Secretase in Alzheimer's Disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhou, Shuxia; Zhou, Hua; Walian, Peter

    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 andmore » 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.« less

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

    PubMed

    Bilkei-Gorzo, Andras

    2014-05-01

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

  6. Reductive stress in young healthy individuals at risk of Alzheimer disease.

    PubMed

    Badía, Mari-Carmen; Giraldo, Esther; Dasí, Francisco; Alonso, Dolores; Lainez, Jose M; Lloret, Ana; Viña, Jose

    2013-10-01

    Oxidative stress is a hallmark of Alzheimer disease (AD) but this has not been studied in young healthy persons at risk of the disease. Carrying an Apo ε4 allele is the major genetic risk factor for AD. We have observed that lymphocytes from young, healthy persons carrying at least one Apo ε4 allele suffer from reductive rather than oxidative stress, i.e., lower oxidized glutathione and P-p38 levels and higher expression of enzymes involved in antioxidant defense, such as glutamylcysteinyl ligase and glutathione peroxidase. In contrast, in the full-blown disease, the situation is reversed and oxidative stress occurs, probably because of the exhaustion of the antioxidant mechanisms just mentioned. These results provide insights into the early events of the progression of the disease that may allow us to find biomarkers of AD at its very early stages. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease.

    PubMed

    Egan, Michael F; Kost, James; Tariot, Pierre N; Aisen, Paul S; Cummings, Jeffrey L; Vellas, Bruno; Sur, Cyrille; Mukai, Yuki; Voss, Tiffini; Furtek, Christine; Mahoney, Erin; Harper Mozley, Lyn; Vandenberghe, Rik; Mo, Yi; Michelson, David

    2018-05-03

    Alzheimer's disease is characterized by the deposition of amyloid-beta (Aβ) plaques in the brain. Aβ is produced from the sequential cleavage of amyloid precursor protein by β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aβ level in the cerebrospinal fluid of patients with Alzheimer's disease. We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (P=0.49 for the comparison

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

    PubMed

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

    2015-08-01

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

  9. Fibre-specific white matter reductions in Alzheimer's disease and mild cognitive impairment.

    PubMed

    Mito, Remika; Raffelt, David; Dhollander, Thijs; Vaughan, David N; Tournier, J-Donald; Salvado, Olivier; Brodtmann, Amy; Rowe, Christopher C; Villemagne, Victor L; Connelly, Alan

    2018-01-04

    Alzheimer's disease is increasingly considered a large-scale network disconnection syndrome, associated with progressive aggregation of pathological proteins, cortical atrophy, and functional disconnections between brain regions. These pathological changes are posited to arise in a stereotypical spatiotemporal manner, targeting intrinsic networks in the brain, most notably the default mode network. While this network-specific disruption has been thoroughly studied with functional neuroimaging, changes to specific white matter fibre pathways within the brain's structural networks have not been closely investigated, largely due to the challenges of modelling complex white matter structure. Here, we applied a novel technique known as 'fixel-based analysis' to comprehensively investigate fibre tract-specific differences at a within-voxel level (called 'fixels') to assess potential axonal loss in subjects with Alzheimer's disease and mild cognitive impairment. We hypothesized that patients with Alzheimer's disease would exhibit extensive degeneration across key fibre pathways connecting default network nodes, while patients with mild cognitive impairment would exhibit selective degeneration within fibre pathways connecting regions previously identified as functionally implicated early in Alzheimer's disease. Diffusion MRI data from Alzheimer's disease (n = 49), mild cognitive impairment (n = 33), and healthy elderly control subjects (n = 95) were obtained from the Australian Imaging, Biomarkers and Lifestyle study of ageing. We assessed microstructural differences in fibre density, and macrostructural differences in fibre bundle morphology using fixel-based analysis. Whole-brain analysis was performed to compare groups across all white matter fixels. Subsequently, we performed a tract of interest analysis comparing fibre density and cross-section across 11 selected white matter tracts, to investigate potentially subtle degeneration within fibre pathways in mild

  10. Inheritance pattern of platelet membrane fluidity in Alzheimer disease.

    PubMed Central

    Chakravarti, A; Slaugenhaupt, S A; Zubenko, G S

    1989-01-01

    The fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene in labeled platelet membranes, an index of membrane fluidity, is a stable, familial trait that is associated with a clinically distinct subtype of Alzheimer disease. Complex segregation analysis of this continuous variable was performed on 95 members of 14 pedigrees identified through probands who had autopsy-confirmed or clinically diagnosed Alzheimer disease. The results suggest that platelet membrane fluidity is controlled by a single genetic locus, PMF, with two alleles that have additive effects. The PMF locus appears to explain approximately 80% of the total variation in platelet membrane fluidity within the families of patients with Alzheimer disease. PMID:2729275

  11. 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. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  12. Lexical priming in Alzheimer's disease and aphasia.

    PubMed

    Arroyo-Anlló, Eva Maria; Beauchamps, Mireille; Ingrand, Pierre; Neau, Jean Philippe; Gil, Roger

    2013-01-01

    Lexical priming was examined in patients with Alzheimer's disease and in aphasic patients. Control participants were divided into young and elderly [cf. Arroyo-Anlló et al.: Eur J Cogn Psychol 2004;16:535-553]. For lexical priming, a word-stem completion task was used. Normal elderly participants had lexical priming scores that were significantly lower than those of young individuals. Analysis of covariance with age and educational level as covariates showed that the control participants, aphasic and Alzheimer patients did not differ significantly on the lexical priming task. Our results suggest that performance in the lexical priming task diminishes with physiological aging, but is not significantly affected by mild or moderate Alzheimer's disease or by fluent or non-fluent aphasia. Copyright © 2013 S. Karger AG, Basel.

  13. 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

  14. Management of neurodegenerative disorders: Parkinson's disease and Alzheimer's disease.

    PubMed

    Pal, P K; Netravathi, M

    2005-03-01

    Neurodegenerative disorders result from premature progressive degeneration of specific neurons, and manifest as diseases or syndromes with varied combinations of cognitive, motor, sensory and autonomic dysfunctions. The management involves pharmacotherapy as well as non-pharmacological measures and also to lessen the burden of the care-givers. The medications available for medical treatment are: Levodopa, dopamine agonists, amantadine, anticholinergics, enzyme inhibitors, etc. Advanced Parkinson's disease is concerned with management of motor complications and non-motor complications. Recently surgical treatment is a great option for managing motor complication. Orthostatic hypotension, gait distiurbances, emotional and psychiatric problems, sleep disturbances can be managed and had been discussed in brief. Currently there is no medication available for the cure of Alzheimer's disease. The specific medications claimed to improve patient's well being and cognition include cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonist, anti-oxidants, and anti-amyloid therapy. While medical and surgical treatments for Parkinson's disease have revolutionised the management, still drug therapy for Alzheimer's disease is dismal.

  15. Impaired Semantic Knowledge Underlies the Reduced Verbal Short-Term Storage Capacity in Alzheimer's Disease

    ERIC Educational Resources Information Center

    Peters, Frederic; Majerus, Steve; De Baerdemaeker, Julie; Salmon, Eric; Collette, Fabienne

    2009-01-01

    A decrease in verbal short-term memory (STM) capacity is consistently observed in patients with Alzheimer's disease (AD). Although this impairment has been mainly attributed to attentional deficits during encoding and maintenance, the progressive deterioration of semantic knowledge in early stages of AD may also be an important determinant of poor…

  16. Efficient mining of association rules for the early diagnosis of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Chaves, R.; Górriz, J. M.; Ramírez, J.; Illán, I. A.; Salas-Gonzalez, D.; Gómez-Río, M.

    2011-09-01

    In this paper, a novel technique based on association rules (ARs) is presented in order to find relations among activated brain areas in single photon emission computed tomography (SPECT) imaging. In this sense, the aim of this work is to discover associations among attributes which characterize the perfusion patterns of normal subjects and to make use of them for the early diagnosis of Alzheimer's disease (AD). Firstly, voxel-as-feature-based activation estimation methods are used to find the tridimensional activated brain regions of interest (ROIs) for each patient. These ROIs serve as input to secondly mine ARs with a minimum support and confidence among activation blocks by using a set of controls. In this context, support and confidence measures are related to the proportion of functional areas which are singularly and mutually activated across the brain. Finally, we perform image classification by comparing the number of ARs verified by each subject under test to a given threshold that depends on the number of previously mined rules. Several classification experiments were carried out in order to evaluate the proposed methods using a SPECT database that consists of 41 controls (NOR) and 56 AD patients labeled by trained physicians. The proposed methods were validated by means of the leave-one-out cross validation strategy, yielding up to 94.87% classification accuracy, thus outperforming recent developed methods for computer aided diagnosis of AD.

  17. Memory Loss, Alzheimer's Disease and General Anesthesia: A Preoperative Concern.

    PubMed

    Thaler, Adam; Siry, Read; Cai, Lufan; García, Paul S; Chen, Linda; Liu, Renyu

    2012-02-20

    The long-term cognitive effects of general anesthesia are under intense scrutiny. Here we present 5 cases from 2 academic institutions to analyze some common features where the patient's or the patient family member has made a request to address their concern on memory loss, Alzheimer's disease and general anesthesia before surgery. Records of anesthesia consultation separate from standard preoperative evaluation were retrieved to identify consultations related to memory loss and Alzheimer's disease from the patient and/or patient family members. The identified cases were extensively reviewed for features in common. We used Google® (http://www. google.com/) to identify available online information using "anesthesia memory loss" as a search phrase. Five cases were collected as a specific preoperative consultation related to memory loss, Alzheimer's disease and general anesthesia from two institutions. All of the individuals either had perceived memory impairment after a prior surgical procedure with general anesthesia or had a family member with Alzheimer's disease. They all accessed public media sources to find articles related to anesthesia and memory loss. On May 2 nd , 2011, searching "anesthesia memory loss" in Google yielded 764,000 hits. Only 3 of the 50 Google top hits were from peer-reviewed journals. Some of the lay media postings made a causal association between general anesthesia and memory loss and/or Alzheimer's disease without conclusive scientific literature support. The potential link between memory loss and Alzheimer's disease with general anesthesia is an important preoperative concern from patients and their family members. This concern arises from individuals who have had history of cognitive impairment or have had a family member with Alzheimer disease and have tried to obtain information from public media. Proper preoperative consultation with the awareness of the lay literature can be useful in reducing patient and patient family member

  18. Preventive role of Indian black pepper in animal models of Alzheimer's disease.

    PubMed

    Subedee, Lokraj; Suresh, R N; Mk, Jayanthi; Hl, Kalabharathi; Am, Satish; Vh, Pushpa

    2015-04-01

    Dementia is the clinical symptom of alzheimer's disease. Brain cholinesterase levels and behavioural changes are the markers for Alzheimer's disease and aluminium chloride is one causative agent for polymerization of tau protein and amyloid plaque formation in Alzheimer's disease. Effect of piper nigrum and its role in prevention of alzhimer's disease and symptoms are well linked in this study. To study the effect of piper nigrum for the prevention of alzheimer's associated histopathological, biochemical and behaviour changes in rat model. Twenty four rats were taken in this study. Their baseline behavioural parameters were noted and group was separated randomly in four. Rats were pretreated with piper nigrum and Alzheimer's disease was induced. Biochemical and histopathological changes were noted at the end of experiment. There was marked decrease in cholinesterase level, amyloidal plaque formation in rats brain who were pretreated with piper nigrum. At the same time there was decrease in escape latency time (ELT) and increase in memory in piper treated rats. Piper nigrum prove to be effective for prevention of Alzheimer's disease. This finding has to be confirmed with studies including larger population. Further research on cholinesterase inhibitors, role of flavonoids on prevention of neurodegeneration in Alzheimer's disease can be encouraged.

  19. The Role of Biomarkers in Clinical Trials for Alzheimer Disease

    PubMed Central

    Thal, Leon J.; Kantarci, Kejal; Reiman, Eric M.; Klunk, William E.; Weiner, Michael W.; Zetterberg, Henrik; Galasko, Douglas; Praticò, Domenico; Griffin, Sue; Schenk, Dale; Siemers, Eric

    2007-01-01

    Biomarkers are likely to be important in the study of Alzheimer disease (AD) for a variety of reasons. A clinical diagnosis of Alzheimer disease is inaccurate even among experienced investigators in about 10% to 15% of cases, and biomarkers might improve the accuracy of diagnosis. Importantly for the development of putative disease-modifying drugs for Alzheimer disease, biomarkers might also serve as indirect measures of disease severity. When used in this way, sample sizes of clinical trials might be reduced, and a change in biomarker could be considered supporting evidence of disease modification. This review summarizes a meeting of the Alzheimer’s Association’s Research Roundtable, during which existing and emerging biomarkers for AD were evaluated. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or ligands binding to amyloid plaque are discussed. Additionally, biochemical biomarkers in blood or cerebrospinal fluid are assessed. Currently appropriate uses of biomarkers in the study of Alzheimer disease, and areas where additional work is needed, are discussed. PMID:16493230

  20. Impaired default network functional connectivity in autosomal dominant Alzheimer disease

    PubMed Central

    Chhatwal, Jasmeer P.; Schultz, Aaron P.; Johnson, Keith; Benzinger, Tammie L.S.; Jack, Clifford; Ances, Beau M.; Sullivan, Caroline A.; Salloway, Stephen P.; Ringman, John M.; Koeppe, Robert A.; Marcus, Daniel S.; Thompson, Paul; Saykin, Andrew J.; Correia, Stephen; Schofield, Peter R.; Rowe, Christopher C.; Fox, Nick C.; Brickman, Adam M.; Mayeux, Richard; McDade, Eric; Bateman, Randall; Fagan, Anne M.; Goate, Allison M.; Xiong, Chengjie; Buckles, Virginia D.; Morris, John C.

    2013-01-01

    Objective: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network. Methods: Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO). Results: We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO. Conclusion: Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease. PMID:23884042

  1. Impairment of vocal expression of negative emotions in patients with Alzheimer's disease.

    PubMed

    Han, Kyung-Hun; Zaytseva, Yuliya; Bao, Yan; Pöppel, Ernst; Chung, Sun Yong; Kim, Jong Woo; Kim, Hyun Taek

    2014-01-01

    Vocal expression of emotions (EE) in retrieval of events from autobiographical memory was investigated in patients in early stages of Alzheimer's disease (AD). Twenty-one AD patients and 19 controls were interviewed, and EE of the reported memories was rated by 8 independent evaluators. The AD group had lower EE of both recent and remote memory than controls, although EE in remote memories was better preserved in both groups. We observed positive correlations between EE and indicators of cognitive competence in AD patients. AD Patients are impaired in the ability to express emotions already at early stages of the disease, and EE seems to deteriorate along with the progression of cognitive impairment.

  2. Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease: Methodology and Baseline Sample Characteristics.

    PubMed

    Byun, Min Soo; Yi, Dahyun; Lee, Jun Ho; Choe, Young Min; Sohn, Bo Kyung; Lee, Jun-Young; Choi, Hyo Jung; Baek, Hyewon; Kim, Yu Kyeong; Lee, Yun-Sang; Sohn, Chul-Ho; Mook-Jung, Inhee; Choi, Murim; Lee, Yu Jin; Lee, Dong Woo; Ryu, Seung-Ho; Kim, Shin Gyeom; Kim, Jee Wook; Woo, Jong Inn; Lee, Dong Young

    2017-11-01

    The Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) aimed to recruit 650 individuals, aged from 20 to 90 years, to search for new biomarkers of Alzheimer's disease (AD) and to investigate how multi-faceted lifetime experiences and bodily changes contribute to the brain changes or brain pathologies related to the AD process. All participants received comprehensive clinical and neuropsychological evaluations, multi-modal brain imaging, including magnetic resonance imaging, magnetic resonance angiography, [ 11 C]Pittsburgh compound B-positron emission tomography (PET), and [ 18 F]fluorodeoxyglucose-PET, blood and genetic marker analyses at baseline, and a subset of participants underwent actigraph monitoring and completed a sleep diary. Participants are to be followed annually with clinical and neuropsychological assessments, and biannually with the full KBASE assessment, including neuroimaging and laboratory tests. As of March 2017, in total, 758 individuals had volunteered for this study. Among them, in total, 591 participants-291 cognitively normal (CN) old-aged individuals, 74 CN young- and middle-aged individuals, 139 individuals with mild cognitive impairment (MCI), and 87 individuals with AD dementia (ADD)-were enrolled at baseline, after excluding 162 individuals. A subset of participants (n=275) underwent actigraph monitoring. The KBASE cohort is a prospective, longitudinal cohort study that recruited participants with a wide age range and a wide distribution of cognitive status (CN, MCI, and ADD) and it has several strengths in its design and methodologies. Details of the recruitment, study methodology, and baseline sample characteristics are described in this paper.

  3. Purine-related metabolites and their converting enzymes are altered in frontal, parietal and temporal cortex at early stages of Alzheimer's disease pathology.

    PubMed

    Alonso-Andrés, Patricia; Albasanz, José Luis; Ferrer, Isidro; Martín, Mairena

    2018-01-24

    Adenosine, hypoxanthine, xanthine, guanosine and inosine levels were assessed by HPLC, and the activity of related enzymes 5'-nucleotidase (5'-NT), adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) measured in frontal (FC), parietal (PC) and temporal (TC) cortices at different stages of disease progression in Alzheimer's disease (AD) and in age-matched controls. Significantly decreased levels of adenosine, guanosine, hypoxanthine and xanthine, and apparently less inosine, are found in FC from the early stages of AD; PC and TC show an opposing pattern, as adenosine, guanosine and inosine are significantly increased at least at determinate stages of AD whereas hypoxanthine and xanthine levels remain unaltered. 5'-NT is reduced in membranes and cytosol in FC mainly at early stages but not in PC, and only at advanced stages in cytosol in TC. ADA activity is decreased in AD when considered as a whole but increased at early stages in TC. Finally, PNP activity is increased only in TC at early stages. Purine metabolism alterations occur at early stages of AD independently of neurofibrillary tangles and β-amyloid plaques. Alterations are stage dependent and region dependent, the latter showing opposite patterns in FC compared with PC and TC. Adenosine is the most affected of the assessed purines. © 2018 International Society of Neuropathology.

  4. The genetics of Alzheimer disease.

    PubMed

    Tanzi, Rudolph E

    2012-10-01

    Family history is the second strongest risk factor for Alzheimer disease (AD) following advanced age. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations in APP, PSEN1, and PSEN2 virtually guarantee early-onset (<60 years) familial AD, which represents ∼5% of AD. On the other hand, common gene polymorphisms, such as the ε4 and ε2 variants of the APOE gene, can influence susceptibility for ∼50% of the common late-onset AD. These four genes account for 30%-50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of 11 additional AD candidate genes. This paper reviews the past, present, and future attempts to elucidate the complex and heterogeneous genetic underpinnings of AD.

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

    PubMed

    Bane, Tabitha J; Cole, Connie

    2015-05-15

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

  6. The cell cycle in Alzheimer disease: a unique target for neuropharmacology.

    PubMed

    Webber, Kate M; Raina, Arun K; Marlatt, Michael W; Zhu, Xiongwei; Prat, María I; Morelli, Laura; Casadesus, Gemma; Perry, George; Smith, Mark A

    2005-10-01

    Several hypotheses have been proposed attempting to explain the pathogenesis of Alzheimer disease including, among others, theories involving amyloid deposition, tau phosphorylation, oxidative stress, metal ion dysregulation and inflammation. While there is strong evidence suggesting that each one of these proposed mechanisms contributes to disease pathogenesis, none of these mechanisms are able to account for all the physiological changes that occur during the course of the disease. For this reason, we and others have begun the search for a causative factor that predates known features found in Alzheimer disease, and that might therefore be a fundamental initiator of the pathophysiological cascade. We propose that the dysregulation of the cell cycle that occurs in neurons susceptible to degeneration in the hippocampus during Alzheimer disease is a potential causative factor that, together with oxidative stress, would initiate all known pathological events. Neuronal changes supporting alterations in cell cycle control in the etiology of Alzheimer disease include the ectopic expression of markers of the cell cycle, organelle kinesis and cytoskeletal alterations including tau phosphorylation. Such mitotic alterations are not only one of the earliest neuronal abnormalities in the disease, but as discussed herein, are also intimately linked to all of the other pathological hallmarks of Alzheimer disease including tau protein, amyloid beta protein precursor and oxidative stress, and even risk factors such as mutations in the presenilin genes. Therefore, therapeutic interventions targeted toward ameliorating mitotic changes would be predicted to have a profound and positive impact on Alzheimer disease progression.

  7. Inclusion-Body Myositis Associated with Alzheimer's Disease

    PubMed Central

    Levacic, Danijela; Peddareddygari, Leema Reddy; Nochlin, David; Sharer, Leroy R.; Grewal, Raji P.

    2013-01-01

    Sporadic inclusion-body myositis (s-IBM) is a myopathy that is characterized by progressive weakness and muscle pathology demonstrating inflammation and rimmed vacuoles. In addition, similar to the pathology observed in the brains of patients with Alzheimer's disease, the deposition of beta-amyloid and phosphorylated tau proteins in muscle fibers has been reported. These shared pathologic features have prompted hypotheses suggesting a shared etiology of these two conditions. We report a case of a 73-year-old woman initially diagnosed with s-IBM who later developed Alzheimer's disease. PMID:23606855

  8. 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)

  9. Disrupting beta-amyloid aggregation for Alzheimer disease treatment.

    PubMed

    Estrada, L D; Soto, C

    2007-01-01

    Alzheimer's disease is a devastating degenerative disorder for which there is no cure or effective treatment. Although the etiology of Alzheimer's disease is not fully understood, compelling evidence indicates that deposition of aggregates composed by a misfolded form of the amyloid beta peptide (Abeta) is the central event in the disease pathogenesis. Therefore, an attractive therapeutic strategy is to prevent or reverse Abeta misfolding and aggregation. Diverse strategies have been described to identify inhibitors of this process, including screening of libraries of small molecules chemical compounds, rational design of synthetic peptides, assessment of natural Abeta-binding proteins and stimulation of the immune system by vaccination. In this article we describe these different approaches, their principles and their potential strengths and weaknesses. Overall the available data suggest that the development of drugs to interfere with Abeta misfolding and aggregation is a feasible target that hold great promise for the treatment of Alzheimer's disease.

  10. The Use of Errorless Learning Strategies for Patients with Alzheimer's Disease: A Literature Review

    ERIC Educational Resources Information Center

    Li, Ruijie; Liu, Karen P. Y.

    2012-01-01

    The aim of this article was to review the evidence of errorless learning on learning outcomes in patients with early-stage Alzheimer's disease. A computer-aided literature search from 1999 to 2011 was carried out using MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and PsycArticles. Keywords included…

  11. Low-dose divalproex in agitated patients with Alzheimer's disease.

    PubMed

    Dolder, Christian; McKinsey, Jonathan

    2010-01-01

    Adequate treatment of behavioral disturbances in Alzheimer's disease is both important and difficult. This report describes a case series that examined the effectiveness and safety of low-dose divalproex in the treatment of agitated patients with Alzheimer's disease who were admitted to an inpatient geriatric psychiatry unit over a 1-year period. All patients had agitation due to probable Alzheimer's disease or mixed dementia and were prescribed divalproex monotherapy at low and completely flexible doses. Patients and nursing staff were blind to study enrollment. Clinical global impression scale scores, divalproex serum levels, and a variety of medical chart data were collected. Twenty patients met selection criteria and were included in the study. Of those, 13 patients (65%) were considered responders, while 4 patients (20%) required augmentation with other psychotropic medications; divalproex was discontinued in 1 patient. Adverse events occurred in 25% of patients. This case series suggests that low-dose divalproex may offer behavioral improvement and a reduced risk of side effects for some patients with agitation in Alzheimer's disease.

  12. Challenges associated with transition to caregiver role following diagnostic disclosure of Alzheimer disease: a descriptive study.

    PubMed

    Ducharme, Francine; Lévesque, Louise; Lachance, Lise; Kergoat, Marie-Jeanne; Coulombe, Renée

    2011-09-01

    The prevalence of Alzheimer's disease is rising. The large number of new cases identified each year means that many new families will set upon a long trajectory of caring for a relative with dementia. Diagnostic disclosure of Alzheimer's disease marks the official transition to the caregiver role, yet this early period of the caregiver career have rarely been studied. Based on Meleis's theoretical framework for role transition, the objectives of this study were to document the characteristics of the caregiving context during the transition to the caregiver role following diagnostic disclosure of Alzheimer's disease and to compare these characteristics by caregiver gender and kinship tie to the relative. A descriptive design was used. Data were collected using standardized measures selected in accordance with the role transition theoretical framework. The sample recruited in Quebec (Canada) cognition clinics comprised 122 caregivers of an elderly relative diagnosed with Alzheimer's disease in the past nine months. Findings reveal the context of care to be marked by several challenges for caregivers. The majority of caregivers receives little informal support, has poor knowledge of available formal services, and has difficulty planning ahead for the relative's future care needs. Caregivers themselves report a lack of preparedness to provide care. Compared with men caregivers, women seem to have more problems controlling disturbing thoughts about their new caregiver role and to experience more family conflicts and psychological distress. Compared with offspring caregivers, spouse caregivers are less able to respond to the relative's disruptive behaviors, make less use of problem-solving strategies, and report fewer family conflicts. The challenges faced by caregivers during the transition to the caregiver role are sensitive to nursing interventions. Pro-active interventions from the outset of the caregiving career, such as early assessment of caregiver needs for

  13. [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. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  14. Clinically Unsuspected Prion Disease Among Patients With Dementia Diagnoses in an Alzheimer's Disease Database.

    PubMed

    Maddox, Ryan A; Blase, J L; Mercaldo, N D; Harvey, A R; Schonberger, L B; Kukull, W A; Belay, E D

    2015-12-01

    Brain tissue analysis is necessary to confirm prion diseases. Clinically unsuspected cases may be identified through neuropathologic testing. National Alzheimer's Coordinating Center (NACC) Minimum and Neuropathologic Data Set for 1984 to 2005 were reviewed. Eligible patients had dementia, underwent autopsy, had available neuropathologic data, belonged to a currently funded Alzheimer's Disease Center (ADC), and were coded as having an Alzheimer's disease clinical diagnosis or a nonprion disease etiology. For the eligible patients with neuropathology indicating prion disease, further clinical information, collected from the reporting ADC, determined whether prion disease was considered before autopsy. Of 6000 eligible patients in the NACC database, 7 (0.12%) were clinically unsuspected but autopsy-confirmed prion disease cases. The proportion of patients with dementia with clinically unrecognized but autopsy-confirmed prion disease was small. Besides confirming clinically suspected cases, neuropathology is useful to identify unsuspected clinically atypical cases of prion disease. © The Author(s) 2015.

  15. A review on cholinesterase inhibitors for Alzheimer's disease.

    PubMed

    Anand, Preet; Singh, Baldev

    2013-04-01

    Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by the deficits in the cholinergic system and deposition of beta amyloid (Aβ) in the form of neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes, it has been targetted for the design of anti-Alzheimer's drugs. Cholinesterase inhibitors enhance cholinergic transmission directly by inhibiting the enzyme acetylcholinesterase (AChE) which hydrolyses acetylcholine. Furthermore, it has been also demonstrated that both acetylcholinesterase and butrylcholinesterase (BuChE) play an important role in Aβ-aggregation during the early stages of senile plaque formation. Therefore, AChE and BuChE inhibition have been documented as critical targets for the effective management of AD by an increase in the availability of acetylcholine in the brain regions and decrease in the Aβ deposition. This review discusses the different classes of cholinesterase inhibitors including tacrine, donepezil, rivastigmine, galantamine, xanthostigmine, para-aminobenzoic acid, coumarin, flavonoid, and pyrrolo-isoxazole analogues developed for the treatment of AD.

  16. Magnetic resonance imaging relaxation time in Alzheimer's disease.

    PubMed

    Tang, Xiang; Cai, Feng; Ding, Dong-Xue; Zhang, Lu-Lu; Cai, Xiu-Ying; Fang, Qi

    2018-05-05

    The magnetic resonance imaging (MRI) relaxation time constants, T1 and T2, are sensitive to changes in brain tissue microstructure integrity. Quantitative T1 and T2 relaxation times have been proposed to serve as non-invasive biomarkers of Alzheimer's disease (AD), in which alterations are believed to not only reflect AD-related neuropathology but also cognitive impairment. In this review, we summarize the applications and key findings of MRI techniques in the context of both AD subjects and AD transgenic mouse models. Furthermore, the possible mechanisms of relaxation time alterations in AD will be discussed. Future studies could focus on relaxation time alterations in the early stage of AD, and longitudinal studies are needed to further explore relaxation time alterations during disease progression. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Construction of a yeast artificial chromosome contig encompassing the chromosome 14 Alzheimer`s disease locus

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    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 contigmore » 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.« less

  18. Similar autobiographical memory impairment in long-term secondary progressive multiple sclerosis and Alzheimer's disease.

    PubMed

    Müller, S; Saur, R; Greve, B; Melms, A; Hautzinger, M; Fallgatter, A J; Leyhe, T

    2013-02-01

    Memory disturbance is a common symptom of multiple sclerosis (MS), but little is known about autobiographical memory deficits in the long-term course of different MS subtypes. Inflammatory activity and demyelination is pronounced in relapsing-remitting multiple sclerosis (RRMS) whereas, similar to Alzheimer's disease, neurodegeneration affecting autobiographical memory-associated areas is seen in secondary progressive multiple sclerosis (SPMS). In light of distinct disease mechanisms, we evaluated autobiographical memory in different MS subtypes and hypothesized similarities between elderly patients with SPMS and Alzheimer's disease. We used the Autobiographical Memory Interview to assess episodic and semantic autobiographical memory in 112 education- and gender-matched participants, including healthy controls and patients with RRMS, SPMS, amnesic mild cognitive impairment (aMCI) and early Alzheimer's dementia (AD). Patients with SPMS, AD, and aMCI, but not with RRMS, exhibited a pattern of episodic autobiographical memory impairment that followed Ribot's Law; older memories were better preserved than more recent memories. In contrast to aMCI and AD, neither SPMS nor RRMS was associated with semantic autobiographical memory impairment. Our neuropsychological findings suggest that episodic autobiographical memory is affected in long-term patients with SPMS, possibly due to neurodegenerative processes in functional relevant brain regions.

  19. The relative contributions of disease label and disease prognosis to Alzheimer's stigma: A vignette-based experiment.

    PubMed

    Johnson, Rebecca; Harkins, Kristin; Cary, Mark; Sankar, Pamela; Karlawish, Jason

    2015-10-01

    The classification of Alzheimer's disease is undergoing a significant transformation. Researchers have created the category of "preclinical Alzheimer's," characterized by biomarker pathology rather than observable symptoms. Diagnosis and treatment at this stage could allow preventing Alzheimer's cognitive decline. While many commentators have worried that persons given a preclinical Alzheimer's label will be subject to stigma, little research exists to inform whether the stigma attached to the label of clinical Alzheimer's will extend to a preclinical disorder that has the label of "Alzheimer's" but lacks the symptoms or expected prognosis of the clinical form. The present study sought to correct this gap by examining the foundations of stigma directed at Alzheimer's. It asked: do people form stigmatizing reactions to the label "Alzheimer's disease" itself or to the condition's observable impairments? How does the condition's prognosis modify these reactions? Data were collected through a web-based experiment with N = 789 adult members of the U.S. general population (median age = 49, interquartile range, 32-60, range = 18-90). Participants were randomized through a 3 × 3 design to read one of 9 vignettes depicting signs and symptoms of mild stage dementia that varied the disease label ("Alzheimer's" vs. "traumatic brain injury" vs. no label) and prognosis (improve vs. static vs. worsen symptoms). Four stigma outcomes were assessed: discrimination, negative cognitive attributions, negative emotions, and social distance. The study found that the Alzheimer's disease label was generally not associated with more stigmatizing reactions. In contrast, expecting the symptoms to get worse, regardless of which disease label those symptoms received, resulted in higher levels of perceived structural discrimination, higher pity, and greater social distance. These findings suggest that stigma surrounding pre-clinical Alzheimer's categories will depend highly on the expected

  20. Attention Measures of Accuracy, Variability, and Fatigue Detect Early Response to Donepezil in Alzheimer's Disease: A Randomized, Double-blind, Placebo-Controlled Pilot Trial.

    PubMed

    Vila-Castelar, Clara; Ly, Jenny J; Kaplan, Lillian; Van Dyk, Kathleen; Berger, Jeffrey T; Macina, Lucy O; Stewart, Jennifer L; Foldi, Nancy S

    2018-04-09

    Donepezil is widely used to treat Alzheimer's disease (AD), but detecting early response remains challenging for clinicians. Acetylcholine is known to directly modulate attention, particularly under high cognitive conditions, but no studies to date test whether measures of attention under high load can detect early effects of donepezil. We hypothesized that load-dependent attention tasks are sensitive to short-term treatment effects of donepezil, while global and other domain-specific cognitive measures are not. This longitudinal, randomized, double-blind, placebo-controlled pilot trial (ClinicalTrials.gov Identifier: NCT03073876) evaluated 23 participants newly diagnosed with AD initiating de novo donepezil treatment (5 mg). After baseline assessment, participants were randomized into Drug (n = 12) or Placebo (n = 11) groups, and retested after approximately 6 weeks. Cognitive assessment included: (a) attention tasks (Foreperiod Effect, Attentional Blink, and Covert Orienting tasks) measuring processing speed, top-down accuracy, orienting, intra-individual variability, and fatigue; (b) global measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental Status Examination, Dementia Rating Scale); and (c) domain-specific measures (memory, language, visuospatial, and executive function). The Drug but not the Placebo group showed benefits of treatment at high-load measures by preserving top-down accuracy, improving intra-individual variability, and averting fatigue. In contrast, other global or cognitive domain-specific measures could not detect treatment effects over the same treatment interval. The pilot-study suggests that attention measures targeting accuracy, variability, and fatigue under high-load conditions could be sensitive to short-term cholinergic treatment. Given the central role of acetylcholine in attentional function, load-dependent attentional measures may be valuable cognitive markers of early treatment response.

  1. Managing Alzheimer dementia tomorrow.

    PubMed

    Rosenthal, Thomas C; Khotianov, Natan

    2003-01-01

    Acetylcholinesterase inhibitors are the first drugs to alter the devastating effects of Alzheimer disease. The next generation of drugs will prevent the beta-amyloid plaques and neurofibrillary tangles or block enzymes that lead to neuron destruction. Effective use of these medications will require early identification of patients at risk. Using the PubMed service of the National Library of Medicine, all English language articles published in 2000, 2001 and the first half of 2002 with a key word of 'dementia' were reviewed for articles that described the emerging pathophysiologic model for Alzheimer disease. Standardized clinical screening tools, such as the mini-mental status examination and the clock test, administered longitudinally and correlated with family observations, can identify many at-risk patients. Genetic testing can identify a known mutation in 70% of patients who have a high family incidence of Alzheimer disease but awaits effective prevention before being useful. The molecular mechanisms of Alzheimer disease will eventually lead to prevention. Today, these patients benefit from nutritional support and lifestyle enhancement encouraged through a continuous primary care relationship.

  2. Potential of chromatin modifying compounds for the treatment of Alzheimer's disease

    PubMed Central

    Karagiannis, Tom C.; Ververis, Katherine

    2012-01-01

    Alzheimer's disease is a very common progressive neurodegenerative disorder affecting the learning and memory centers in the brain. The hallmarks of disease are the accumulation of β-amyloid neuritic plaques and neurofibrillary tangles formed by abnormally phosphorylated tau protein. Alzheimer's disease is currently incurable and there is an intense interest in the development of new potential therapies. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors have been evaluated in models of Alzheimer's disease with some promising results. For example, the natural antioxidant and sirtuin 1 activator resveratrol has been shown to have beneficial effects in animal models of disease. Similarly, numerous histone deacetylase inhibitors including Trichostatin A, suberoylanilide hydroxamic acid, valproic acid and phenylbutyrate reduction have shown promising results in models of Alzheimer's disease. These beneficial effects include a reduction of β-amyloid production and stabilization of tau protein. In this review we provide an overview of the histone deacetylase enzymes, with a focus on enzymes that have been identified to have an important role in the pathobiology of Alzheimer's disease. Further, we discuss the potential for pharmacological intervention with chromatin modifying compounds that modulate histone deacetylase enzymes. PMID:22953035

  3. Potential of chromatin modifying compounds for the treatment of Alzheimer's disease.

    PubMed

    Karagiannis, Tom C; Ververis, Katherine

    2012-01-01

    Alzheimer's disease is a very common progressive neurodegenerative disorder affecting the learning and memory centers in the brain. The hallmarks of disease are the accumulation of β-amyloid neuritic plaques and neurofibrillary tangles formed by abnormally phosphorylated tau protein. Alzheimer's disease is currently incurable and there is an intense interest in the development of new potential therapies. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors have been evaluated in models of Alzheimer's disease with some promising results. For example, the natural antioxidant and sirtuin 1 activator resveratrol has been shown to have beneficial effects in animal models of disease. Similarly, numerous histone deacetylase inhibitors including Trichostatin A, suberoylanilide hydroxamic acid, valproic acid and phenylbutyrate reduction have shown promising results in models of Alzheimer's disease. These beneficial effects include a reduction of β-amyloid production and stabilization of tau protein. In this review we provide an overview of the histone deacetylase enzymes, with a focus on enzymes that have been identified to have an important role in the pathobiology of Alzheimer's disease. Further, we discuss the potential for pharmacological intervention with chromatin modifying compounds that modulate histone deacetylase enzymes.

  4. Pharmacologic management of Alzheimer disease.

    PubMed

    Downey, Deborah

    2008-02-01

    Although the diagnosis of AD can be devastating, treatment options exist that can slow the disease's progression and allow patients to continue performing ADLs, thereby improving the quality of life for both patient and caregiver. Research is ongoing, and it is estimated by the Alzheimer's Association that finding a treatment that could delay onset by only 5 years could reduce the number of individuals with AD by nearly 50% over the next 50 years (Alzheimer's Association, 2007). Although pharmacotherapy is not yet a cure, it does remain an important part of a total approach to caring for patients and families affected by AD.

  5. On the Parallel Deterioration of Lexico-Semantic Processes in the Bilinguals' Two Languages: Evidence from Alzheimer's Disease

    ERIC Educational Resources Information Center

    Costa, Albert; Calabria, Marco; Marne, Paula; Hernandez, Mireia; Juncadella, Montserrat; Gascon-Bayarri, Jordi; Lleo, Alberto; Ortiz-Gil, Jordi; Ugas, Lidia; Blesa, Rafael; Rene, Ramon

    2012-01-01

    In this article we aimed to assess how Alzheimer's disease (AD), which is neurodegenerative, affects the linguistic performance of early, high-proficient bilinguals in their two languages. To this end, we compared the Picture Naming and Word Translation performances of two groups of AD patients varying in disease progression (Mild and Moderate)…

  6. An Evaluation of Recollection and Familiarity in Alzheimer's Disease and Mild Cognitive Impairment Using Receiver Operating Characteristics

    ERIC Educational Resources Information Center

    Ally, Brandon A.; Gold, Carl A.; Budson, Andrew E.

    2009-01-01

    There is a need to investigate exactly how memory breaks down in the course of Alzheimer's disease (AD). Examining what aspects of memorial processing remain relatively intact early in the disease process will allow us to develop behavioral interventions and possible drug therapies focused on these intact processes. Several recent studies have…

  7. Neuropsychiatric signs and symptoms of Alzheimer's disease: New treatment paradigms.

    PubMed

    Lanctôt, Krista L; Amatniek, Joan; Ancoli-Israel, Sonia; Arnold, Steven E; Ballard, Clive; Cohen-Mansfield, Jiska; Ismail, Zahinoor; Lyketsos, Constantine; Miller, David S; Musiek, Erik; Osorio, Ricardo S; Rosenberg, Paul B; Satlin, Andrew; Steffens, David; Tariot, Pierre; Bain, Lisa J; Carrillo, Maria C; Hendrix, James A; Jurgens, Heidi; Boot, Brendon

    2017-09-01

    Neuropsychiatric symptoms (NPSs) are hallmarks of Alzheimer's disease (AD), causing substantial distress for both people with dementia and their caregivers, and contributing to early institutionalization. They are among the earliest signs and symptoms of neurocognitive disorders and incipient cognitive decline, yet are under-recognized and often challenging to treat. With this in mind, the Alzheimer's Association convened a Research Roundtable in May 2016, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of NPSs and review the development of therapeutics and biomarkers of NPSs in AD. This review will explore the neurobiology of NPSs in AD and specific symptoms common in AD such as psychosis, agitation, apathy, depression, and sleep disturbances. In addition, clinical trial designs for NPSs in AD and regulatory considerations will be discussed.

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

    PubMed

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

    2015-01-01

    Cerebrovascular impairment is frequent in patients with Alzheimer disease and is believed to influence clinical manifestation and severity of the disease. Cardiovascular risk factors, especially hypertension, have been associated with higher risk of developing Alzheimer disease. To investigate the mechanisms underlying the hypertension, Alzheimer disease cross talk, we established a mouse model of dual pathology by infusing hypertensive doses of angiotensin II into transgenic APPPS1 mice overexpressing mutated human amyloid precursor and presenilin 1 proteins. At 4.5 months, at the early stage of disease progression, only hypertensive APPPS1 mice presented impairment of temporal order memory performance in the episodic-like memory task. This cognitive deficit was associated with an increased number of cortical amyloid deposits (223±5 versus 207±5 plaques/mm(2); P<0.05) and a 2-fold increase in soluble amyloid levels in the brain and in plasma. Hypertensive APPPS1 mice presented several cerebrovascular alterations, including a 25% reduction in cerebral microvessel density and a 30% to 40% increase in cerebral vascular amyloid deposits, as well as a decrease in vascular endothelial growth factor A expression in the brain, compared with normotensive APPPS1 mice. Moreover, the brain levels of nitric oxide synthase 1 and 3 and the nitrite/nitrate levels were reduced in hypertensive APPPS1 mice (by 49%, 34%, and 33%, respectively, compared with wild-type mice; P<0.05). Our results indicate that hypertension accelerates the development of Alzheimer disease-related structural and functional alterations, partially through cerebral vasculature impairment and reduced nitric oxide production. © 2014 American Heart Association, Inc.

  9. [A case report of early-onset Alzheimer's disease with multiple psychotic symptoms, finally diagnosed as APPV717I mutation by genetic testing].

    PubMed

    Ishimaru, Takashi; Ochi, Shinichiro; Matsumoto, Teruhisa; Yoshida, Taku; Abe, Masao; Toyota, Yasutaka; Fukuhara, Ryuji; Tanimukai, Satoshi; Ueno, Shu-ichi

    2013-01-01

    It is difficult to confirm a diagnosis of early-onset Alzheimer's disease (EOAD) because patients sometimes have non-specific cortical features, such as psychiatric symptoms, executive functional impairment, and pyramidal symptoms, along with typical symptoms, such as recent memory impairment and disorientation. We encountered a patient with multiple psychotic symptoms, finally diagnosed with EOAD on genetic testing. A right-handed sixty-year-old man, whose mother was suspected of having dementia, developed memory impairment at the age of fifty, disorientation at the age of fifty-six, and both visual hallucination and dressing apraxia at the age of fifty-nine. After admission to a psychiatric hospital for treatment, his symptoms disappeared with antipsychotic medication. However, his ADL were declining and so he was referred to our university hospital. He had frontal lobe symptoms, pyramidal signs, and extrapyramidal signs with severe dementia. Neuropsychological examinations were not possible because of sedation. On brain MRI, he showed diffuse atrophy of the cerebral cortex and hippocampus. HMPO-SPECT showed hypoperfusion of cerebral cortices diffusely. We decided to perform genetic testing because he had both family and alcohol abuse histories. He showed EOAD with V717I mutation of the amyloid precursor protein gene. After the discontinuation of antipsychotics, excessive sedation and extrapyramidal signs disappeared. A dose of 10 mg of donepezil was effective to improve motivation and activity, and his mini mental examination score was calculable after recovery. The case supports usefulness of applying genetic testing for Alzheimer's disease to patients with early onset dementia, even when they do not have a family history.

  10. Medication for Alzheimer's disease and associated fall hazard: a retrospective cohort study from the Alzheimer's Disease Neuroimaging Initiative.

    PubMed

    Epstein, Noam U; Guo, Rong; Farlow, Martin R; Singh, Jaswinder P; Fisher, Morris

    2014-02-01

    Falls are common in the elderly, especially in those with cognitive impairment. The elderly are often treated with several medications, which may have both beneficial and deleterious effects. The use and type of medication in Alzheimer's disease (AD) patients and association with falls is limited. We examined the association between falls and medication use in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Diagnosis, demographics, medication use, apolipoprotein E4 allele status and functional activity level at baseline were gathered for 810 participants enrolled in the ADNI, including healthy controls and subjects with mild cognitive impairment or Alzheimer's. Reports detailing adverse event falls were tabulated. Baseline characteristics were compared between subjects with and without one or more falls. Cox proportional hazards models were conducted to evaluate the association between subject characteristics and hazard of the first fall. Age (p < 0.0001), Functional Activities Questionnaire (p = 0.035), Beers List (p = 0.0477) and medications for treating cognitive symptoms of Alzheimer's (p = 0.0019) were associated with hazard of fall in the univariate model. In the final multivariate model, after adjusting for covariates, Alzheimer's medication use (p = 0.0005) was associated with hazard of fall. Medication was changed by the clinician after an adverse fall event in 9% of the falls. About 7% of the falls were reported as serious adverse events and 6% were reported to be severe. We found a significant association between the use of symptomatic medication treating cognitive symptoms in AD and hazard of fall after adjusting for age and Beers List medication use. Additional pharmacovigilance of the association between falls and Alzheimer's medication use is warranted.

  11. Apolipoprotein E in the genetics and epidemiology of Alzheimer`s disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    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 agemore » 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.« less

  12. Magnetic resonance imaging biomarkers for the early diagnosis of Alzheimer's disease: a machine learning approach.

    PubMed

    Salvatore, Christian; Cerasa, Antonio; Battista, Petronilla; Gilardi, Maria C; Quattrone, Aldo; Castiglioni, Isabella

    2015-01-01

    Determination of sensitive and specific markers of very early AD progression is intended to aid researchers and clinicians to develop new treatments and monitor their effectiveness, as well as to lessen the time and cost of clinical trials. Magnetic Resonance (MR)-related biomarkers have been recently identified by the use of machine learning methods for the in vivo differential diagnosis of AD. However, the vast majority of neuroimaging papers investigating this topic are focused on the difference between AD and patients with mild cognitive impairment (MCI), not considering the impact of MCI patients who will (MCIc) or not convert (MCInc) to AD. Morphological T1-weighted MRIs of 137 AD, 76 MCIc, 134 MCInc, and 162 healthy controls (CN) selected from the Alzheimer's disease neuroimaging initiative (ADNI) cohort, were used by an optimized machine learning algorithm. Voxels influencing the classification between these AD-related pre-clinical phases involved hippocampus, entorhinal cortex, basal ganglia, gyrus rectus, precuneus, and cerebellum, all critical regions known to be strongly involved in the pathophysiological mechanisms of AD. Classification accuracy was 76% AD vs. CN, 72% MCIc vs. CN, 66% MCIc vs. MCInc (nested 20-fold cross validation). Our data encourage the application of computer-based diagnosis in clinical practice of AD opening new prospective in the early management of AD patients.

  13. Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms.

    PubMed

    Cruchaga, Carlos; Del-Aguila, Jorge L; Saef, Benjamin; Black, Kathleen; Fernandez, Maria Victoria; Budde, John; Ibanez, Laura; Deming, Yuetiva; Kapoor, Manav; Tosto, Giuseppe; Mayeux, Richard P; Holtzman, David M; Fagan, Anne M; Morris, John C; Bateman, Randall J; Goate, Alison M; Harari, Oscar

    2018-02-01

    To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer's Disease (sLOAD), familial late-onset AD (fLOAD), sporadic early-onset AD (sEOAD), and autosomal dominant early-onset AD (eADAD). Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk. We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10 -7 ) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10 -7 ) and sLOAD (OR = 1.40; P = 1.21 × 10 -3 ). The PRS was associated with cerebrospinal fluid ptau 181 -Aβ 42 on eADAD (P = 4.36 × 10 -2 ). Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

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

    PubMed

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

    2018-07-01

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

  15. Looking for signs of Alzheimer's disease.

    PubMed

    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 children with a living parent with a diagnosis of probable AD; and 2) 150 adults in a matched group with no parental history of AD. Bivariate and multivariate analyses were used to identify significant predictors of symptom seeking, which was measured by a composite index comprised of responses from three questions about checking for signs of AD, interpreting signs as symptoms of AD, and soliciting external validation for concerns. Four clusters of predictors were examined: memory assessment, AD experience, sociodemographics, and well-being. Within these clusters, the constellations of significant predictors varied by subsample, but the most robust predictors were aspects of subjective assessments of memory functioning and AD experience. An understanding of the correlates of symptom seeking for AD has implications for early detection of the disease as well as identifying populations under stress from excessive worry about their own future health.

  16. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease.

    PubMed

    Jack, Clifford R; Lowe, Val J; Weigand, Stephen D; Wiste, Heather J; Senjem, Matthew L; Knopman, David S; Shiung, Maria M; Gunter, Jeffrey L; Boeve, Bradley F; Kemp, Bradley J; Weiner, Michael; Petersen, Ronald C

    2009-05-01

    The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimer's disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial (11)C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimer's disease. Subjects were drawn from two sources--ongoing longitudinal registries at Mayo Clinic, and the Alzheimer's disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm(3) by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P = 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm(3)/year) < amnestic mild cognitive impairment (2.5 cm(3)/year) < Alzheimer's disease (7.7 cm(3)/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r = -0.01, P = 0.97) but some evidence of a weak correlation with MMSE (r =-0.22, P = 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r = 0.42, P < 0.01) and MMSE (r =-0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimer's disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow

  17. 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…

  18. Protein-protein interaction analysis of Alzheimer`s disease and NAFLD based on systems biology methods unhide common ancestor pathways.

    PubMed

    Karbalaei, Reza; Allahyari, Marzieh; Rezaei-Tavirani, Mostafa; Asadzadeh-Aghdaei, Hamid; Zali, Mohammad Reza

    2018-01-01

    Analysis reconstruction networks from two diseases, NAFLD and Alzheimer`s diseases and their relationship based on systems biology methods. NAFLD and Alzheimer`s diseases are two complex diseases, with progressive prevalence and high cost for countries. There are some reports on relation and same spreading pathways of these two diseases. In addition, they have some similar risk factors, exclusively lifestyle such as feeding, exercises and so on. Therefore, systems biology approach can help to discover their relationship. DisGeNET and STRING databases were sources of disease genes and constructing networks. Three plugins of Cytoscape software, including ClusterONE, ClueGO and CluePedia, were used to analyze and cluster networks and enrichment of pathways. An R package used to define best centrality method. Finally, based on degree and Betweenness, hubs and bottleneck nodes were defined. Common genes between NAFLD and Alzheimer`s disease were 190 genes that used construct a network with STRING database. The resulting network contained 182 nodes and 2591 edges and comprises from four clusters. Enrichment of these clusters separately lead to carbohydrate metabolism, long chain fatty acid and regulation of JAK-STAT and IL-17 signaling pathways, respectively. Also seven genes selected as hub-bottleneck include: IL6, AKT1, TP53, TNF, JUN, VEGFA and PPARG. Enrichment of these proteins and their first neighbors in network by OMIM database lead to diabetes and obesity as ancestors of NAFLD and AD. Systems biology methods, specifically PPI networks, can be useful for analyzing complicated related diseases. Finding Hub and bottleneck proteins should be the goal of drug designing and introducing disease markers.

  19. Loss of serum IGF-I input to the brain as an early biomarker of disease onset in Alzheimer mice

    PubMed Central

    Trueba-Sáiz, A; Cavada, C; Fernandez, A M; Leon, T; González, D A; Fortea Ormaechea, J; Lleó, A; Del Ser, T; Nuñez, A; Torres-Aleman, I

    2013-01-01

    Circulating insulin-like growth factor I (IGF-I) enters the brain and promotes clearance of amyloid peptides known to accumulate in Alzheimer's disease (AD) brains. Both patients and mouse models of AD show decreased level of circulating IGF-I enter the brain as evidenced by a lower ratio of cerebrospinal fluid/plasma IGF-I. Importantly, in presymptomatic AD mice this reduction is already manifested as a decreased brain input of serum IGF-I in response to environmental enrichment. To explore a potential diagnostic use of this early loss of IGF-I input, we monitored electrocorticogram (ECG) responses to systemic IGF-I in mice. Whereas control mice showed enhanced ECG activity after IGF-I, presymptomatic AD mice showed blunted ECG responses. Because nonhuman primates showed identically enhanced electroencephalogram (EEG) activity in response to systemic IGF-I, loss of the EEG signature of serum IGF-I may be exploited as a disease biomarker in AD patients. PMID:24301648

  20. Diagnosis of Cognitive Impairment Compatible with Early Diagnosis of Alzheimer's Disease. A Bayesian Network Model based on the Analysis of Oral Definitions of Semantic Categories.

    PubMed

    Guerrero, J M; Martínez-Tomás, R; Rincón, M; Peraita, H

    2016-01-01

    Early detection of Alzheimer's disease (AD) has become one of the principal focuses of research in medicine, particularly when the disease is incipient or even prodromic, because treatments are more effective in these stages. Lexical-semantic-conceptual deficit (LSCD) in the oral definitions of semantic categories for basic objects is an important early indicator in the evaluation of the cognitive state of patients. The objective of this research is to define an economic procedure for cognitive impairment (CI) diagnosis, which may be associated with early stages of AD, by analysing cognitive alterations affecting declarative semantic memory. Because of its low cost, it could be used for routine clinical evaluations or screenings, leading to more expensive and selective tests that confirm or rule out the disease accurately. It should necessarily be an explanatory procedure, which would allow us to study the evolution of the disease in relation to CI, the irregularities in different semantic categories, and other neurodegenerative diseases. On the basis of these requirements, we hypothesise that Bayesian networks (BNs) are the most appropriate tool for this purpose. We have developed a BN for CI diagnosis in mild and moderate AD patients by analysing the oral production of semantic features. The BN causal model represents LSCD in certain semantic categories, both of living things (dog, pine, and apple) and non-living things (chair, car, and trousers), as symptoms of CI. The model structure, the qualitative part of the model, uses domain knowledge obtained from psychology experts and epidemiological studies. Further, the model parameters, the quantitative part of the model, are learnt automatically from epidemiological studies and Peraita and Grasso's linguistic corpus of oral definitions. This corpus was prepared with an incidental sampling and included the analysis of the oral linguistic production of 81 participants (42 cognitively healthy elderly people and 39

  1. The Genetics of Alzheimer Disease

    PubMed Central

    Tanzi, Rudolph E.

    2012-01-01

    Family history is the second strongest risk factor for Alzheimer disease (AD) following advanced age. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations in APP, PSEN1, and PSEN2 virtually guarantee early-onset (<60 years) familial AD, which represents ∼5% of AD. On the other hand, common gene polymorphisms, such as the ε4 and ε2 variants of the APOE gene, can influence susceptibility for ∼50% of the common late-onset AD. These four genes account for 30%–50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of 11 additional AD candidate genes. This paper reviews the past, present, and future attempts to elucidate the complex and heterogeneous genetic underpinnings of AD. PMID:23028126

  2. Genetic study of multimodal imaging Alzheimer's disease progression score implicates novel loci.

    PubMed

    Scelsi, Marzia A; Khan, Raiyan R; Lorenzi, Marco; Christopher, Leigh; Greicius, Michael D; Schott, Jonathan M; Ourselin, Sebastien; Altmann, Andre

    2018-05-30

    Identifying genetic risk factors underpinning different aspects of Alzheimer's disease has the potential to provide important insights into pathogenesis. Moving away from simple case-control definitions, there is considerable interest in using quantitative endophenotypes, such as those derived from imaging as outcome measures. Previous genome-wide association studies of imaging-derived biomarkers in sporadic late-onset Alzheimer's disease focused only on phenotypes derived from single imaging modalities. In contrast, we computed a novel multi-modal neuroimaging phenotype comprising cortical amyloid burden and bilateral hippocampal volume. Both imaging biomarkers were used as input to a disease progression modelling algorithm, which estimates the biomarkers' long-term evolution curves from population-based longitudinal data. Among other parameters, the algorithm computes the shift in time required to optimally align a subjects' biomarker trajectories with these population curves. This time shift serves as a disease progression score and it was used as a quantitative trait in a discovery genome-wide association study with n = 944 subjects from the Alzheimer's Disease Neuroimaging Initiative database diagnosed as Alzheimer's disease, mild cognitive impairment or healthy at the time of imaging. We identified a genome-wide significant locus implicating LCORL (rs6850306, chromosome 4; P = 1.03 × 10-8). The top variant rs6850306 was found to act as an expression quantitative trait locus for LCORL in brain tissue. The clinical role of rs6850306 in conversion from healthy ageing to mild cognitive impairment or Alzheimer's disease was further validated in an independent cohort comprising healthy, older subjects from the National Alzheimer's Coordinating Center database. Specifically, possession of a minor allele at rs6850306 was protective against conversion from mild cognitive impairment to Alzheimer's disease in the National Alzheimer's Coordinating Center cohort (hazard

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

    PubMed

    Viola, Kirsten L; Klein, William L

    2015-02-01

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

  4. Chromosome 14 and late-onset familial alzheimer disease (FAD)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Schellenberg, G.D.; Anderson, L.; Nemens, E.

    1993-09-01

    Familial Alzheimer disease (FAD) is genetically heterogeneous. Two loci responsible for early-onset FAD have been identified: the amyloid precursor protein gene on chromosome 21 and the as-yet-unidentified locus on chromosome 14. The genetics of late-onset FAD is unresolved. Maximum-likelihood, affected-pedigree-member (APM), and sib-pair analysis were used, in 49 families with a mean age at onset [>=]60 years, to determine whether the chromosome 14 locus is responsible for late-onset FAD. The markers used were D14S53, D14S43, and D14S52. The LOD score method was used to test for linkage of late-onset FAD to the chromosome 14 markers, under three different models: age-dependentmore » penetrance, an affected-only analysis, and age-dependent penetrance with allowance for possible age-dependent sporadic cases. No evidence for linkage was obtained under any of these conditions for the late-onset kindreds, and strong evidence against linkage (LOD score [>=]2.0) to this region was obtained. Heterogeneity tests of the LOD score results for the combined group of families (early onset, Volga Germans, and late onset) favored the hypothesis of linkage to chromosome 14 with genetic heterogeneity. The positive results are primarily from early-onset families. APM analysis gave significant evidence for linkage of D14S43 and D14S52 to FAD in early-onset kindreds (P<.02). No evidence for linkage was found for the entire late-onset family group. Significant evidence for linkage to D14S52, however, was found for a subgroup of families of intermediate age at onset (mean age at onset [>=]60 years and <70 years). These results indicate that the chromosome 14 locus is not responsible for Alzheimer disease in most late-onset FAD kindreds but could play a role in a subset of these kindreds. 37 refs., 1 fig., 6 tabs.« less

  5. Recognition and treatment of Alzheimer's disease: a case-based review.

    PubMed

    Marseille, Dana M; Silverman, Daniel H S

    2006-01-01

    Early recognition and treatment initiation are pivotal in managing Alzheimer's disease (AD). Once a diagnosis of AD is made, a treatment plan is developed and should include treatment initiation with cholinesterase inhibitors (ChEIs) to improve cognition, management of comorbid conditions, and treat behavioral symptoms. Caregiver compliance is integral to AD treatment success. The purpose of this report is to present two real case studies of "suspected" AD or related dementia and stress the significance of early and accurate diagnosis in disease management. In case 1, a caregiver reports gradual but progressive loss of memory, and the patient himself complains of memory impairment. Neuroimaging analysis confirms "typical " AD. In case 2, initiation of ChEI therapy is followed by substantial clinical improvement in the face of a complex medical picture, and neuroimaging revealing more neurodegenerative changes than could be accounted for by "pure" AD.

  6. 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…

  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. Machine learning and social network analysis applied to Alzheimer's disease biomarkers.

    PubMed

    Di Deco, Javier; González, Ana M; Díaz, Julia; Mato, Virginia; García-Frank, Daniel; Álvarez-Linera, Juan; Frank, Ana; Hernández-Tamames, Juan A

    2013-01-01

    Due to the fact that the number of deaths due Alzheimer is increasing, the scientists have a strong interest in early stage diagnostic of this disease. Alzheimer's patients show different kind of brain alterations, such as morphological, biochemical, functional, etc. Currently, using magnetic resonance imaging techniques is possible to obtain a huge amount of biomarkers; being difficult to appraise which of them can explain more properly how the pathology evolves instead of the normal ageing. Machine Learning methods facilitate an efficient analysis of complex data and can be used to discover which biomarkers are more informative. Moreover, automatic models can learn from historical data to suggest the diagnostic of new patients. Social Network Analysis (SNA) views social relationships in terms of network theory consisting of nodes and connections. The resulting graph-based structures are often very complex; there can be many kinds of connections between the nodes. SNA has emerged as a key technique in modern sociology. It has also gained a significant following in medicine, anthropology, biology, information science, etc., and has become a popular topic of speculation and study. This paper presents a review of machine learning and SNA techniques and then, a new approach to analyze the magnetic resonance imaging biomarkers with these techniques, obtaining relevant relationships that can explain the different phenotypes in dementia, in particular, different stages of Alzheimer's disease.

  9. In vivo detection of microstructural correlates of brain pathology in preclinical and early Alzheimer Disease with magnetic resonance imaging.

    PubMed

    Zhao, Yue; Raichle, Marcus E; Wen, Jie; Benzinger, Tammie L; Fagan, Anne M; Hassenstab, Jason; Vlassenko, Andrei G; Luo, Jie; Cairns, Nigel J; Christensen, Jon J; Morris, John C; Yablonskiy, Dmitriy A

    2017-03-01

    Alzheimer disease (AD) affects at least 5 million individuals in the USA alone stimulating an intense search for disease prevention and treatment therapies as well as for diagnostic techniques allowing early identification of AD during a long pre-symptomatic period that can be used for the initiation of prevention trials of disease-modifying therapies in asymptomatic individuals. Our approach to developing such techniques is based on the Gradient Echo Plural Contrast Imaging (GEPCI) technique that provides quantitative in vivo measurements of several brain-tissue-specific characteristics of the gradient echo MRI signal (GEPCI metrics) that depend on the integrity of brain tissue cellular structure. Preliminary data were obtained from 34 participants selected from the studies of aging and dementia at the Knight Alzheimer's Disease Research Center at Washington University in St. Louis. Cognitive status was operationalized with the Clinical Dementia Rating (CDR) scale. The participants, assessed as cognitively normal (CDR=0; n=23) or with mild AD dementia (CDR=0.5 or 1; n=11) underwent GEPCI MRI, a collection of cognitive performance tests and CSF amyloid (Aβ) biomarker Aβ 42 . A subset of 19 participants also underwent PET PiB studies to assess their brain Aβ burden. According to the Aβ status, cognitively normal participants were divided into normal (Aβ negative; n=13) and preclinical (Aβ positive; n=10) groups. GEPCI quantitative measurements demonstrated significant differences between all the groups: normal and preclinical, normal and mild AD, and preclinical and mild AD. GEPCI quantitative metrics characterizing tissue cellular integrity in the hippocampus demonstrated much stronger correlations with psychometric tests than the hippocampal atrophy. Importantly, GEPCI-determined changes in the hippocampal tissue cellular integrity were detected even in the hippocampal areas not affected by the atrophy. Our studies also uncovered strong correlations between

  10. A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families.

    PubMed

    Athan, E S; Williamson, J; Ciappa, A; Santana, V; Romas, S N; Lee, J H; Rondon, H; Lantigua, R A; Medrano, M; Torres, M; Arawaka, S; Rogaeva, E; Song, Y Q; Sato, C; Kawarai, T; Fafel, K C; Boss, M A; Seltzer, W K; Stern, Y; St George-Hyslop, P; Tycko, B; Mayeux, R

    2001-11-14

    Genetic determinants of Alzheimer disease (AD) have not been comprehensively examined in Caribbean Hispanics, a population in the United States in whom the frequency of AD is higher compared with non-Hispanic whites. To identify variant alleles in genes related to familial early-onset AD among Caribbean Hispanics. Family-based case series conducted in 1998-2001 at an AD research center in New York, NY, and clinics in the Dominican Republic. Among 206 Caribbean Hispanic families with 2 or more living members with AD who were identified, 19 (9.2%) had at least 1 individual with onset of AD before the age of 55 years. The entire coding region of the presenilin 1 gene and exons 16 and 17 of the amyloid precursor protein gene were sequenced in probands from the 19 families and their living relatives. A G-to-C nucleotide change resulting in a glycine-alanine amino acid substitution at codon 206 (Gly206Ala) in exon 7 of presenilin 1 was observed in 23 individuals from 8 (42%) of the 19 families. A Caribbean Hispanic individual with the Gly206Ala mutation and early-onset familial disease was also found by sequencing the corresponding genes of 319 unrelated individuals in New York City. The Gly206Ala mutation was not found in public genetic databases but was reported in 5 individuals from 4 Hispanic families with AD referred for genetic testing. None of the members of these families were related to one another, yet all carriers of the Gly206Ala mutation tested shared a variant allele at 2 nearby microsatellite polymorphisms, indicating a common ancestor. No mutations were found in the amyloid precursor protein gene. The Gly206Ala mutation was found in 8 of 19 unrelated Caribbean Hispanic families with early-onset familial AD. This genetic change may be a prevalent cause of early-onset familial AD in the Caribbean Hispanic population.

  11. Semantic Memory in the Clinical Progression of Alzheimer Disease.

    PubMed

    Tchakoute, Christophe T; Sainani, Kristin L; Henderson, Victor W

    2017-09-01

    Semantic memory measures may be useful in tracking and predicting progression of Alzheimer disease. We investigated relationships among semantic memory tasks and their 1-year predictive value in women with Alzheimer disease. We conducted secondary analyses of a randomized clinical trial of raloxifene in 42 women with late-onset mild-to-moderate Alzheimer disease. We assessed semantic memory with tests of oral confrontation naming, category fluency, semantic recognition and semantic naming, and semantic density in written narrative discourse. We measured global cognition (Alzheimer Disease Assessment Scale, cognitive subscale), dementia severity (Clinical Dementia Rating sum of boxes), and daily function (Activities of Daily Living Inventory) at baseline and 1 year. At baseline and 1 year, most semantic memory scores correlated highly or moderately with each other and with global cognition, dementia severity, and daily function. Semantic memory task performance at 1 year had worsened one-third to one-half standard deviation. Factor analysis of baseline test scores distinguished processes in semantic and lexical retrieval (semantic recognition, semantic naming, confrontation naming) from processes in lexical search (semantic density, category fluency). The semantic-lexical retrieval factor predicted global cognition at 1 year. Considered separately, baseline confrontation naming and category fluency predicted dementia severity, while semantic recognition and a composite of semantic recognition and semantic naming predicted global cognition. No individual semantic memory test predicted daily function. Semantic-lexical retrieval and lexical search may represent distinct aspects of semantic memory. Semantic memory processes are sensitive to cognitive decline and dementia severity in Alzheimer disease.

  12. The Role of Genetics in Advancing Precision Medicine for Alzheimer's Disease-A Narrative Review.

    PubMed

    Freudenberg-Hua, Yun; Li, Wentian; Davies, Peter

    2018-01-01

    Alzheimer's disease (AD) is the most common type of dementia, which has a substantial genetic component. AD affects predominantly older people. Accordingly, the prevalence of dementia has been rising as the population ages. To date, there are no effective interventions that can cure or halt the progression of AD. The only available treatments are the management of certain symptoms and consequences of dementia. The current state-of-the-art medical care for AD comprises three simple principles: prevent the preventable, achieve early diagnosis, and manage the manageable symptoms. This review provides a summary of the current state of knowledge of risk factors for AD, biological diagnostic testing, and prospects for treatment. Special emphasis is given to recent advances in genetics of AD and the way genomic data may support prevention, early intervention, and development of effective pharmacological treatments. Mutations in the APP, PSEN1 , and PSEN2 genes cause early onset Alzheimer's disease (EOAD) that follows a Mendelian inheritance pattern. For late onset Alzheimer's disease (LOAD), APOE4 was identified as a major risk allele more than two decades ago. Population-based genome-wide association studies of late onset AD have now additionally identified common variants at roughly 30 genetic loci. Furthermore, rare variants (allele frequency <1%) that influence the risk for LOAD have been identified in several genes. These genetic advances have broadened our insights into the biological underpinnings of AD. Moreover, the known genetic risk variants could be used to identify presymptomatic individuals at risk for AD and support diagnostic assessment of symptomatic subjects. Genetic knowledge may also facilitate precision medicine. The goal of precision medicine is to use biological knowledge and other health information to predict individual disease risk, understand disease etiology, identify disease subcategories, improve diagnosis, and provide personalized treatment

  13. Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease.

    PubMed

    De Roeck, Arne; Van den Bossche, Tobi; van der Zee, Julie; Verheijen, Jan; De Coster, Wouter; Van Dongen, Jasper; Dillen, Lubina; Baradaran-Heravi, Yalda; Heeman, Bavo; Sanchez-Valle, Raquel; Lladó, Albert; Nacmias, Benedetta; Sorbi, Sandro; Gelpi, Ellen; Grau-Rivera, Oriol; Gómez-Tortosa, Estrella; Pastor, Pau; Ortega-Cubero, Sara; Pastor, Maria A; Graff, Caroline; Thonberg, Håkan; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; de Mendonça, Alexandre; Martins, Madalena; Borroni, Barbara; Padovani, Alessandro; Almeida, Maria Rosário; Santana, Isabel; Diehl-Schmid, Janine; Alexopoulos, Panagiotis; Clarimon, Jordi; Lleó, Alberto; Fortea, Juan; Tsolaki, Magda; Koutroumani, Maria; Matěj, Radoslav; Rohan, Zdenek; De Deyn, Peter; Engelborghs, Sebastiaan; Cras, Patrick; Van Broeckhoven, Christine; Sleegers, Kristel

    2017-09-01

    Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may

  14. Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities.

    PubMed

    Parent, Maxime J; Zimmer, Eduardo R; Shin, Monica; Kang, Min Su; Fonov, Vladimir S; Mathieu, Axel; Aliaga, Antonio; Kostikov, Alexey; Do Carmo, Sonia; Dea, Doris; Poirier, Judes; Soucy, Jean-Paul; Gauthier, Serge; Cuello, A Claudio; Rosa-Neto, Pedro

    2017-12-13

    Imaging biomarkers are frequently proposed as endpoints for clinical trials targeting brain amyloidosis in Alzheimer's disease (AD); however, the specific impact of amyloid-β (Aβ) aggregation on biomarker abnormalities remains elusive in AD. Using the McGill-R-Thy1-APP transgenic rat as a model of selective Aβ pathology, we characterized the longitudinal progression of abnormalities in biomarkers commonly used in AD research. Middle-aged (9-11 months) transgenic animals (both male and female) displayed mild spatial memory impairments and disrupted cingulate network connectivity measured by resting-state fMRI, even in the absence of hypometabolism (measured with PET [ 18 F]FDG) or detectable fibrillary amyloidosis (measured with PET [ 18 F]NAV4694). At more advanced ages (16-19 months), cognitive deficits progressed in conjunction with resting connectivity abnormalities; furthermore, hypometabolism, Aβ plaque accumulation, reduction of CSF Aβ 1-42 concentrations, and hippocampal atrophy (structural MRI) were detectable at this stage. The present results emphasize the early impact of Aβ on brain connectivity and support a framework in which persistent Aβ aggregation itself is sufficient to impose memory circuits dysfunction, which propagates to adjacent brain networks at later stages. SIGNIFICANCE STATEMENT The present study proposes a "back translation" of the Alzheimer pathological cascade concept from human to animals. We used the same set of Alzheimer imaging biomarkers typically used in large human cohorts and assessed their progression over time in a transgenic rat model, which allows for a finer spatial resolution not attainable with mice. Using this translational platform, we demonstrated that amyloid-β pathology recapitulates an Alzheimer-like profile of biomarker abnormalities even in the absence of other hallmarks of the disease such as neurofibrillary tangles and widespread neuronal losses. Copyright © 2017 Parent et al.

  15. Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities

    PubMed Central

    Parent, Maxime J.; Kang, Min Su; Mathieu, Axel; Aliaga, Antonio; Do Carmo, Sonia; Dea, Doris; Gauthier, Serge; Cuello, A. Claudio

    2017-01-01

    Imaging biomarkers are frequently proposed as endpoints for clinical trials targeting brain amyloidosis in Alzheimer's disease (AD); however, the specific impact of amyloid-β (Aβ) aggregation on biomarker abnormalities remains elusive in AD. Using the McGill-R-Thy1-APP transgenic rat as a model of selective Aβ pathology, we characterized the longitudinal progression of abnormalities in biomarkers commonly used in AD research. Middle-aged (9–11 months) transgenic animals (both male and female) displayed mild spatial memory impairments and disrupted cingulate network connectivity measured by resting-state fMRI, even in the absence of hypometabolism (measured with PET [18F]FDG) or detectable fibrillary amyloidosis (measured with PET [18F]NAV4694). At more advanced ages (16–19 months), cognitive deficits progressed in conjunction with resting connectivity abnormalities; furthermore, hypometabolism, Aβ plaque accumulation, reduction of CSF Aβ1-42 concentrations, and hippocampal atrophy (structural MRI) were detectable at this stage. The present results emphasize the early impact of Aβ on brain connectivity and support a framework in which persistent Aβ aggregation itself is sufficient to impose memory circuits dysfunction, which propagates to adjacent brain networks at later stages. SIGNIFICANCE STATEMENT The present study proposes a “back translation” of the Alzheimer pathological cascade concept from human to animals. We used the same set of Alzheimer imaging biomarkers typically used in large human cohorts and assessed their progression over time in a transgenic rat model, which allows for a finer spatial resolution not attainable with mice. Using this translational platform, we demonstrated that amyloid-β pathology recapitulates an Alzheimer-like profile of biomarker abnormalities even in the absence of other hallmarks of the disease such as neurofibrillary tangles and widespread neuronal losses. PMID:29097597

  16. ADO: a disease ontology representing the domain knowledge specific to Alzheimer's disease.

    PubMed

    Malhotra, Ashutosh; Younesi, Erfan; Gündel, Michaela; Müller, Bernd; Heneka, Michael T; Hofmann-Apitius, Martin

    2014-03-01

    Biomedical ontologies offer the capability to structure and represent domain-specific knowledge semantically. Disease-specific ontologies can facilitate knowledge exchange across multiple disciplines, and ontology-driven mining approaches can generate great value for modeling disease mechanisms. However, in the case of neurodegenerative diseases such as Alzheimer's disease, there is a lack of formal representation of the relevant knowledge domain. Alzheimer's disease ontology (ADO) is constructed in accordance to the ontology building life cycle. The Protégé OWL editor was used as a tool for building ADO in Ontology Web Language format. ADO was developed with the purpose of containing information relevant to four main biological views-preclinical, clinical, etiological, and molecular/cellular mechanisms-and was enriched by adding synonyms and references. Validation of the lexicalized ontology by means of named entity recognition-based methods showed a satisfactory performance (F score = 72%). In addition to structural and functional evaluation, a clinical expert in the field performed a manual evaluation and curation of ADO. Through integration of ADO into an information retrieval environment, we show that the ontology supports semantic search in scientific text. The usefulness of ADO is authenticated by dedicated use case scenarios. Development of ADO as an open ADO is a first attempt to organize information related to Alzheimer's disease in a formalized, structured manner. We demonstrate that ADO is able to capture both established and scattered knowledge existing in scientific text. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  17. Chalcone-based carbamates for Alzheimer's disease treatment.

    PubMed

    Rampa, Angela; Montanari, Serena; Pruccoli, Letizia; Bartolini, Manuela; Falchi, Federico; Feoli, Alessandra; Cavalli, Andrea; Belluti, Federica; Gobbi, Silvia; Tarozzi, Andrea; Bisi, Alessandra

    2017-05-01

    Alzheimer's disease is a still untreatable multifaceted pathology, and drugs able to stop or reverse its progression are urgently needed. In this picture, the recent reformulation of the cholinergic hypothesis renewed the interest for acetylcholinesterase inhibitors. In this paper, a series of naturally inspired chalcone-based carbamates was designed to target cholinesterase enzymes and possibly generate fragments endowed with neuroprotective activity in situ. Results & methodology: All compounds presented in this study showed nanomolar potency for cholinesterase inhibition. Notably, fragment 11d also displayed an interesting neuroprotective profile. These new derivatives are able to simultaneously modulate different key targets involved in Alzheimer's disease, and could be regarded as promising starting points for the development of disease-modifying drug candidates. [Formula: see text].

  18. Alzheimer's Dye Test?

    ERIC Educational Resources Information Center

    Science Teacher, 2005

    2005-01-01

    Massachusetts Institute of Technology (MIT) scientists have developed a new dye that could offer noninvasive early diagnosis of Alzheimer's disease, a discovery that could aid in monitoring the progression of the disease and in studying the efficacy of new treatments to stop it. The work is published in Angewandte Chemie. Today, doctors can only…

  19. Profiling of Alzheimer's disease patients in Puerto Rico: A comparison of two distinct socioeconomic areas.

    PubMed

    Camacho-Mercado, Clara L; Figueroa, Raúl; Acosta, Heriberto; Arnold, Steven E; Vega, Irving E

    2016-01-01

    The Latino/Hispanic community in the United States is at higher risk of developing Alzheimer's disease than other ethnic groups. Specifically, Caribbean Hispanics showed a more severe Alzheimer's disease symptomatology than any other ethnic group. In a previous study, we demonstrated that the mortality rate associated with Alzheimer's disease in Puerto Rico is higher than that reported in the United States. Moreover, the mortality rate associated with Alzheimer's disease was higher among Puerto Rican living in Puerto Rico than those in the mainland United States. There is also a differential geographical distribution of mortality rate associated with Alzheimer's disease in Puerto Rico, which may be associated with differential socioeconomic status and/or access to healthcare. However, there is no information regarding the clinical profile of Alzheimer's disease patients in Puerto Rico. Here, we present the results of a retrospective study directed to profile Alzheimer's disease patients clustered into two groups based on areas previously determined with low (Metro Region) and high (Northwest-Central Region) mortality rate associated with Alzheimer's disease in Puerto Rico. Significant difference in the age-at-diagnosis and years of education was found among patients within the two studied regions. Despite these differences, both regions showed comparable levels of initial and last Mini Mental State Examination scores and rate of cognitive decline. Significant difference was also observed in the occurance of co-morbidities associated with Alzheimer's disease. The differential profile of Alzheimer's disease patients correlated with differences in socioeconomic status between these two regions, suggesting that covariant associated with social status may contribute to increased risk of developing Alzheimer's disease. Further studies should be conducted to determine the role of socioeconomic factors and healthy living practices as risk factors for Alzheimer's disease.

  20. The ubiquitin proteasomal system: a potential target for the management of Alzheimer's disease.

    PubMed

    Gadhave, Kundlik; Bolshette, Nityanand; Ahire, Ashutosh; Pardeshi, Rohit; Thakur, Krishan; Trandafir, Cristiana; Istrate, Alexandru; Ahmed, Sahabuddin; Lahkar, Mangala; Muresanu, Dafin F; Balea, Maria

    2016-07-01

    The cellular quality control system degrades abnormal or misfolded proteins and consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy and molecular chaperones. Any disturbance in this system causes proteins to accumulate, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and prion or polyglutamine diseases. Alzheimer's disease is currently one of the most common age-related neurodegenerative diseases. However, its exact cause and pathogenesis are unknown. Currently approved medications for AD provide symptomatic relief; however, they fail to influence disease progression. Moreover, the components of the cellular quality control system represent an important focus for the development of targeted and potent therapies for managing AD. This review aims to evaluate whether existing evidence supports the hypothesis that UPS impairment causes the early pathogenesis of neurodegenerative disorders. The first part presents basic information about the UPS and its molecular components. The next part explains how the UPS is involved in neurodegenerative disorders. Finally, we emphasize how the UPS influences the management of AD. This review may help in the design of future UPS-related therapies for AD. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  1. Biomarkers in the Diagnosis and Prognosis of Alzheimer's Disease.

    PubMed

    Schaffer, Cole; Sarad, Nakia; DeCrumpe, Ashton; Goswami, Disha; Herrmann, Sara; Morales, Jose; Patel, Parth; Osborne, Jim

    2015-10-01

    Alzheimer's disease (AD) is a neurodegenerative disease that inhibits cognitive functions and has no cure. This report reviews the current diagnostic standards for AD with an emphasis on early diagnosis using the cerebrospinal fluid (CSF) biomarkers amyloid-beta, t-tau, and p-tau and fluorodeoxyglucose positron emission tomography imaging. Abnormal levels of these CSF biomarkers and decreased cerebral uptake of glucose have recently been used in the early diagnosis of AD in experimental studies. These promising biomarkers can be measured using immunoassays performed in singleplex or multiplex formats. Although presently, there are no Food and Drug Administration-approved in vitro diagnostics (IVDs) for early detection of AD, a multiplex immunoassay measuring a panel of promising AD biomarkers in CSF may be a likely IVD candidate for the clinical AD diagnostic market. Specifically, the INNO-BIA AlzBio3 immunoassay kit, performed using bead arrays on the xMAP Luminex analyzer, allows simultaneous quantification of amyloid-beta, t-tau, and p-tau biomarkers. AD biomarkers can also be screened using enzyme-linked immunosorbent assays that are offered as laboratory-developed tests. © 2014 Society for Laboratory Automation and Screening.

  2. Discriminative analysis of early Alzheimer's disease based on two intrinsically anti-correlated networks with resting-state fMRI.

    PubMed

    Wang, Kun; Jiang, Tianzi; Liang, Meng; Wang, Liang; Tian, Lixia; Zhang, Xinqing; Li, Kuncheng; Liu, Zhening

    2006-01-01

    In this work, we proposed a discriminative model of Alzheimer's disease (AD) on the basis of multivariate pattern classification and functional magnetic resonance imaging (fMRI). This model used the correlation/anti-correlation coefficients of two intrinsically anti-correlated networks in resting brains, which have been suggested by two recent studies, as the feature of classification. Pseudo-Fisher Linear Discriminative Analysis (pFLDA) was then performed on the feature space and a linear classifier was generated. Using leave-one-out (LOO) cross validation, our results showed a correct classification rate of 83%. We also compared the proposed model with another one based on the whole brain functional connectivity. Our proposed model outperformed the other one significantly, and this implied that the two intrinsically anti-correlated networks may be a more susceptible part of the whole brain network in the early stage of AD.

  3. [Alzheimer disease and society: an analysis of its social representation].

    PubMed

    Ngatcha-Ribert, Laëtitia

    2004-03-01

    The purpose of this article is to analyze the social representations of Alzheimer's disease as well as the rhetorical logic, through a study of the literature, newspapers and about thirty interviews. The entry of the disease in the medical field, thanks to the drugs, and in the scientific research allowed a re-civilization of the patients and a generalization of Alzheimer disease which the media seized, therefore the emergence of positive representations. This evolution remains however fragile insofar as the negative and sinister images persist and are seized in the collective imagination. The Alzheimer disease in particular became a label to report the senile collapse. In face of the still sordidly realistic social image, patients themselves can change the perception of the public opinion.

  4. Early Alzheimer's and Parkinson's disease pathology in urban children: Friend versus Foe responses--it is time to face the evidence.

    PubMed

    Calderón-Garcidueñas, Lilian; Franco-Lira, Maricela; Mora-Tiscareño, Antonieta; Medina-Cortina, Humberto; Torres-Jardón, Ricardo; Kavanaugh, Michael

    2013-01-01

    Chronic exposure to particulate matter air pollution is known to cause inflammation leading to respiratory- and cardiovascular-related sickness and death. Mexico City Metropolitan Area children exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, and innate and adaptive immune responses. Early dysregulated neuroinflammation, brain microvascular damage, production of potent vasoconstrictors, and perturbations in the integrity of the neurovascular unit likely contribute to progressive neurodegenerative processes. The accumulation of misfolded proteins coincides with the anatomical distribution observed in the early stages of both Alzheimer's and Parkinson's diseases. We contend misfolding of hyperphosphorylated tau (HPπ), alpha-synuclein, and beta-amyloid could represent a compensatory early protective response to the sustained systemic and brain inflammation. However, we favor the view that the chronic systemic and brain dysregulated inflammation and the diffuse vascular damage contribute to the establishment of neurodegenerative processes with childhood clinical manifestations. Friend turns Foe early; therefore, implementation of neuroprotective measures to ameliorate or stop the inflammatory and neurodegenerative processes is warranted in exposed children. Epidemiological, cognitive, structural, and functional neuroimaging and mechanistic studies into the association between air pollution exposures and the development of neuroinflammation and neurodegeneration in children are of pressing importance for public health.

  5. Early Alzheimer's and Parkinson's Disease Pathology in Urban Children: Friend versus Foe Responses—It Is Time to Face the Evidence

    PubMed Central

    Calderón-Garcidueñas, Lilian; Franco-Lira, Maricela; Mora-Tiscareño, Antonieta; Medina-Cortina, Humberto; Torres-Jardón, Ricardo; Kavanaugh, Michael

    2013-01-01

    Chronic exposure to particulate matter air pollution is known to cause inflammation leading to respiratory- and cardiovascular-related sickness and death. Mexico City Metropolitan Area children exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, and innate and adaptive immune responses. Early dysregulated neuroinflammation, brain microvascular damage, production of potent vasoconstrictors, and perturbations in the integrity of the neurovascular unit likely contribute to progressive neurodegenerative processes. The accumulation of misfolded proteins coincides with the anatomical distribution observed in the early stages of both Alzheimer's and Parkinson's diseases. We contend misfolding of hyperphosphorylated tau (HPπ), alpha-synuclein, and beta-amyloid could represent a compensatory early protective response to the sustained systemic and brain inflammation. However, we favor the view that the chronic systemic and brain dysregulated inflammation and the diffuse vascular damage contribute to the establishment of neurodegenerative processes with childhood clinical manifestations. Friend turns Foe early; therefore, implementation of neuroprotective measures to ameliorate or stop the inflammatory and neurodegenerative processes is warranted in exposed children. Epidemiological, cognitive, structural, and functional neuroimaging and mechanistic studies into the association between air pollution exposures and the development of neuroinflammation and neurodegeneration in children are of pressing importance for public health. PMID:23509683

  6. Review: Impact of Helicobacter pylori on Alzheimer's disease: What do we know so far?

    PubMed

    Doulberis, Michael; Kotronis, Georgios; Thomann, Robert; Polyzos, Stergios A; Boziki, Marina; Gialamprinou, Dimitra; Deretzi, Georgia; Katsinelos, Panagiotis; Kountouras, Jannis

    2018-02-01

    Helicobacter pylori has changed radically gastroenterologic world, offering a new concept in patients' management. Over time, more medical data gave rise to diverse distant, extragastric manifestations and interactions of the "new" discovered bacterium. Special interest appeared within the field of neurodegenerative diseases and particularly Alzheimer's disease, as the latter and Helicobacter pylori infection are associated with a large public health burden and Alzheimer's disease ranks as the leading cause of disability. However, the relationship between Helicobacter pylori infection and Alzheimer's disease remains uncertain. We performed a narrative review regarding a possible connection between Helicobacter pylori and Alzheimer's disease. All accessible relevant (pre)clinical studies written in English were included. Both affected pathologies were briefly analyzed, and relevant studies are discussed, trying to focus on the possible pathogenetic role of this bacterium in Alzheimer's disease. Data stemming from both epidemiologic studies and animal experiments seem to be rather encouraging, tending to confirm the hypothesis that Helicobacter pylori infection might influence the course of Alzheimer's disease pleiotropically. Possible main mechanisms may include the bacterium's access to the brain via the oral-nasal-olfactory pathway or by circulating monocytes (infected with Helicobacter pylori due to defective autophagy) through disrupted blood-brain barrier, thereby possibly triggering neurodegeneration. Current data suggest that Helicobacter pylori infection might influence the pathophysiology of Alzheimer's disease. However, further large-scale randomized controlled trials are mandatory to clarify a possible favorable effect of Helicobacter pylori eradication on Alzheimer's disease pathophysiology, before the recommendation of short-term and cost-effective therapeutic regimens against Helicobacter pylori-related Alzheimer's disease. © 2017 John Wiley & Sons

  7. The Effects of Aerobic Exercise on Cognitive Function of Alzheimer's Disease Patients.

    PubMed

    Yang, Si-Yu; Shan, Chun-Lei; Qing, He; Wang, Wei; Zhu, Yi; Yin, Meng-Mei; Machado, Sergio; Yuan, Ti-Fei; Wu, Ting

    2015-01-01

    To evaluate the effect of moderate intensity of aerobic exercise on elderly people with mild Alzheimer's disease, we recruited fifty volunteers aged 50 years to 80 years with cognitive impairment. They were randomized into two groups: aerobic group (n=25) or control group (n=25). The aerobic group was treated with cycling training at 70% of maximal intensity for 40 min/d, 3 d/wk for 3 months. The control group was only treated with heath education. Both groups were received cognitive evaluation, laboratory examination before and after 3 months. The results showed that the Minimum Mental State Examination score, Quality of Life Alzheimer's Disease score and the plasma Apo-a1 level was significantly increased (P<0.05), the Alzheimer's Disease Assessment Scale-cognition score, Neuropsychiatric Inventory Questionnaire score was significantly decreased.(P<0.05) in aerobic group before and after 3 months in aerobic group. For the control group, there was no significant difference in scores of Alzheimer's Disease Assessment Scale-cognition, Neuropsychiatric Inventory Questionnaire, Quality of Life Alzheimer's Disease, Apo-a1 (P>0.05), while Minimum Mental State Examination scores decreased significantly after 3 months (P<0.05). In conclusion, moderate intensity of aerobic exercise can improve cognitive function in patients with mild Alzheimer's disease.

  8. No Association Between CALHM1 Variation and Risk of Alzheimer Disease

    PubMed Central

    Minster, Ryan L.; Demirci, F. Yesim; DeKosky, Steven T.; Kamboh, M. Ilyas

    2010-01-01

    A polymorphism in the calcium homeostasis modulator 1 gene (CALHM1) has recently been associated with risk of late-onset Alzheimer disease. We examined this variant (rs2986017) in 945 Caucasian Americans with late-onset Alzheimer disease and 875 age-matched Caucasian American controls. No association with risk of late-onset Alzheimer disease (p = 0.368 for genotypes; p = 0.796 for alleles) was observed in our sample. However, a potential modest association of minor allele homozygosity (TT) with an earlier age-at-onset was seen (p = 0.034). PMID:19191331

  9. No association between CALHM1 variation and risk of Alzheimer disease.

    PubMed

    Minster, Ryan L; Demirci, F Yesim; DeKosky, Steven T; Kamboh, M Ilyas

    2009-04-01

    A polymorphism in the calcium homeostasis modulator 1 gene (CALHM1) has recently been associated with risk of late-onset Alzheimer disease. We examined this variant (rs2986017) in 945 Caucasian Americans with late-onset Alzheimer disease and 875 age-matched Caucasian American controls. No association with risk of late-onset Alzheimer disease (p=0.368 for genotypes; p=0.796 for alleles) was observed in our sample. However, a potential modest association of minor allele homozygosity (TT) with an earlier age-at-onset was seen (p=0.034). (c) 2009 Wiley-Liss, Inc.

  10. Fear Recognition Impairment in Early-Stage Alzheimer's Disease: When Focusing on the Eyes Region Improves Performance

    ERIC Educational Resources Information Center

    Hot, Pascal; Klein-Koerkamp, Yanica; Borg, Celine; Richard-Mornas, Aurelie; Zsoldos, Isabella; Adeline, Adeline Paignon; Anterion, Catherine Thomas; Baciu, Monica

    2013-01-01

    A decline in the ability to identify fearful expression has been frequently reported in patients with Alzheimer's disease (AD). In patients with severe destruction of the bilateral amygdala, similar difficulties have been reduced by using an explicit visual exploration strategy focusing on gaze. The current study assessed the possibility of…

  11. The effects of verbal reaction time in Alzheimer's disease.

    PubMed

    Midi, Ipek; Doǧan, Müzeyyen; Pata, Yavuz Selim; Kocak, Ismail; Mollahasanoglu, Aynur; Tuncer, Nese

    2011-07-01

    Verbal fluency deteriorates with normal aging, but is much more severe in Alzheimer's Disease (AD). Verbal functions were analyzed to find differences between normal aging subjects in patients with mild cognitive impairment (MCI), and in patients with early and moderate stages of AD. This study measured the verbal response time in patients with AD, MCI, and in control subjects This study measured the verbal response time in patients with AD, MCI, and in control subjects Fifteen patients with MCI, 15 patients with early AD, 8 patients with moderate AD, and 15 subjects for controls were included in the study. Word length in milliseconds, reaction time to a phoneme, word, or sentence and acoustic analysis of voice quality and speech diadochokinetic rate (DDK) were measured. Reaction time for a phoneme, word, or sentence especially the initiation period for them were longer in patients with early AD compared to patients with MCI (P < .001). The mean DDK rate was lower with increased severity of the disease, and was much more severe in patients with moderate AD. Clinical discrimination of the early stages of AD and MCI is challenging. Unfortunately, there are no laboratory markers present for the diagnosis of preclinical cases of AD. With the results of this study, the assessments of verbal reaction time may helpful for diagnosis of early AD. Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.

  12. Alternative Medicine and Alzheimer's Disease

    PubMed Central

    Kelley, Brendan J.; Knopman, David S.

    2009-01-01

    Background Alternative medicine has an extensive worldwide history and is commonly used by older patients. A number of different alternative medicines are used by patients having Alzheimer's disease. It is both desirable and expected for clinicians to be acquainted with these medications. Review Summary This paper discusses the available clinical trial evidence regarding eight agents commonly used by people having Alzheimer's disease. We provide an overview of the history and basic scientific evidence available for each agent, followed by a critical analysis of the evidence available from clinical trials, including the number of participants, trial duration and specific outcomes evaluated. Conclusion While many of these compounds have been associated with interesting basic science, none has shown clear clinical benefit to date. Data available for some, such as ginkgo biloba, curcumin and huperzine A, suggest that further evaluation is warranted. Familiarity with this literature will allow clinicians to provide meaningful recommendations to patients who wish to use these agents. PMID:18784599

  13. The Ubiquitin–Proteasome System and the Autophagic–Lysosomal System in Alzheimer Disease

    PubMed Central

    Ihara, Yasuo; Morishima-Kawashima, Maho; Nixon, Ralph

    2012-01-01

    As neurons age, their survival depends on eliminating a growing burden of damaged, potentially toxic proteins and organelles—a capability that declines owing to aging and disease factors. Here, we review the two proteolytic systems principally responsible for protein quality control in neurons and their important contributions to Alzheimer disease pathogenesis. In the first section, the discovery of paired helical filament ubiquitination is described as a backdrop for discussing the importance of the ubiquitin–proteasome system in Alzheimer disease. In the second section, we review the prominent involvement of the lysosomal system beginning with pathological endosomal–lysosomal activation and signaling at the very earliest stages of Alzheimer disease followed by the progressive failure of autophagy. These abnormalities, which result in part from Alzheimer-related genes acting directly on these lysosomal pathways, contribute to the development of each of the Alzheimer neuropathological hallmarks and represent a promising therapeutic target. PMID:22908190

  14. Curcumin and Apigenin – novel and promising therapeutics against chronic neuroinflammation in Alzheimer's disease

    PubMed Central

    Venigalla, Madhuri; Gyengesi, Erika; Münch, Gerald

    2015-01-01

    Alzheimer's disease is a progressive neurodegenerative disorder, characterized by deposition of amyloid beta, neurofibrillary tangles, astrogliosis and microgliosis, leading to neuronal dysfunction and loss in the brain. Current treatments for Alzheimer's disease primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for Alzheimer's disease patients. This review will provide an overview of the proven antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects of curcumin and apigenin and discuss the potential of these compounds for Alzheimer's disease prevention and treatment. We suggest that these compounds might delay the onset of Alzheimer's disease or slow down its progression, and they should enter clinical trials as soon as possible. PMID:26487830

  15. Investigating Interventions in Alzheimer's Disease with Computer Simulation Models

    PubMed Central

    Proctor, Carole J.; Boche, Delphine; Gray, Douglas A.; Nicoll, James A. R.

    2013-01-01

    Progress in the development of therapeutic interventions to treat or slow the progression of Alzheimer's disease has been hampered by lack of efficacy and unforeseen side effects in human clinical trials. This setback highlights the need for new approaches for pre-clinical testing of possible interventions. Systems modelling is becoming increasingly recognised as a valuable tool for investigating molecular and cellular mechanisms involved in ageing and age-related diseases. However, there is still a lack of awareness of modelling approaches in many areas of biomedical research. We previously developed a stochastic computer model to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau. Here we show how we extended this model to include the main processes involved in passive and active immunisation against Aβ and then demonstrate the effects of this intervention on soluble Aβ, plaques, phosphorylated tau and tangles. The model predicts that immunisation leads to clearance of plaques but only results in small reductions in levels of soluble Aβ, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against Aβ. Since, soluble Aβ, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against Aβ may not be effective unless it is performed very early in the disease process or combined with other therapies. PMID:24098635

  16. Clinical and neurocognitive aspects of hallucinations in Alzheimer's disease.

    PubMed

    El Haj, Mohamad; Roche, Jean; Jardri, Renaud; Kapogiannis, Dimitrios; Gallouj, Karim; Antoine, Pascal

    2017-12-01

    Due to their prevalence, hallucinations are considered as one of the most frequent psychotic symptoms in Alzheimer's disease (AD). These psychotic manifestations reduce patients' well-being, increase the burden of caregivers, contribute to early institutionalization, and are related with the course of cognitive decline in AD. Considering their consequences, we provide a comprehensive account of the current state of knowledge about the prevalence and characteristics of hallucinations in AD. We propose a comprehensive and testable theoretical model about hallucinations in AD: the ALZHA (ALZheimer and HAllucinations) model. In this model, neurological, genetic, cognitive, affective, and iatrogenic factors associated with hallucinations in AD are highlighted. According to the ALZHA model, hallucinations in AD first involve trait markers (i.e., cognitive deficits, neurological deficits, genetic predisposition and/or sensory deficits) to which state markers that may trigger these experiences are added (e.g., psychological distress and/or iatrogenic factors). Finally, we provide recommendations for assessment and management of these psychotic manifestations in AD, with the aim to benefit patients, caregivers, and health professionals. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Attitude Towards Alzheimer's Disease Among Undergraduate Students of University of the West Indies, Trinidad and Tobago.

    PubMed

    Rawlins, Joan; Mcgrowder, Donovan A; Kampradi, Lirmala; Ali, Allan; Austin, Travis; Beckles, Annalisa; Dass, Renesha; Diaram, Mahesh; Jahorie, Preenita; Mohammed, Marika; Dialsingh, Isaac

    2015-09-01

    Alzheimer's disease is most common among the dementias and is characterized by gradual declines in functional and cognitive abilities. Caregivers including family members play a key role in providing critically needed care for these patients. This study compared the knowledge and attitudes of pre-healthcare and non-medical undergraduate students towards patients with Alzheimer's disease. A cross-sectional study was conducted involving quota sampling of 691 undergraduate students (369 pre-healthcare and 322 non-medical). A 28-item questionnaire was utilised comprising of closed-ended questions and some based on a scale rating. The students' knowledge of Alzheimer's disease was arranged into categories such as: 0 for no knowledge about Alzheimer's disease, 1 for very little knowledge about Alzheimer's disease, 2 for fair knowledge about Alzheimer's disease and 3 for great knowledge about Alzheimer's disease. The data was analysed using the computer software SPSS and the Chi squared test of independence was also used to determine which knowledge variables were independent of student's status. Overall, 40.01% of the students have great or fair knowledge of Alzheimer's disease, with that of pre-healthcare students being satisfactory (54.47%). Pre-healthcare students have a more positive attitude towards Alzheimer's disease and 82.2% of students wished to take advantage of predictive test for Alzheimer's disease. Age and genetics were identified as risk factors of the disease. Pre-healthcare students had greater understanding of Alzheimer's disease and depicted a more empathetic and caring attitude towards patients. This can be attributed mainly to their knowledge and exposure toward the disease.

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

    PubMed

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

    2015-08-01

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

  19. Characterizing Alzheimer's disease through metabolomics and investigating anti-Alzheimer's disease effects of natural products.

    PubMed

    Yi, Lunzhao; Liu, Wenbin; Wang, Zhe; Ren, Dabing; Peng, Weijun

    2017-06-01

    Alzheimer's disease (AD) is the most common cause of dementia in elderly people and is among the greatest healthcare challenges of the 21st century. However, the etiology and pathogenesis of AD remain poorly understood, and no curative treatments are available to slow down or stop the degenerative effects of AD. As a high-throughput approach, metabolomics is gaining significant attention in AD research, because it has a powerful potential to discover novel biomarkers, unravel new therapeutic targets for AD, and identify perturbed metabolic pathways involved in AD progression. Here, we systematically review metabolomics with regard to its recent advances and applications in the identification of potential biomarkers for early AD diagnosis and pathogenesis research. In addition, we illustrate the developments in metabolomics as an effective tool for understanding the anti-AD mechanisms of natural products. We believe that the insights from these advances can narrow the gap between metabolomics research and clinical applications of laboratory findings. Moreover, we discuss some limitations and perspectives of biomarker identification in metabolomics. © 2017 New York Academy of Sciences.

  20. Tau truncation is a productive posttranslational modification of neurofibrillary degeneration in Alzheimer's disease.

    PubMed

    Kovacech, B; Novak, M

    2010-12-01

    Deposits of the misfolded neuronal protein tau are major hallmarks of neurodegeneration in Alzheimer's disease (AD) and other tauopathies. The etiology of the transformation process of the intrinsically disordered soluble protein tau into the insoluble misordered aggregate has attracted much attention. Tau undergoes multiple modifications in AD, most notably hyperphosphorylation and truncation. Hyperphosphorylation is widely regarded as the hottest candidate for the inducer of the neurofibrillary pathology. However, the true nature of the impetus that initiates the whole process in the human brains remains unknown. In AD, several site-specific tau cleavages were identified and became connected to the progression of the disease. In addition, western blot analyses of tau species in AD brains reveal multitudes of various truncated forms. In this review we summarize evidence showing that tau truncation alone is sufficient to induce the complete cascade of neurofibrillary pathology, including hyperphosphorylation and accumulation of misfolded insoluble forms of tau. Therefore, proteolytical abnormalities in the stressed neurons and production of aberrant tau cleavage products deserve closer attention and should be considered as early therapeutic targets for Alzheimer's disease.

  1. 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…

  2. Aerobic Exercise Sustains Performance of Instrumental Activities of Daily Living in Early-Stage Alzheimer Disease.

    PubMed

    Vidoni, Eric D; Perales, Jaime; Alshehri, Mohammed; Giles, Abdul-Mannaan; Siengsukon, Catherine F; Burns, Jeffrey M

    2017-12-28

    Individuals with Alzheimer disease (AD) experience progressive loss of independence-performing activities of daily living. Identifying interventions to support independence and reduce the economic and psychosocial burden of caregiving for individuals with AD is imperative. The purpose of this analysis was to examine functional disability and caregiver time in individuals with early-stage AD. This was a secondary analysis of a randomized controlled trial of 26 weeks of aerobic exercise (AEx) versus stretching and toning (ST). We measured functional dependence using the Disability Assessment for Dementia, informal caregiver time required using the Resources Utilization in Dementia Lite, and cognition using a standard cognitive battery. We saw a stable function in the AEx group compared with a significant decline in the ST group (4%; F = 4.2, P = .04). This was especially evident in more complex, instrumental activities of daily living, with individuals in the AEx group increasing 1% compared with an 8% loss in the ST group over 26 weeks (F = 8.3, P = .006). Change in memory was a significant predictor of declining instrumental activities of daily living performance (r = 0.28, 95% confidence interval = 0.08 ∞, P = .01). Informal caregiver time was not different between the AEx and ST groups. Our analysis extends recent work by revealing specific benefits for instrumental activities of daily living for individuals in the early stages of AD and supports the value of exercise for individuals with cognitive impairment.

  3. Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease

    PubMed Central

    Lalli, M A; Bettcher, B M; Arcila, M L; Garcia, G; Guzman, C; Madrigal, L; Ramirez, L; Acosta-Uribe, J; Baena, A; Wojta, K J; Coppola, G; Fitch, R; de Both, M D; Huentelman, M J; Reiman, E M; Brunkow, M E; Glusman, G; Roach, J C; Kao, A W; Lopera, F; Kosik, K S

    2015-01-01

    We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0±5.2 years compared with 41.1±7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy. PMID:26324103

  4. Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease.

    PubMed

    Lalli, M A; Bettcher, B M; Arcila, M L; Garcia, G; Guzman, C; Madrigal, L; Ramirez, L; Acosta-Uribe, J; Baena, A; Wojta, K J; Coppola, G; Fitch, R; de Both, M D; Huentelman, M J; Reiman, E M; Brunkow, M E; Glusman, G; Roach, J C; Kao, A W; Lopera, F; Kosik, K S

    2015-11-01

    We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0 ± 5.2 years compared with 41.1 ± 7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.

  5. To what degree does cognitive impairment in Alzheimer's disease predict dependence of patients on caregivers?

    PubMed Central

    Caro, Jaime; Ward, Alexandra; Ishak, Khajak; Migliaccio-Walle, Kristen; Getsios, Denis; Papadopoulos, George; Torfs, Koen

    2002-01-01

    Background Patients with Alzheimer's disease experience a progressive loss of cognitive function, and the ability to independently perform activities of daily life. Sometimes a dependent stage is reached quite early in the disease, when caregivers decide that the patients can no longer be left alone safely. This is an important aspect of Alzheimer's for patients, their families, and also health care providers. Understanding the relationship between a patient's current cognitive status and their need for care may assist clinicians when recommending an appropriate management plan. In this study, we investigated the relationship of cognitive function to dependence on caregivers before the patients reach a severe stage of the disease. Methods Data were obtained on 1,289 patients with mild-to-moderate Alzheimer's disease studied in two randomised clinical trials of galantamine (Reminyl®). Cognition was assessed using the cognitive part of the Alzheimer's Disease Assessment Scale (ADAS-cog) and Mini-Mental State Examination (MMSE). Patients were considered dependent if they required >12 hours of supervision each day or had high care needs. The Disability Assessment for Dementia (DAD) scale was also used as a measure of dependence. Disability was predicted directly using MMSE and ADAS-cog and compared to predictions from converted scores. Results The odds ratio of dependence was significantly higher amongst the patients with worse cognitive impairment, adjusting for age, gender and antipsychotic medication use. For example, a 4-point difference in ADAS-cog score was associated with an increase of 17% (95% CI 11–23) in the adjusted odds for >12 hours of supervision, and of 35% (95% CI 28–43) for dependence. Disability predicted directly using actual ADAS-cog and scores converted from MMSE values had close agreement using the models developed. Conclusion In patients with mild-to-moderate Alzheimer's disease, even relatively small degrees of poorer cognitive function

  6. Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses.

    PubMed

    Bertram, Lars; Tanzi, Rudolph E

    2008-10-01

    The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (APOE)). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors.

  7. Aging and Alzheimer's disease: lessons from the Nun Study.

    PubMed

    Snowdon, D A

    1997-04-01

    Sister Mary, the gold standard for the Nun Study, was a remarkable woman who had high cognitive test scores before her death at 101 years of age. What is more remarkable is that she maintained this high status despite having abundant neurofibrillary tangles and senile plaques, the classic lesions of Alzheimer's disease. Findings from Sister Mary and all 678 participants in the Nun Study may provide unique clues about the etiology of aging and Alzheimer's disease, exemplify what is possible in old age, and show how the clinical expression of some diseases may be averted.

  8. 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

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

    PubMed

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

    2013-08-15

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

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

    ERIC Educational Resources Information Center

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

    2010-01-01

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

  11. Novel white matter tract integrity metrics sensitive to Alzheimer disease progression.

    PubMed

    Fieremans, E; Benitez, A; Jensen, J H; Falangola, M F; Tabesh, A; Deardorff, R L; Spampinato, M V S; Babb, J S; Novikov, D S; Ferris, S H; Helpern, J A

    2013-01-01

    Along with cortical abnormalities, white matter microstructural changes such as axonal loss and myelin breakdown are implicated in the pathogenesis of Alzheimer disease. Recently, a white matter model was introduced that relates non-Gaussian diffusional kurtosis imaging metrics to characteristics of white matter tract integrity, including the axonal water fraction, the intra-axonal diffusivity, and the extra-axonal axial and radial diffusivities. This study reports these white matter tract integrity metrics in subjects with amnestic mild cognitive impairment (n = 12), Alzheimer disease (n = 14), and age-matched healthy controls (n = 15) in an effort to investigate their sensitivity, diagnostic accuracy, and associations with white matter changes through the course of Alzheimer disease. With tract-based spatial statistics and region-of-interest analyses, increased diffusivity in the extra-axonal space (extra-axonal axial and radial diffusivities) in several white matter tracts sensitively and accurately discriminated healthy controls from those with amnestic mild cognitive impairment (area under the receiver operating characteristic curve = 0.82-0.95), while widespread decreased axonal water fraction discriminated amnestic mild cognitive impairment from Alzheimer disease (area under the receiver operating characteristic curve = 0.84). Additionally, these white matter tract integrity metrics in the body of the corpus callosum were strongly correlated with processing speed in amnestic mild cognitive impairment (r = |0.80-0.82|, P < .001). These findings have implications for the course and spatial progression of white matter degeneration in Alzheimer disease, suggest the mechanisms by which these changes occur, and demonstrate the viability of these white matter tract integrity metrics as potential neuroimaging biomarkers of the earliest stages of Alzheimer disease and disease progression.

  12. Cost-Effectiveness of Magnetic Resonance Imaging with a New Contrast Agent for the Early Diagnosis of Alzheimer's Disease

    PubMed Central

    Biasutti, Maria; Dufour, Natacha; Ferroud, Clotilde; Dab, William; Temime, Laura

    2012-01-01

    Background Used as contrast agents for brain magnetic resonance imaging (MRI), markers for beta-amyloid deposits might allow early diagnosis of Alzheimer's disease (AD). We evaluated the cost-effectiveness of such a diagnostic test, MRI+CLP (contrastophore-linker-pharmacophore), should it become clinically available. Methodology/Principal Findings We compared the cost-effectiveness of MRI+CLP to that of standard diagnosis using currently available cognition tests and of standard MRI, and investigated the impact of a hypothetical treatment efficient in early AD. The primary analysis was based on the current French context for 70-year-old patients with Mild Cognitive Impairment (MCI). In alternative “screen and treat” scenarios, we analyzed the consequences of systematic screenings of over-60 individuals (either population-wide or restricted to the ApoE4 genotype population). We used a Markov model of AD progression; model parameters, as well as incurred costs and quality-of-life weights in France were taken from the literature. We performed univariate and probabilistic multivariate sensitivity analyses. The base-case preferred strategy was the standard MRI diagnosis strategy. In the primary analysis however, MRI+CLP could become the preferred strategy under a wide array of scenarios involving lower cost and/or higher sensitivity or specificity. By contrast, in the “screen and treat” analyses, the probability of MRI+CLP becoming the preferred strategy remained lower than 5%. Conclusions/Significance It is thought that anti-beta-amyloid compounds might halt the development of dementia in early stage patients. This study suggests that, even should such treatments become available, systematically screening the over-60 population for AD would only become cost-effective with highly specific tests able to diagnose early stages of the disease. However, offering a new diagnostic test based on beta-amyloid markers to elderly patients with MCI might prove cost

  13. Cost-effectiveness of magnetic resonance imaging with a new contrast agent for the early diagnosis of Alzheimer's disease.

    PubMed

    Biasutti, Maria; Dufour, Natacha; Ferroud, Clotilde; Dab, William; Temime, Laura

    2012-01-01

    Used as contrast agents for brain magnetic resonance imaging (MRI), markers for beta-amyloid deposits might allow early diagnosis of Alzheimer's disease (AD). We evaluated the cost-effectiveness of such a diagnostic test, MRI+CLP (contrastophore-linker-pharmacophore), should it become clinically available. We compared the cost-effectiveness of MRI+CLP to that of standard diagnosis using currently available cognition tests and of standard MRI, and investigated the impact of a hypothetical treatment efficient in early AD. The primary analysis was based on the current French context for 70-year-old patients with Mild Cognitive Impairment (MCI). In alternative "screen and treat" scenarios, we analyzed the consequences of systematic screenings of over-60 individuals (either population-wide or restricted to the ApoE4 genotype population). We used a Markov model of AD progression; model parameters, as well as incurred costs and quality-of-life weights in France were taken from the literature. We performed univariate and probabilistic multivariate sensitivity analyses. The base-case preferred strategy was the standard MRI diagnosis strategy. In the primary analysis however, MRI+CLP could become the preferred strategy under a wide array of scenarios involving lower cost and/or higher sensitivity or specificity. By contrast, in the "screen and treat" analyses, the probability of MRI+CLP becoming the preferred strategy remained lower than 5%. It is thought that anti-beta-amyloid compounds might halt the development of dementia in early stage patients. This study suggests that, even should such treatments become available, systematically screening the over-60 population for AD would only become cost-effective with highly specific tests able to diagnose early stages of the disease. However, offering a new diagnostic test based on beta-amyloid markers to elderly patients with MCI might prove cost-effective.

  14. Alzheimer Disease Signature Neurodegeneration and APOE Genotype in Mild Cognitive Impairment With Suspected Non-Alzheimer Disease Pathophysiology.

    PubMed

    Schreiber, Stefanie; Schreiber, Frank; Lockhart, Samuel N; Horng, Andy; Bejanin, Alexandre; Landau, Susan M; Jagust, William J

    2017-06-01

    There are conflicting results claiming that Alzheimer disease signature neurodegeneration may be more, less, or similarly advanced in individuals with β-amyloid peptide (Aβ)-negative (Aβ-) suspected non-Alzheimer disease pathophysiology (SNAP) than in Aβ-positive (Aβ+) counterparts. To examine patterns of neurodegeneration in individuals with SNAP compared with their Aβ+ counterparts. A longitudinal cohort study was conducted among individuals with mild cognitive impairment (MCI) and cognitively normal individuals receiving care at Alzheimer's Disease Neuroimaging Initiative sites in the United States and Canada for a mean follow-up period of 30.5 months from August 1, 2005, to June 30, 2015. Several neurodegeneration biomarkers and longitudinal cognitive function were compared between patients with distinct SNAP (Aβ- and neurodegeneration-positive [Aβ-N+]) subtypes and their Aβ+N+ counterparts. Participants were classified according to the results of their florbetapir F-18 (Aβ) positron emission tomography and their Alzheimer disease-associated neurodegeneration status (temporoparietal glucose metabolism determined by fluorodeoxyglucose F 18 [FDG]-labeled positron emission tomography and/or hippocampal volume [HV] determined by magnetic resonance imaging: participants with subthreshold HV values were regarded as exhibiting hippocampal volume atrophy [HV+], while subthreshold mean FDG values were considered as FDG hypometabolism [FDG+]). The study comprised 265 cognitively normal individuals (135 women and 130 men; mean [SD] age, 75.5 [6.7] years) and 522 patients with MCI (225 women and 297 men; mean [SD] age, 72.6 [7.8] years). A total of 469 individuals with MCI had data on neurodegeneration biomarkers; of these patients, 107 were Aβ-N+ (22.8%; 63 FDG+, 82 HV+, and 38 FDG+HV+) and 187 were Aβ+N+ (39.9%; 135 FDG+, 147 HV+, and 95 FDG+HV+ cases). A total of 209 cognitively normal participants had data on neurodegeneration biomarkers; of these, 52 were

  15. Family History of Alzheimer's Disease and Cortical Thickness in Patients With Dementia.

    PubMed

    Ganske, Steffi; Haussmann, Robert; Gruschwitz, Antonia; Werner, Annett; Osterrath, Antje; Baumgaertel, Johanna; Lange, Jan; Donix, Katharina L; Linn, Jennifer; Donix, Markus

    2016-08-01

    A first-degree family history of Alzheimer's disease reflects genetic risks for the neurodegenerative disorder. Recent imaging data suggest localized effects of genetic risks on brain structure in healthy people. It is unknown whether this association can also be found in patients who already have dementia. Our aim was to investigate whether family history risk modulates regional medial temporal lobe cortical thickness in patients with Alzheimer's disease. We performed high-resolution magnetic resonance imaging and cortical unfolding data analysis on 54 patients and 53 nondemented individuals. A first-degree family history of Alzheimer's disease was associated with left hemispheric cortical thinning in the subiculum among patients and controls. The contribution of Alzheimer's disease family history to regional brain anatomy changes independent of cognitive impairment may reflect genetic risks that modulate onset and clinical course of the disease. © The Author(s) 2016.

  16. Gray matter atrophy in patients with mild cognitive impairment/Alzheimer's disease over the course of developing delusions.

    PubMed

    Fischer, Corinne E; Ting, Windsor Kwan-Chun; Millikin, Colleen P; Ismail, Zahinoor; Schweizer, Tom A

    2016-01-01

    We conducted a neuroimaging analysis to understand the neuroanatomical correlates of gray matter loss in a group of mild cognitive impairment and early Alzheimer's disease patients who developed delusions. With data collected as part of the Alzheimer's Disease Neuroimaging Initiative, we conducted voxel-based morphometry to determine areas of gray matter change in the same Alzheimer's Disease Neuroimaging Initiative participants, before and after they developed delusions. We identified 14 voxel clusters with significant gray matter decrease in patient scans post-delusional onset, correcting for multiple comparisons (false discovery rate, p < 0.05). Major areas of difference included the right and left insulae, left precuneus, the right and left cerebellar culmen, the left superior temporal gyrus, the right posterior cingulate, the right thalamus, and the left parahippocampal gyrus. Although contrary to our initial predictions of enhanced right frontal atrophy, our preliminary work identifies several neuroanatomical areas, including the cerebellum and left posterior hemisphere, which may be involved in delusional development in these patients. Copyright © 2015 John Wiley & Sons, Ltd.

  17. Selective Attention in Early Dementia of Alzheimer Type

    ERIC Educational Resources Information Center

    Fernandez-Duque, Diego; Black, Sandra E.

    2008-01-01

    This study explored possible deficits in selective attention brought about by Dementia of Alzheimer Type (DAT). In three experiments, we tested patients with early DAT, healthy elderly, and young adults under low memory demands to assess perceptual filtering, conflict resolution, and set switching abilities. We found no evidence of impaired…

  18. Abnormality of G-protein-coupled receptor kinases at prodromal and early stages of Alzheimer's disease: an association with early beta-amyloid accumulation.

    PubMed

    Suo, Zhiming; Wu, Min; Citron, Bruce A; Wong, Gwendolyn T; Festoff, Barry W

    2004-03-31

    Overwhelming evidence indicates that the effects of beta-amyloid (Abeta) are dose dependent both in vitro and in vivo, which implies that Abeta is not directly detrimental to brain cells until it reaches a threshold concentration. In an effort to understand early Alzheimer's disease (AD) pathogenesis, this study focused on the effects of subthreshold soluble Abeta and the underlying molecular mechanisms in murine microglial cells and an AD transgenic mouse model. We found that there were two phases of dose-dependent Abeta effects on microglial cells: at the threshold of 5 microm and above, Abeta directly induced tumor necrosis factor-alpha (TNF-alpha) release, and at subthreshold doses, Abeta indirectly potentiated TNF-alpha release induced by certain G-protein-coupled receptor (GPCR) activators. Mechanistic studies revealed that subthreshold Abeta pretreatment in vitro reduced membrane GPCR kinase-2/5 (GRK2/5), which led to retarded GPCR desensitization, prolonged GPCR signaling, and cellular hyperactivity to GPCR agonists. Temporal analysis in an early-onset AD transgenic model, CRND8 mice, revealed that the membrane (functional) GRK2/5 in brain cortices were significantly reduced. More importantly, such a GRK abnormality took place before cognitive decline and changed in a manner corresponding with the mild to moderate soluble Abeta accumulation in these transgenic mice. Together, this study not only discovered a novel link between subthreshold Abeta and GRK dysfunction, it also demonstrated that the GRK abnormality in vivo occurs at prodromal and early stages of AD.

  19. Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease.

    PubMed

    1997-01-01

    This report summarizes the consensus recommendations of a panel of neuropathologists from the United States and Europe to improve the postmortem diagnostic criteria for Alzheimer's disease. The recommendations followed from a two-day workshop sponsored by the National Institute on Aging (NIA) and the Ronald and Nancy Reagan Institute of the Alzheimer's Association to reassess the original NIA criteria for the postmortem diagnosis of Alzheimer's disease published in 1985. The consensus recommendations for improving the neuropathological criteria for the postmortem diagnosis of Alzheimer's disease are reported here, and the "position papers" by members of the Working Group that accompany this report elaborate on the research findings and concepts upon which these recommendations were based. Further, commentaries by other experts in the field also are included here to provide additional perspectives on these recommendations. Finally, it is anticipated that future meetings of the Working Group will reassess these recommendations and the implementation of postmortem diagnostic criteria for Alzheimer's disease.

  20. Drug-induced cerebral glucose metabolism resembling Alzheimer's Disease: a case study.

    PubMed

    Riepe, Matthias W; Walther, Britta; Vonend, Catharina; Beer, Ambros J

    2015-07-11

    With aging of society the absolute number and the proportion of patients with cognitive deficits increase. Multiple disorders and diseases can foster cognitive impairment, e.g., Alzheimer's disease (AD), depressive disorder, or polypharmacy. A 74 year old man presented to the Old Age Psychiatry Service with cognitive deficits while being treated for recurrent depressive episodes and essential tremor with Venlafaxine, Lithium, and Primidone. Neuropsychological testing revealed a medio-temporal pattern of deficits with pronounced impairment of episodic memory, particularly delayed recall. Likewise, cognitive flexibility, semantic fluency, and attention were impaired. Positron emission tomography (PET) with fluorodeoxyglucose was performed and revealed a pattern of glucose utilization deficit resembling AD. On cessation of treatment with Lithium and Primidone, cognitive performance improved, particularly episodic memory performance and cognitive flexibility. Likewise, glucose metabolism normalized. Despite normalization of both, clinical symptoms and glucose utilization, the patient remained worried about possible underlying Alzheimer's disease pathology. To rule this out, an amyloid-PET was performed. No cortical amyloid was observed. Pharmacological treatment of older subjects may mimic glucose metabolism and clinical symptoms of Alzheimer's disease. In the present case both, imaging and clinical findings, reversed to normal on change of treatment. Amyloid PET is a helpful tool to additionally rule out underlying Alzheimer's disease in situations of clinical doubt even if clinical or other imaging findings are suggestive of Alzheimer's disease.