Science.gov

Sample records for alzheimer type onset

  1. Allele doses of apolipoprotein E type {epsilon}4 in sporadic late-onset Alzheimer`s disease

    SciTech Connect

    Lucotte, G.; Aouizerate, A.; Gerard, N.

    1995-12-18

    Apoliprotein E, type {epsilon}4 allele (ApoE-{epsilon}4) is associated with late-onset sporadic Alzheimer`s disease (AD). We have found that the cumulative probability of remaining unaffected over time decreases for each dose of ApoE-{epsilon}4 in sporadic, late-onset French AD. The effect of genotypes on age at onset of AD was analyzed using the product limit method, to compare unaffected groups during aging. 26 refs., 2 figs., 1 tab.

  2. Type 2 diabetes and late-onset Alzheimer's disease.

    PubMed

    Cheng, D; Noble, J; Tang, M X; Schupf, N; Mayeux, R; Luchsinger, J A

    2011-01-01

    To confirm in a cohort recruited in 1999-2001 our finding in a cohort recruited in 1992-1994 relating type 2 diabetes (T2D) to late-onset Alzheimer's disease (LOAD). Participants were 1,488 persons aged 65 years and older without dementia at baseline from New York City. T2D was ascertained by self-report. Dementia and LOAD were ascertained by standard research procedures. Proportional hazard regression was used for analyses relating T2D and LOAD. The prevalence of T2D was 17%. There were 161 cases of dementia and 149 cases of LOAD. T2D was related to dementia (hazard ratio = 1.7; 95% confidence interval = 1.4-2.9) and LOAD (1.6; 1.0-2.6) after adjustment for age, sex, education, ethnic group and apolipoprotein E ε4. This association was weaker when only AD - excluding cases of mixed dementia - was considered (hazard ratio = 1.3; 95% confidence interval = 0.8-2.2). T2D is associated with LOAD. Cerebrovascular disease may be an important mediator. Copyright © 2011 S. Karger AG, Basel.

  3. 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

  4. 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.

  5. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families

    SciTech Connect

    Corder, E.H.; Saunders, A.M.; Strittmatter, W.J.; Gaskell, P.C.; Roses, A.D.; Petricak-Vance, M.A. ); Schmechel, D.E. Durham VA Medical Center, CA ); Small, G.W. ); Haines, J.L. )

    1993-08-13

    The apolipoprotein E type 4 allele (APOE-[epsilon]4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-[epsilon]4 alleles in 42 families with late onset AD. Thus APOE-[epsilon]4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-[epsilon]4 was virtually sufficient to cause AD by age 80.

  6. Symptom onset in autosomal dominant Alzheimer disease

    PubMed Central

    Acosta-Baena, Natalia; Aisen, Paul S.; Bird, Thomas; Danek, Adrian; Fox, Nick C.; Goate, Alison; Frommelt, Peter; Ghetti, Bernardino; Langbaum, Jessica B.S.; Lopera, Francisco; Martins, Ralph; Masters, Colin L.; Mayeux, Richard P.; McDade, Eric; Moreno, Sonia; Reiman, Eric M.; Ringman, John M.; Salloway, Steve; Schofield, Peter R.; Sperling, Reisa; Tariot, Pierre N.; Xiong, Chengjie; Morris, John C.; Bateman, Randall J.

    2014-01-01

    Objective: To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD. Methods: We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study. Results: We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p < 10−16, r2 > 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex. Conclusions: Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research. PMID:24928124

  7. 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…

  8. Early-Onset Alzheimer Disease.

    PubMed

    Mendez, Mario F

    2017-05-01

    Early-onset Alzheimer disease (EOAD), with onset in individuals younger than 65 years, although overshadowed by the more common late-onset AD (LOAD), differs significantly from LOAD. EOAD comprises approximately 5% of AD and is associated with delays in diagnosis, aggressive course, and age-related psychosocial needs. One source of confusion is that a substantial percentage of EOAD are phenotypic variants that differ from the usual memory-disordered presentation of typical AD. The management of EOAD is similar to that for LOAD, but special emphasis should be placed on targeting the specific cognitive areas involved and more age-appropriate psychosocial support and education. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    SciTech Connect

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

    1995-04-24

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

  10. Late-Onset Alzheimer Disease.

    PubMed

    Pierce, Aimee L; Bullain, Szofia S; Kawas, Claudia H

    2017-05-01

    The oldest-old represent the fastest growing segment of society, and the risk of developing dementia continues to increase with advancing age into the 9th and 10th decades of life. The most common form of dementia in the oldest-old is Alzheimer disease (AD), although there are often mixed pathologies contributing to dementia in addition to amyloid plaques and neurofibrillary tangles. Diagnosing AD in the oldest-old is challenging due to cognitive and physical changes associated with aging. Treatment remains supportive, with current approved medications able to provide modest symptomatic benefit but unable to slow the progression of disease. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    SciTech Connect

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

    1994-09-15

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

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

    SciTech Connect

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

    1995-06-19

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

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

    SciTech Connect

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

    1994-09-01

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

  14. Differences in lateral hemispheric asymmetries of glucose utilization between early- and late-onset Alzheimer-type dementia

    SciTech Connect

    Koss, E.; Friedland, R.P.; Ober, B.A.; Jagust, W.J.

    1985-05-01

    Positron emission tomography with (/sup 18/F)fluorodeoxyglucose revealed greater right than left hemispheric impairment of cortical glucose metabolism in patients with probable Alzheimer's disease who were younger than 65 but not in those over 65. This asymmetry was related to poor visuospatial performance.

  15. Delaying the onset of Alzheimer disease

    PubMed Central

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

    2010-01-01

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

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

    PubMed

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

    2014-01-01

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

  17. Early Onset Alzheimer's Disease and Oxidative Stress

    PubMed Central

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

    2014-01-01

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

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

    DTIC Science & Technology

    2014-04-01

    Mayeux RP, Alzheimer’s Disease Genetics Consortium. Whole-exome sequencing of Hispanic early-onset Alzheimer disease families identifies rare variants...majority of genetic risk for this form of Alzheimer disease unexplained. We performed Whole-Exome Sequencing (WES) on 55 individuals in 19 Caribbean...EOAD and ~11% of EOAD overall, leaving the majority of genetic risk for the most severe form of Alzheimer disease unexplained. Methods We

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

    PubMed

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

    2015-06-01

    Given the lack of effective treatments for late-onset Alzheimer's disease (LOAD) and the substantial burden on patients, families, health care systems, and economies, finding an effective therapy is one of the highest medical priorities. The past few years have seen a growing interest in the medicinal uses of cannabinoids, the bioactive components of the cannabis plant, including the treatment of LOAD and other physical conditions that are common in older people. Several in vitro and in vivo studies have demonstrated that cannabinoids can reduce oxidative stress, neuroinflammation, and the formation of amyloid plaques and neurofibrillary tangles, the key hallmarks of LOAD. In addition, in population-based studies, cannabinoids reduced dementia-related symptoms (e.g., behavioral disturbances). The current article provides an overview of the potential of cannabinoids in the treatment of LOAD and related neuropsychiatric symptoms in older people. We also discuss the efficacy, safety, and pharmacokinetics of cannabinoid-based drugs in older people with dementia. © 2015 American Society for Clinical Pharmacology and Therapeutics.

  20. Chromosome 14 and late-onset familial alzheimer disease (FAD)

    SciTech Connect

    Schellenberg, G.D.; Anderson, L.; Nemens, E.; Bird, T.D.; Wijsman, E.M.; Martin, G.M.; Payami, H.; Orr, H.T.; White, J.A.; Alonso, M.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-dependent 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.

  1. Chromosome 14 and late-onset familial Alzheimer disease (FAD)

    PubMed Central

    Schellenberg, Gerard D.; Payami, Haydeh; Wijsman, Ellen M.; Orr, Harry T.; Goddard, Katrina A. B.; Anderson, Leojean; Nemens, Ellen; White, June A.; Alonso, M. Elisa; Ball, Melvyn J.; Kaye, Jeffrey; Morris, John C.; Chui, Helena; Sadovnick, A. Dessa; Heston, Leonard L.; Martin, George M.; Bird, Thomas D.

    1993-01-01

    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 analyses 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-dependent 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. PMID:8352272

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

    ERIC Educational Resources Information Center

    Baker, Julie; Ryalls, Jack; Brice, Alejandro; Whiteside, Janet

    2007-01-01

    In the present study, voice onset time (VOT) measurements were compared between a group of individuals with moderate Alzheimer's disease (AD) and a group of healthy age- and gender-matched peers. Participants read a list of consonant-vowel-consonant (CVC) words, which included the six stop consonants. The VOT measurements were made from…

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

    ERIC Educational Resources Information Center

    Baker, Julie; Ryalls, Jack; Brice, Alejandro; Whiteside, Janet

    2007-01-01

    In the present study, voice onset time (VOT) measurements were compared between a group of individuals with moderate Alzheimer's disease (AD) and a group of healthy age- and gender-matched peers. Participants read a list of consonant-vowel-consonant (CVC) words, which included the six stop consonants. The VOT measurements were made from…

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

    SciTech Connect

    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 before 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.

  5. Autosomal recessive causes likely in early-onset Alzheimer disease.

    PubMed

    Wingo, Thomas S; Lah, James J; Levey, Allan I; Cutler, David J

    2012-01-01

    To determine the genetic contribution to non-autosomal dominant early-onset Alzheimer disease (EOAD) (onset age ≤60 years) cases and identify the likely mechanism of inheritance in those cases. A liability threshold model of disease was used to estimate heritability of EOAD and late-onset Alzheimer disease (AD) using concordance for AD among parent-offspring pairs. The Uniform Data Set, whose participants were collected from 32 US Alzheimer's Disease Centers, maintained by the National Alzheimer's Coordinating Center. Individuals with probable AD and detailed parental history (n = 5370). The concordance among relatives and heritability of EOAD and late-onset AD. For late-onset AD (n = 4302), we found sex-specific parent-offspring concordance that ranged from approximately 10% to 30%, resulting in a heritability of 69.8% (95% confidence interval, 64.6%-75.0%), and equal heritability for both sexes regardless of parental sex. For EOAD (n = 702), we found that the parent-offspring concordance was 10% or less and concordance among siblings was 21.6%. Early-onset AD heritability was 92% to 100% for all likely values of EOAD prevalence. We confirm late-onset AD is a highly polygenic disease. By contrast, the data for EOAD suggest it is an almost entirely genetically based disease, and the patterns of observed concordance for parent-offspring pairs and among siblings lead us to reject the hypotheses that EOAD is a purely dominant, mitochondrial, X-linked, or polygenic disorder. The most likely explanation of the data is that approximately 90% of EOAD cases are due to autosomal recessive causes.

  6. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis.

    PubMed

    Ryman, Davis C; Acosta-Baena, Natalia; Aisen, Paul S; Bird, Thomas; Danek, Adrian; Fox, Nick C; Goate, Alison; Frommelt, Peter; Ghetti, Bernardino; Langbaum, Jessica B S; Lopera, Francisco; Martins, Ralph; Masters, Colin L; Mayeux, Richard P; McDade, Eric; Moreno, Sonia; Reiman, Eric M; Ringman, John M; Salloway, Steve; Schofield, Peter R; Sperling, Reisa; Tariot, Pierre N; Xiong, Chengjie; Morris, John C; Bateman, Randall J

    2014-07-15

    To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD. We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study. We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p < 10(-16), r2 > 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex. Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research. © 2014 American Academy of Neurology.

  7. Clustering and age of onset in familial late onset Alzheimer`s disease are determined at the apoliopoprotein E locus

    SciTech Connect

    Houlden, H.; Rossor, M.

    1994-09-01

    Recent work has demonstrated that the apolipoprotein E (ApoE) genotype is of great importance in the etiology of Alzheimer`s disease (AD). Thus, inheritance of the ApoE4 allele predisposes to the occurrences of late onset disease and decreases the onset age in families with pathogenic mutations in the amyloid precursor protein gene. We analysed ApoE genotypes in 35 families multiply affected by AD and confirm that familial clustering in late onset AD is associated with the ApoE4 allele. This allele occurs in the great majority (82%) of late onset familial Alzheimer cases. Elderly unaffected sibs (80-90 years) have an allele frequency that is not significantly different to that of normal controls. Data presented from our family sets together previously published data is suggestive that the effect of a single ApoE4 allele is to increase the risk of developing AD by an amount equivalent to 5 years and that the effect of ApoE4 homozygosity is to increase the risk of developing AD by an amount equivalent to 10 years of age. Data shows significant difference between the frequency of the ApoE4 allele in the familial AD probands and controls and in both sets of unaffected sibs, p<0.01.

  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.

  9. Age-at-Onset in Late Onset Alzheimer Disease is Modified by Multiple Genetic Loci

    PubMed Central

    Naj, Adam C.; Jun, Gyungah; Reitz, Christiane; Kunkle, Brian W.; Perry, William; Park, YoSon; Beecham, Gary W.; Rajbhandary, Ruchita A.; Hamilton-Nelson, Kara L.; Wang, Li-San; Kauwe, John S.K.; Huentelman, Matthew J.; Myers, Amanda J.; Bird, Thomas D.; Boeve, Bradley F.; Baldwin, Clinton T.; Jarvik, Gail P.; Crane, Paul K.; Rogaeva, Ekaterina; Barmada, Michael M.; Demirci, F. Yesim; Cruchaga, Carlos; Kramer, Patricia; Ertekin-Taner, Nilufer; Hardy, John; Graff-Radford, Neill R.; Green, Robert C.; Larson, Eric B.; St George-Hyslop, Peter; Buxbaum, Joseph D.; Evans, Denis; Schneider, Julie A.; Lunetta, Kathryn L.; Kamboh, M. Ilyas; Saykin, Andrew J.; Reiman, Eric M.; De Jager, Philip L.; Bennett, David A.; Morris, John C.; Montine, Thomas J.; Goate, Alison M.; Blacker, Deborah; Tsuang, Debby W.; Hakonarson, Hakon; Kukull, Walter A.; Foroud, Tatiana M.; Martin, Eden R.; Haines, Jonathan L.; Mayeux, Richard; Farrer, Lindsay A.; Schellenberg, Gerard D.; Pericak-Vance, Margaret A.

    2015-01-01

    Importance As APOE locus variants contribute to both risk of late-onset Alzheimer disease and differences in age-at-onset, it is important to know if other established late-onset Alzheimer disease risk loci also affect age-at-onset in cases. Objectives To investigate the effects of known Alzheimer disease risk loci in modifying age-at-onset, and to estimate their cumulative effect on age-at-onset variation, using data from genome-wide association studies in the Alzheimer’s Disease Genetics Consortium (ADGC). Design, Setting and Participants The ADGC comprises 14 case-control, prospective, and family-based datasets with data on 9,162 Caucasian participants with Alzheimer’s occurring after age 60 who also had complete age-at-onset information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single nucleotide polymorphisms (SNPs) most significantly associated with risk at ten confirmed LOAD loci were examined in linear modeling of AAO, and individual dataset results were combined using a random effects, inverse variance-weighted meta-analysis approach to determine if they contribute to variation in age-at-onset. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. Main Outcomes and Measures Age at disease onset abstracted from medical records among participants with late-onset Alzheimer disease diagnosed per standard criteria. Results Analysis confirmed association of APOE with age-at-onset (rs6857, P=3.30×10−96), with associations in CR1 (rs6701713, P=7.17×10−4), BIN1 (rs7561528, P=4.78×10−4), and PICALM (rs561655, P=2.23×10−3) reaching statistical significance (P<0.005). Risk alleles individually reduced age-at-onset by 3-6 months. Burden analyses demonstrated that APOE contributes to 3.9% of variation in age-at-onset (R2=0.220) over baseline (R2=0.189) whereas the other nine loci together contribute to 1.1% of

  10. What can we learn from study of Alzheimer's disease in patients with Down syndrome for early-onset Alzheimer's disease in the general population?

    PubMed Central

    2011-01-01

    The clinical and scientific study of dementia in adults with Down syndrome led to the development of the amyloid hypothesis as a fundamental concept in Alzheimer's disease pathogenesis. The journey started with the discovery of the structure and metabolic processing of β-amyloid brain deposits associated with Alzheimer's dementia in adults with Down syndrome, and then the prediction and confirmation of the amyloid precursor protein gene on chromosome 21. The processes and genes responsible for tau hyperphosphorylation contributing to toxic brain deposits were additionally identified. With increasing sophistication in genetic experimental techniques, additional mechanisms associated with excessive amyloid deposits were postulated and tested in brains of people with Down syndrome and Alzheimer's disease and in those with early-onset Alzheimer's disease. This in turn led to the proposal and testing for particular genetic defects associated with familial early-onset Alzheimer's disease. Nearly 200 genetic causes of early-onset types of Alzheimer's disease have since been identified. Only a minority of these causes are on chromosome 21, although the aetiology of excess amyloid production remains fundamental to their pathogenesis. Knowledge of the pathogenic mechanisms of Alzheimer's disease in predisposed families and in people with Down syndrome is a step closer to prevention or cure of this devastating disease. PMID:21542885

  11. Age at onset of Alzheimer's disease: clue to the relative importance of etiologic factors

    SciTech Connect

    Horner, R.D.

    1987-09-01

    Clues to the relative importance of possible etiologic factors for dementia of the Alzheimer type may be gained by examining the fit of case series to Sartwell's model of the distribution of incubation periods. If age at disease onset is used as the incubation period of this disease, a genetic or environmental factor acting during the prenatal period is suggested if the distribution of these ages fits the lognormal curve; otherwise, environmental factors acting after birth are implicated. Case series were identified from the literature. Four case series were found which contained sufficiently detailed data to permit this secondary analysis; only one case series was population-based. The distribution of age at disease onset for each series was graphically and statistically assessed for fit to the logarithmic normal distribution. Each case series fit the lognormal curve well. This suggests that research into the etiology of dementia of the Alzheimer type should focus on the prenatal experiences of patients with this disease.

  12. TYROBP genetic variants in early-onset Alzheimer's disease.

    PubMed

    Pottier, Cyril; Ravenscroft, Thomas A; Brown, Patricia H; Finch, NiCole A; Baker, Matt; Parsons, Meeia; Asmann, Yan W; Ren, Yingxue; Christopher, Elizabeth; Levitch, Denise; van Blitterswijk, Marka; Cruchaga, Carlos; Campion, Dominique; Nicolas, Gaël; Richard, Anne-Claire; Guerreiro, Rita; Bras, Jose T; Zuchner, Stephan; Gonzalez, Michael A; Bu, Guojun; Younkin, Steven; Knopman, David S; Josephs, Keith A; Parisi, Joseph E; Petersen, Ronald C; Ertekin-Taner, Nilüfer; Graff-Radford, Neill R; Boeve, Bradley F; Dickson, Dennis W; Rademakers, Rosa

    2016-12-01

    We aimed to identify new candidate genes potentially involved in early-onset Alzheimer's disease (EOAD). Exome sequencing was conducted on 45 EOAD patients with either a family history of Alzheimer's disease (AD, <65 years) or an extremely early age at the onset (≤55 years) followed by multiple variant filtering according to different modes of inheritance. We identified 29 candidate genes potentially involved in EOAD, of which the gene TYROBP, previously implicated in AD, was selected for genetic and functional follow-up. Using 3 patient cohorts, we observed rare coding TYROBP variants in 9 out of 1110 EOAD patients, whereas no such variants were detected in 1826 controls (p = 0.0001), suggesting that at least some rare TYROBP variants might contribute to EOAD risk. Overexpression of the p.D50_L51ins14 TYROBP mutant led to a profound reduction of TREM2 expression, a well-established risk factor for AD. This is the first study supporting a role for genetic variation in TYROBP in EOAD, with in vitro support for a functional effect of the p.D50_L51ins14 TYROBP mutation on TREM2 expression.

  13. 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

    2015-11-03

    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. Published by Elsevier España, S.L.U. All rights reserved.

  14. Effect of PSEN1 mutations on MAPT methylation in early-onset Alzheimer's disease.

    PubMed

    Coupland, Kirsten G; Kim, Woojin S; Halliday, Glenda M; Hallupp, Marianne; Dobson-Stone, Carol; Kwok, John B J

    2015-01-01

    The MAPT gene is a risk locus for multiple neurodegenerative diseases, including idiopathic Parkinson's and Alzheimer's disease. We examined whether altered DNA methylation of the MAPT promoter, with its potential to modulate gene expression, was a common phenomenon in Alzheimer's disease patients with differing aetiologies. We measured MAPT promoter methylation in a brain tissue cohort of early-onset Alzheimer's disease (EOAD) with defined causative mutations in the PSEN1 gene (Normal = 10, PSEN1 AD = 10), and idiopathic late-onset Alzheimer's disease (Normal = 12, LOAD = 12). We found a brain-region-specific decrease in MAPT promoter methylation in PSEN1 AD patients. Overexpression of PSEN1 reduced MAPT promoter activity in an in vitro luciferase study, and led to an increase in methylation of the endogenous MAPT promoter. Overexpression of PSEN1 with a deletion of exon 9 mutation (Δex9) led to a smaller reduction in MAPT promoter activity relative to wild-type PSEN1 in the luciferase assay, consistent with a decreased ability to modulate endogenous MAPT gene methylation. Our study indicates a novel effect of PSEN1 on MAPT methylation, and suggests a mutation-specific effect of the PSEN1 Δex9 mutation.

  15. Deciphering the mechanism underlying late-onset Alzheimer disease.

    PubMed

    Krstic, Dimitrije; Knuesel, Irene

    2013-01-01

    Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of Aβ accumulation in late-onset AD.

  16. [Verbal fluency among healthy elderly: a study of three complex verbal fluency tasks under healthy older people and patients with neurocognitive disorder or onset dementia of the Alzheimer type].

    PubMed

    Op de Beeck, S; Galoppin, A; Willemarck, N

    2014-06-01

    The aim of this study is to provide normative data for a phonological alternating task (FAT), a semantic alternating task (SAT) and an excluded letter task (ELT). The tasks were administered to 146 Flemish-speaking, cognitively healthy elderly. Data from 102 were used and were classified according to the significant variables. Subsequently, these tasks were administered to seven patients diagnosed with mild neurocognitive impairment (mild cognitive impairment, MCI) and seven patients with onset dementia of the Alzheimer type (DAT). Results of the standard study show that the level of education is a significant variable for all complex VFT and age for the SAT and the ELT, while age related deterioration is highest for the ELT. The error rate is highest for the ELT and lowest for the SAT. Analysis of the time duration shows that data should be collected for at least 2 min. The patients scored significantly lower than the normgroup of healthy adults. The error rate is highest for the SAT and lowest for the ELT.

  17. Identifying genetic interactions associated with late-onset Alzheimer's disease.

    PubMed

    Floudas, Charalampos S; Um, Nara; Kamboh, M Ilyas; Barmada, Michael M; Visweswaran, Shyam

    2014-01-01

    Identifying genetic interactions in data obtained from genome-wide association studies (GWASs) can help in understanding the genetic basis of complex diseases. The large number of single nucleotide polymorphisms (SNPs) in GWASs however makes the identification of genetic interactions computationally challenging. We developed the Bayesian Combinatorial Method (BCM) that can identify pairs of SNPs that in combination have high statistical association with disease. We applied BCM to two late-onset Alzheimer's disease (LOAD) GWAS datasets to identify SNPs that interact with known Alzheimer associated SNPs. We also compared BCM with logistic regression that is implemented in PLINK. Gene Ontology analysis of genes from the top 200 dataset SNPs for both GWAS datasets showed overrepresentation of LOAD-related terms. Four genes were common to both datasets: APOE and APOC1, which have well established associations with LOAD, and CAMK1D and FBXL13, not previously linked to LOAD but having evidence of involvement in LOAD. Supporting evidence was also found for additional genes from the top 30 dataset SNPs. BCM performed well in identifying several SNPs having evidence of involvement in the pathogenesis of LOAD that would not have been identified by univariate analysis due to small main effect. These results provide support for applying BCM to identify potential genetic variants such as SNPs from high dimensional GWAS datasets.

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

    SciTech Connect

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

    1995-02-27

    Early onset familial Alzheimer`s disease (AD) has an autosomal dominant mode of inheritance. Two genes are responsible for the majority of cases of this subtype of AD. Mutations in the {beta}-amyloid precursor protein ({beta}APP) gene on chromosome 21 have been shown to completely cosegregate with the disease. We and others have previously described the clinical features of families with {beta}APP mutations at the codon 717 locus in an attempt to define the phenotype associated with a valine to isoleucine (Val {r_arrow} Ile) or a valine to glycine (Val {r_arrow} Gly) change. More recently, a second locus for very early onset disease has been localized to chromosome 14. The results of linkage studies in some families suggesting linkage to both chromosomes have been explained by the suggestion of a second (centromeric) locus on chromosome 21. Here we report the clinical features and genetic analysis of a British pedigree (F74) with early onset AD in which neither the {beta}APP locus nor any other chromosome 21 locus segregates with the disease, but in which good evidence is seen for linkage on the long arm of chromosome 14. In particular we report marker data suggesting that the chromosome 14 disease locus is close to D14S43 and D14S77. Given the likelihood that F74 represents a chromosome 14 linked family, we describe the clinical features and make a limited clinical comparison with the {beta}APP717 Val {r_arrow} Ile and {beta}APP717 Val {r_arrow} Gly encoded families that have been previously described. We conclude that although several previously reported clinical features occur to excess in early onset familial AD, no single clinical feature demarcates either the chromosome 14 or {beta}APP codon 717 mutated families except mean age of onset. 52 refs., 2 figs., 5 tabs.

  19. Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease

    PubMed Central

    Thomas, Jewell B; Brier, Matthew R; Bateman, Randall J; Snyder, Abraham Z; Benzinger, Tammie L; Xiong, Chengjie; Raichle, Marcus; Holtzman, David M; Sperling, Reisa A; Mayeux, Richard; Ghetti, Bernardino; Ringman, John M; Salloway, Stephen; McDade, Eric; Rossor, Martin N; Ourselin, Sebastien; Schofield, Peter R; Masters, Colin L; Martins, Ralph N; Weiner, Michael W; Thompson, Paul M; Fox, Nick C; Koeppe, Robert A; Jack, Clifford R; Mathis, Chester A; Oliver, Angela; Blazey, Tyler M; Moulder, Krista; Buckles, Virginia; Hornbeck, Russ; Chhatwal, Jasmeer; Schultz, Aaron P; Goate, Alison M; Fagan, Anne M; Cairns, Nigel J; Marcus, Daniel S; Morris, John C; Ances, Beau M

    2014-01-01

    Importance Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in three specific genes, in contrast to late-onset Alzheimer Disease (LOAD), which has a more polygenetic risk profile. Design, Setting, and Participants We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of ADAD (N=79) and LOAD (N=444) human participants using resting state functional connectivity MRI (rs-fcMRI) at multiple international academic sites. Main Outcomes and Measures For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity as measured by clinical dementia rating (CDR). In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within five RSNs. Results Functional connectivity decreases with increasing CDR were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in each type of AD accurately predicted CDR stage in the other, further demonstrating similarity of functional connectivity loss in each disease type. Among ADAD participants, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared to asymptomatic mutation non-carriers. Conclusions and Relevance rs-fcMRI changes with progressing AD severity are similar between ADAD and LOAD. Rs-fcMRI may be a useful endpoint for LOAD and ADAD therapy trials. ADAD disease process may be an effective model for LOAD disease process. PMID:25069482

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

    SciTech Connect

    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} = 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.

  1. Successful Scene Encoding in Presymptomatic Early-Onset Alzheimer's Disease.

    PubMed

    Quiroz, Yakeel T; Willment, Kim Celone; Castrillon, Gabriel; Muniz, Martha; Lopera, Francisco; Budson, Andrew; Stern, Chantal E

    2015-01-01

    Brain regions critical to episodic memory are altered during the preclinical stages of Alzheimer's disease (AD). However, reliable means of identifying cognitively-normal individuals at higher risk to develop AD have not been established. To examine whether functional MRI can detect early functional changes associated with scene encoding in a group of presymptomatic presenilin-1 (PSEN1) E280A mutation carriers. Participants were 39 young, cognitively-normal individuals from an autosomal dominant early-onset AD kindred, located in Antioquia, Colombia. Participants performed a functional MRI scene encoding task and a post-scan subsequent memory test. PSEN1 mutation carriers exhibited hyperactivation within medial temporal lobe regions (hippocampus,parahippocampal formation) during successful scene encoding compared to age-matched non-carriers. Hyperactivation in medial temporal lobe regions during scene encoding is seen in individuals genetically-determined to develop AD years before their clinical onset. Our findings will guide future research with the ultimate goal of using functional neuroimaging in the early detection of preclinical AD.

  2. Factors of Rapid Cognitive Decline in Late Onset Alzheimer's Disease.

    PubMed

    Koskas, Pierre; Henry-Feugeas, Marie Cecile; Feugeas, Jean-Paul; Ou, Phalla; Drunat, Olivier

    2017-01-01

    Rapid Cognitive Decline (RCD) in Alzheimer's Disease (AD) is associated with a worse disease progression. There is no consensual predictor of RCD and only a few studies have focused on RCD in late-onset dementia, the most common form of AD. To identify the predictors of RCD, in a population of community-dwelling patients with recently diagnosed late onset AD. Community-dwelling subjects aged >75 consulting for the first time in Old Age Memory outpatient center from 2009 to 2012 were considered. All patients underwent a standardized clinical dementia investigation. Patients were classified as rapid decliners when they demonstrated a loss of 3 points or greater in MMSE during the first six months. 130 patients were included (42 males, 88 females, mean ages 82.7±4.58). The average baseline MMSE score was 23.36±3.78. In regression analysis, the Free Recall Scores, categorical fluency scores were the most highly predictive of RCD. These results are important for the design of clinical trials and also, in clinical practice, for both physicians and families in planning long-term care. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

    PubMed Central

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

    2016-01-01

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

  4. Functional connectivity in autosomal dominant and late-onset Alzheimer disease.

    PubMed

    Thomas, Jewell B; Brier, Matthew R; Bateman, Randall J; Snyder, Abraham Z; Benzinger, Tammie L; Xiong, Chengjie; Raichle, Marcus; Holtzman, David M; Sperling, Reisa A; Mayeux, Richard; Ghetti, Bernardino; Ringman, John M; Salloway, Stephen; McDade, Eric; Rossor, Martin N; Ourselin, Sebastien; Schofield, Peter R; Masters, Colin L; Martins, Ralph N; Weiner, Michael W; Thompson, Paul M; Fox, Nick C; Koeppe, Robert A; Jack, Clifford R; Mathis, Chester A; Oliver, Angela; Blazey, Tyler M; Moulder, Krista; Buckles, Virginia; Hornbeck, Russ; Chhatwal, Jasmeer; Schultz, Aaron P; Goate, Alison M; Fagan, Anne M; Cairns, Nigel J; Marcus, Daniel S; Morris, John C; Ances, Beau M

    2014-09-01

    Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in 3 specific genes in contrast to late-onset Alzheimer disease (LOAD), which has a more polygenetic risk profile. To assess the similarities and differences in functional connectivity changes owing to ADAD and LOAD. We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of participants with ADAD (n = 79) and LOAD (n = 444), using resting-state functional connectivity magnetic resonance imaging at multiple international academic sites. For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity measured by the Clinical Dementia Rating Scale. In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within 5 RSNs. A decrease in functional connectivity with increasing Clinical Dementia Rating scores were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in one type of Alzheimer disease accurately predicted clinical dementia rating scores in the other, further demonstrating the similarity of functional connectivity loss in each disease type. Among participants with ADAD, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared with asymptomatic mutation noncarriers. Resting-state functional connectivity magnetic resonance imaging changes with progressing AD severity are similar between ADAD and LOAD. Resting-state functional connectivity magnetic resonance imaging may be a useful end point for LOAD and ADAD therapy trials. Moreover, the disease process of ADAD may be an effective model for the LOAD disease process.

  5. Integrated late onset Alzheimer's disease (LOAD) susceptibility genes: Cholesterol metabolism and trafficking perspectives.

    PubMed

    Dong, Hee Kim; Gim, Jeong-An; Yeo, Seung Hyeon; Kim, Heui-Soo

    2017-01-15

    Late onset Alzheimer's disease (LOAD) is the most common type of dementia and is characterized by decreased amyloid-β (Aβ) clearance from the brain. Cholesterol regulates the production and clearance of Aβ. Genome-wide association study (GWAS) suggests that at least 20 genes are associated with LOAD. The genes APOE, CLU, SORL1, PICALM, and BIN1 have a relatively high LOAD susceptibility. Additional experimental and bioinformatic approaches to integrate data from genetics, epigenetics, and molecular networks may further increase our understanding of LOAD in relation to cholesterol metabolism and trafficking. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. 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.

  7. Mutations modifying sporadic Alzheimer's disease age of onset.

    PubMed

    Vélez, Jorge I; Lopera, Francisco; Patel, Hardip R; Johar, Angad S; Cai, Yeping; Rivera, Dora; Tobón, Carlos; Villegas, Andrés; Sepulveda-Falla, Diego; Lehmann, Shaun G; Easteal, Simon; Mastronardi, Claudio A; Arcos-Burgos, Mauricio

    2016-12-01

    The identification of mutations modifying the age of onset (AOO) in Alzheimer's disease (AD) is crucial for understanding the natural history of AD and, therefore, for early interventions. Patients with sporadic AD (sAD) from a genetic isolate in the extremes of the AOO distribution were whole-exome genotyped. Single- and multi-locus linear mixed-effects models were used to identify functional variants modifying AOO. A posteriori enrichment and bioinformatic analyses were applied to evaluate the non-random clustering of the associate variants to physiopathological pathways involved in AD. We identified more than 20 pathogenic, genome-wide statistically significant mutations of major modifier effect on the AOO. These variants are harbored in genes implicated in neuron apoptosis, neurogenesis, inflammatory processes linked to AD, oligodendrocyte differentiation, and memory processes. This set of new genes harboring these mutations could be of importance for prediction, follow-up and eventually as therapeutical targets of AD. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  8. Could clinical profile influence CSF biomarkers in early-onset Alzheimer disease?

    PubMed

    Koric, Lejla; Felician, Olivier; Guedj, Eric; Hubert, Anne Michele; Mancini, Julien; Boucraut, Jose; Ceccaldi, Mathieu

    2010-01-01

    In common forms of Alzheimer disease (AD), anterograde memory impairment is the first deficit to occur. However, the disease, especially in its presenile forms, may also manifest itself through initial deficits that are predominantly of a nonmemory type. These distinct clinical profiles, which reflect the distinct topography of the underlying pathologic processes, may also differ in terms of their cerebrospinal fluid (CSF) markers. The aim of this study was to assess the levels of total tau, phosphorylated tau, and amyloid-beta 42 peptide in the CSF of "atypical" (nonmemory) early-onset AD patients. CSF biomarkers were evaluated in 22 atypical patients, and compared with those from a group of 13 "typical" patients, with a memory onset form of the disease. Our results show that independently of age, disease duration, education level, and clinical severity indices, patients with an atypical onset have significantly higher levels of total tau in the CSF (P=0.023). These findings indicate that an assessment of CSF biomarkers may be of particular use in the clinical diagnosis of "atypical-onset" forms of early-onset AD in which the initial symptoms involve language and visuospatial abilities rather than memory. In addition, they highlight the heterogeneity of pathologic processes in AD, suggesting more intense degeneration in the forms of the disease that primarily involve neocortical structures.

  9. Tumor diagnosis preceding Alzheimer's disease onset: is there a link between cancer and Alzheimer's disease?

    PubMed

    Realmuto, Sabrina; Cinturino, Antonio; Arnao, Valentina; Mazzola, Maria Antonietta; Cupidi, Chiara; Aridon, Paolo; Ragonese, Paolo; Savettieri, Giovanni; D'Amelio, Marco

    2012-01-01

    Studies reporting an inverse association between Alzheimer's disease (AD) and cancer are scant. Available data are mostly based on ancillary findings of mortality data or obtained from studies evaluating frequency of neoplasms in AD patients independently if they occurred before or after AD. Moreover, some studies estimated frequencies of neoplasms in demented individuals, who were not necessarily AD patients. We estimated frequency of tumors preceding the onset of AD in AD patients and compared it to that of age- and gender-matched AD-free individuals. Occurrence of tumors preceding AD onset was assessed through a semi-structured questionnaire. Tumors were categorized as benign, malignant, or of uncertain classification and as endocrine-related or not. Odds ratios (OR), used as measure of the association between the two diseases, were adjusted for tumor categories and known risk factors for AD and tumors. We included 126 AD patients and 252 matched controls. Tumor frequency before AD onset was 18.2% among cases and 24.2% among controls. There was a suggestive trend of an overall inverse association between the two diseases (adjusted OR 0.6; 95% CI 0.4-1.1; p = 0.11). Risk for neoplasms was significantly reduced only for women (adjusted OR, 0.5; 95% CI 0.3-0.9; p = 0.03) and for endocrine related tumors (adjusted OR, 0.5; 95% CI 0.2-1; p = 0.04). Our study confirms the inverse association reported in previous epidemiological studies. Though our findings might be explained by processes playing an opposite role in tumors development and neurodegeneration, they are also suggestive for a possible role of estrogen.

  10. Late-onset Alzheimer's risk variants in memory decline, incident mild cognitive impairment, and Alzheimer's disease.

    PubMed

    Carrasquillo, Minerva M; Crook, Julia E; Pedraza, Otto; Thomas, Colleen S; Pankratz, V Shane; Allen, Mariet; Nguyen, Thuy; Malphrus, Kimberly G; Ma, Li; Bisceglio, Gina D; Roberts, Rosebud O; Lucas, John A; Smith, Glenn E; Ivnik, Robert J; Machulda, Mary M; Graff-Radford, Neill R; Petersen, Ronald C; Younkin, Steven G; Ertekin-Taner, Nilüfer

    2015-01-01

    We tested association of nine late-onset Alzheimer's disease (LOAD) risk variants from genome-wide association studies (GWAS) with memory and progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD) in older Caucasians, cognitively normal at baseline and longitudinally evaluated at Mayo Clinic Rochester and Jacksonville (n>2000). Each variant was tested both individually and collectively using a weighted risk score. APOE-e4 associated with worse baseline memory and increased decline with highly significant overall effect on memory. CLU-rs11136000-G associated with worse baseline memory and incident MCI/LOAD. MS4A6A-rs610932-C associated with increased incident MCI/LOAD and suggestively with lower baseline memory. ABCA7-rs3764650-C and EPHA1-rs11767557-A associated with increased rates of memory decline in subjects with a final diagnosis of MCI/LOAD. PICALM-rs3851179-G had an unexpected protective effect on incident MCI/LOAD. Only APOE-inclusive risk scores associated with worse memory and incident MCI/LOAD. The collective influence of the nine top LOAD GWAS variants on memory decline and progression to MCI/LOAD appears limited. Discovery of biologically functional variants at these loci may uncover stronger effects on memory and incident disease.

  11. Evidence that PICALM affects age at onset of Alzheimer's dementia in Down syndrome.

    PubMed

    Jones, Emma L; Mok, Kin; Hanney, Marisa; Harold, Denise; Sims, Rebecca; Williams, Julie; Ballard, Clive

    2013-10-01

    It is known that individuals with Down syndrome develop Alzheimer's disease with an early age at onset, although associated genetic risk factors have not been widely studied. We tested whether genes that increase the risk of late-onset Alzheimer's disease influence the age at onset in Down syndrome using genome-wide association data for age at onset of dementia in a small sample of individuals (N = 67) with Down syndrome. We tested for association with loci previously associated with Alzheimer's disease risk and, despite the small size of the study, we detected associations with age at onset of Alzheimer's disease in Down syndrome with PICALM (β = 3.31, p = 0.011) and the APOE loci (β = 3.58, p = 0.014). As dementia in people with Down syndrome is relatively understudied, we make all of these data publicly available to encourage further analyses of the problem of Alzheimer's disease in Down syndrome.

  12. 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

  13. Prevalence of Comorbidity in Patients With Young-Onset Alzheimer Disease Compared With Late-Onset: A Comparative Cohort Study.

    PubMed

    Gerritsen, Adrie A J; Bakker, Christian; Verhey, Frans R J; de Vugt, Marjolein E; Melis, René J F; Koopmans, Raymond T C M

    2016-04-01

    With the lack of a cure for Alzheimer disease (AD), the identification of comorbidity is important to reduce the possibility of excess disability. Although comorbidity in patients with late-onset AD (LO-AD) is common, for people with young-onset AD (YO-AD), it is unclear how often comorbidity occurs. Furthermore, it is uncertain whether comorbidity in patients with YO-AD differs from that in patients with LO-AD. The aim of this study was to explore the prevalence, types of morbidity, and morbidity profiles in patients with YO-AD compared with those of patients with LO-AD. Explorative cohort study from 2 separate Dutch cohorts (Needs in Young-onset Dementia [NeedYD] and the Clinical Course of Cognition and Comorbidity-Dementia Study [4C-Dementia study]). Participants were recruited in 2007 and 2008 from (1) the memory clinics of 3 Dutch Alzheimer centers, (2) the memory clinics of general hospitals, (3) mental health services in the southern part of the Netherlands, and (4) young-onset dementia specialized day care facilities. A comparison group of community-dwelling, elderly patients with AD was selected from the 4C-Dementia study. Patients in this study were recruited in 2010 and 2011 from the aforementioned Alzheimer centers. The prevalence rates of comorbidity were compared between 177 patients with YO-AD and 155 patients with LO-AD. Comorbidity was classified using the International Classification of Diseases, 10th Revision (ICD-10). The total amount of comorbidity was established by counting the number of existing diseases (ICD categories or chapters) and comorbidity was also dichotomized as present or absent. Furthermore, a hierarchical cluster analysis was performed to study clusters of comorbidity. Compared with LO-AD, patients with YO-AD showed less (P < .001) overall comorbidity (58.2% vs 86.5%) and had lower prevalence rates of diabetes, obesity, and circulatory diseases; however, the prevalence rates of diseases of the nervous system in YO-AD (6

  14. 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

    2017-03-16

    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.

  15. Factors affecting the age of onset and rate of progression of Alzheimer's disease

    PubMed Central

    Bowler, J.; Munoz, D.; Merskey, H.; Hachinski, V.

    1998-01-01

    OBJECTIVES—To assess the role of cerebrovascular disease, sex, education, occupation, year of birth, leukoaraiosis, congophilic angiopathy, family history, and other demographic factors on the reported age of onset and rate of progression of Alzheimer's disease.
METHODS—Analysis of data from the University of Western Ontario Dementia Study, a prospective longitudinal study of dementia patients with clinical and 6 monthly psychometric follow up to postmortem based in a university memory disorders clinic with secondary and tertiary referrals. There were 172 patients with dementia. The main outcome measures were the reported age of onset of cognitive decline as described by the family (available in 168) and rate of progression as measured during the linear phase of the extended scale for dementia, which could be calculated in 66. The cases subdivided into 49 cases of definite Alzheimer's disease without infarcts, 25 cases of otherwise definite Alzheimer's disease with infarcts, 79 cases of probable Alzheimer's disease without infarcts, and 19 such cases with infarcts.
RESULTS—The age of onset was not influenced by the rate of progression, the presence of cerebral infarcts, or congophilic angiopathy. Educational level, occupational level, sex, family history, year of birth, reported age of onset, severity at entry, an ischaemic score, and the presence of leukoariosis, affected neither age of onset nor the rate of progression. An earlier year of birth had a major effect and higher education had a minor effect on earlier age of onset. The earlier the year of birth, the lower the educational level and the greater the accrual of cerebral infarcts.
CONCLUSIONS—Contrary to series without pathological verification, age of onset in this study was not affected by occupation. Education had a modest effect on earlier reported onset, probably reflecting earlier recognition. As birth year has a strong effect on educational level and the occurrence of cerebral infarcts

  16. Onset of hippocampus-dependent memory impairments in 5XFAD transgenic mouse model of Alzheimer's disease.

    PubMed

    Girard, Stéphane D; Jacquet, Marlyse; Baranger, Kévin; Migliorati, Martine; Escoffier, Guy; Bernard, Anne; Khrestchatisky, Michel; Féron, François; Rivera, Santiago; Roman, François S; Marchetti, Evelyne

    2014-07-01

    The 5XFAD mice are an early-onset transgenic model of Alzheimer's disease (AD) in which amyloid plaques are first observed between two and four months of age in the cortical layer five and in the subiculum of the hippocampal formation. Although cognitive alterations have been described in these mice, there are no studies that focused on the onset of hippocampus-dependent memory deficits, which are a hallmark of the prodromal stage of AD. To identify when the first learning and memory impairments appear, 5XFAD mice of two, four, and six months of age were compared with their respective wild-type littermates using the olfactory tubing maze, which is a very sensitive hippocampal-dependent task. Deficits in learning and memory started at four months with a substantial increase at six months of age while no olfactory impairments were observed. The volumetric study using magnetic resonance imaging of the whole brain and specific areas (olfactory bulb, striatum, and hippocampus) did not reveal neuro-anatomical difference. Slight memory deficits appeared at 4 months of age in correlation with an increased astrogliosis and amyloid plaque formation. This early impairment in learning and memory related to the hippocampal dysfunction is particularly suited to assess preclinical therapeutic strategies aiming to delay or suppress the onset of AD. © 2014 Wiley Periodicals, Inc.

  17. Central obesity in the elderly is related to late-onset Alzheimer disease.

    PubMed

    Luchsinger, José A; Cheng, Derek; Tang, Ming Xin; Schupf, Nicole; Mayeux, Richard

    2012-01-01

    The evidence relating obesity measured with body mass index (BMI) in the elderly to late-onset Alzheimer disease (LOAD) is conflicting. Central obesity in middle age is related to a higher risk of LOAD, but data in the elderly are lacking. We explored whether measures of central obesity, waist circumference, and waist to hip ratio (WHR) were better predictors of LOAD compared with BMI in the elderly. Participants were 1459 persons aged 65 years and older without dementia at baseline, with follow-up, and with anthropometric data from a longitudinal study of aging in New York City. Proportional hazards regression was used for multivariable analyses relating BMI, waist circumference, and WHR to LOAD. There were 145 cases of Alzheimer disease in 5734 person-years of follow-up. Only WHR was related to higher LOAD risk (hazard ratio of the fourth quartile compared with the first=2.5; 95% confidence interval=1.3, 4.7) after adjustment for age, sex, education, ethnic group, Apolipoprotein E-ε4, type 2 diabetes, hypertension, non-high-density lipoprotein-cholesterol, high-density lipoprotein cholesterol, and stroke. Our results support the notion that central obesity is related to a higher risk of LOAD.

  18. Cerebral glucose metabolic patterns in Alzheimer's disease. Effect of gender and age at dementia onset

    SciTech Connect

    Small, G.W.; Kuhl, D.E.; Riege, W.H.; Fujikawa, D.G.; Ashford, J.W.; Metter, E.J.; Mazziotta, J.C.

    1989-06-01

    No previous study of Alzheimer's disease has, to our knowledge, assessed the effect of both age at dementia onset and gender on cerebral glucose metabolic patterns. To this end, we used positron emission tomography (fludeoxyglucose F 18 method) to study 24 patients with clinical diagnoses of probable Alzheimer's disease. Comparisons of the 13 patients with early-onset dementia (less than 65 years of age) with the 11 patients with late-onset dementia (greater than 65 years of age) revealed significantly lower left parietal metabolic ratios (left posterior parietal region divided by the hemispheric average) in the early-onset group. The metabolic ratio of posterior parietal cortex divided by the relatively disease-stable average of caudate and thalamus also separated patients with early-onset dementia from those with late-onset dementia, but not men from women. Further comparisons between sexes showed that, in all brain regions studied, the 9 postmenopausal women had higher nonweighted mean metabolic rates than the 15 men from the same age group, with hemispheric sex differences of 9% on the right and 7% on the left. These results demonstrate decreased parietal ratios in early-onset dementia of Alzheimer's disease, independent of a gender effect.

  19. Late-Onset Alzheimer Risk Variants in Memory Decline, Incident Mild Cognitive Impairment and Alzheimer Disease

    PubMed Central

    Carrasquillo, Minerva M.; Crook, Julia E.; Pedraza, Otto; Thomas, Colleen S.; Pankratz, V. Shane; Allen, Mariet; Nguyen, Thuy; Malphrus, Kimberly G.; Ma, Li; Bisceglio, Gina D.; Roberts, Rosebud O.; Lucas, John A.; Smith, Glenn E.; Ivnik, Robert J.; Machulda, Mary M.; Graff-Radford, Neill R.; Petersen, Ronald C.; Younkin, Steven G.; Ertekin-Taner, Nilüfer

    2014-01-01

    Background Genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) identified risk variants. We assessed the association of nine variants with memory and progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD). Methods Older Caucasians, cognitively normal at baseline and longitudinally evaluated at Mayo Clinic Rochester and Jacksonville, were assessed for associations of genetic variants with memory decline (n=2,262) using linear mixed models and for incident MCI/LOAD (n=2,674) with Cox proportional hazards models. Each variant was tested both individually and collectively using a single weighted risk score. Results APOE-ε4 was significantly associated with worse memory at baseline (β=-0.88, p=2.78E-03) and increased rate of 5-year decline (β=-1.43, p=3.71E-06) with highly significant overall effect on memory (p=3.88E-09). CLU-locus risk allele rs11136000-G was associated with worse memory at baseline (β=-0.51, p=0.012), but not with increased rate of decline. CLU allele was also associated with incident MCI/LOAD (hazard ratio=HR=1.14, p=0.049) in sensitivity analysis. MS4A6A-locus risk allele rs610932-C was associated with increased incident MCI/LOAD in primary analysis (HR=1.17, p=0.016) and had suggestive association with lower baseline memory (β=-0.35, p=0.08). PICALM-locus risk allele rs3851179-G had nominally significant HR in both primary and sensitivity analysis, but with a protective estimate. LOAD risk alleles ABCA7-rs3764650-C and EPHA1-rs11767557-A associated with increased rates of memory decline in the subset of subjects with a final diagnosis of MCI/LOAD. Risk scores excluding APOE were not significant, whereas APOE-inclusive risk scores associated with worse memory and incident MCI/LOAD. Conclusions The collective influence of the nine top LOAD GWAS variants on memory decline and progression to MCI/LOAD appears limited. Given the significant associations observed with APOE-ε4, discovery of the biologically

  20. The APOE locus advances disease progression in late onset familial Alzheimer`s disease but is not causative

    SciTech Connect

    Crawford, F.; Bennett, C.; Osborne, A.

    1994-09-01

    An association has been observed in several independent data sets between late onset Alzheimer`s disease (AD) and the APOE locus on chromosomes 19. We have examined the genotype in family history positive (FHP) and family history negative (FHN) cases and find a distortion of the APOE allele frequencies in accord with previous studies. However, when we examined the allele distribution of the at-risk siblings of the FHP group we found an excess of the {epsilon}4 allele which also differs significantly from historic controls but not from the affected siblings. The age distribution of the affected and unaffected siblings was similar, suggesting that the allelic frequency distortion in the unaffected siblings was not due to their being below the mean age of onset. Lod score linkage analysis, with age dependent onset and nonstringent specification of the genetic parameters, did not suggest linkage to the APOE locus. Furthermore, an analysis of variance of the age of disease-free survival suggested that APOE genotype contributes a small fraction of the total variance, indicating that the APOE locus is a poor predictor of disease-free survival time within late onset families. We suggest that the APOE locus enhances the rate of progression of the disease in otherwise predisposed individuals and that variation at this locus is not able in and of itself to cause this disease.

  1. Prospective Study of the Prevalence of Alzheimer-Type Dementia in Institutionalized Individuals with Down Syndrome.

    ERIC Educational Resources Information Center

    Visser, F. E.; And Others

    1997-01-01

    Institutionalized patients with Down syndrome (N=307) were monitored for 5 to 10 years to determine prevalence of Alzheimer-type dementia. Prevalence increased from 11% between ages 40 and 49 to 77% between 60 and 69. All patients 70 and over had dementia. Mean age of onset of dementia was 56 years. Neuropathological findings were consistent with…

  2. Emotional Prosody Perception and Production in Dementia of the Alzheimer's Type

    ERIC Educational Resources Information Center

    Horley, Kaye; Reid, Amanda; Burnham, Denis

    2010-01-01

    Purpose: In this study, the authors investigated emotional prosody in patients with moderate Dementia of the Alzheimer's type (DAT) With Late Onset. It was expected that both expression and reception of prosody would be impaired relative to age-matched controls. Method: Twenty DAT and 20 control participants engaged in 2 expressive and 2 receptive…

  3. Genome scan in familial late-onset Alzheimer's disease: a locus on chromosome 6 contributes to age-at-onset.

    PubMed

    Zhao, Wei; Marchani, Elizabeth E; Cheung, Charles Y K; Steinbart, Ellen J; Schellenberg, Gerard D; Bird, Thomas D; Wijsman, Ellen M

    2013-03-01

    Alzheimer's disease (AD) is a common, genetically complex, fatal neurodegenerative disorder of late life. Although several genes are known to play a role in early-onset AD, identification of the genetic basis of late onset AD (LOAD) has been challenging, with only the APOE gene known to have a high contribution to both AD risk and age-at-onset. Here, we present the first genome-scan analysis of the complete, well-characterized University of Washington LOAD sample of 119 pedigrees, using age-at-onset as the trait of interest. The analysis approach used allows for a multilocus trait model while at the same time accommodating age censoring, effects of APOE as a known genetic covariate, and full pedigree and marker information. The results provide strong evidence for linkage of loci contributing to age-at-onset to genomic regions on chromosome 6q16.3, and to 19q13.42 in the region of the APOE locus. There was evidence for interaction between APOE and the locus on chromosome 6q and suggestive evidence for linkage to chromosomes 11p13, 15q12-14, and 19p13.12. These results provide the first independent confirmation of an AD age-at-onset locus on chromosome 6 and suggest that further efforts towards identifying the underlying causal locus or loci are warranted.

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

    DTIC Science & Technology

    2015-04-01

    a potential modulator of Abeta toxicity), and NOTCH4 (a presenilin pathway gene). Exome chip results identified variants in MICA encoding the HLA-A...and 2+ Non-white Hispanic families, including the AD-relevant HLA-A (associated with earlier AD age-at-onset), CHST15 (a potential modulator or Abeta

  5. Midlife adiposity predicts earlier onset of Alzheimer's dementia, neuropathology and presymptomatic cerebral amyloid accumulation.

    PubMed

    Chuang, Y-F; An, Y; Bilgel, M; Wong, D F; Troncoso, J C; O'Brien, R J; Breitner, J C; Ferruci, L; Resnick, S M; Thambisetty, M

    2016-07-01

    Understanding how midlife risk factors influence age at onset (AAO) of Alzheimer's disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer's neuropathology. Using a prospective population-based cohort, Baltimore Longitudinal Study of Aging (BLSA), this study aims to examine the relationships between midlife body mass index (BMI) and (1) AAO of AD (2) severity of Alzheimer's neuropathology and (3) fibrillar brain amyloid deposition during aging. We analyzed data on 1394 cognitively normal individuals at baseline (8643 visits; average follow-up interval 13.9 years), among whom 142 participants developed incident AD. In two subsamples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging. Midlife adiposity was derived from BMI data at 50 years of age. We find that each unit increase in midlife BMI predicts earlier onset of AD by 6.7 months (P=0.013). Higher midlife BMI was associated with greater Braak neurofibrillary but not CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuritic plaque scores at autopsy overall. Associations between midlife BMI and brain amyloid burden approached statistical significance. Thus, higher midlife BMI was also associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio (P=0.075) and within the precuneus (left, P=0.061; right, P=0.079). In conclusion, midlife overweight predicts earlier onset of AD and greater burden of Alzheimer's neuropathology. A healthy BMI at midlife may delay the onset of AD.

  6. Genetics of Alzheimer's Disease

    PubMed Central

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

    2013-01-01

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

  7. Transmission and age-at-onset patterns in familial Alzheimer's disease: evidence for heterogeneity.

    PubMed

    Farrer, L A; Myers, R H; Cupples, L A; St George-Hyslop, P H; Bird, T D; Rossor, M N; Mullan, M J; Polinsky, R; Nee, L; Heston, L

    1990-03-01

    We evaluated age at onset and lifetime risk for Alzheimer's disease (AD) in 70 kindreds with familial AD (designated FAD) composed of 541 affected and 1,066 unaffected offspring of demented parents who were identified retrospectively. Using a survival analysis method which takes into account affected persons with unknown onset ages and unaffected persons with unknown censoring ages, we found lifetime risk of AD among at-risk offspring by age 87 to be 64%. Analysis of age at onset among kindreds showed evidence for a bimodal distribution: in this sample, families with a mean onset age of less than 58 years were designated as having early-onset, while late-onset families had a mean onset age greater than 58 years. At-risk offspring in early-onset families had an estimated lifetime risk for dementia of 53%, which is significantly less than the risk of 86% that was estimated for offspring in late-onset families. Men and women in early-onset families had equivalent risk of dementia. In late-onset families, the risk to female offspring was somewhat higher than to male offspring but this difference was marginally significant. Lifetime risk of dementia in early-onset FAD kindreds is consistent with an autosomal dominant inheritance model. Our results may suggest that late-onset FAD has at least 2 etiologies; AD in some families may be transmitted as a dominant trait, whereas a proportion of cases in these and other late-onset families may be caused by other genetic or shared environmental factors.

  8. Typical and atypical appearance of early-onset Alzheimer's disease: A clinical, neuroimaging and neuropathological study.

    PubMed

    Kawakatsu, Shinobu; Kobayashi, Ryota; Hayashi, Hiroshi

    2017-04-01

    The International Working Group (IWG) has classified Alzheimer's disease (AD) as two different types, the typical form and the atypical form, but clinicopathological studies of atypical AD are limited. Because atypical AD cases usually present with early-onset dementia, we investigated 12 patients with early-onset AD, including two patients with typical AD and 10 patients with atypical AD. Of these patients, six had the posterior variant, three had the frontal variant and one had the logopenic variant mixed with semantic dementia. We reported MRI, single-photon emission CT and neuropathological findings in six representative cases. We also described a "left temporal variant" of AD presenting with transcortical cortical sensory aphasia, which has not been reported previously and is another subtype of the posterior variant of AD. We found a significant correlation between regional cerebral blood flow and counts of NFTs in the cerebral cortices. An atypical presentation with focal neuropsychological symptoms roughly correlated with the density of NFTs in the cerebral cortex and more directly related to spongiform changes in the superficial layers of these areas. In contrast, the distribution of amyloid depositions was diffuse and did not necessarily correlate with focal neuropsychological symptoms. Braak staging or ABC score is not necessarily appropriate to evaluate atypical AD, and instead, spongiform changes in addition to tau pathology in the association cortices better explain the diversity of atypical AD. Interestingly, another patient with a posterior variant of AD had a novel type of atypical plaque, which we referred to as "lucent plaque". They were recognizable with HE staining in the circumference and dystrophic neurites were abundant with Gallyas-Braak staining. These plaques demonstrated intense immunoreactivity to both tau AT-8 and amyloid β (Aβ), suggesting a peculiar coexistence pattern of amyloid and tau in these plaques. Clinicopathological studies

  9. Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome.

    PubMed

    Mok, Kin Y; Jones, Emma L; Hanney, Marisa; Harold, Denise; Sims, Rebecca; Williams, Julie; Ballard, Clive; Hardy, John

    2014-06-01

    It is known that Alzheimer's disease (AD) presents at an early age in people with Down syndrome (DS). The trisomy 21 in DS provides an opportunity to study the effect of duplicated genes in AD. APP and BACE2 are 2 genes located in chromosome 21 and related to AD. We looked into our cohort of 67 DS cases with dementia for the effect of BACE2 variants in age of onset of dementia. Of the 83 single-nucleotide polymorphisms (SNPs), 6 were associated with age of onset and another 8 SNPs were borderline associated. Our finding also replicated a previous study showing association of rs2252576 with AD.

  10. 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

    2017-02-21

    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.

  11. Working memory and FDG-PET dissociate early and late onset Alzheimer disease patients.

    PubMed

    Kalpouzos, Grégoria; Eustache, Francis; de la Sayette, Vincent; Viader, Fausto; Chételat, Gaël; Desgranges, Béatrice

    2005-05-01

    The aims of this study were to determine the influence of the onset of Alzheimer's disease (AD) on 1) memory and cerebral glucose metabolism, 2) the relationships between cognitive performance and cerebral glucose metabolism. Brain metabolism was measured by 18FDG-PET in 12 early onset AD patients (age < 65 years) and 26 late onset ones (> 65), with comparable mean MMSE scores. Working memory, semantic memory and episodic memory were assessed. Cognitivo-metabolic correlations (CMC) and complementary interregional correlations were performed in order to identify specific neurocognitive processes within each group. Both AD groups performed poorly on all tasks, except digit span in the late onset group. The early onset group performed more poorly than the late onset one on both the digit span and Brown-Peterson Paradigm (BPP) tasks. Temporo-parietal hypometabolism was found in both groups, the left hemisphere being more affected than the right, especially in the early onset patients, who also showed specific left frontal hypometabolism. For the BPP task, the CMC principally involved left frontal areas in the early onset group, and the cerebellum in the late onset one. For the digit span task, they involved cerebellar and occipital regions in the latter. Regarding the digit span, the occipital and cerebellar involvement may have reflected an effective compensatory mechanism in the late onset patients, while high left supramarginal gyrus hypometabolism in the early onset patients may have explained their failure in this task. In the BPP task, the lower performance of the early onset group may have been due to a frontal lobe dysfunction, as suggested by 1) the hypometabolism of this region, 2) the CMC results, 3) the interregional correlations, which indicated greater disruption of the antero- posterior loop.

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

    PubMed

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

    2017-01-01

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

  13. MTHFR Gene Mutations: A Potential Marker of Late-Onset Alzheimer's Disease?

    PubMed

    Román, Gustavo C

    2015-01-01

    Recent epigenome-wide association studies have confirmed the importance of epigenetic effects mediated by DNA methylation in late-onset Alzheimer's disease (LOAD). Metabolic folate pathways and methyl donor reactions facilitated by B-group vitamins may be critical in the pathogenesis of LOAD. Methylenetetrahydrofolate reductase (MTHFR) gene mutations were studied in consecutive Alzheimer's Disease & Memory Clinic patients up to December 2014. DNA analyses of MTHFR-C667T and - A1298C homozygous and heterozygous polymorphisms in 93 consecutive elderly patients revealed high prevalence of MTHFR mutations (92.5%). Findings require confirmation in a larger series, but MTHFR mutations may become a LOAD marker, opening novel possibilities for prevention and treatment.

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

    PubMed

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

    2017-01-01

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

  15. TOMM40 poly-T repeat lengths, age of onset and psychosis risk in Alzheimer disease

    PubMed Central

    Chu, Su Hee; Roeder, Kathryn; Ferrell, Robert E.; Devlin, Bernie; DeMichele-Sweet, Mary Ann A.; Kamboh, M.Ilyas; Lopez, Oscar L.; Sweet, Robert A.

    2011-01-01

    Apolipoprotein E (APOE) ε4 alleles increase the risk for late-onset Alzheimer disease (LOAD) and decrease the age of onset. Recently, sequencing the APOE region in a small sample of LOAD subjects identified a variable length poly-T repeat sequence in the nearby gene, TOMM40, which may affect age of onset. We genotyped the TOMM40 poly-T repeat using a novel statistical approach to refine the identification of allele length in 892 LOAD subjects and evaluated its effects on age of onset. Because psychosis in LOAD is a heritable phenotype which has shown conflicting associations with APOE genotype, we also evaluated the association of poly-T repeat length with psychosis. Poly-T repeat lengths had a trimodal distribution which differed between APOE genotype groups. After accounting for APOE ε4 there was no association of poly-T repeat length with age of onset. Neither APOE ε4 nor poly-T repeat length was associated with psychosis. Our findings do not support the association of poly-T repeat length with age of onset in LOAD. The clinical implications of this repeat length polymorphism remain to be elucidated. PMID:21820212

  16. Estrogen receptor α variants affect age at onset of Alzheimer's disease in a multiethnic female cohort.

    PubMed

    Janicki, S C; Park, N; Cheng, R; Clark, L N; Lee, J H; Schupf, N

    2014-01-01

    Few studies of gene variants that affect estrogen activity investigate their association with age at onset of Alzheimer's disease (AD) in women of different ethnicities. We examined the influence of ESR1 polymorphisms on age at onset of AD in a multiethnic cohort of women. Among 1,436 women participating in the Washington Heights Inwood Columbia Aging Project, association with age at AD onset was assessed for 41 single-nucleotide polymorphisms (SNPs) on the ESR1 gene using Cox proportional hazard models, adjusting for presence of an APOE ε4 allele, years of education, and body mass index. Six SNPs in self-identified White women were protectively associated with delayed age of AD onset in this self-identified group, including the two restriction fragment length polymorphisms PvuII (rs2234693) and XbaI (rs9340799) (HR range = 0.420-0.483). Two separate SNPs were found to affect age of AD onset in self-identified Black women. ESR1 polymorphisms affect age of onset of AD in women, and risk alleles vary by ethnicity. These effects are possibly due to different linkage disequilibrium patterns or differences in comorbid environmental or cultural risk factors mediating the SNP effect on risk for AD. © 2014 S. Karger AG, Basel.

  17. Apolipoprotein E polymorphism and age at onset of Alzheimer's disease in a quadriethnic sample.

    PubMed

    Kwon, Oh Dae; Khaleeq, Aisha; Chan, Wenyaw; Pavlik, Valory N; Doody, Rachelle S

    2010-01-01

    The relationship between the apolipoprotein E (ApoE) genotype and the risk for developing Alzheimer's disease (AD) or age at onset of AD is relatively well established in Caucasians, but less established in other ethnicities. We examined the association between the ApoE genotype and age at onset of AD in a quadriethnic group of community-dwelling AD patients. AD patients were evaluated at 2 university-based outpatient memory disorder clinics. The ethnic distribution was as follows: Caucasians (n = 1,083), Hispanics (n = 55), African Americans (n = 84) and Koreans (n = 87). All were diagnosed with probable AD according to NINCDS-ADRDA diagnostic criteria. After adjusting for ethnicity, the ε4 allele was significantly associated with earlier age at onset (p < 0.0001) for the combined group. Within ethnic groups, the effect of Apo ε4 on age at onset was significant in Caucasians (p < 0.0001) and African Americans (p < 0.05), but nonsignificant in Koreans (p = 0.43) and in the smaller Hispanic (p = 0.07) group. The association between Apo ε4 and younger age at onset was significant in Caucasians and African Americans, where the ε4 allele was also most frequent. This study suggests that the impact of ApoE polymorphism on age at onset of AD may be different among distinct ethnic groups. Copyright © 2011 S. Karger AG, Basel.

  18. The Number of Trait Loci in Late-Onset Alzheimer Disease

    PubMed Central

    Daw, E. Warwick; Payami, Haydeh; Nemens, Ellen J.; Nochlin, David; Bird, Thomas D.; Schellenberg, Gerard D.; Wijsman, Ellen M.

    2000-01-01

    Summary Although it is clear that apoE plays an important role in the genetics of late-onset Alzheimer disease (AD), evidence exists that additional genes may play a role in AD, and estimates of the total contribution of apoE to the variance in onset of AD vary widely. Unfortunately, little information is available on the number and contribution of additional genes. We estimated the number of additional quantitative-trait loci and their contribution to the variance in age at onset of AD, as well as the contribution of apoE and sex, in an oligogenic segregation analysis of 75 families (742 individuals) ascertained for members with late-onset AD. We found evidence that four additional loci make a contribution to the variance in age at onset of late-onset AD that is similar to or greater in magnitude than that made by apoE, with one locus making a contribution several times greater than that of apoE. Additionally, we confirmed previous findings of a dose effect for the apoE ɛ4 allele, a protective effect for the ɛ2 allele, evidence for allelic interactions at the apoE locus, and a small protective effect for males. Furthermore, although we estimate that the apoE genotype can make a difference of ⩽17 years in age at onset of AD, our estimate of the contribution of apoE (7%–9%) to total variation in onset of AD is somewhat smaller than that which has previously been reported. Our results suggest that several genes that have not yet been localized may play a larger role than does apoE in late-onset AD. PMID:10631151

  19. Senile dementia of the Alzheimer type

    SciTech Connect

    Hutton, J.T.; Kenny, A.D.

    1985-01-01

    This book contains papers on Alzheimer's Disease. They are divided into several topics. The topic headings are: Clinical Evaluation, Management, and Treatment; Related Clinical Disorders; Epidemiology and Genetics; Basic Science; and National Perspectives and Future Directions.

  20. Regional neuronal network failure and cognition in late-onset sporadic Alzheimer disease.

    PubMed

    Carter, S F; Embleton, K V; Anton-Rodriguez, J M; Burns, A; Ralph, M A L; Herholz, K

    2014-06-01

    The severe cognitive deficits in Alzheimer disease are associated with structural lesions in gray and white matter in addition to changes in synaptic function. The current investigation studied the breakdown of the structure and function in regional networks involving the Papez circuit and extended neocortical association areas. Cortical volumetric and diffusion tensor imaging (3T MR imaging), positron-emission tomography with (18)F fluorodeoxyglucose on a high-resolution research tomograph, and comprehensive neuropsychological assessments were performed in patients with late-onset sporadic Alzheimer disease, those with mild cognitive impairment, and elderly healthy controls. Atrophy of the medial temporal lobes was the strongest and most consistent abnormality in patients with mild cognitive impairment and Alzheimer disease. Atrophy in the temporal, frontal, and parietal regions was most strongly related to episodic memory deficits, while deficits in semantic cognition were also strongly related to reductions of glucose metabolism in the posterior cingulate cortex and temporoparietal regions. Changes in fractional anisotropy within white matter tracts, particularly in the left cingulum bundle, uncinate fasciculus, superior longitudinal fasciculus, and inferior fronto-occipital fasciculus, were significantly associated with the cognitive deficits in multiple regression analyses. Posterior cingulate and orbitofrontal metabolic deficits appeared to be related to microstructural changes in projecting white matter tracts. Many lesioned network components within the Papez circuit and extended neocortical association areas were significantly associated with cognitive dysfunction in both mild cognitive impairment and late-onset sporadic Alzheimer disease. Hippocampal atrophy was the most prominent lesion, with associated impairment of the uncinate and cingulum white matter microstructures and hippocampal and posterior cingulate metabolic impairment. © 2014 by American

  1. Rare autosomal copy number variations in early-onset familial Alzheimer's disease.

    PubMed

    Hooli, B V; Kovacs-Vajna, Z M; Mullin, K; Blumenthal, M A; Mattheisen, M; Zhang, C; Lange, C; Mohapatra, G; Bertram, L; Tanzi, R E

    2014-06-01

    Over 200 rare and fully penetrant pathogenic mutations in amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) cause a subset of early-onset familial Alzheimer's disease (EO-FAD). Of these, 21 cases of EO-FAD families carrying unique APP locus duplications remain the only pathogenic copy number variations (CNVs) identified to date in Alzheimer's disease (AD). Using high-density DNA microarrays, we performed a comprehensive genome-wide analysis for the presence of rare CNVs in 261 EO-FAD and early/mixed-onset pedigrees. Our analysis revealed 10 novel private CNVs in 10 EO-FAD families overlapping a set of genes that includes: A2BP1, ABAT, CDH2, CRMP1, DMRT1, EPHA5, EPHA6, ERMP1, EVC, EVC2, FLJ35024 and VLDLR. In addition, CNVs encompassing two known frontotemporal dementia genes, CHMP2B and MAPT were found. To our knowledge, this is the first study reporting rare gene-rich CNVs in EO-FAD and early/mixed-onset AD that are likely to underlie pathogenicity in familial AD and perhaps related dementias.

  2. The dramatic effects of Galantamine in a patient with early-onset Alzheimer's disease.

    PubMed

    Dev, Harveer; Agius, Mark; Zaman, Rashid

    2010-06-01

    We discuss the case of a 51 year old former mid-wife presented to the NHS Luton and Bedfordshire psychiatric services with a 2 year history of increasing forgetfulness with significant impairment to her daily function. She was diagnosed with non-familial early-onset Alzheimer's Disease (EOAD) and started on 8mg daily of the acetylcholinesterase inhibitor Galantamine. The information for this study was gathered from patient notes, consultant, collateral and personal accounts. Periodic outpatient consultations at the NHS Luton and Bedfordshire psychiatric services were used to monitor Mrs LF's global, functional and behavioral progress. These were supplemented with the mini mental state examination (MMSE) at each outpatient appointment. The graph of MMSE scores illustrates severe decline in scores, followed eventually by increase in score to sustained improvement while continuing on galantamine. Functionally, this lady has successfully negotiated a divorce, moved into her own accommodation, began travelling on holidays, including abroad, with friends, and has now embarked on a new relationship. Whilst only being a single case study, this demonstrates the significant benefits which are attainable with Galantamine in EOAD. The extent of this improvement may be a result of individual variation, or perhaps a greater efficacy for this drug in the subset of 'early-onset' AD patients, which has long been thought to share the same mechanism as traditional AD. The responsiveness to Galantamine in this patient may suggest an alternative mechanism of Early Onset Alzheimer's Disease to typical Alzheimer's Disease in the over 65's. The case raises interesting questions as to whether EOAD should be considered distinct to typical (over 65's) AD, given the greater than expected response to Galantamine.

  3. Multilingualism (but not always bilingualism) delays the onset of Alzheimer disease: evidence from a bilingual community.

    PubMed

    Chertkow, Howard; Whitehead, Victor; Phillips, Natalie; Wolfson, Christina; Atherton, Julie; Bergman, Howard

    2010-01-01

    A recent paper by Bialystok et al in Neuropsychologia (vol. 45, pgs. 459 to 464) suggested that early bilingualism produced a statistically significant 4.1-year delay in onset of memory loss symptoms in older individuals with Alzheimer disease, possibly reflecting an increase in the cognitive reserve of these individuals. That study focused on multilingual elderly patients of whom 90% were immigrants. Our memory clinic, in Montreal Canada, has the advantage of having a large set of individuals who are either multilingual immigrants to Canada, or who are nonimmigrants but raised in both official languages of Canada--French and English. We thus attempted to replicate the above findings using a larger cohort in a different setting. We examined age at diagnosis of Alzheimer disease and age at symptom onset for all unilingual versus multilingual participants, and then for those who were nonimmigrant English/French bilinguals. Overall, we found a small but significant protective effect of more than 2 languages spoken, but we found no significant benefit in bilinguals overall in relation to age at diagnosis or age at symptom onset. However, in the immigrant group, the results mirrored those of Bialystok et al with 2 or more languages delaying the diagnosis of Alzheimer disease by almost 5 years. A trend toward the same effect was also seen in nonimmigrants whose first language was French. In contrast, in nonimmigrants whose first language was English, no such effect was found. These results are discussed in relation to the earlier findings and the theory of cognitive reserve.

  4. Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease.

    PubMed

    Goodman, Ann B

    2006-12-01

    Vitamin A (retinoid) is required in the adult brain to enable cognition, learning, and memory. While brain levels of retinoid diminish over the course of normal ageing, retinoid deficit is greater in late onset Alzheimer disease (LOAD) brains than in normal-aged controls. This paper reviews recent evidence supporting these statements and further suggests that genes necessary for the synthesis, transport and function of retinoid to and within the ageing brain are appropriate targets for treatment of LOAD. These genes tend to be clustered with genes that have been proposed as candidates in LOAD, are found at chromosomal regions linked to LOAD, and suggest the possibility of an overall coordinated regulation. This phenomenon is termed Chromeron and is analogous to the operon mechanism observed in prokaryotes. Suggested treatment targets are the retinoic-acid inactivating enzymes (CYP26)s, the retinol binding and transport proteins, retinol-binding protein (RBP)4 and transthyretin (TTR), and the retinoid receptors. TTR as a LOAD target is the subject of active investigation. The retinoid receptors and the retinoid-inactivating enzymes have previously been proposed as targets. This is the first report to suggest that RBP4 is an amenable treatment target in LOAD. RBP4 is elevated in type-2 diabetes and obesity, conditions associated with increased risk for LOAD. Fenretinide, a novel synthetic retinoic acid (RA) analog lowers RBP4 in glucose intolerant obese mice. The feasibility of using fenretinide either as an adjunct to present LOAD therapies, or on its own as an early prevention strategy should be determined. (c) 2006 Wiley-Liss, Inc.

  5. Case Studies Illustrating Focal Alzheimer's, Fluent Aphasia, Late-Onset Memory Loss, and Rapid Dementia.

    PubMed

    Camsari, Gamze Balci; Murray, Melissa E; Graff-Radford, Neill R

    2016-08-01

    Many dementia subtypes have more shared signs and symptoms than defining ones. We review 8 cases with 4 overlapping syndromes and demonstrate how to distinguish the cases. These include focal cortical presentations of Alzheimer's disease (AD; posterior cortical atrophy and corticobasal syndrome [CBS]), fluent aphasia (semantic dementia and logopenic aphasia), late-onset slowly progressive dementia (hippocampal sclerosis and limbic predominant AD) and rapidly progressive dementia (Creutzfeldt-Jakob disease and limbic encephalitis). Recognizing the different syndromes can help the clinician to improve their diagnostic skills, leading to improved patient outcomes by early and accurate diagnosis, prompt treatment, and appropriate counseling and guidance. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Preventive benefits of natural nutrition and lifestyle counseling against Alzheimer's disease onset.

    PubMed

    Polidori, Maria Cristina

    2014-01-01

    Malnutrition-, obesity-, and Alzheimer's disease (AD)-related burden to patients and society are among the main public health challenges of our time in both developed and developing countries. Poor nutrition as part of an unhealthy lifestyle is one of the modifiable risk factors for AD, and its improvement has been the recent focus of several interventional and epidemiologic studies. There is an impressive body of evidence supporting the beneficial role of balanced nutrition in lowering the risk of dementia, but despite worldwide dementia epidemics, lack of information still leads to (too) late diagnosis and (symptomatic) interventions. The aim of this work is to critically summarize knowledge on the preventive effects of natural nutrition against AD onset and to present a multidimensional and individualized approach aimed at delaying AD onset in community dwellers with subjective and mild cognitive complaints.

  7. Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array.

    PubMed

    Barber, Imelda S; Braae, Anne; Clement, Naomi; Patel, Tulsi; Guetta-Baranes, Tamar; Brookes, Keeley; Medway, Christopher; Chappell, Sally; Guerreiro, Rita; Bras, Jose; Hernandez, Dena; Singleton, Andrew; Hardy, John; Mann, David M; Morgan, Kevin

    2017-01-01

    We have screened sporadic early-onset Alzheimer's disease (sEOAD, n = 408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found 2 sEOAD individuals harboring a known causative variant in PARK2 known to cause early-onset Parkinson's disease; p.T240M (n = 1) and p.Q34fs delAG (n = 1). In addition, we identified 3 sEOAD individuals harboring a predicted pathogenic variant in MAPT (p.A469T), which has previously been associated with AD. It is currently unknown if these variants affect susceptibility to sEOAD, further studies would be needed to establish this. This work highlights the need to screen sEOAD individuals for variants that are more classically attributed to other forms of neurodegeneration.

  8. Age-specific epigenetic drift in late-onset Alzheimer's disease.

    PubMed

    Wang, Sun-Chong; Oelze, Beatrice; Schumacher, Axel

    2008-07-16

    Despite an enormous research effort, most cases of late-onset Alzheimer's disease (LOAD) still remain unexplained and the current biomedical science is still a long way from the ultimate goal of revealing clear risk factors that can help in the diagnosis, prevention and treatment of the disease. Current theories about the development of LOAD hinge on the premise that Alzheimer's arises mainly from heritable causes. Yet, the complex, non-Mendelian disease etiology suggests that an epigenetic component could be involved. Using MALDI-TOF mass spectrometry in post-mortem brain samples and lymphocytes, we have performed an analysis of DNA methylation across 12 potential Alzheimer's susceptibility loci. In the LOAD brain samples we identified a notably age-specific epigenetic drift, supporting a potential role of epigenetic effects in the development of the disease. Additionally, we found that some genes that participate in amyloid-beta processing (PSEN1, APOE) and methylation homeostasis (MTHFR, DNMT1) show a significant interindividual epigenetic variability, which may contribute to LOAD predisposition. The APOE gene was found to be of bimodal structure, with a hypomethylated CpG-poor promoter and a fully methylated 3'-CpG-island, that contains the sequences for the epsilon4-haplotype, which is the only undisputed genetic risk factor for LOAD. Aberrant epigenetic control in this CpG-island may contribute to LOAD pathology. We propose that epigenetic drift is likely to be a substantial mechanism predisposing individuals to LOAD and contributing to the course of disease.

  9. Conditional Deletion of Prnp Rescues Behavioral and Synaptic Deficits after Disease Onset in Transgenic Alzheimer's Disease.

    PubMed

    Salazar, Santiago V; Gallardo, Christopher; Kaufman, Adam C; Herber, Charlotte S; Haas, Laura T; Robinson, Sophie; Manson, Jean C; Lee, Michael K; Strittmatter, Stephen M

    2017-09-20

    Biochemical and genetic evidence implicate soluble oligomeric amyloid-β (Aβo) in triggering Alzheimer's disease (AD) pathophysiology. Moreover, constitutive deletion of the Aβo-binding cellular prion protein (PrP(C)) prevents development of memory deficits in APPswe/PS1ΔE9 mice, a model of familial AD. Here, we define the role of PrP(C) to rescue or halt established AD endophenotypes in a therapeutic disease-modifying time window after symptom onset. Deletion of Prnp at either 12 or 16 months of age fully reverses hippocampal synapse loss and completely rescues preexisting behavioral deficits by 17 months. In contrast, but consistent with a neuronal function for Aβo/PrP(C) signaling, plaque density, microgliosis, and astrocytosis are not altered. Degeneration of catecholaminergic neurons remains unchanged by PrP(C) reduction after disease onset. These results define the potential of targeting PrP(C) as a disease-modifying therapy for certain AD-related phenotypes after disease onset.SIGNIFICANCE STATEMENT The study presented here further elucidates our understanding of the soluble oligomeric amyloid-β-Aβo-binding cellular prion protein (PrP(C)) signaling pathway in a familial form of Alzheimer's disease (AD) by implicating PrP(C) as a potential therapeutic target for AD. In particular, genetic deletion of Prnp rescued several familial AD (FAD)-associated phenotypes after disease onset in a mouse model of FAD. This study underscores the therapeutic potential of PrP(C) deletion given that patients already present symptoms at the time of diagnosis. Copyright © 2017 the authors 0270-6474/17/379207-15$15.00/0.

  10. Retirement age and the age of onset of Alzheimer's disease: results from the ICTUS study.

    PubMed

    Grotz, Catherine; Letenneur, Luc; Bonsang, Eric; Amieva, Hélène; Meillon, Céline; Quertemont, Etienne; Salmon, Eric; Adam, Stéphane

    2015-01-01

    To test whether deferred retirement is associated with delayed onset of Alzheimer's disease (AD), and, if so, to determine whether retirement age still predicts the age at onset of AD when two potential biases are considered. The study sample was gathered from the Impact of Cholinergic Treatment Use/Data Sharing Alzheimer cohort (ICTUS/DSA), a European study of 1,380 AD patients. Information regarding retirement age, onset of symptoms and covariates was collected at baseline whereas age at diagnosis was gathered from the patient's medical record prior to study entry. Linear mixed models, adjusted for gender, education, occupation, center, country, household income, depression and cardiovascular risk factors were conducted on 815 patients. (1) The global analyses (n = 815) revealed that later age at retirement was associated with later age at diagnosis (β = 0.31, p < 0.0001); (2) once the selection bias was considered (n = 637), results showed that this association was weaker but remained significant (β = 0.15, p = 0.004); (3) once the bias of the reverse causality (i.e., the possibility that subjects may have left the workforce due to prior cognitive impairment) was considered (n = 447), the effect was no longer significant (β = 0.06, p = 0.18). The present study supports that there is an association between retirement age and age at onset of AD. However, the strength of this association appears to be overestimated due to the selection bias. Moreover, the causality issue remains unresolved. Further prospective investigations are mandatory in order to correctly address this question.

  11. The apolipoprotein E/CI/CII gene cluster and late-onset Alzheimer disease

    SciTech Connect

    Yu, Chang-En; Nemens, E.; Olson, J.M.; Goddard, K.A.B.; Kukull, W.A.; Payami, H.; Boehnke, M.; Wijsman, E.M.; Orr, H.T.; White, J.A.

    1994-04-01

    The chromosome 19 apolipoprotein E/CI/CII gene cluster was examined for evidence of linkage to a familial Alzheimer disease (FAD) locus. The family groups studied were Volga German (VG), early-onset non-VG (ENVG; mean age at onset <60 years), and late-onset families. A genetic association was observed between apolipoprotein E (ApoE) allele E4 and FAD in late-onset families; the E4 allele frequency was .51 in affected subjects, .37 in at-risk subjects, .11 in spouses, and .19 in unrelated controls. The differences between the E4 frequencies in affected subjects versus controls and in at-risk subjects versus controls were highly significant. No association between the E4 allele and FAD was observed in the ENVG or VG groups. A statistically significant allelic association between E4 and AD was also observed in a group of unrelated subjects; the E4 frequency was .26 in affected subjects, versus .19 in controls (Z[sub SND] = 2.20, P < .03). Evidence of linkage of ApoE and ApoCII to FAD was examined by maximum-likelihood methods, using three models and assuming autosomal dominant inheritance: (1) age-dependent penetrance, (2) extremely low (1%) penetrance, and (3) age-dependent penetrance corrected for sporadic Alzheimer disease (AD). For ApoCII in late-onset families, results for close linkage were negative, and only small positive lod-score-statistic (Z) values were obtained. For ApoE in late-onset kindreds, positive Z values were obtained when either allele frequencies from controls or allele frequencies from the families were used. When linkage disequilibrium was incorporated into the analysis, the Z values increased. For the ENVG group, results for ApoE and ApoCII were uniformly negative. Affected-pedigree-member analysis gave significant results for the late-onset kindreds, for ApoE, when control allele frequencies were used but not when allele frequencies were derived from the families. 58 refs., 6 tabs.

  12. The Apolipoprotein E/CI/CII Gene Cluster and Late-Onset Alzheimer Disease

    PubMed Central

    Yu, Chang-En; Payami, Haydeh; Olson, Jane M.; Boehnke, Michael; Wijsman, Ellen M.; Orr, Harry T.; Kukull, Walter A.; Goddard, Katrina A. B.; Nemens, Ellen; White, June A.; Alonso, M. Elisa; Taylor, Todd D.; Ball, Melvyn J.; Kaye, Jeffrey; Morris, John; Chui, Helena; Sadovnick, Adele D.; Martin, George M.; Larson, Eric B.; Heston, Leonard L.; Bird, Thomas D.; Schellenberg, Gerard D.

    1994-01-01

    The chromosome 19 apolipoprotein E/CI/CII gene cluster was examined for evidence of linkage to a familial Alzheimer disease (FAD) locus. The family groups studied were Volga German (VG), early-onset non-VG (ENVG; mean age at onset <60 years), and late-onset families. A genetic association was observed between apolipoprotein E (ApoE) allele ε4 and FAD in late-onset families; the ε4 allele frequency was .51 in affected subjects, .37 in at-risk subjects, .11 in spouses, and .19 in unrelated controls. The differences between the ε4 frequencies in affected subjects versus controls and in at-risk subjects versus controls were highly significant (standard normal deviate [ZSND]) = 7.37, P < 10−9; and ZSND = 4.07, P < .00005, respectively). No association between the ε4 allele and FAD was observed in the ENVG or VG groups. A statistically significant allelic association between ε4 and AD was also observed in a group of unrelated subjects; the ε4 frequency was .26 in affected subjects, versus .19 in controls (ZSND = 2.20, P < .03). Evidence of linkage of ApoE and ApoCII to FAD was examined by maximum-likelihood methods, using three models and assuming autosomal dominant inheritance: (1) age-dependent penetrance, (2) extremely low (1%) penetrance, and (3) age-dependent penetrance corrected for sporadic Alzheimer disease (AD). For ApoCII in late-onset families, results for close linkage were negative, and only small positive lod-score-statistic (Z) values were obtained (model 1, maximum Z [Zmax] = 0.61, recombination fraction [θ] = .30; model 2, Zmax = 0.47, θ = .20). For ApoE in late-onset kindreds, positive Z values were obtained when either allele frequencies from controls (model 1, Zmax = 2.02, θ = .15; model 2, Zmax = 3.42, θ = .05) or allele frequencies from the families (model 1, Zmax = 1.43, θ = .15; model 2, Zmax = 1.70, θ = .05) were used. When linkage disequilibrium was incorporated into the analysis, the Z values increased (model 1, Zmax = 3.17,

  13. SORL1 mutations in early- and late-onset Alzheimer disease

    PubMed Central

    Cuccaro, Michael L.; Carney, Regina M.; Zhang, Yalun; Bohm, Christopher; Kunkle, Brian W.; Vardarajan, Badri N.; Whitehead, Patrice L.; Cukier, Holly N.; Mayeux, Richard; St. George-Hyslop, Peter

    2016-01-01

    Objective: To characterize the clinical and molecular effect of mutations in the sortilin-related receptor (SORL1) gene. Methods: We performed whole-exome sequencing in early-onset Alzheimer disease (EOAD) and late-onset Alzheimer disease (LOAD) families followed by functional studies of select variants. The phenotypic consequences associated with SORL1 mutations were characterized based on clinical reviews of medical records. Functional studies were completed to evaluate β-amyloid (Aβ) production and amyloid precursor protein (APP) trafficking associated with SORL1 mutations. Results: SORL1 alterations were present in 2 EOAD families. In one, a SORL1 T588I change was identified in 4 individuals with AD, 2 of whom had parkinsonian features. In the second, an SORL1 T2134 alteration was found in 3 of 4 AD cases, one of whom had postmortem Lewy bodies. Among LOAD cases, 4 individuals with either SORL1 A528T or T947M alterations had parkinsonian features. Functionally, the variants weaken the interaction of the SORL1 protein with full-length APP, altering levels of Aβ and interfering with APP trafficking. Conclusions: The findings from this study support an important role for SORL1 mutations in AD pathogenesis by way of altering Aβ levels and interfering with APP trafficking. In addition, the presence of parkinsonian features among select individuals with AD and SORL1 mutations merits further investigation. PMID:27822510

  14. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum.

    PubMed Central

    Campion, D; Dumanchin, C; Hannequin, D; Dubois, B; Belliard, S; Puel, M; Thomas-Anterion, C; Michon, A; Martin, C; Charbonnier, F; Raux, G; Camuzat, A; Penet, C; Mesnage, V; Martinez, M; Clerget-Darpoux, F; Brice, A; Frebourg, T

    1999-01-01

    To determine the prevalence of early-onset Alzheimer disease (EOAD) and of autosomal dominant forms of EOAD (ADEOAD), we performed a population-based study in the city of Rouen (426,710 residents). EOAD was defined as onset of disease at age <61 years, and ADEOAD was defined as the occurrence of at least three EOAD cases in three generations. Using these stringent criteria, we calculated that the EOAD and ADEOAD prevalences per 100,000 persons at risk were 41.2 and 5.3, respectively. We then performed a mutational analysis of the genes for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) in 34 families with ADEOAD ascertained in France. In 19 (56%) of these families, we identified 16 distinct PSEN1 missense mutations, including 4 (Thr147Ile, Trp165Cys, Leu173Trp, and Ser390Ile) not reported elsewhere. APP mutations, including a novel mutation located at codon 715, were identified in 5 (15%) of the families. In the 10 remaining ADEOAD families and in 9 additional autosomal dominant Alzheimer disease families that did not fulfill the strict criteria for ADEOAD, no PSEN1, PSEN2, or APP mutation was identified. These results show that (1) PSEN1 and APP mutations account for 71% of ADEOAD families and (2) nonpenetrance at age <61 years is probably infrequent for PSEN1 or APP mutations. PMID:10441572

  15. LONGITUDINAL FOLLOW-UP OF LATE-ONSET ALZHEIMER DISEASE FAMILIES

    PubMed Central

    Carney, R.M.; Slifer, M.A.; Lin, P.I.; Gaskell, P. C.; Scott, W. K.; Potocky, C.F.; Hulette, C. M.; Welsh-Bohmer, K. A.; Schmechel, D. E.; Vance, J.M.; Pericak-Vance, M. A.

    2009-01-01

    Historically, data for genetic studies are collected at one time point. However, for diseases with late onset or with complex phenotypes, such as Alzheimer disease (AD), restricting diagnosis to a single ascertainment contact may not be sufficient. Affection status may change over time, and some initial diagnoses may be inconclusive. Follow-up provides the opportunity to resolve these complications. However, to date, previous studies have not formally demonstrated that longitudinally re-contacting families is practical or productive. To update data initially collected for linkage analysis of late-onset Alzheimer disease (LOAD), we successfully re-contacted 63 of 81 (78%) multiplex families (two to 17 years after ascertainment). Clinical status changed for 73 of the 230 (32%) non-affected participants. Additionally, expanded family history identified 20 additional affected individuals to supplement the data set. Furthermore, fostering ongoing relationships with participating families helped recruit 101 affected participants into an autopsy and tissue donation program. Despite similar presentations, discordance between clinical diagnosis and neuropathologic diagnosis was observed in 28% of those with tissue diagnoses. Most of the families were successfully re-contacted, and significant refinement and supplementation of the data was achieved. We concluded that serial contact with longitudinal evaluation of families has significant implications for genetic analyses. PMID:18361431

  16. Delaying the onset of Alzheimer disease: bilingualism as a form of cognitive reserve.

    PubMed

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

    2010-11-09

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

  17. 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

  18. A genetic screen of the mutations in the Korean patients with early-onset Alzheimer's disease.

    PubMed

    An, Seong Soo; Park, Sun Ah; Bagyinszky, Eva; Bae, Sun Oh; Kim, Yoon-Jeong; Im, Ji Young; Park, Kyung Won; Park, Kee Hyung; Kim, Eun-Joo; Jeong, Jee Hyang; Kim, Jong Hun; Han, Hyun Jeong; Choi, Seong Hye; Kim, SangYun

    2016-01-01

    Early-onset Alzheimer's disease (EOAD) has distinct clinical characteristics in comparison to late-onset Alzheimer's disease (LOAD). The genetic contribution is suggested to be more potent in EOAD. However, the frequency of causative mutations in EOAD could be variable depending on studies. Moreover, no mutation screening study has been performed yet employing large population in Korea. Previously, we reported that the rate of family history of dementia in EOAD patients was 18.7% in a nationwide hospital-based cohort study, the Clinical Research Center for Dementia of South Korea (CREDOS) study. This rate is much lower than in other countries and is even comparable to the frequency of LOAD patients in our country. To understand the genetic characteristics of EOAD in Korea, we screened the common Alzheimer's disease (AD) mutations in the consecutive EOAD subjects from the CREDOS study from April 2012 to February 2014. We checked the sequence of APP (exons 16-17), PSEN1 (exons 3-12), and PSEN2 (exons 3-12) genes. We identified different causative or probable pathogenic AD mutations, PSEN1 T116I, PSEN1 L226F, and PSEN2 V214L, employing 24 EOAD subjects with a family history and 80 without a family history of dementia. PSEN1 T116I case demonstrated autosomal dominant trait of inheritance, with at least 11 affected individuals over 2 generations. However, there was no family history of dementia within first-degree relation in PSEN1 L226F and PSEN2 V214L cases. Approximately, 55.7% of the EOAD subjects had APOE ε4 allele, while none of the mutation-carrying subjects had the allele. The frequency of genetic mutation in this study is lower compared to the studies from other countries. The study design that was based on nationwide cohort, which minimizes selection bias, is thought to be one of the contributors to the lower frequency of genetic mutation. However, the possibility of the greater likeliness of earlier onset of sporadic AD in Korea cannot be excluded. We

  19. Dermatoglyphic patterns in dementia of the Alzheimer type: a case-control study.

    PubMed Central

    Berr, C; Okra-Podrabinek, N; Feteanu, D; Taurand, S; Hervy, M P; Forette, F; Piette, F; Sebag-Lanoe, R; Alperovitch, A

    1992-01-01

    STUDY OBJECTIVE--The aim was to compare digital and palmar dermatoglyphics in subjects with dementia of Alzheimer type and in mentally healthy elderly controls. DESIGN--This design was a case-control study. SETTING--The study was carried out in geriatric units and retirement communities in the Paris area. PARTICIPANTS--Cases were women with clinically diagnosed Alzheimer type dementia according to DSM III-R criteria (n = 82), mainly with late onset of the disease. Controls were women aged 85 years or older without cognitive deterioration (n = 76). MEASUREMENTS AND MAIN RESULTS--Finger and palm prints obtained from both hands by the classical ink method were examined. Fingerprints were classified into four types of figures. On palms, palmar flexion creases, palmar axial triradii, true patterns of the hypothenar area, and main line terminations were described. Examinations were performed by two examiners blind to the subjects's diagnostic category. For the different patterns studied, no major differences between dementia patients and elderly controls were found. Nor was there evidence of high frequencies of features commonly observed in Down's syndrome (trisomy 21), which have previously, though sporadically, been reported. CONCLUSIONS--On one of the largest samples of Alzheimer dementia patients studied, and with evaluation blind to diagnosis, no evidence has been found that particular dermatoglyphic patterns occur like those observed in Down's syndrome, a disease which is related to dementia of the Alzheimer type. PMID:1479321

  20. Familial late-onset Alzheimer's disease: description of an Italian family with four affected siblings and one case of early-onset dementia in the preceding generation.

    PubMed

    Abbate, Carlo; Arosio, Beatrice; Cantatore, Alessandra; Viti, Niccolò; Giunco, Fabrizio; Bagarolo, Renzo; Nicolini, Paola; Gussago, Cristina; Ferri, Evelyn; Casati, Martina; Rossi, Paolo Dionigi; Casè, Alessandra; Bergamaschini, Luigi; Vergani, Carlo; Mari, Daniela

    2016-10-01

    We describe a family composed of six siblings, four of which affected by late-onset Alzheimer's disease (LOAD). We constructed the family pedigree, evaluated mutations usually associated with early-onset Alzheimer's disease (APP, PSEN1, PSEN2), and assessed polymorphisms in the apolipoprotein E (APOE) gene and in cytokine genes that we had previously found to be associated with a higher risk of LOAD (IL-10, IL-6, TNF-α). Results showed that all subjects carried one ε4 allele of the APOE gene and those with the earliest age of onset exhibited the AA (-1082) IL-10 and the CC (-174) IL-6 genotypes. The only male had a genetic profile which also included the A (-308) TNF-α allele. These data confirm the role of the APOE gene as genetic risk factor in LOAD, and suggest that the risk of developing AD may be governed by a "susceptibility profile" involving polymorphisms in inflammatory genes.

  1. Multipoint oligogenic analysis of age-at-onset data with applications to Alzheimer disease pedigrees.

    PubMed Central

    Daw, E W; Heath, S C; Wijsman, E M

    1999-01-01

    It is usually difficult to localize genes that cause diseases with late ages at onset. These diseases frequently exhibit complex modes of inheritance, and only recent generations are available to be genotyped and phenotyped. In this situation, multipoint analysis using traditional exact linkage analysis methods, with many markers and full pedigree information, is a computationally intractable problem. Fortunately, Monte Carlo Markov chain sampling provides a tool to address this issue. By treating age at onset as a right-censored quantitative trait, we expand the methods used by Heath (1997) and illustrate them using an Alzheimer disease (AD) data set. This approach estimates the number, sizes, allele frequencies, and positions of quantitative trait loci (QTLs). In this simultaneous multipoint linkage and segregation analysis method, the QTLs are assumed to be diallelic and to interact additively. In the AD data set, we were able to localize correctly, quickly, and accurately two known genes, despite the existence of substantial genetic heterogeneity, thus demonstrating the great promise of these methods for the dissection of late-onset oligogenic diseases. PMID:10053019

  2. Age-Specific Epigenetic Drift in Late-Onset Alzheimer's Disease

    PubMed Central

    Wang, Sun-Chong; Oelze, Beatrice; Schumacher, Axel

    2008-01-01

    Despite an enormous research effort, most cases of late-onset Alzheimer's disease (LOAD) still remain unexplained and the current biomedical science is still a long way from the ultimate goal of revealing clear risk factors that can help in the diagnosis, prevention and treatment of the disease. Current theories about the development of LOAD hinge on the premise that Alzheimer's arises mainly from heritable causes. Yet, the complex, non-Mendelian disease etiology suggests that an epigenetic component could be involved. Using MALDI-TOF mass spectrometry in post-mortem brain samples and lymphocytes, we have performed an analysis of DNA methylation across 12 potential Alzheimer's susceptibility loci. In the LOAD brain samples we identified a notably age-specific epigenetic drift, supporting a potential role of epigenetic effects in the development of the disease. Additionally, we found that some genes that participate in amyloid-β processing (PSEN1, APOE) and methylation homeostasis (MTHFR, DNMT1) show a significant interindividual epigenetic variability, which may contribute to LOAD predisposition. The APOE gene was found to be of bimodal structure, with a hypomethylated CpG-poor promoter and a fully methylated 3′-CpG-island, that contains the sequences for the ε4-haplotype, which is the only undisputed genetic risk factor for LOAD. Aberrant epigenetic control in this CpG-island may contribute to LOAD pathology. We propose that epigenetic drift is likely to be a substantial mechanism predisposing individuals to LOAD and contributing to the course of disease. PMID:18628954

  3. Impact of home visit capacity on genetic association studies of late-onset Alzheimer's disease.

    PubMed

    Fardo, David W; Gibbons, Laura E; Mukherjee, Shubhabrata; Glymour, M Maria; McCormick, Wayne; McCurry, Susan M; Bowen, James D; Larson, Eric B; Crane, Paul K

    2017-08-01

    Findings for genetic correlates of late-onset Alzheimer's disease (LOAD) in studies that rely solely on clinic visits may differ from those with capacity to follow participants unable to attend clinic visits. We evaluated previously identified LOAD-risk single nucleotide variants in the prospective Adult Changes in Thought study, comparing hazard ratios (HRs) estimated using the full data set of both in-home and clinic visits (n = 1697) to HRs estimated using only data that were obtained from clinic visits (n = 1308). Models were adjusted for age, sex, principal components to account for ancestry, and additional health indicators. LOAD associations nominally differed for 4 of 21 variants; CR1 and APOE variants were significant after Bonferroni correction. Estimates of genetic associations may differ for studies limited to clinic-only designs. Home visit capacity should be explored as a possible source of heterogeneity and potential bias in genetic studies. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  4. Clinical, genetic, and neuroimaging features of Early Onset Alzheimer Disease: the challenges of diagnosis and treatment.

    PubMed

    Alberici, Antonella; Benussi, Alberto; Premi, Enrico; Borroni, Barbara; Padovani, Alessandro

    2014-01-01

    Early Onset Alzheimer Disease (EOAD) is a rare condition, frequently associated with genetic causes. The dissemination of genetic testing along with biomarker determinations have prompted a wider recognition of EOAD in experienced clinical settings. However, despite the great efforts in establishing the contribution of causative genes to EOAD, atypical disease presentation and clinical features still makes its diagnosis and treatment a challenge for the clinicians. This review aims to provide an extensive evaluation of literature data on EOAD, in order to improve understanding and knowledge of EOAD, underscore its significant impact on patients and their caregivers and influence public policies. This would be crucial to define the urgency of evidence-based treatment approaches.

  5. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset.

    PubMed Central

    Brookmeyer, R; Gray, S; Kawas, C

    1998-01-01

    OBJECTIVES: The goal of this study was to project the future prevalence and incidence of Alzheimer's disease in the United States and the potential impact of interventions to delay disease onset. METHODS: The numbers of individuals in the United States with Alzheimer's disease and the numbers of newly diagnosed cases that can be expected over the next 50 years were estimated from a model that used age-specific incidence rates summarized from several epidemiological studies, US mortality rates, and US Bureau of the Census projections. RESULTS: in 1997, the prevalence of Alzheimer's disease in the United States was 2.32 million (range: 1.09 to 4.58 million); of these individuals, 68% were female. It is projected that the prevalence will nearly quadruple in the next 50 years, by which time approximately 1 in 45 Americans will be afflicted with the disease. Currently, the annual number of new incident cases in 360,000. If interventions could delay onset of the disease by 2 years, after 50 years there would be nearly 2 million fewer cases than projected; if onset could be delayed by 1 year, there would be nearly 800,000 fewer prevalent cases. CONCLUSIONS: As the US population ages, Alzheimer's disease will become an enormous public health problem. interventions that could delay disease onset even modestly would have a major public health impact. PMID:9736873

  6. Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study

    PubMed Central

    Lee, Joseph H.; Cheng, Rong; Graff-Radford, Neill; Foroud, Tatiana; Mayeux, Richard

    2009-01-01

    Objective To identify putative genetic loci related to the risk of late-onset Alzheimer disease (LOAD). Design Linkage analysis and family-based and case-control association analyses from a genomewide scan using approximately 6000 single-nucleotide polymorphic markers at an average intermarker distance of 0.65 cM. Setting The National Institute on Aging Genetics Initiative for Late-Onset Alzheimer's Disease (NIA-LOAD) was created to expand the resources for studies to identify additional genes contributing to the risk for LOAD. Participants We investigated 1902 individuals from 328 families with LOAD and 236 unrelated control subjects. Main Outcome Measures Clinical diagnosis of LOAD. Results The strongest overall finding was at chromosome 19q13.32, confirming the effect of the apolipoprotein E gene on LOAD risk in the family-based and case-control analyses. However, single-nucleotide polymorphisms at the following loci were also statistically significant in 1 or more of the analyses performed: 7p22.2, 7p21.3, and 16q21 in the linkage analyses; 17q21.31 and 22q11.21 in the family-based association analysis; and 7q31.1 and 22q12.3 in the case-control analysis. Positive associations at 7q31.1 and 20q13.33 were also significant in the meta-analysis results in a publicly available database. Conclusions Several additional loci may harbor genetic variants associated with LOAD. This data set provides a wealth of phenotypic and genotypic information for use as a resource in discovery and confirmatory research. PMID:19001172

  7. Association Between Exercise Capacity and Late Onset of Dementia, Alzheimer Disease, and Cognitive Impairment.

    PubMed

    Müller, Jan; Chan, Khin; Myers, Jonathan N

    2017-02-01

    To address the association between exercise capacity and the onset of dementia, Alzheimer disease, and cognitive impairment. For 6104 consecutive veteran patients (mean ± SD age: 59.2±11.4 years) referred for treadmill exercise testing, the combined end point of dementia, Alzheimer disease, and cognitive impairment was abstracted from the Veterans Affairs computerized patient record system. After mean ± SD follow-up of 10.3±5.5 years, 353 patients (5.8%) developed the composite end point at a mean ± SD age of 76.7±10.3 years. After correction for confounders in multivariate Cox proportional hazards regression, higher age at exercise testing (hazard ratio [HR]=1.08; 95% CI, 1.07-1.09; P<.001), current smoking (HR=1.44; 95% CI, 1.08-1.93; P=.01), and exercise capacity (HR=0.92; 95% CI, 0.89-0.96; P<.001) emerged as predictors of cognitive impairment. Each 1-metabolic equivalent increase in exercise capacity conferred a nearly 8% reduction in the incidence of cognitive impairment. Meeting the recommendations for daily activity was not associated with a delay in onset of cognitive impairment (HR=1.07; 95% CI, 0.86-1.32; P=.55). Exercise capacity is strongly associated with cognitive function; the inverse association between fitness and cognitive impairment provides an additional impetus for health care providers to promote physical activity. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  8. A comparative study of caregiver burden in late-onset depression and Alzheimer's disease.

    PubMed

    Kazhungil, Firoz; Velayudhan, Rajmohan; Kumar, Manoj; Thazhe Mangool, Raghuram

    2016-05-01

    Alzheimer's disease (AD) and major depressive disorder are the two most common psychogeriatric disorders. Late-onset depression (LOD) is the most common cause of emotional suffering in the elderly and is associated with a poor quality of life in caregivers. Although the burden on caregivers of individuals suffering from AD has been well studied, there is a paucity of comparative studies on caregiver burden between AD and LOD. The objectives of this study were to compare the caregiver burden in LOD and AD and to identify factors associated with caregiver burden in LOD. The study included two groups of 25 patients and their caregivers. Group 1 consisted of LOD patients diagnosed with major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision, with onset after age 60, and their caregivers. Group 2 consisted of AD patients and their caregivers. Caregiver burden was assessed by the Zarit Caregiver Burden Interview. Sociodemographic and clinical correlates of caregiver burden in LOD and AD were analyzed. There was no significant difference in caregiver burden between LOD and AD (P = 0.27). In LOD, the factors positively associated with caregiver burden included the patient's education and the caregiver being a woman, married, unmarried, and a student. Factors negatively associated with caregiver burden included being the son of the patient and high income status. Multivariate stepwise regression analysis showed that caregiver burden in AD is predicted by the Behavioural Pathology in Alzheimer's Disease Scale score, income, presence of diabetes, and in-laws as caregivers (adjusted R(2) = 0.847, P < 0.001). In LOD, caregiver burden is predicted by income, the patient's education, and whether the caregiver is a student or spouse (adjusted R(2) = 0.388, P < 0.001). This study highlights the finding that caregiver burden in LOD is comparable to that in AD and requires interventions to reduce the caregiver

  9. Executive Abilities as Reflected by Clock Hand Placement: Frontotemporal Dementia Versus Early-Onset Alzheimer Disease.

    PubMed

    Barrows, Robin J; Barsuglia, Joseph; Paholpak, Pongsatorn; Eknoyan, Donald; Sabodash, Valeriy; Lee, Grace J; Mendez, Mario F

    2015-12-01

    The clock-drawing test (CDT) is widely used in clinical practice to diagnose and distinguish patients with dementia. It remains unclear, however, whether the CDT can distinguish among the early-onset dementias. Accordingly, we examined the ability of both quantitative and qualitative CDT analyses to distinguish behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer disease (eAD), the 2 most common neurodegenerative dementias with onset <65 years of age. We hypothesized that executive aspects of the CDT would discriminate between these 2 disorders. The study compared 15 patients with bvFTD and 16 patients with eAD on the CDT using 2 different scales and correlated the findings with neuropsychological testing and magnetic resonance imaging. The total CDT scores did not discriminate bvFTD and eAD; however, specific analysis of executive hand placement items successfully distinguished the groups, with eAD exhibiting greater errors than bvFTD. The performance on those executive hand placement items correlated with measures of naming as well as visuospatial and executive function. On tensor-based morphometry of the magnetic resonance images, executive hand placement correlated with right frontal volume. These findings suggest that lower performance on executive hand placement items occurs with involvement of the right dorsolateral frontal-parietal network for executive control in eAD, a network disproportionately affected in AD of early onset. Rather than the total performance on the clock task, the analysis of specific errors, such as executive hand placement, may be useful for early differentiation of eAD, bvFTD, and other conditions.

  10. Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease.

    PubMed

    Barber, Imelda S; García-Cárdenas, Jennyfer M; Sakdapanichkul, Chidchanok; Deacon, Christopher; Zapata Erazo, Gabriela; Guerreiro, Rita; Bras, Jose; Hernandez, Dena; Singleton, Andrew; Guetta-Baranes, Tamar; Braae, Anne; Clement, Naomi; Patel, Tulsi; Brookes, Keeley; Medway, Christopher; Chappell, Sally; Mann, David M; Morgan, Kevin

    2016-03-01

    Early-onset Alzheimer's disease (EOAD) can be familial (FAD) or sporadic EOAD (sEOAD); both have a disease onset ≤65 years of age. A total of 451 sEOAD samples were screened for known causative mutations in exons 16 and 17 of the amyloid precursor protein (APP) gene. Four samples were shown to be heterozygous for 1 of 3 known causative mutations: p.A713T, p.V717I, and p.V717G; this highlights the importance of screening EOAD patients for causative mutations. Additionally, we document an intronic 6 base pair (bp) deletion located 83 bp downstream of exon 17 (rs367709245, IVS17 83-88delAAGTAT), which has a nonsignificantly increased minor allele frequency in our sEOAD cohort (0.006) compared to LOAD (0.002) and controls (0.002). To assess the effect of the 6-bp deletion on splicing, COS-7 and BE(2)-C cells were transfected with a minigene vector encompassing exon 17. There was no change in splicing of exon 17 from constructs containing either wild type or deletion inserts. Sequencing of cDNA generated from cerebellum and temporal cortex of a patient harboring the deletion found no evidence of transcripts with exon 17 removed.

  11. Cholesterol and Alzheimer Type Dementia among Adults with Down Syndrome

    ERIC Educational Resources Information Center

    Buckley, Frank

    2008-01-01

    This article reports a summary of research by Warren Zigman and colleagues investigating the link between cholesterol levels and Alzheimer type dementia among adults with Down syndrome. Warren Zigman and colleagues followed 123 adults with Down syndrome between May 1998 and April 2006. The participants were aged between 41 and 78 years at the…

  12. 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…

  13. Cholesterol and Alzheimer Type Dementia among Adults with Down Syndrome

    ERIC Educational Resources Information Center

    Buckley, Frank

    2008-01-01

    This article reports a summary of research by Warren Zigman and colleagues investigating the link between cholesterol levels and Alzheimer type dementia among adults with Down syndrome. Warren Zigman and colleagues followed 123 adults with Down syndrome between May 1998 and April 2006. The participants were aged between 41 and 78 years at the…

  14. Allelic association but only weak evidence for linkage to the apolipoprotein E locus in late-onset Swedish Alzheimer families

    SciTech Connect

    Liu, L.; Forsell, C.; Lilius, L.

    1996-05-31

    An association between the {epsilon}4 allele of the apolipoprotein E gene (APOE) and late-onset Alzheimer`s disease (AD) was recently demonstrated. In order to confirm the association and to gauge the ability of standard genetic linkage methods to identify susceptibility genes, we investigated 15 Swedish late-onset AD families. We found an association of familial AD to the APOE {epsilon}4 allele (P = 0.01) but no indication of linkage to the APOE region using 2-point linkage analysis, and only weak evidence using the affected pedigree-member (APM) method. Our results confirm an APOE {epsilon}4 association with late-onset familial AD and indicate that susceptibility genes can easily be missed when using standard lod score and APM genetic linkage analysis. 19 refs., 1 fig., 4 tabs.

  15. The Neuronal Sortilin-Related Receptor Gene SORL1 and Late-Onset Alzheimer's Disease

    PubMed Central

    Lee, Joseph H.; Barral, Sandra; Reitz, Christiane

    2009-01-01

    Recent studies indicate that two clusters of single nucleotide polymorphisms in the neuronal sortilin-related receptor gene (SORL1) are causally associated with late-onset Alzheimer's disease (AD). At the cellular level, SORL1 is thought to be involved in intracellular trafficking of amyloid precursor protein. When this gene is suppressed, toxic amyloid β production is increased, and high levels of amyloid β are associated with a higher AD risk. Extending the cellular findings, gene expression studies show that SORL1 is differentially expressed in AD patients compared with controls. Furthermore, several genetic studies have identified allelic and haplotypic SORL1 variants associated with late-onset AD, and these variants confer small to modest risk of AD. Taken together, the evidence for SORL1 as a causative gene is compelling. However, putative variants have not yet been identified. Further research is necessary to determine its utility as a diagnostic marker of AD or as a target for new therapeutic approaches. PMID:18713574

  16. Evaluation of late-onset Alzheimer disease genetic susceptibility risks in a Canadian population.

    PubMed

    Omoumi, Ardeshir; Fok, Alice; Greenwood, Talitha; Sadovnick, A Dessa; Feldman, Howard H; Hsiung, Ging-Yuek R

    2014-04-01

    We performed case-control studies using 2 Canadian cohorts to examine the role of 10 promising Alzheimer's disease (AD) loci identified in recent genomewide association studies. Patients age 65 years and older diagnosed with AD at baseline (prevalent cases) or who developed AD during follow-up assessments (incident cases) were compared with control subjects with no cognitive impairment. Our prevalent case study comparing prevalent AD cases (n = 428) with participants with no cognitive impairment (n = 524) revealed a significant association of rs6656401 and rs3818361 (CR1), rs2075650 (TOMM40), rs7561528 (BIN1), and rs3865444 (CD33) with late-onset AD that were robust to adjustment with age and apolipoprotein E ε4 genotype. The incident case study comparing patients who developed AD during longitudinal observation (n = 152) with participants with no cognitive impairment found that rs2075650 (TOMM40) and rs3865444 (CD33) influence the risk of developing AD in this population. In addition, pooled analysis of our AD patients confirmed that CR1, TOMM40, BIN1, and CD33 contribute to late-onset AD susceptibility, in addition to apolipoprotein E.

  17. Eyetracking Metrics in Young Onset Alzheimer's Disease: A Window into Cognitive Visual Functions.

    PubMed

    Pavisic, Ivanna M; Firth, Nicholas C; Parsons, Samuel; Rego, David Martinez; Shakespeare, Timothy J; Yong, Keir X X; Slattery, Catherine F; Paterson, Ross W; Foulkes, Alexander J M; Macpherson, Kirsty; Carton, Amelia M; Alexander, Daniel C; Shawe-Taylor, John; Fox, Nick C; Schott, Jonathan M; Crutch, Sebastian J; Primativo, Silvia

    2017-01-01

    Young onset Alzheimer's disease (YOAD) is defined as symptom onset before the age of 65 years and is particularly associated with phenotypic heterogeneity. Atypical presentations, such as the clinic-radiological visual syndrome posterior cortical atrophy (PCA), often lead to delays in accurate diagnosis. Eyetracking has been used to demonstrate basic oculomotor impairments in individuals with dementia. In the present study, we aim to explore the relationship between eyetracking metrics and standard tests of visual cognition in individuals with YOAD. Fifty-seven participants were included: 36 individuals with YOAD (n = 26 typical AD; n = 10 PCA) and 21 age-matched healthy controls. Participants completed three eyetracking experiments: fixation, pro-saccade, and smooth pursuit tasks. Summary metrics were used as outcome measures and their predictive value explored looking at correlations with visuoperceptual and visuospatial metrics. Significant correlations between eyetracking metrics and standard visual cognitive estimates are reported. A machine-learning approach using a classification method based on the smooth pursuit raw eyetracking data discriminates with approximately 95% accuracy patients and controls in cross-validation tests. Results suggest that the eyetracking paradigms of a relatively simple and specific nature provide measures not only reflecting basic oculomotor characteristics but also predicting higher order visuospatial and visuoperceptual impairments. Eyetracking measures can represent extremely useful markers during the diagnostic phase and may be exploited as potential outcome measures for clinical trials.

  18. Diabetes mellitus and risk of early-onset Alzheimer's disease: a population-based case-control study.

    PubMed

    Kadohara, K; Sato, I; Kawakami, K

    2017-07-01

    Previous studies have reported that diabetes is a risk factor for both all-cause and vascular dementia; however, diabetes as a risk factor for Alzheimer's disease (AD) remains controversial. Therefore, the aim was to elucidate the association between diabetes and early-onset AD. A case-control study was conducted using a population-based database that included medical and pharmacy claims and insurance eligibility data, from beneficiaries of corporate employees and their dependent family members. Cases were aged 40-64 years and were first prescribed medications for AD between 2005 and 2016. Up to four controls matched for age, sex and hospital type were included for each case. Data were analyzed using conditional logistic regression and compared between the sexes. Data from 371 patients with AD (mean age 56.3 ± 5.3 years; 48% female) and 1484 controls were analyzed. Use of antidepressants, antipsychotics and antithrombotics during the index month was higher amongst patients with AD (19.4%, 34.5% and 11.3%, respectively) than amongst controls (2.9%, 10.3% and 7.3%, respectively). Our findings suggest no evidence for an association between diabetes and risk of early-onset AD (adjusted odds ratio 1.31; 95% confidence interval 0.90-1.92). In the subgroup analyses, adjusted odds ratios in patients with diabetes were 0.73 (95% confidence interval 0.38-1.39) and 1.68 (95% confidence interval 1.06-2.67) for female and male patients, respectively. There is no apparent association between diabetes and risk of early-onset AD in the total study population, although a weak association was observed amongst male patients. © 2017 EAN.

  19. A Unified Hypothesis of Early- and Late-Onset Alzheimer's Disease Pathogenesis.

    PubMed

    Atwood, Craig S; Bowen, Richard L

    2015-01-01

    Early-onset familial Alzheimer's disease (EOFAD) and late-onset sporadic AD (LOSAD) both follow a similar pathological and biochemical course that includes: neuron and synapse loss and dysfunction, microvascular damage, microgliosis, extracellular amyloid-β deposition, tau phosphorylation, formation of intracellular neurofibrillary tangles, endoreduplication and related cell cycle events in affected brain regions. Any mechanistic explanation of AD must accommodate these biochemical and neuropathological features for both forms of the disease. In this insight paper we provide a unifying hypothesis for EOFAD and LOSAD that proposes that the aberrant re-entry of terminally differentiated, post-mitotic neurons into the cell division cycle is a common pathway that explains both early and late-onset forms of AD. Cell cycle abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles, and explain the biochemical (e.g. tau phosphorylation), neuropathological (e.g. neuron hypertrophy; polypoidy) and cognitive changes observed in EOFAD and LOSAD. Genetic mutations in AβPP, PSEN1, and PSEN2 that alter amyloid-β precursor protein and Notch processing drive reactivation of the cell cycle in EOFAD, while age-related reproductive endocrine dyscrasia that upregulates mitogenic TNF signaling and AβPP processing toward the amyloidogenic pathway drives reactivation of the cell cycle in LOSAD. In essence, AβPP and presenilin mutations initiate early, what endocrine dyscrasia initiates later: aberrant cell cycle re-entry of post-mitotic neurons leading to neurodegeneration and cognitive decline in AD. Inhibition of cell cycle re-entry in post-mitotic neurons may be a useful therapeutic strategy to prevent, slow or halt disease progression.

  20. Amyloid burden and metabolic function in early-onset Alzheimer's disease: parietal lobe involvement.

    PubMed

    Ossenkoppele, Rik; Zwan, Marissa D; Tolboom, Nelleke; van Assema, Danielle M E; Adriaanse, Sofie F; Kloet, Reina W; Boellaard, Ronald; Windhorst, Albert D; Barkhof, Frederik; Lammertsma, Adriaan A; Scheltens, Philip; van der Flier, Wiesje M; van Berckel, Bart N M

    2012-07-01

    Alzheimer's disease with early onset often presents with a distinct cognitive profile, potentially reflecting a different distribution of underlying neuropathology. The purpose of this study was to examine the relationships between age and both in vivo fibrillary amyloid deposition and glucose metabolism in patients with Alzheimer's disease. Dynamic [(11)C]Pittsburgh compound-B (90 min) and static [(18)F]fluorodeoxyglucose (15 min) scans were obtained in 100 patients with Alzheimer's disease and 20 healthy controls. Parametric non-displaceable binding potential images of [(11)C]Pittsburgh compound-B and standardized uptake value ratio images of [(18)F]fluorodeoxyglucose were generated using cerebellar grey matter as reference tissue. Nine [(11)C]Pittsburgh compound-B-negative patients were excluded. The remaining patients were categorized into younger (n=45, age: 56 ± 4 years) and older (n=46, age: 69 ± 5 years) groups, based on the median age (62 years) at time of diagnosis. Younger patients showed more severe impairment on visuo-spatial function, attention and executive function composite scores (P<0.05), while we found a trend towards poorer memory performance for older patients (P=0.11). Differences between groups were assessed using a general linear model with repeated measures (gender adjusted) with age as between subjects factor, region (frontal, temporal, parietal and occipital and posterior cingulate cortices) as within subjects factor and [(11)C]Pittsburgh compound-B binding/[(18)F]fluorodeoxyglucose uptake as dependent variables. There was no main effect of age for [(11)C]Pittsburgh compound-B or [(18)F]fluorodeoxyglucose, suggesting that overall, the extent of amyloid deposition or glucose hypometabolism did not differ between groups. Regional distributions of [(11)C]Pittsburgh compound-B binding and [(18)F]fluorodeoxyglucose uptake (both P for interaction <0.05) differed between groups, however, largely due to increased [(11)C]Pittsburgh compound

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

    PubMed Central

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

    2000-01-01

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

  2. Comorbidity and progression of late onset Alzheimer's disease: A systematic review.

    PubMed

    Haaksma, Miriam L; Vilela, Lara R; Marengoni, Alessandra; Calderón-Larrañaga, Amaia; Leoutsakos, Jeannie-Marie S; Olde Rikkert, Marcel G M; Melis, René J F

    2017-01-01

    Alzheimer's disease is a neurodegenerative syndrome characterized by multiple dimensions including cognitive decline, decreased daily functioning and psychiatric symptoms. This systematic review aims to investigate the relation between somatic comorbidity burden and progression in late-onset Alzheimer's disease (LOAD). We searched four databases for observational studies that examined cross-sectional or longitudinal associations of cognitive or functional or neuropsychiatric outcomes with comorbidity in individuals with LOAD. From the 7966 articles identified originally, 11 studies were included in this review. The Newcastle-Ottawa quality assessment was used. The large variation in progression measures, comorbidity indexes and study designs hampered the ability to perform a meta-analysis. This review was registered with PROSPERO under DIO: 10.15124/CRD42015027046. Nine studies indicated that comorbidity burden was associated with deterioration in at least one of the three dimensions of LOAD examined. Seven out of ten studies investigating cognition found comorbidities to be related to decreased cognitive performance. Five out of the seven studies investigating daily functioning showed an association between comorbidity burden and decreased daily functioning. Neuropsychiatric symptoms (NPS) increased with increasing comorbidity burden in two out of three studies investigating NPS. Associations were predominantly found in studies analyzing the association cross-sectionally, in a time-varying manner or across short follow-up (≤2 years). Rarely baseline comorbidity burden appeared to be associated with outcomes in studies analyzing progression over longer follow-up periods (>2 years). This review provides evidence of an association between somatic comorbidities and multifaceted LOAD progression. Given that time-varying comorbidity burden, but much less so baseline comorbidity burden, was associated with the three dimensions prospectively, this relationship cannot be

  3. Candidate blood proteome markers of Alzheimer's disease onset and progression: a systematic review and replication study.

    PubMed

    Kiddle, Steven J; Sattlecker, Martina; Proitsi, Petroula; Simmons, Andrew; Westman, Eric; Bazenet, Chantal; Nelson, Sally K; Williams, Stephen; Hodges, Angela; Johnston, Caroline; Soininen, Hilkka; Kłoszewska, Iwona; Mecocci, Patrizia; Tsolaki, Magda; Vellas, Bruno; Newhouse, Stephen; Lovestone, Simon; Dobson, Richard J B

    2014-01-01

    A blood-based protein biomarker, or set of protein biomarkers, that could predict onset and progression of Alzheimer's disease (AD) would have great utility; potentially clinically, but also for clinical trials and especially in the selection of subjects for preventative trials. We reviewed a comprehensive list of 21 published discovery or panel-based (> 100 proteins) blood proteomics studies of AD, which had identified a total of 163 candidate biomarkers. Few putative blood-based protein biomarkers replicate in independent studies but we found that some proteins do appear in multiple studies; for example, four candidate biomarkers are found to associate with AD-related phenotypes in five independent research cohorts in these 21 studies: α-1-antitrypsin, α-2-macroglobulin, apolipoprotein E, and complement C3. Using SomaLogic's SOMAscan proteomics technology, we were able to conduct a large-scale replication study for 94 of the 163 candidate biomarkers from these 21 published studies in plasma samples from 677 subjects from the AddNeuroMed (ANM) and the Alzheimer's Research UK/Maudsley BRC Dementia Case Registry at King's Health Partners (ARUK/DCR) research cohorts. Nine of the 94 previously reported candidates were found to associate with AD-related phenotypes (False Discovery Rate (FDR) q-value < 0.1). These proteins show sufficient replication to be considered for further investigation as a biomarker set. Overall, we show that there are some signs of a replicable signal in the range of proteins identified in previous studies and we are able to further replicate some of these. This suggests that AD pathology does affect the blood proteome with some consistency.

  4. How do periodontal infections affect the onset and progression of Alzheimer's disease?

    PubMed

    Shaik, Munvar M; Ahmad, Sultan; Gan, Siew H; Abuzenadah, Adel M; Ahmad, Ejaz; Tabrez, Shams; Ahmed, Farid; Kamal, Mohammad A

    2014-04-01

    Chronic infection can cause slow progressive dementia, cortical atrophy and amyloid deposition in the atrophic form of general paresis. Due to the fact that specific bacterial ligands can increase the expression of proinflammatory molecules that can activate innate and adaptive immune systems, inflammation may play a significant role in the pathogenesis of Alzheimer's disease (AD). Furthermore, there is a significant association between AD and various types of spirochete. Periodontitis is a prevalent and persistent peripheral infection that is associated with gram-negative anaerobic bacteria and is capable of showing localized and systemic infections in the host. Periodontal disease related pathogens and their inflammatory products contribute to systemic inflammation and the pathogenesis of AD. In this minireview, we propose a hypothetical link between periodontitis, type 2 diabetes and AD. We also present the possible mechanistic links between periodontitis-related inflammation, type 2 diabetes and AD. Since this condition is treatable, periodontitis may be a readily-modifiable risk factor for AD.

  5. 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

  6. A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population.

    PubMed

    Liu, Fan; Arias-Vásquez, Alejandro; Sleegers, Kristel; Aulchenko, Yurii S; Kayser, Manfred; Sanchez-Juan, Pascual; Feng, Bing-Jian; Bertoli-Avella, Aida M; van Swieten, John; Axenovich, Tatiana I; Heutink, Peter; van Broeckhoven, Christine; Oostra, Ben A; van Duijn, Cornelia M

    2007-07-01

    Alzheimer disease (AD) is the most common cause of dementia. We conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that is conducted in a recently isolated population from the southwestern area of The Netherlands. All patients and their 170 closely related relatives were genotyped using 402 microsatellite markers. Extensive genealogy information was collected, which resulted in an extremely large and complex pedigree of 4,645 members. The pedigree was split into 35 subpedigrees, to reduce the computational burden of linkage analysis. Simulations aiming to evaluate the effect of pedigree splitting on false-positive probabilities showed that a LOD score of 3.64 corresponds to 5% genomewide type I error. Multipoint analysis revealed four significant and one suggestive linkage peaks. The strongest evidence of linkage was found for chromosome 1q21 (heterogeneity LOD [HLOD]=5.20 at marker D1S498). Approximately 30 cM upstream of this locus, we found another peak at 1q25 (HLOD=4.0 at marker D1S218). These two loci are in a previously established linkage region. We also confirmed the AD locus at 10q22-24 (HLOD=4.15 at marker D10S185). There was significant evidence of linkage of AD to chromosome 3q22-24 (HLOD=4.44 at marker D3S1569). For chromosome 11q24-25, there was suggestive evidence of linkage (HLOD=3.29 at marker D11S1320). We next tested for association between cognitive function and 4,173 single-nucleotide polymorphisms in the linked regions in an independent sample consisting of 197 individuals from the GRIP region. After adjusting for multiple testing, we were able to detect significant associations for cognitive function in four of five AD-linked regions, including the new region on chromosome 3q22-24 and regions 1q25, 10q22-24, and 11q25. With use of cognitive function as an endophenotype of AD, our study indicates the that the RGSL2, RALGPS2, and C1orf49 genes

  7. Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.

    PubMed

    Naj, Adam C; Jun, Gyungah; Reitz, Christiane; Kunkle, Brian W; Perry, William; Park, Yo Son; Beecham, Gary W; Rajbhandary, Ruchita A; Hamilton-Nelson, Kara L; Wang, Li-San; Kauwe, John S K; Huentelman, Matthew J; Myers, Amanda J; Bird, Thomas D; Boeve, Bradley F; Baldwin, Clinton T; Jarvik, Gail P; Crane, Paul K; Rogaeva, Ekaterina; Barmada, M Michael; Demirci, F Yesim; Cruchaga, Carlos; Kramer, Patricia L; Ertekin-Taner, Nilufer; Hardy, John; Graff-Radford, Neill R; Green, Robert C; Larson, Eric B; St George-Hyslop, Peter H; Buxbaum, Joseph D; Evans, Denis A; Schneider, Julie A; Lunetta, Kathryn L; Kamboh, M Ilyas; Saykin, Andrew J; Reiman, Eric M; De Jager, Philip L; Bennett, David A; Morris, John C; Montine, Thomas J; Goate, Alison M; Blacker, Deborah; Tsuang, Debby W; Hakonarson, Hakon; Kukull, Walter A; Foroud, Tatiana M; Martin, Eden R; Haines, Jonathan L; Mayeux, Richard P; Farrer, Lindsay A; Schellenberg, Gerard D; Pericak-Vance, Margaret A; Albert, Marilyn S; Albin, Roger L; Apostolova, Liana G; Arnold, Steven E; Barber, Robert; Barnes, Lisa L; Beach, Thomas G; Becker, James T; Beekly, Duane; Bigio, Eileen H; Bowen, James D; Boxer, Adam; Burke, James R; Cairns, Nigel J; Cantwell, Laura B; Cao, Chuanhai; Carlson, Chris S; Carney, Regina M; Carrasquillo, Minerva M; Carroll, Steven L; Chui, Helena C; Clark, David G; Corneveaux, Jason; Cribbs, David H; Crocco, Elizabeth A; DeCarli, Charles; DeKosky, Steven T; Dick, Malcolm; Dickson, Dennis W; Duara, Ranjan; Faber, Kelley M; Fallon, Kenneth B; Farlow, Martin R; Ferris, Steven; Frosch, Matthew P; Galasko, Douglas R; Ganguli, Mary; Gearing, Marla; Geschwind, Daniel H; Ghetti, Bernardino; Gilbert, John R; Glass, Jonathan D; Growdon, John H; Hamilton, Ronald L; Harrell, Lindy E; Head, Elizabeth; Honig, Lawrence S; Hulette, Christine M; Hyman, Bradley T; Jicha, Gregory A; Jin, Lee-Way; Karydas, Anna; Kaye, Jeffrey A; Kim, Ronald; Koo, Edward H; Kowall, Neil W; Kramer, Joel H; LaFerla, Frank M; Lah, James J; Leverenz, James B; Levey, Allan I; Li, Ge; Lieberman, Andrew P; Lin, Chiao-Feng; Lopez, Oscar L; Lyketsos, Constantine G; Mack, Wendy J; Martiniuk, Frank; Mash, Deborah C; Masliah, Eliezer; McCormick, Wayne C; McCurry, Susan M; McDavid, Andrew N; McKee, Ann C; Mesulam, Marsel; Miller, Bruce L; Miller, Carol A; Miller, Joshua W; Murrell, Jill R; Olichney, John M; Pankratz, Vernon S; Parisi, Joseph E; Paulson, Henry L; Peskind, Elaine; Petersen, Ronald C; Pierce, Aimee; Poon, Wayne W; Potter, Huntington; Quinn, Joseph F; Raj, Ashok; Raskind, Murray; Reisberg, Barry; Ringman, John M; Roberson, Erik D; Rosen, Howard J; Rosenberg, Roger N; Sano, Mary; Schneider, Lon S; Seeley, William W; Smith, Amanda G; Sonnen, Joshua A; Spina, Salvatore; Stern, Robert A; Tanzi, Rudolph E; Thornton-Wells, Tricia A; Trojanowski, John Q; Troncoso, Juan C; Valladares, Otto; Van Deerlin, Vivianna M; Van Eldik, Linda J; Vardarajan, Badri N; Vinters, Harry V; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A; Williamson, Jennifer; Wishnek, Sarah; Woltjer, Randall L; Wright, Clinton B; Younkin, Steven G; Yu, Chang-En; Yu, Lei

    2014-11-01

    Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242). We confirmed an association of APOE (OMIM 107741) variants with AAO among

  8. 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; Kapoor, Manav; Tosto, Giuseppe; Mayeux, Richard P; Holtzman, David M; Fagan, Anne M; Morris, John C; Bateman, Randall J; Goate, Alison M; Harari, Oscar

    2017-09-21

    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 ptau181-Aβ42 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.

  9. Chromosome-12 Mapping of Late-Onset Alzheimer Disease among Caribbean Hispanics

    PubMed Central

    Mayeux, R.; Lee, J. H.; Romas, S. N.; Mayo, D.; Santana, V.; Williamson, J.; Ciappa, A.; Rondon, H. Z.; Estevez, P.; Lantigua, R.; Medrano, M.; Torres, M.; Stern, Y.; Tycko, B.; Knowles, J. A.

    2002-01-01

    Linkage to chromosome 12p for familial Alzheimer disease (AD) has been inconsistent. Using 35 markers near the centromere of chromosome 12, we investigated 79 Caribbean Hispanic families with AD. Two-point linkage analysis using affected sib pairs yielded LOD scores of 3.15 at D12S1623 and 1.43 at D12S1042. The LOD score at D12S1623 decreased to 1.62 in families with late-onset (age >65 years) AD (LOAD), but the LOD score at D12S1042 was unchanged. Among families negative for the apolipoprotein E (APOE-ε4) allele, the LOD score for D12S1623 was lower (1.01), whereas that for D12S1042 increased to 1.73. Among families positive for the APOE-ε4 allele, none of the LOD scores reached 1. Multipoint affected-relative-pair analysis showed peaks at D12S1623 (nonparametric linkage [NPL] score 1.52; P=.028) and near D12S1042, at D12S1057 (NPL score 1.57; P=.027). NPL scores for both D12S1623 and D12S1057 increased in families affected with LOAD, but, in APOE-ε4–negative families, only scores for the region flanking D12S1623 remained elevated (NPL score 1.74; P=.013). This study of Caribbean Hispanics with familial AD extends and provides modest evidence of linkage to loci on chromosome 12p. Linkage varied by age at onset of AD and by the presence or absence of the APOE-ε4 allele. PMID:11715112

  10. 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.

  11. Three novel presenilin 1 mutations marking the wide spectrum of age at onset and clinical patterns in familial Alzheimer's disease.

    PubMed

    Roeber, Sigrun; Müller-Sarnowski, Felix; Kress, Julia; Edbauer, Dieter; Kuhlmann, Tanja; Tüttelmann, Frank; Schindler, Christoph; Winter, Pia; Arzberger, Thomas; Müller, Ulrich; Danek, Adrian; Kretzschmar, Hans A

    2015-12-01

    Presenilin 1 (PSEN1) mutations are the major cause of autosomal dominant Alzheimer's disease (ADAD). Here we report three novel PSEN1 mutations: Ile238_Lys239insIle, Ala246Pro and Ala164Val from patients who manifested in their twenties, forties and seventies, respectively, with variant clinical presentations of dementia. These cases exemplify the tremendous heterogeneity of clinical phenotypes and age of onset associated with PSEN1 mutations. The possibility of ADAD--not previously suspected in two of our patients--should always be considered in neurodegenerative conditions albeit they might neither exhibit the typical clinical picture of Alzheimer's disease nor early onset dementia, which is regarded the primary clinical sign of hereditary neurodegeneration.

  12. Association of GWAS Top Genes With Late-Onset Alzheimer's Disease in Colombian Population.

    PubMed

    Moreno, Diana Jennifer; Ruiz, Susana; Ríos, Ángela; Lopera, Francisco; Ostos, Henry; Via, Marc; Bedoya, Gabriel

    2017-02-01

    The association of variants in CLU, CR1, PICALM, BIN1, ABCA7, and CD33 genes with late-onset Alzheimer's disease (LOAD) was evaluated and confirmed through genome-wide association study. However, it is unknown whether these associations can be replicated in admixed populations. The association of 14 single-nucleotide polymorphisms in those genes was evaluated in 280 LOAD cases and 357 controls from the Colombian population. In a multivariate analysis using age, gender, APOE∊4 status, and admixture covariates, significant associations were obtained ( P < .05) for variants in BIN1 (rs744373, odds ratio [OR]: 1.42), CLU (rs11136000, OR: 0.66), PICALM (rs541458, OR: 0.69), ABCA7 (rs3764650, OR: 1.7), and CD33 (rs3865444, OR: 1.12). Likewise, a significant interaction effect was observed between CLU and CR1 variants with APOE. This study replicated the associations previously reported in populations of European ancestry and shows that APOE variants have a regulatory role on the effect that variants in other loci have on LOAD, reflecting the importance of gene-gene interactions in the etiology of neurodegenerative diseases.

  13. Systemic oxidative stress in older patients with mild cognitive impairment or late onset Alzheimer's disease.

    PubMed

    Cervellati, Carlo; Cremonini, Eleonora; Bosi, Cristina; Magon, Stefania; Zurlo, Amedeo; Bergamini, Carlo M; Zuliani, Giovanni

    2013-05-01

    A large body of evidences obtained in human and animal brain tissue suggest a role of oxidative stress (OxS) in the pathogenesis of late onset Alzheimer's disease (LOAD); on the contrary, data on peripheral markers of OxS in LOAD are still controversial. We evaluated the serum levels of products of lipid peroxidation, hydroperoxides, advanced oxidation protein products, total and residual antioxidant power, thiols, and uric acid in a sample of 334 older individuals: 101 LOAD patients, 134 patients with mild cognitive impairment (MCI), and 99 controls. At univariate analysis, serum hydroperoxides were higher while residual antioxidant power was lower in MCI and LOAD compared with in controls. By multivariate logistic regression analysis we found that, compared with controls, high levels (over median value) of serum hydroperoxides were independently associated with an increase in the likehood of having MCI (Odd Ratio: 2.59, 95% Confidence Interval: 1.08-6.21) or LOAD (OR: 4.09, 95%CI: 1.36-11.81). Furthermore, low levels of residual antioxidant power (below the median value) were associated with increased risk of having MCI (OR: 3.97, 95% CI: 1.62-9.72), but not dementia (OR: 2.31, 95%CI: 0.83-6.63). Our study suggests that a systemic redox-imbalance leading to OxS might be associated not only with LOAD but also with MCI.

  14. Neuropsychiatric Symptoms, Endophenotypes, and Syndromes in Late-Onset Alzheimer's Disease: Focus on APOE Gene

    PubMed Central

    Panza, Francesco; Seripa, Davide; D'Onofrio, Grazia; Frisardi, Vincenza; Solfrizzi, Vincenzo; Mecocci, Patrizia; Pilotto, Alberto

    2011-01-01

    Neuropsychiatric symptoms, previously denominated as behavioural and psychological symptoms of dementia, are common features of Alzheimer's disease (AD) and are one of the major risk factors for institutionalization. At present, the role of the apolipoprotein E (APOE) gene in the development of neuropsychiatric symptoms in AD patients is unclear. In this paper, we summarized the findings of the studies of neuropsychiatric symptoms and neuropsychiatric syndromes/endophenotypes in AD in relation to APOE genotypes, with special attention to the possible underlying mechanisms. While some studies failed to find a significant association between APOE and neuropsychiatric symptoms in late-onset AD, other studies reported a significant association between the APOE ε4 allele and an increase in agitation/aggression, hallucinations, delusions, and late-life depression or anxiety. Furthermore, some negative studies that focused on the distribution of APOE genotypes between AD patients with or without neuropsychiatric symptoms further emphasized the importance of subgrouping neuropsychiatric symptoms in distinct neuropsychiatric syndromes. Explanations for the variable findings in the existing studies included differences in patient populations, differences in the assessment of neuropsychiatric symptomatology, and possible lack of statistical power to detect associations in the negative studies. PMID:21559196

  15. Association of HMGCR polymorphism with late-onset Alzheimer's disease in Han Chinese

    PubMed Central

    Tan, Meng-Shan; Wang, Hui-Fu; Tan, Chen-Chen; Zhang, Wei; Zheng, Zhan-Jie; Kong, Ling-Li; Wang, Zi-Xuan; Jiang, Teng; Yu, Jin-Tai; Tan, Lan

    2016-01-01

    The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) acts as a potential genetic modifier for Alzheimer's disease (AD). Previous reports identified that HMGCR rs3846662 polymorphism is associated with biosynthesis of cholesterol in AD pathology. In order to assess the involvement of the HMGCR polymorphism in the risk of late-onset AD (LOAD) in northern Han Chinese, we performed a case–control study of 2334 unrelated subjects (984 cases and 1350 age- and gender-matched controls) to evaluate the genotype and allele distributions of the HMGCR rs3846662 with LOAD. The genotype distribution (GG, AG, AA) of rs3846662 was significantly different between LOAD patients and controls (P = 0.003), but the allele distribution did not reach a significant difference (P = 0.614). After adjusting for age, gender and the APOE ε4 status, the minor A allele of rs3846662 was validated as a protective factor for LOAD in dominant model (OR = 0.796, P = 0.02, 95% CI = 0.657–0.965). Interestingly, we observed rs3846662 polymorphism was only significantly associated with LOAD in APOE ε4 non-carriers (OR = 0.735, P = 0.005, 95% CI = [0.593, 0.912]). In conclusion, our study demonstrates A allele of HMGCR rs3846662 acts as a protective factor for LOAD in northern Han Chinese. PMID:27009838

  16. 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.

  17. Evidence for defective retinoid transport and function in late onset Alzheimer's disease

    PubMed Central

    Goodman, Ann B.; Pardee, Arthur B.

    2003-01-01

    The hypothesis of this article is that late onset Alzheimer's disease (AD) is influenced by the availability in brain of retinoic acid (RA), the final product of the vitamin A (retinoid) metabolic cascade. Genetic, metabolic, and environmental/dietary evidence is cited supporting this hypothesis. Significant genetic linkages to AD are demonstrated for markers close to four of the six RA receptors, RA receptor G at 12q13, retinoid X receptor B at 6p21.3, retinoid X receptor G at 1q21, and RA receptor A at 17q21. Three of the four retinol-binding proteins at 3q23 and 10q23 and the RA-degrading cytochrome P450 enzymes at 10q23 and 2p13 map to AD linkages. Synthesis of the evidence supports retinoid hypofunction and impaired transport as contributing factors. These findings suggest testable experiments to determine whether increasing the availability of retinoid in brain, possibly through pharmacologic targeting of the RA receptors and the cytochrome P450 RA-inactivating enzymes, can prevent or decrease amyloid plaque formation. PMID:12604774

  18. Case-control study of dementia of the Alzheimer type

    SciTech Connect

    French, L.R.; Schuman, L.M.; Mortimer, J.A.; Hutton, J.T.; Boatman, R.A.; Christians, B.

    1985-03-01

    A case-control study to assess factors of possible etiologic significance to dementia of the Alzheimer type was conducted with 78 male cases diagnosed in 1979-1982 at the Veterans Administration Medical Center in Minneapolis, Minnesota and age-race-sex-matched hospital and neighborhood controls (14 of 16 autopsied cases were histopathologically confirmed). Information was obtained on variables relevant to vital, genetic, and immunologic hypotheses, and on possible occupational and environmental exposures, drug use, psychologic stress, smoking, and alcohol consumption. The only major difference between patients with dementia of the Alzheimer type and controls was a significantly greater occurrence of antecedent head trauma in the patients (odds ratio = 4.50). This finding is consistent with the literature on posttraumatic dementia but its importance is presently unclear.

  19. 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.

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

    PubMed Central

    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

    2015-01-01

    ABSTRACT 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. PMID:26411346

  1. Niemann-Pick type C: focus on the adolescent/adult onset form.

    PubMed

    Di Lazzaro, Vincenzo; Marano, Massimo; Florio, Lucia; De Santis, Stefano

    2016-11-01

    Niemann-Pick disease type C (NP-C) is an inherited sphingolipidosis characterized by progressive neurological deterioration and early mortality. The symptomatology and disease progression of NP-C are markedly affected by the age at onset of neurological manifestations, and categorization into early-infantile, late-infantile, juvenile, adolescent/adult neurological onset forms can aid evaluation of disease course and responses to therapy. Here, we review current information on the detection, diagnosis, monitoring and treatment of NP-C, with a focus on the adolescent/adult-onset form. A recent analysis indicated that the combined incidence of NP-C related to NPC1 gene mutations (NPC1) and NP-C related to NPC2 gene mutations (NPC2) is approximately 1 case in every 89 000 live births. In particular, late-onset phenotypes might well provide a greater contribution to the overall incidence than has previously been reported. Some neuropathological features in NP-C are held in common with other advanced age-onset diseases such as Alzheimer's disease. Visceral symptoms such as splenomegaly are frequently asymptomatic in patients with adolescent/adult-onset NP-C, and are only occasionally detected during routine ultrasound assessments. In contrast, most patients with adolescent/adult-onset exhibit some degree of slowly progressive, non-disease-specific movement disorders (e.g. cerebellar ataxia), and/or more pathognomonic neurological signs such as vertical supranuclear gaze palsy. An increasing number of adolescent/adult-onset cases have been reported following initial recognition of cognitive impairment and/or psychiatric signs. The recent development and implementation of new clinical screening tools (e.g. the NP-C suspicion index) and biomarkers (e.g. plasma oxysterols) should help identify patients who warrant further investigation and possible treatment.

  2. Diagnostic criteria for primary neuronal degeneration of the Alzheimer's type.

    PubMed

    Eisdorfer, C; Cohen, D

    1980-10-01

    The diagnosis of patients presenting with memory or attentional deficits characteristic of dementia is a growing problem. Dementia may be symptomatic of a range of reversible medical and psychiatric conditions which appear to be indistinguishable from primary neuronal degeneration of the Alzheimer's type. While Alzheimer's disease is a neuropathological diagnosis, the importance of establishing a presumptive diagnosis which can be employed for investigational as well as clinical use is underscored. This paper proposes a diagnostic schema which reflects the current understanding of this disorder. There must be evidence of gradual progressive mental deterioration in attention, learning, memory, cognitive style, motivation, and higher order thinking. A comprehensive medical and psychiatric evaluation is obligatory to eliminate reversible physical illness, psychiatric disorder, or cerebrovascular condition as underlying causes of cognitive dysfunction.

  3. Simultaneous onset of Alzheimer's disease in a husband and wife in their mid-fifties: what do we really know about environmental factors?

    PubMed

    Pelcovits, Ari; Marriotti, Rachel; Heath, Jonathan; Perry, George; Castellani, Rudy J

    2015-01-01

    Environmental factors can play a role in the pathogenesis of Alzheimer's disease. We present a case of the simultaneous onset of Alzheimer's disease in two middle aged adults. A married couple ages 54 year and 51-year-old female cohabiting together were diagnosed with Alzheimer's disease within the same year. The patient's both developed cognitive decline shortly after a major renovation of their property and followed a similar disease course. The diagnosis was supported by clinical presentation and tissue pathology on autopsy. Environmental factors may play a role in the pathogenesis of Alzheimer's disease. Further understanding of the disease cascade is required.

  4. An advanced white matter tract analysis in frontotemporal dementia and early-onset Alzheimer's disease.

    PubMed

    Daianu, Madelaine; Mendez, Mario F; Baboyan, Vatche G; Jin, Yan; Melrose, Rebecca J; Jimenez, Elvira E; Thompson, Paul M

    2016-12-01

    Cortical and subcortical nuclei degenerate in the dementias, but less is known about changes in the white matter tracts that connect them. To better understand white matter changes in behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer's disease (EOAD), we used a novel approach to extract full 3D profiles of fiber bundles from diffusion-weighted MRI (DWI) and map white matter abnormalities onto detailed models of each pathway. The result is a spatially complex picture of tract-by-tract microstructural changes. Our atlas of tracts for each disease consists of 21 anatomically clustered and recognizable white matter tracts generated from whole-brain tractography in 20 patients with bvFTD, 23 with age-matched EOAD, and 33 healthy elderly controls. To analyze the landscape of white matter abnormalities, we used a point-wise tract correspondence method along the 3D profiles of the tracts and quantified the pathway disruptions using common diffusion metrics - fractional anisotropy, mean, radial, and axial diffusivity. We tested the hypothesis that bvFTD and EOAD are associated with preferential degeneration in specific neural networks. We mapped axonal tract damage that was best detected with mean and radial diffusivity metrics, supporting our network hypothesis, highly statistically significant and more sensitive than widely studied fractional anisotropy reductions. From white matter diffusivity, we identified abnormalities in bvFTD in all 21 tracts of interest but especially in the bilateral uncinate fasciculus, frontal callosum, anterior thalamic radiations, cingulum bundles and left superior longitudinal fasciculus. This network of white matter alterations extends beyond the most commonly studied tracts, showing greater white matter abnormalities in bvFTD versus controls and EOAD patients. In EOAD, network alterations involved more posterior white matter - the parietal sector of the corpus callosum and parahipoccampal cingulum bilaterally

  5. Genetic variants associated with susceptibility to psychosis in late-onset Alzheimer's disease families.

    PubMed

    Barral, Sandra; Vardarajan, Badri N; Reyes-Dumeyer, Dolly; Faber, Kelley M; Bird, Thomas D; Tsuang, Debby; Bennett, David A; Rosenberg, Roger; Boeve, Bradley F; Graff-Radford, Neill R; Goate, Alison M; Farlow, Martin; Lantigua, Rafael; Medrano, Martin Z; Wang, Xinbing; Kamboh, M Ilyas; Barmada, Mahmud Muhiedine; Schaid, Daniel J; Foroud, Tatiana M; Weamer, Elise A; Ottman, Ruth; Sweet, Robert A; Mayeux, Richard

    2015-11-01

    Psychotic symptoms are frequent in late-onset Alzheimer's disease (LOAD) patients. Although the risk for psychosis in LOAD is genetically mediated, no genes have been identified. To identify loci potentially containing genetic variants associated with risk of psychosis in LOAD, a total of 263 families from the National Institute of Aging-LOAD cohort were classified into psychotic (LOAD+P, n = 215) and nonpsychotic (LOAD-P, n = 48) families based on the presence/absence of psychosis during the course of LOAD. The LOAD+P families yielded strong evidence of linkage on chromosome 19q13 (two-point [2-pt] ​logarithm of odds [LOD] = 3.8, rs2285513 and multipoint LOD = 2.7, rs541169). Joint linkage and association in 19q13 region detected strong association with rs2945988 (p = 8.7 × 10(-7)). Linkage results for the LOAD-P families yielded nonsignificant 19q13 LOD scores. Several 19q13 single-nucleotide polymorphisms generalized the association of LOAD+P in a Caribbean Hispanic (CH) cohort, and the strongest signal was rs10410711 (pmeta = 5.1 × 10(-5)). A variant located 24 kb upstream of rs10410711 and rs10421862 was strongly associated with LOAD+P (pmeta = 1.0 × 10(-5)) in a meta-analysis of the CH cohort and an additional non-Hispanic Caucasian dataset. Identified variants rs2945988 and rs10421862 affect brain gene expression levels. Our results suggest that genetic variants in genes on 19q13, some of which are involved in brain development and neurodegeneration, may influence the susceptibility to psychosis in LOAD patients. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Common variants of ACE contribute to variable age-at-onset of Alzheimer's disease.

    PubMed

    Kehoe, Patrick G; Katzov, Hagit; Andreasen, Niels; Gatz, Maragaret; Wilcock, Gordon K; Cairns, Nigel J; Palmgren, Juni; de Faire, Ulf; Brookes, Anthony J; Pedersen, Nancy L; Blennow, Kaj; Prince, Jonathan A

    2004-04-01

    Studies on the role that genetic variation may play in a complex human disease can be empowered by an assessment of both disease risk in case-control or family models and of quantitative traits that reflect elements of disease etiology. An excellent example of this can be found for the epsilon4 allele of APOE in relation to Alzheimer's disease (AD) for which association with both risk and age-at-onset (AAO) is evident. Following a recent demonstration that variants of the gene encoding angiotensin I converting enzyme ( ACE) contribute to AD risk, we have explored the potential influence of ACE upon AAO in AD. A total of 2861 individuals from three European populations, including six independent AD samples, have been examined in this study. Three single nucleotide polymorphisms (SNPs) previously demonstrated to have maximum effects upon ACE plasma levels and that span the ACE locus were genotyped in these materials. A strong effect upon AAO was observed for marker rs4343 in exon 17 ( P<0.0001), but evidence was also obtained indicating a possible independent effect of marker rs4291 ( P=0.0095) located in the ACE promoter. Effects were consistent with data from previous studies suggesting association with AD in case-control models, whereby alleles demonstrated to confer risk to disease also appear to reduce AAO. Equivalent effects were evident regardless of APOE epsilon4 carrier status and in both males and females. These results provide an important complement to existing AD risk data, confirming that ACE harbors sequence variants that contribute to aspects of AD pathology.

  7. Performance Metrics for Selecting Single Nucleotide Polymorphisms in Late-onset Alzheimer's Disease.

    PubMed

    Chen, Yen-Ching; Hsiao, Chi-Jung; Jung, Chien-Cheng; Hu, Hui-Han; Chen, Jen-Hau; Lee, Wen-Chung; Chiou, Jeng-Min; Chen, Ta-Fu; Sun, Yu; Wen, Li-Li; Yip, Ping-Keung; Chu, Yi-Min; Chen, Chien-Jen; Yang, Hwai-I

    2016-11-02

    Previous genome-wide association studies using P-values to select single nucleotide polymorphisms (SNPs) have suffered from high false-positive and false-negative results. This case-control study recruited 713 late-onset Alzheimer's disease (LOAD) cases and controls aged ≥65 from three teaching hospitals in northern Taiwan from 2007 to 2010. Performance metrics were used to select SNPs in stage 1, which were then genotyped to another dataset (stage 2). Four SNPs (CPXM2 rs2362967, APOC1 rs4420638, ZNF521 rs7230380, and rs12965520) were identified for LOAD by both traditional P-values (without correcting for multiple tests) and performance metrics. After correction for multiple tests, no SNPs were identified by traditional P-values. Simultaneous testing of APOE e4 and APOC1 rs4420638 (the SNP with the best performance in the performance metrics) significantly improved the low sensitivity of APOE e4 from 0.50 to 0.78. A point-based genetic model including these 2 SNPs and important covariates was constructed. Compared with elders with low-risks score (0-6), elders belonging to moderate-risk (score = 7-11) and high-risk (score = 12-18) groups showed a significantly increased risk of LOAD (adjusted odds ratio = 7.80 and 46.93, respectively; Ptrend < 0.0001). Performance metrics allow for identification of markers with moderate effect and are useful for creating genetic tests with clinical and public health implications.

  8. Disrupted rich club network in behavioral variant frontotemporal dementia and early-onset Alzheimer's disease

    PubMed Central

    Daianu, Madelaine; Mezher, Adam; Mendez, Mario F.; Jahanshad, Neda; Jimenez, Elvira E.; Thompson, Paul M.

    2016-01-01

    In network analysis, the so-called ‘rich club’ describes the core areas of the brain that are more densely interconnected among themselves than expected by chance, and has been identified as a fundamental aspect of the human brain connectome. This is the first in-depth diffusion imaging study to investigate the rich club along with other organizational changes in the brain's anatomical network in behavioral frontotemporal dementia (bvFTD), and a matched cohort with early-onset Alzheimer's disease (EOAD). Our study sheds light on how bvFTD and EOAD affect connectivity of white matter fiber pathways in the brain, revealing differences and commonalities in the connectome among the dementias. To analyze the breakdown in connectivity, we studied 3 groups: 20 bvFTD, 23 EOAD and 37 healthy elderly controls. All participants were scanned with diffusion-weighted MRI, and based on whole-brain probabilistic tractography and cortical parcellations, we analyzed the rich club of the brain's connectivity network. This revealed distinct patterns of disruption in both forms of dementia. In the connectome, we detected less disruption overall in EOAD than in bvFTD (False Discovery Rate (FDR) critical Pperm=5.7×10−3, 10,000 permutations), with more involvement of richly interconnected areas of the brain (chi-squared PΧ2=1.4×10−4) – predominantly posterior cognitive alterations. In bvFTD, we found a greater spread of disruption including the rich club (FDR critical Pperm=6×10−4), but especially more peripheral alterations (PΧ2=6.5×10−3), particularly in medial frontal areas of the brain, in line with the known behavioral socioemotional deficits seen in these patients. PMID:26678225

  9. When aging-onset diabetes is coming across with Alzheimer disease: comparable pathogenesis and therapy.

    PubMed

    Tang, Jun; Pei, Yijin; Zhou, Guangji

    2013-08-01

    Diabetes mellitus is a metabolic disorder that is characterized by high blood glucose because of the insulin-resistance and insulin-deficiency in Type 2, while the insulin deficiency due to destruction of islet cells in the pancreas in Type 1. The development of Type 2 diabetes is caused by a combination of lifestyle and genetic factors. Aging patients with diabetes are at increased risk of developing cognitive and memory dysfunctions, which is one of the significant symptoms of Alzheimer disease (AD). Also, over 2/3 of AD patients were clinically indentified with impairment of glucose. Cognitive dysfunction would be associated with poor self-care ability in diabetes patients. This review will briefly summarize the current knowledge of the pathogenesis of these two diseases and highlight similarities in their pathophysiologies. Furthermore, we will shortly discuss recent progress in the insulin-targeted strategy, aiming to explore the inner linkage between these two diseases in aging populations. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Evidence that the APOE locus influences rate of disease progression in late onset familial Alzheimer`s disease but is not causative

    SciTech Connect

    Bennett, C.; Crawford, F.; Osborne, A.; Diaz, P.

    1995-02-27

    An association has been observed in several independent data sets between late onset Alzheimer`s Disease (AD) and the APOE locus on chromosome 19. We have examined the genotype in family history positive (FHP) and family history negative (FHN) cases and find a distortion of the APOE allele frequencies in accord with previous studies. However, when we examined the allele distribution of the at-risk siblings of the FHP group we found an excess of the {epsilon}4 allele which also differs significantly from historic controls but not from the affected siblings. The age distribution of the affected and unaffected siblings was similar, suggesting that the allelic frequency distortion in the unaffected siblings was not due to their being below the mean age of onset. Lod score linkage analysis, with age dependent onset and non-stringent specification of the genetic parameters, did not suggest linkage to the APOE locus. Furthermore, an analysis of variance of the age of disease free survival suggested that APOE genotype contributes a small fraction of the total variance indicating that the APOE locus is a poor predictor of disease free survival age within late onset families. One explanation for the age dependent association reported by other groups, and our results, is that the APOE locus enhances the rate of progression of the disease process in otherwise predisposed individuals and that variation at this locus is not able in and of itself to cause the disease. We suggest this hypothesis is compatible with the current literature regarding APOE and AD. 19 refs., 1 fig., 2 tabs.

  11. 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.

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

    SciTech Connect

    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. 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.

  13. Comparison between Early-Onset and Late-Onset Alzheimer's Disease Patients with Amnestic Presentation: CSF and 18F-FDG PET Study

    PubMed Central

    Chiaravalloti, Agostino; Koch, Giacomo; Toniolo, Sofia; Belli, Lorena; Lorenzo, Francesco Di; Gaudenzi, Sara; Schillaci, Orazio; Bozzali, Marco; Sancesario, Giuseppe; Martorana, Alessandro

    2016-01-01

    Background/Aims To investigate the differences in brain glucose consumption between patients with early onset of Alzheimer's disease (EOAD, aged ≤65 years) and patients with late onset of Alzheimer's disease (LOAD, aged >65 years). Methods Differences in brain glucose consumption between the groups have been evaluated by means of Statistical Parametric Mapping version 8, with the use of age, sex, Mini-Mental State Examination and cerebrospinal fluid values of AΒ1-42, phosphorylated Tau and total Tau as covariates in the comparison between EOAD and LOAD. Results As compared to LOAD, EOAD patients showed a significant decrease in glucose consumption in a wide portion of the left parietal lobe (BA7, BA31 and BA40). No significant differences were obtained when subtracting the EOAD from the LOAD group. Conclusions The results of our study show that patients with EOAD show a different metabolic pattern as compared to those with LOAD that mainly involves the left parietal lobe. PMID:27195000

  14. Haloperidol disrupts, clozapine reinstates the circadian rest-activity cycle in a patient with early-onset Alzheimer disease.

    PubMed

    Wirz-Justice, A; Werth, E; Savaskan, E; Knoblauch, V; Gasio, P F; Müller-Spahn, F

    2000-01-01

    Measurement of the circadian rest-activity cycle in a patient with early-onset Alzheimer disease for 555 days revealed marked changes in the timing and amount of nocturnal activity. After neuroleptic medication was changed to haloperidol, the rest-activity cycle became completely arrhythmic for two months, concomitant with a marked worsening of cognitive state. Circadian integrity returned together with clinical improvement when the patient was subsequently treated with clozapine. This observation suggests that the known tendency for patients with Alzheimer disease to develop sleep-wake cycle disturbances may be aggravated by a classic neuroleptic; in contrast, the atypical neuroleptic clozapine may consolidate it. Similar observations in schizophrenic patients indicate that this chronobiological finding is drug- and not illness-related.

  15. Social cognition: an early impairment in dementia of the Alzheimer type.

    PubMed

    Verdon, Claire-Marie; Fossati, Philippe; Verny, Marc; Dieudonné, Bénédicte; Teillet, Laurent; Nadel, Jacqueline

    2007-01-01

    A core component of social functioning is the capacity to attribute mental states to others and to understand intention as psychologic cause. The hypothesis of this study was that dementia of the Alzheimer type (DAT) patients show an impaired understanding of psychologic cause although they remain able to understand physical causality. To test this hypothesis, 20 elderly adults with DAT, 20 healthy age-matched controls, and 20 healthy young adults were presented a cartoon task requiring them to process physical or psychologic cause of events. Patients with DAT at onset scored significantly lower than controls when they had to reason about psychologic causation, while they did not differ for reasoning about physical causation. Consistent with these results, patients with DAT showed significantly lower scores in psychologic reasoning as compared with their scores for physical causality. Instead young and elderly healthy adults scored similarly for the 2 types of causality and the 2 groups did not differ in their scores. These results suggest that impaired understanding of intention in others may be considered as an early socio-cognitive index of onset of DAT. A post hoc division of the group of patients with DAT into 2 subgroups according to Mini Mental State (MMS) scores showed that the group with the more severe MMS scores not only had lower scores for psychologic causality but also showed impairment in reasoning about physical causality involving persons. Physical causality involving objects remained relatively preserved. The remarkable deficit in attribution of intention in our patients with DAT at onset and the following deterioration of their performance in reasoning about physical causality with persons may reflect progressive dysfunction of the superior temporal sulcus in Alzheimer disease.

  16. Phenotypic Similarities Between Late-Onset Autosomal Dominant and Sporadic Alzheimer Disease: A Single-Family Case-Control Study.

    PubMed

    Day, Gregory S; Musiek, Erik S; Roe, Catherine M; Norton, Joanne; Goate, Alison M; Cruchaga, Carlos; Cairns, Nigel J; Morris, John C

    2016-09-01

    The amyloid hypothesis posits that disrupted β-amyloid homeostasis initiates the pathological process resulting in Alzheimer disease (AD). Autosomal dominant AD (ADAD) has an early symptomatic onset and is caused by single-gene mutations that result in overproduction of β-amyloid 42. To the extent that sporadic late-onset AD (LOAD) also results from dysregulated β-amyloid 42, the clinical phenotypes of ADAD and LOAD should be similar when controlling for the effects of age. To use a family with late-onset ADAD caused by a presenilin 1 (PSEN1) gene mutation to mitigate the potential confound of age when comparing ADAD and LOAD. This case-control study was conducted at the Knight Alzheimer Disease Research Center at Washington University, St Louis, Missouri, and other National Institutes of Aging-funded AD centers in the United States. Ten PSEN1 A79V mutation carriers from multiple generations of a family with late-onset ADAD and 12 noncarrier family members were followed up at the Knight Alzheimer Disease Research Center (1985-2015) and 1115 individuals with neuropathologically confirmed LOAD were included from the National Alzheimer Coordinating Center database (September 2005-December 2014). Data analysis was completed in January 2016, including Knight Alzheimer Disease Research Center patient data collected up until the end of 2015. Planned comparison of clinical characteristics between cohorts, including age at symptom onset, associated symptoms and signs, rates of progression, and disease duration. Of the PSEN1 A79V carriers in the family with late-onset ADAD, 4 were female (57%); among those with LOAD, 529 were female (47%). Seven mutation carriers (70%) developed AD dementia, while 3 were yet asymptomatic in their seventh and eighth decades of life. No differences were observed between mutation carriers and individuals with LOAD concerning age at symptom onset (mutation carriers: mean, 75 years [range, 63-77 years] vs those with LOAD: mean, 74 years [range

  17. Early onset APOE E4-negative Alzheimer's disease patients show faster cognitive decline on non-memory domains.

    PubMed

    Smits, Lieke L; Pijnenburg, Yolande A L; van der Vlies, Annelies E; Koedam, Esther L G E; Bouwman, Femke H; Reuling, Ilona E W; Scheltens, Philip; van der Flier, Wiesje M

    2015-07-01

    Age at onset and APOE E4-genotype have been shown to influence clinical manifestation of Alzheimer's disease (AD). We investigated rate of decline in specific cognitive domains according to age at onset and APOE E4-genotype in patients with AD. 199 patients with probable AD underwent at least two annual neuropsychological assessments. Patients were classified according to age-at-onset (≤ 65 years vs >65 years) and APOE genotype (positive vs negative). The neuropsychological test battery compromised tests for memory, language, attention, executive and visuo-spatial functioning. For each domain compound z-scores were calculated, based on the baseline performance of patients. Average duration of follow-up was 1.5 ± 1 years. We used linear mixed models (LMM) to estimate effects of age, APOE and age⁎APOE on cognitive decline over time. At baseline, patients were 65 ± 8 years, 98(49%) were female and MMSE was 22 ± 4. LMM showed that early onset patients declined faster on executive functioning (β ± SE:-0.09 ± 0.06) than late onset patients, but age was not related to decline in the other cognitive domains. APOE E4 negative patients declined faster on language than APOE E4 positive patients (β ± SE:-0.1 ± 0.06). When we took age and APOE genotype into account simultaneously, we found that compared to late onset-E4 positive patients, early onset-E4 negative patients declined faster on language (β ± SE:-0.36 ± 0.1), attention (β ± SE:-0.42 ± 0.1), executive (β ± SE:-0.41 ± 0.1) and visuo-spatial functioning (β ± SE:-0.43 ± 0.1). Late onset-E4 negative and early onset-E4 positive patients showed intermediate rates of decline. We found no differences in decline on memory. We found that patients who develop AD despite absence of the two most important risk factors, show steepest cognitive decline on non-memory cognitive domains. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  18. Discrimination between Alzheimer's Disease and Late Onset Bipolar Disorder Using Multivariate Analysis.

    PubMed

    Besga, Ariadna; Gonzalez, Itxaso; Echeburua, Enrique; Savio, Alexandre; Ayerdi, Borja; Chyzhyk, Darya; Madrigal, Jose L M; Leza, Juan C; Graña, Manuel; Gonzalez-Pinto, Ana Maria

    2015-01-01

    Late onset bipolar disorder (LOBD) is often difficult to distinguish from degenerative dementias, such as Alzheimer disease (AD), due to comorbidities and common cognitive symptoms. Moreover, LOBD prevalence in the elder population is not negligible and it is increasing. Both pathologies share pathophysiological neuroinflammation features. Improvements in differential diagnosis of LOBD and AD will help to select the best personalized treatment. The aim of this study is to assess the relative significance of clinical observations, neuropsychological tests, and specific blood plasma biomarkers (inflammatory and neurotrophic), separately and combined, in the differential diagnosis of LOBD versus AD. It was carried out evaluating the accuracy achieved by classification-based computer-aided diagnosis (CAD) systems based on these variables. A sample of healthy controls (HC) (n = 26), AD patients (n = 37), and LOBD patients (n = 32) was recruited at the Alava University Hospital. Clinical observations, neuropsychological tests, and plasma biomarkers were measured at recruitment time. We applied multivariate machine learning classification methods to discriminate subjects from HC, AD, and LOBD populations in the study. We analyzed, for each classification contrast, feature sets combining clinical observations, neuropsychological measures, and biological markers, including inflammation biomarkers. Furthermore, we analyzed reduced feature sets containing variables with significative differences determined by a Welch's t-test. Furthermore, a battery of classifier architectures were applied, encompassing linear and non-linear Support Vector Machines (SVM), Random Forests (RF), Classification and regression trees (CART), and their performance was evaluated in a leave-one-out (LOO) cross-validation scheme. Post hoc analysis of Gini index in CART classifiers provided a measure of each variable importance. Welch's t-test found one biomarker (Malondialdehyde) with

  19. [The Global Deterioration Scale (GDS) and Functional Assessment Staging (FAST) in the diagnosis of Alzheimer type dementia].

    PubMed

    Krzymińska, E; Rossa, G; Krzymiński, S

    1993-01-01

    Described are two scales for the diagnosis of dementia of the Alzheimer type and for identifying its following stages solely on the basis of social functioning and on daily activity level of the patient. The authors of the scale, Resiberg et al. based their findings on the conclusion that dementia of the Alzheimer type is a rare clinical syndrome with a characteristic onset and development which are identical in over 90% of patients. The GDS (Global Deterioration Scale) separates the course of dementia into 6 stages. The FAST (Functional Assessment Scale) separates deterioration into 16 stages. Both scales, especially allow for the systematic tracking of course of the uncomplicated Alzheimer's case. They also show the appearance of any additional somatic and psychopathological factors which cause the state of the patient to appear worst than could result from the current stage the patient is in. They ease the differentiation between dementia of the Alzheimer type and dementia of other aetiology. Apart from these scales, especially the FAST, allow to the estimation with significant accuracy how long the current stage, as well as the whole illness will last in a given patient. Similarly, predictions may be made as to the time and in what order particular life functions will be diminishing in specific patients until the terminal state.

  20. The effect of alcohol and tobacco consumption, and apolipoprotein E genotype, on the age of onset in Alzheimer's disease.

    PubMed

    Harwood, Dylan G; Kalechstein, Ari; Barker, Warren W; Strauman, Silvia; St George-Hyslop, Peter; Iglesias, Casandra; Loewenstein, David; Duara, Ranjan

    2010-05-01

    This study examined the association between a history of heavy alcohol use and smoking, presence of the apolipoprotein-E epsilon 4 allele (APOE epsilon4), and age of disease onset in a community dwelling sample of 685 Alzheimer's disease (AD) patients spanning three ethnic groups. Cross-sectional study of AD patients evaluated at a University-affiliated outpatient memory disorders clinic. A clinic-based cohort of white non-Hispanic (WNH; n = 397), white Hispanic (WH; n = 264), and African-American (AA; n = 24) patients diagnosed with possible or probable AD according to NINCDS-ADRDA diagnostic criteria. The age of onset of AD was obtained from a knowledgeable family member. All patients were assessed for APOE genotype. History of alcohol and tobacco consumption prior to the onset of dementia was obtained via an interview with the patient and the primary caregiver. A history of heavy drinking was defined as >2 drinks per day and a history of heavy smoking was defined as > or =1 pack per day. Presence of an APOE epsilon4 allele, a history of heavy drinking, or a history of heavy smoking were each associated with an earlier onset of AD by 2-3 years. Patients with all three risk factors were likely to be diagnosed with AD nearly 10 years earlier than those with none of the risk factors. The results suggest that APOE epsilon4 and heavy drinking and heavy smoking lower the age of onset for AD in an additive fashion.

  1. The Nature and Natural History of Posterior Cortical Atrophy Syndrome: A Variant of Early-onset Alzheimer Disease.

    PubMed

    Panegyres, Peter K; Goh, Judy; McCarthy, Michael; Campbell, Andrew I

    2017-08-08

    A prospective longitudinal evaluation of 12 patients over a 16-year interval using clinical neurological and imaging data to determine whether posterior cortical atrophy syndrome (PCA) related to early-onset Alzheimer disease (AD) and to examine its natural history. Our 12 patients had a median age of onset of 56 years (range, 48 to 63 y) and were followed for a median of 6 years (range, 3 to 9 y). Patients either presented with complex visual phenomena or developed them with time. Six patients underwent flurodeoxyglucose and Pittsburgh investigational compound B imaging which showed a mismatch between metabolic activity and amyloid deposition with reduced metabolism in parieto-occipital regions on flurodeoxyglucose positron emission tomography and diffuse neocortical uptake of amyloid without occipital predominance. All patients progressively deteriorated using a quality of life and total functional capacity assessments and this change is similar to the natural history of other early-onset AD variants (typical amnestic presentation, logopenic, and frontal). Two patients had neuropathologic assessments and were shown to have AD using standard pathologic criteria. Of interest, 5 of our 12 patients had occupations strongly dependent on visuospatial functioning. PCA is a syndrome that is most likely a variant of early-onset AD and our correlative clinical, structural, functional, and amyloid imaging data, along with neuropathologic studies in 2 patients, support this concept. The natural history of PCA shows progression with time and this trajectory seems to reflect that of other variants of early-onset AD.

  2. Posterior Accumulation of Tau and Concordant Hypometabolism in an Early-Onset Alzheimer's Disease Patient with Presenilin-1 Mutation.

    PubMed

    Smith, Ruben; Wibom, Moa; Olsson, Tomas; Hägerström, Douglas; Jögi, Jonas; Rabinovici, Gil D; Hansson, Oskar

    2016-01-01

    It is unclear whether the distribution of tau pathology differs between cases with early-onset familial Alzheimer's disease (AD) and sporadic AD. We present positron emission tomography (PET) data from a young patient with a presenilin-1 mutation (Thr116Asn). 18F-flutemetamol PET showed a distribution of amyloid-β fibrils similar to sporadic AD. However, the pattern of tau pathology, revealed using 18F-AV1451 PET, showed higher uptake in posterior cingulate, precuneus, parietal and occipital cortices compared to late-onset sporadic AD. Further, the tau pathology, but not amyloid pathology, exhibited a very clear inverse relationship with 18F-fluorodeoxyglucose-metabolism, indicating neuronal hypometabolism in regions affected by tau aggregates.

  3. Discovery of gene-gene interactions across multiple independent datasets of Late Onset Alzheimer Disease from the Alzheimer Disease Genetics Consortium

    PubMed Central

    Hohman, Timothy J.; Bush, William S.; Jiang, Lan; Brown-Gentry, Kristin D.; Torstenson, Eric S.; Dudek, Scott M.; Mukherjee, Shubhabrata; Naj, Adam; Kunkle, Brian W.; Ritchie, Marylyn D.; Martin, Eden R.; Schellenberg, Gerard D.; Mayeux, Richard; Farrer, Lindsay A.; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Thornton-Wells, Tricia A.

    2015-01-01

    Late-onset Alzheimer disease (LOAD) has a complex genetic etiology, involving locus heterogeneity, polygenic inheritance and gene-gene interactions; however, the investigation of interactions in recent GWAS has been limited. We used a biological knowledge-driven approach to evaluate gene-gene interactions for consistency across thirteen datasets from the Alzheimer Disease Genetics Consortium. Fifteen SNP-SNP pairs within three gene-gene combinations were identified: SIRT1 x ABCB1, PSAP x PEBP4, and GRIN2B x ADRA1A. Additionally, we extend a previously identified interaction from an endophenotype analysis between RYR3 x CACNA1C. Finally, post hoc gene expression analyses of the implicated SNPs further implicate SIRT1 and ABCB1, and implicate CDH23 which was most recently identified as an AD risk locus in an epigenetic analysis of AD. The observed interactions in this manuscript highlight ways in which genotypic variation related to disease may depend on the genetic context in which it occurs. Further, our results highlight the utility of evaluating genetic interactions to explain additional variance in AD risk and identify novel molecular mechanisms of AD pathogenesis. PMID:26827652

  4. Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium.

    PubMed

    Hohman, Timothy J; Bush, William S; Jiang, Lan; Brown-Gentry, Kristin D; Torstenson, Eric S; Dudek, Scott M; Mukherjee, Shubhabrata; Naj, Adam; Kunkle, Brian W; Ritchie, Marylyn D; Martin, Eden R; Schellenberg, Gerard D; Mayeux, Richard; Farrer, Lindsay A; Pericak-Vance, Margaret A; Haines, Jonathan L; Thornton-Wells, Tricia A

    2016-02-01

    Late-onset Alzheimer disease (AD) has a complex genetic etiology, involving locus heterogeneity, polygenic inheritance, and gene-gene interactions; however, the investigation of interactions in recent genome-wide association studies has been limited. We used a biological knowledge-driven approach to evaluate gene-gene interactions for consistency across 13 data sets from the Alzheimer Disease Genetics Consortium. Fifteen single nucleotide polymorphism (SNP)-SNP pairs within 3 gene-gene combinations were identified: SIRT1 × ABCB1, PSAP × PEBP4, and GRIN2B × ADRA1A. In addition, we extend a previously identified interaction from an endophenotype analysis between RYR3 × CACNA1C. Finally, post hoc gene expression analyses of the implicated SNPs further implicate SIRT1 and ABCB1, and implicate CDH23 which was most recently identified as an AD risk locus in an epigenetic analysis of AD. The observed interactions in this article highlight ways in which genotypic variation related to disease may depend on the genetic context in which it occurs. Further, our results highlight the utility of evaluating genetic interactions to explain additional variance in AD risk and identify novel molecular mechanisms of AD pathogenesis.

  5. Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease

    PubMed Central

    De Ferrari, Giancarlo V.; Papassotiropoulos, Andreas; Biechele, Travis; Wavrant De-Vrieze, Fabienne; Avila, Miguel E.; Major, Michael B.; Myers, Amanda; Sáez, Katia; Henríquez, Juan P.; Zhao, Alice; Wollmer, M. Axel; Nitsch, Roger M.; Hock, Christoph; Morris, Chris M.; Hardy, John; Moon, Randall T.

    2007-01-01

    Genome-wide linkage studies have defined a broad susceptibility region for late-onset Alzheimer's disease on chromosome 12, which contains the Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) gene, a coreceptor for Wnt signaling. Here, we report the association between common LRP6 variants and late-onset Alzheimer's disease in a multicenter case-control series as well as in a large family-based series ascertained by the National Institute of Mental Health–National Institute on Aging Genetics Initiative. As shown in the genome-wide linkage studies, our association depends mainly on apolipoprotein E-ε4 (APOE-ε4) carrier status. Haplotype tagging single-nucleotide polymorphisms (SNPs) with a set of seven allelic variants of LRP6 identified a putative risk haplotype, which includes a highly conserved coding sequence SNP: Ile-1062 → Val. Functional analyses revealed that the associated allele Val-1062, an allele previously linked to low bone mass, has decreased β-catenin signaling in HEK293T cells. Our study unveils a genetic relationship between LRP6 and APOE and supports the hypothesis that altered Wnt/β-catenin signaling may be involved in this neurodegenerative disease. PMID:17517621

  6. Multiple-threshold models for genetic influences on age of onset for Alzheimer disease: findings in Swedish twins.

    PubMed

    Pedersen, N L; Posner, S F; Gatz, M

    2001-12-08

    Twin studies of dementia have typically used relatively simple 2 x 2 contingency tables with one threshold to estimate the relative importance of genetic variance for liability to disease. These designs are inadequate for addressing issues of age at onset, censoring of data, and distinguishing shared environmental effects from age effects. Meyer and Breitner [1998: Am J Med Genet 81:92-97] applied a multiple-threshold model to the NAS-NRC Twin Panel (average age of onset, 63.5 years) and report that additive genetic effects and shared environmental effects account for 37% and 35% of the variation, respectively, in age of onset for Alzheimer disease. We apply a modified version of their model to the Study of Dementia in Swedish Twins (average age of onset, 75 years) and find that genetic effects account for 57%-78% of the variance, whereas shared environmental effects are of no importance. Heritability is lower when thresholds are freely estimated rather than fixed to the population prevalences. We interpret the findings to suggest that models with free thresholds confound influences on longevity with influences for the disease. Multiple-threshold models, however, do not confound age effects with shared environmental influences. Copyright 2001 Wiley-Liss, Inc.

  7. Current view from Alzheimer disease to type 2 diabetes mellitus.

    PubMed

    Rasool, Mahmood; Malik, Arif; Qazi, Aamer M; Sheikh, Ishfaq A; Manan, Abdul; Shaheen, Sumaira; Qazi, Mahmood H; Chaudhary, Adeel G; Abuzenadah, Adel M; Asif, Muhammad; Alqahtani, Mohammed H; Iqbal, Zafar; Shaik, Munvar M; Gan, Siew H; Kamal, Mohammad A

    2014-04-01

    Alzheimer's disease (AD) is a neurodegenerative disorder that leads to memory problems. It has been associated with type 2 diabetes mellitus at both the molecular and biochemical level. Pancreatic cells have molecular similarities to the brain at the transcriptomic and proteomic levels. Several genes have been reported to be responsible for both AD and diabetes. Currently, no proper treatment is available but various therapeutic approaches are utilized worldwide for the management of these disorders and may be nanoparticles and herbal treatment of Bacopa monnieri will make promise for the treatment of AD in future. The formation of amyloids in neurons and the formation of amylin in pancreatic cells are potential links between these two disorders, which can be silent killers.

  8. Increased B-type natriuretic peptide levels in early-onset versus late-onset preeclampsia.

    PubMed

    Szabó, Gábor; Molvarec, Attila; Nagy, Bálint; Rigó, János

    2014-02-01

    We compared B-type natriuretic peptide (BNP) levels, clinical and laboratory findings in early-onset preeclampsia (EOP), late-onset preeclampsia (LOP) and healthy pregnant groups. We studied 40 healthy pregnant and 40 preeclamptic patients. Preeclamptics were divided in two groups, the EOP group (n=20) and LOP group (n=20), according to gestational age at the onset of disease. The distinction criterion for early- vs. late-onset was set as week 34 of gestation. The concentration of the BNP levels was measured by a sandwich fluorescence immunoassay. For statistical analysis of the clinical and laboratory findings non-parametric methods were applied. BNP levels were higher in EOP [61.35 (36.95-93.25) pg/mL] and LOP patients [32.4 (19.15-39.2) pg/mL] than in healthy pregnant women [10.05 (6.08-16.03) pg/mL] (both p<0.001). Furthermore, EOPs had significantly higher BNP levels as compared to LOP patients (p<0.001). A BNP cut-off <24.5 pg/mL had a negative-predictive value of 85.1% excluding preeclampsia. There was a significant inverse correlation between plasma BNP levels of EOP patients and sodium (p<0.05) and total protein concentrations (p<0.05). In the EOP group, a significant positive correlation was observed between plasma levels of BNP and hematocrit (p<0.05), serum potassium (p<0.05), urea (p<0.05) and 24-h proteinuria (p<0.05). BNP levels were significantly higher in EOP than in LOP patients. The cut-off value <24.5 pg/mL seems to be a powerful discriminative indicator excluding preeclampsia. The amount of proteinuria and total protein levels correlate with the elevation of the BNP levels. In EOP the extent of proteinuria is higher than in the LOP.

  9. The association between APOE ε4 and Alzheimer-type dementia among memory clinic patients is confined to those with a higher education. The DESCRIPA Study.

    PubMed

    Vermeiren, Angelique P A; Bosma, Hans; Visser, Pieter-Jelle; Zeegers, Maurice P; Graff, Caroline; Ewers, Michael; Frisoni, Giovanni B; Frölich, Lutz; Hampel, Harald; Jones, Roy W; Kehoe, Patrick G; Lenoir, Hermine; Minthon, Lennart; Nobili, Flavio M; Olde Rikkert, Marcel; Rigaud, Anne-Sophie; Scheltens, Philip; Soininen, Hilkka; Spiru, Luiza; Tsolaki, Magda; Wahlund, Lars-Olof; Vellas, Bruno; Wilcock, Gordon; Elias-Sonnenschein, Lyzel S; Verhey, Frans R J

    2013-01-01

    We assessed the interaction between the APOE ε4 allele and education level in the etiology of Alzheimer's disease (AD) among memory clinic patients from the multicenter DESCRIPA study. Subjects (n = 544) were followed for 1 to 5 years. We used Cox's stratified survival modeling, adjusted for age, gender, and center. APOE ε4 predicted the onset of AD-type dementia in middle (HR 3.45 95% CI 1.79-6.65, n = 222) and high (HR 3.67 95% CI 1.36-9.89, n = 139) but not in low educated subjects (HR 0.81, 95% CI 0.38-1.72, n = 183). This suggests that mechanisms in developing Alzheimer-type dementia may differ between educational groups that raises questions related to Alzheimer-type dementia prevention.

  10. Alzheimer disease and type 2 diabetes mellitus: the link to tyrosine hydroxylase and probable nutritional strategies.

    PubMed

    Aliev, Gjumrakch; Shahida, Khan; Gan, Siew Hua; Firoz, Ck; Khan, Aziz; Abuzenadah, Adel M; Kamal, Warda; Kamal, Mohammad A; Tan, Yi; Qu, Xianqin; Reale, Marcella

    2014-04-01

    Alzheimer disease (AD) and type 2 diabetes mellitus (T2DM) are chronic health disorders that affect millions of people around the world. According to recent studies, there are molecular similarities in the inflammatory pathways involved in both AD and T2DM, which opens a new avenue for researchers with different perspectives to target the cause of these diseases rather than their obvious symptoms. Several links between inflammation, cardiovascular disease, T2DM and central nervous system disorders such as AD and Parkinson's disease have been elucidated. Mutations in the hippocampal-β-amyloid precursor protein gene in genetically high-risk individuals have been shown to cause the early onset of AD symptoms. The overexpression of β-amyloid protein in the hippocampal region and the synaptotoxicity that occurs as a result have been considered a typical feature of AD and leads to neuronal loss and cognitive decline. However, the identity of the cellular components that cause the late onset of the disease seen in the majority of the cases is still unknown. Synaptic insults associated with neuronal dysfunction may involve several cascades and molecules, one of which has been hypothesized to be tyrosine hydroxylase (TH). The axons of the noradrenergic cells that project to the hippocampus appear to be affected by the β-amyloid protein, which subsequently contributes to TH loss in Alzheimer brain cells. In this review, we attempt to shed light on the important mechanisms involved in AD as well as T2DM such as inflammatory factors, abnormalities in the insulin signaling system and the possible role of the endocrine enzyme TH.

  11. Calcium-sensing receptor (CaSR) in human brain's pathophysiology: roles in late-onset Alzheimer's disease (LOAD).

    PubMed

    Chiarini, Anna; Dal Pra, Ilaria; Marconi, Maddalena; Chakravarthy, Balu; Whitfield, James F; Armato, Ubaldo

    2009-04-01

    Although the calcium-sensing receptor (CaSR) is expressed by all types of nerve cells in widespread areas of the human central nervous system (CNS), so far its roles in brain pathophysiology remain largely unknown. Here, we review the available evidence concerning the stages of development of sporadic late-onset Alzheimer's disease (LOAD) and the roles therein played by CaSR signaling. As the brain ages, its ability to dispose of dangerous synapse-targeting soluble amyloid beta-(1-42) (sAbeta42) oligomers released from normal neuronal activity declines. As their levels slowly rise, these oligomers increasingly target and eliminate synapses and prevent synapse formation, thereby eroding the foundations of memory formation and cognitive functions. In this initial stage, neurons, even though synaptically impaired, remain alive. Concurrently, sAbeta42 oligomers by binding to CaSR on human astrocytes induce via mitogen activated protein kinase (MAPK) activity the release of huge amounts nitric oxide (NO), which by itself and after conversion to peroxynitrite (ONOO(-)) damages neighboring neurons. When the sAbeta42 oligomers increasingly aggregate into fibrillar plaques, they attract and activate microglial macrophages that, while trying to clear the plaques, produce via Abeta-activated CaSR signaling several proinflammatory cytokines and reactive oxygen species (ROS). Notably, the microglial cytokines, like sAbeta42 oligomers, induce human astrocytes to make large amounts of NO and hence ONOO(-) via CaSR signal-dependent MAPK activity. The microglial cytokines-activated astrocytes might also produce their own sAbeta42, which would combine with neuron- and microglia-released sAbeta42 to increase the fibrillar burden and promote the further production of reactive oxygen species (ROS), NO/ONOO(-), and proinflammatory cytokines to efficiently kill both normal and functionally impaired (undead) neurons. But, on a somewhat positive note, we speculate that the astrocytes' Ca

  12. Hyperspectral imaging signatures detect amyloidopathy in Alzheimer's mouse retina well before onset of cognitive decline.

    PubMed

    More, Swati S; Vince, Robert

    2015-02-18

    Amyloidopathic disorders such as Alzheimer's disease present symptomology years after the entrenchment of amyloidogenic imbalance. The pathologic α-helix → β-strand conversion of amyloid β(1-42) and amyloid β(1-40) peptides causes neuronal death in the vicinity. Symptomology often presents only after significant neurodegeneration. This thus warrants early detection of amyloidopathy in Alzheimer's disease. Nonexistent modalities for direct identification and quantitation of soluble amyloid aggregates or (proto)fibrils forced us to undertake the development of a spectrophotometric technique to support ongoing drug design. Key requirements were independence from the need for extraneous staining, unambiguous amyloid aggregate detection, and minimal influence of interpretative errors. A Cytoviva instrument pivotal to this study captures scattering of light of visible-near-infrared (VNIR, 400-1000 nm) wavelengths within each pixel of the microscopic view field. We thus assembled a scattering intensity pattern database that provided "signatures" of amyloid aggregates. Comparison of unknown samples against this database enabled direct detection of amyloid aggregates. The technique was found useful for monitoring retinal and brain amyloidopathy in an ongoing preclinical anti-AD study, attesting to the technique's sensitivity and specificity. Interestingly, the technique was found applicable not just to excised brain tissue but also to isolated mouse retina. With the retina being heralded widely as a (diagnostic) extension of the CNS and retinal amyloidopathy occurring well before that in the brain, this development raises a possibility for the first direct retinal imaging diagnosis of early asymptomatic Alzheimer's disease.

  13. The midlife cognitive profiles of adults at high risk of late-onset Alzheimer's disease: The PREVENT study.

    PubMed

    Ritchie, Karen; Carrière, Isabelle; Su, Li; O'Brien, John T; Lovestone, Simon; Wells, Katie; Ritchie, C W

    2017-03-29

    Although biomarker studies of late-onset Alzheimer's disease suggest pathology to be present decades before diagnosis, little is known about cognitive performance at this stage. A sample of 210 adults (aged 40-59) of whom 103 have a parent diagnosed with dementia (family history subgroup) underwent computerized cognitive testing. ApoE status was determined, and 193 subjects had magnetic resonance imaging. Distance from dementia onset was estimated in relation to age of parental diagnosis, and Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Scores were calculated. Lower hippocampal volumes (P = .04) were associated with poorer spatial location recall and higher Dementia Risk Scores with poorer visual recognition (P = .0005), and lower brain and hippocampal volume (P < .0001, P = .04, respectively). Family history subgroup participants closer to dementia onset had lower scores on visual working memory (P = .05), whereas those with an ApoE ε4 allele performed better on form perception (P = .005). Middle-aged adults at risk of dementia show evidence of poorer cognitive performance, principally in visuospatial functions.

  14. Microscopic and macroscopic models for the onset and progression of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Bertsch, Michiel; Franchi, Bruno; Carla Tesi, Maria; Tosin, Andrea

    2017-10-01

    In the first part of this paper we review a mathematical model for the onset and progression of Alzheimer’s disease (AD) that was developed in subsequent steps over several years. The model is meant to describe the evolution of AD in vivo. In Achdou et al (2013 J. Math. Biol. 67 1369–92) we treated the problem at a microscopic scale, where the typical length scale is a multiple of the size of the soma of a single neuron. Subsequently, in Bertsch et al (2017 Math. Med. Biol. 34 193–214) we concentrated on the macroscopic scale, where brain neurons are regarded as a continuous medium, structured by their degree of malfunctioning. In the second part of the paper we consider the relation between the microscopic and the macroscopic models. In particular we show under which assumptions the kinetic transport equation, which in the macroscopic model governs the evolution of the probability measure for the degree of malfunctioning of neurons, can be derived from a particle-based setting. The models are based on aggregation and diffusion equations for β-Amyloid (Aβ from now on), a protein fragment that healthy brains regularly produce and eliminate. In case of dementia Aβ monomers are no longer properly washed out and begin to coalesce forming eventually plaques. Two different mechanisms are assumed to be relevant for the temporal evolution of the disease: (i) diffusion and agglomeration of soluble polymers of amyloid, produced by damaged neurons; (ii) neuron-to-neuron prion-like transmission. In the microscopic model we consider mechanism (i), modelling it by a system of Smoluchowski equations for the amyloid concentration (describing the agglomeration phenomenon), with the addition of a diffusion term as well as of a source term on the neuronal membrane. At the macroscopic level instead we model processes (i) and (ii) by a system of Smoluchowski equations for the amyloid concentration, coupled to a kinetic-type transport equation for the distribution function of

  15. Gene Interactions and Structural Brain Change in Early-Onset Alzheimer's Disease Subjects Using the Pipeline Environment

    PubMed Central

    Dinov, Ivo D.; Zamanyan, Alen; Shi, Ran; Genco, Alex; Hobel, Sam; Thompson, Paul M.; Toga, Arthur W.

    2015-01-01

    Objective This article investigates subjects aged 55 to 65 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to broaden our understanding of early-onset (EO) cognitive impairment using neuroimaging and genetics biomarkers. Methods Nine of the subjects had EO-AD (Alzheimer's disease) and 27 had EO-MCI (mild cognitive impairment). The 15 most important neuroimaging markers were extracted with the Global Shape Analysis (GSA) Pipeline workflow. The 20 most significant single nucleotide polymorphisms (SNPs) were chosen and were associated with specific neuroimaging biomarkers. Results We identified associations between the neuroimaging phenotypes and genotypes for a total of 36 subjects. Our results for all the subjects taken together showed the most significant associations between rs7718456 and L_hippocampus (volume), and between rs7718456 and R_hippocampus (volume). For the 27 MCI subjects, we found the most significant associations between rs6446443 and R_superior_frontal_gyrus (volume), and between rs17029131 and L_Precuneus (volume). For the nine AD subjects, we found the most significant associations between rs16964473 and L_rectus gyrus (surface area), and between rs12972537 and L_rectus_gyrus (surface area). Conclusion We observed significant correlations between the SNPs and the neuroimaging phenotypes in the 36 EO subjects in terms of neuroimaging genetics. However, larger sample sizes are needed to ensure that the effects will be detectable for a reasonable false-positive error rate using the GSA and Plink Pipeline workflows. PMID:25670955

  16. Specific BACE1 genotypes provide additional risk for late-onset Alzheimer disease in APOE epsilon 4 carriers.

    PubMed

    Gold, Gabriel; Blouin, Jean-Louis; Herrmann, François R; Michon, Agnès; Mulligan, Reinhild; Duriaux Saïl, Geneviève; Bouras, Constantin; Giannakopoulos, Panteleimon; Antonarakis, Stylianos E

    2003-05-15

    Alzheimer disease (AD) is characterized neuropathologically by neurofibrillary tangles and senile plaques. A key component of plaques is A beta, a polypeptide derived from A beta-precursor protein (APP) through proteolytic cleavage catalyzed by beta and gamma-secretase. We hypothesized that sequence variation in genes BACE1 (on chromosome 11q23.3) and BACE2 (on chromosome 21q22.3), which encode two closely related proteases that seem to act as the APP beta-secretase, may represent a genetic risk factor for AD. We analyzed the frequencies of single nucleotide polymorphisms (SNPs) in BACE1 and BACE2 genes in a community-based sample of 96 individuals with late-onset AD and 170 controls selected randomly among residents of the same community. The genotype data in both study groups did not demonstrate any association between AD and BACE1 or BACE2. After stratification for APOE status, however, an association between a BACE1 polymorphism located within codon V262 and AD in APOE epsilon 4 carriers was observed (P = 0.03). We conclude that sequence variation in the BACE1 or BACE 2 gene is not a significant risk factor for AD; however, a combination of a specific BACE1 allele and APOE epsilon 4 may increase the risk for Alzheimer disease over and above that attributed to APOE epsilon 4 alone.

  17. Global long interspersed nuclear element 1 DNA methylation in a Colombian sample of patients with late-onset Alzheimer's disease.

    PubMed

    Hernández, Hernán G; Mahecha, María F; Mejía, Adriana; Arboleda, Humberto; Forero, Diego A

    2014-02-01

    Alterations in DNA methylation have implicated as an epigenetic event in the pathogenesis of late-onset Alzheimer's disease (LOAD). The objective of this work was to evaluate global DNA methylation levels for long interspersed nuclear element 1 (LINE-1) repetitive sequences in Colombian patients with LOAD and controls. The LINE-1 DNA methylation levels in peripheral blood samples from 28 Colombian patients with LOAD and 30 healthy participants were assessed using a methylation-sensitive high-resolution melting (MS-HRM) quantitative assay. We did not find differences in LINE-1 methylation levels between patients with Alzheimer's disease (AD; median 76.2%, interquartile range [IQR]: 69.8-81.9) and control participants (median 79.8%, IQR: 73.2-83.8; P = .3). Additional stratified analyses did not show differences in LINE-1 methylation levels for male or female patients versus controls nor for apolipoprotein E4 carriers and noncarriers. This is the first report of LINE-1 methylation levels in patients with LOAD using the cost-effective MS-HRM technique, and this is the first global DNA methylation study in Latin American patients with AD.

  18. Labor market consequences of childhood onset type 1 diabetes.

    PubMed

    Persson, Sofie; Gerdtham, Ulf-G; Steen Carlsson, Katarina

    2016-12-01

    This paper examines the effect of the onset of Type 1 Diabetes Mellitus (T1DM) before 15 years of age on labor market outcomes and contributes to the literature on effects of childhood health on adult socioeconomic status. Using national Swedish socioeconomic register data 1991-2010 for 2485 individuals born 1972-1978 with onset of T1DM in 1977-1993, we find that T1DM in childhood has a negative effect on labor market outcomes later in life. Part of the T1DM effect is channeled through occupational field which may be related to both choice and opportunities. Although the magnitude of the effect is only directly generalizable to illnesses with similar attributes as T1DM, the results suggest that causality in the often observed correlation between health and socioeconomic status, at least partly, is explained by an effect running from health to earnings. This has implications for research and policy on strategies to reduce socioeconomic-related health inequality. Our findings also shed light on productivity losses, measured by employment status and earnings due to childhood onset T1DM, which have implications for both the individual and society. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. In their own words: The experience and needs of children in younger-onset Alzheimer's disease and other dementias families.

    PubMed

    Gelman, Caroline Rosenthal; Rhames, Kate

    2016-05-26

    Because of the age of persons diagnosed with younger-onset Alzheimer's disease or other dementias (YOD), an important and as yet relatively little explored area of YOD, particularly in the United States, is the impact on young children of having a parent with YOD. After reviewing the small but growing research in this area, we report on findings from 12 in-depth interviews with children and well-parents in families with a parent with YOD on the experience and needs of children having a parent with this diagnosis. Children report disruption in many aspects of their lives: their developmental trajectory, emotional and psychological development, familial and broader social relationships, and financial stability. Despite these significant disruptions, and a dearth of information, resources, and services tailored to their individual and familial needs, these children demonstrate remarkable resilience and self-awareness. We discuss implications for interventions with these families.

  20. A novel PSEN1 (S230N) mutation causing early-onset Alzheimer's Disease associated with prosopagnosia, hoarding, and Parkinsonism.

    PubMed

    Ringman, John M; Casado, Maria; Van Berlo, Victoria; Pa, Judy; Joseph-Mathurin, Nelly; Fagan, Anne M; Benzinger, Tammie; Bateman, Randall J; Morris, John C

    2017-09-14

    We describe clinical and biomarker findings in an index patient with the onset of Alzheimer's disease (AD) symptoms at age 57 and a family history consistent with an autosomal dominant pattern of inheritance. She had the atypical early features of visual agnosia and prosopagnosia followed by hoarding behavior and Parkinsonism. Structural MRI revealed global atrophy that was most severe in the lateral temporal lobes and insular cortex bilaterally. CSF biomarker assessment showed Aβ42, p-tau181, and total tau levels consistent with AD. Genetic assessment revealed a novel mutation in the PSEN1 gene (S230N) in the index patient and her affected brother which was absent in her two clinically unaffected and AD-biomarker negative sisters. The serine residue at codon 230 in PSEN1 is highly conserved across species and in PSEN2, providing strong evidence for its pathogenicity in this family. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study: implication of additional loci.

    PubMed

    Lee, Joseph H; Cheng, Rong; Graff-Radford, Neill; Foroud, Tatiana; Mayeux, Richard

    2008-11-01

    To identify putative genetic loci related to the risk of late-onset Alzheimer disease (LOAD). Linkage analysis and family-based and case-control association analyses from a genomewide scan using approximately 6000 single-nucleotide polymorphic markers at an average intermarker distance of 0.65 cM. The National Institute on Aging Genetics Initiative for Late-Onset Alzheimer's Disease (NIA-LOAD) was created to expand the resources for studies to identify additional genes contributing to the risk for LOAD. We investigated 1902 individuals from 328 families with LOAD and 236 unrelated control subjects. Clinical diagnosis of LOAD. The strongest overall finding was at chromosome 19q13.32, confirming the effect of the apolipoprotein E gene on LOAD risk in the family-based and case-control analyses. However, single-nucleotide polymorphisms at the following loci were also statistically significant in 1 or more of the analyses performed: 7p22.2, 7p21.3, and 16q21 in the linkage analyses; 17q21.31 and 22q11.21 in the family-based association analysis; and 7q31.1 and 22q12.3 in the case-control analysis. Positive associations at 7q31.1 and 20q13.33 were also significant in the meta-analysis results in a publicly available database. Several additional loci may harbor genetic variants associated with LOAD. This data set provides a wealth of phenotypic and genotypic information for use as a resource in discovery and confirmatory research.

  2. De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease.

    PubMed

    Rovelet-Lecrux, A; Charbonnier, C; Wallon, D; Nicolas, G; Seaman, M N J; Pottier, C; Breusegem, S Y; Mathur, P P; Jenardhanan, P; Le Guennec, K; Mukadam, A S; Quenez, O; Coutant, S; Rousseau, S; Richard, A-C; Boland, A; Deleuze, J-F; Frebourg, T; Hannequin, D; Campion, D

    2015-09-01

    We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aβ) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aβ secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aβ-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aβ network alteration in AD.

  3. Relationship between Cognitive and Sleep-wake Variables in Asymptomatic Offspring of Patients with Late-onset Alzheimer's Disease.

    PubMed

    Abulafia, Carolina; Duarte-Abritta, Bárbara; Villarreal, Mirta F; Ladrón-de-Guevara, María S; García, Celeste; Sequeyra, Geraldine; Sevlever, Gustavo; Fiorentini, Leticia; Bär, Karl-Jürgen; Gustafson, Deborah R; Vigo, Daniel E; Guinjoan, Salvador M

    2017-01-01

    Early neuropathological changes characteristic of late-onset Alzheimer's disease (LOAD) involve brain stem and limbic structures that regulate neurovegetative functions, including sleep-wake rhythm. Indeed, sleep pattern is an emerging biomarker and a potential pathophysiological mechanism in LOAD. We hypothesized that cognitively asymptomatic, middle-aged offspring of patients with LOAD (O-LOAD) would display a series of circadian rhythm abnormalities prior to the onset of objective cognitive alterations. We tested 31 children of patients with LOAD (O-LOAD) and 19 healthy individuals without family history of Alzheimer's disease (control subjects, CS) with basic tests of cognitive function, as well as actigraphy measures of sleep-wake rhythm, cardiac autonomic function, and bodily temperature. Unexpectedly, O-LOAD displayed subtle but significant deficits in verbal episodic memory (Rey Auditory Verbal Learning Test delayed recall 10.6 ± 0.4 vs. 8.6 ± 0.6, t = 4.97, df = 49, p < 0.01) and language (Weschler's vocabulary 51.4 ± 1.3 vs. 44.3 ± 1.5, t = 2.49, df = 49, p < 0.001) compared to CS, even though all participants had results within the clinically normal range. O-LOAD showed a phase-delayed rhythm of body temperature (2.56 ± 0.47 h vs. 3.8 ± 0.26 h, t = 2.48, df = 40, p = 0.031). Cognitive performance in O-LOAD was associated with a series of cardiac autonomic sleep-wake variables; specifically indicators of greater sympathetic activity at night were related to poorer cognition. The present results suggest sleep pattern deserves further study as a potential neurobiological signature in LOAD, even in middle-aged, at risk individuals.

  4. Late-onset bipolar illness: the geriatric bipolar type VI.

    PubMed

    Azorin, Jean-Michel; Kaladjian, Arthur; Adida, Marc; Fakra, Eric

    2012-03-01

    In parallel to considerable progress in understanding and treatment of bipolarity and despite growing interest in old age psychiatry, late-onset bipolar illness (LOBI) has remained relatively understudied so far, probably in reason of its complexity. To update available data, a systematic review was conducted, focusing on the main issues addressed in literature in regard to this topic. In addition to data on epidemiology, clinical features and treatment, five main issues could be identified: LOBI as secondary disorder, LOBI as expression of a lower vulnerability to the disease, LOBI as subform of pseudodementia, LOBI as risk factor for developing dementia, and LOBI as bipolar type VI (bipolarity in the context of dementia like processes). Levels of available evidence were found to vary according to the addressed issue. Although the concept of bipolar type VI could be criticized for subsuming under one single heading all the four other issues, this concept may be of pragmatic value in helping clinicians to orientate both diagnosis process and treatment decisions. Among others, the question as to whether some forms of bipolar type VI could constitute a special risk factor for developing dementia deserves further investigation. More studies are also needed to better disentangle the effects of age at onset from those of age itself.

  5. Type 3 Diabetes Mellitus: A Novel Implication of Alzheimers Disease.

    PubMed

    Leszek, Jerzy; Trypka, Elzbieta; Tarasov, Vadim V; Ashraf, Ghulam Md; Aliev, Gjumrakch

    2017-01-01

    The brain of patients with Alzheimer disease (AD) showed the evidence of reduced expression of insulin and neuronal insulin receptors, as compared with those of age-matched controls. This event gradually and certainly leads to a breakdown of the entire insulin-signaling pathway, which manifests insulin resistance. This in turn affects brain metabolism and cognitive functions, which are the bestdocumented abnormalities in AD. These observations led Dr. de la Monte and her colleagues to suggest that AD is actually a neuroendocrine disorder that resembles type 2 diabetes mellitus. The truth would be more complex with understanding the role of low-density lipoprotein receptor-related protein 1, Aβ derived diffusible ligands, and advanced glycation end products. However, now it known as "brain diabetes" and is called type 3 diabetes mellitus (T3DM). This review provides an overview of "brain diabetes" focusing on the reason why the phenomenon is called T3DM. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Elevated galanin may predict the risk of type 2 diabetes mellitus for development of Alzheimer's disease.

    PubMed

    Zhang, Zhenwen; Fang, Penghua; Shi, Mingyi; Zhu, Yan; Bo, Ping

    2015-09-01

    Alzheimer's disease is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. Epidemiological and clinical studies demonstrated that type 2 diabetes mellitus is an important risk factor for the development of Alzheimer's disease, i.e., the patients with type 2 diabetes mellitus are frequently companied with Alzheimer's disease symptoms. Despite many studies recently probed into the comorbid state of both diseases, so far the precise mechanism for this association is poorly understood. Emerging evidences suggest that defects in galanin play a central role on type 2 diabetes mellitus and is considered to be a risk factor for Alzheimer's disease development. This review provides a new insight into the multivariate relationship among galanin, type 2 diabetes mellitus and Alzheimer's disease, highlighting the effect of galanin system on the cross-talk between both diseases in human and rodent models. The current data support that activating central GalR2 attenuates insulin resistance and Alzheimer's disease feature in animal models. These may help us better understanding the pathogenesis of both diseases and provide useful hints for the development of novel therapeutic approaches to treat type 2 diabetes mellitus and Alzheimer's disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Potential role of antimicrobial peptides in the early onset of Alzheimer's disease.

    PubMed

    Welling, Mick M; Nabuurs, Rob J A; van der Weerd, Louise

    2015-01-01

    Cerebral aggregation of amyloid-β (Aβ) is thought to play a major role in the etiology of Alzheimer's disease. Environmental influences, including chronic bacterial or viral infections, are thought to alter the permeability of the blood-brain barrier (BBB) and thereby facilitate cerebral colonization by opportunistic pathogens. This may eventually trigger Aβ overproduction and aggregation. Host biomolecules that target and combat these pathogens, for instance, antimicrobial peptides (AMPs) such as Aβ itself, are an interesting option for the detection and diagnostic follow-up of such cerebral infections. As part of the innate immune system, AMPs are defensive peptides that efficiently penetrate infected cells and tissues beyond many endothelial barriers, most linings, including the BBB, and overall specifically target pathogens. Based on existing literature, we postulate a role for labeled AMPs as a marker to target pathogens that play a role in the aggregation of amyloid in the brain. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  8. TDP-43 stage, mixed pathologies, and clinical Alzheimer's-type dementia.

    PubMed

    James, Bryan D; Wilson, Robert S; Boyle, Patricia A; Trojanowski, John Q; Bennett, David A; Schneider, Julie A

    2016-09-30

    Hyperphosphorylated transactive response DNA-binding protein 43 (TDP-43, encoded by TARDBP) proteinopathy has recently been described in ageing and in association with cognitive impairment, especially in the context of Alzheimer's disease pathology. To explore the role of mixed Alzheimer's disease and TDP-43 pathologies in clinical Alzheimer's-type dementia, we performed a comprehensive investigation of TDP-43, mixed pathologies, and clinical Alzheimer's-type dementia in a large cohort of community-dwelling older subjects. We tested the hypotheses that TDP-43 with Alzheimer's disease pathology is a common mixed pathology; is related to increased likelihood of expressing clinical Alzheimer's-type dementia; and that TDP-43 pathologic stage is an important determinant of clinical Alzheimer's-type dementia. Data came from 946 older adults with (n = 398) and without dementia (n = 548) from the Rush Memory and Aging Project and Religious Orders Study. TDP-43 proteinopathy (cytoplasmic inclusions) was present in 496 (52%) subjects, and the pattern of deposition was classified as stage 0 (none; 48%), stage 1 (amygdala; 18%), stage 2 (extension to hippocampus/entorhinal; 21%), or stage 3 (extension to neocortex; 14%). TDP-43 pathology combined with a pathologic diagnosis of Alzheimer's disease was a common mixed pathology (37% of all participants), and the proportion of subjects with clinical Alzheimer's-type dementia formerly labelled 'pure pathologic diagnosis of Alzheimer's disease' was halved when TDP-43 was considered. In logistic regression models adjusted for age, sex, and education, TDP-43 pathology was associated with clinical Alzheimer's-type dementia (odds ratio = 1.51, 95% confidence interval = 1.11, 2.05) independent of pathological Alzheimer's disease (odds ratio = 4.30, 95% confidence interval = 3.08, 6.01) or other pathologies (infarcts, arteriolosclerosis, Lewy bodies, and hippocampal sclerosis). Mixed Alzheimer's disease and TDP-43 pathologies were

  9. Alzheimer type II astrocytes in the brains of pigs with salt poisoning (water deprivation/intoxication).

    PubMed

    Finnie, J W; Blumbergs, P C; Williamson, M M

    2010-10-01

    The finding of Alzheimer type II astrocytes, in addition to the pathognomonic combination of laminar cerebrocortical necrosis and eosinophil infiltration, in the brains of pigs is reported for the first time in cases of indirect salt poisoning following water deprivation.

  10. Linking insulin with Alzheimer's disease: emergence as type III diabetes.

    PubMed

    Ahmed, Sara; Mahmood, Zahra; Zahid, Saadia

    2015-10-01

    Alzheimer's disease (AD) has characteristic neuropathological abnormalities including regionalized neurodegeneration, neurofibrillary tangles, amyloid beta (Aβ) deposition, activation of pro-apoptotic genes, and oxidative stress. As the brain functions continue to disintegrate, there is a decline in person's cognitive abilities, memory, mood, spontaneity, and socializing behavior. A framework that sequentially interlinks all these phenomenons under one event is lacking. Accumulating evidence has indicated the role of insulin deficiency and insulin resistance as mediators of AD neurodegeneration. Herein, we reviewed the evidence stemming from the development of diabetes agent-induced AD animal model. Striking evidence has attributed loss of insulin receptor-bearing neurons to precede or accompany initial stage of AD. This state seems to progress with AD such that, in the terminal stages, it worsens and becomes global. Oxidative stress, tau hyperphosphorylation, APP-Aβ deposition, and impaired glucose and energy metabolism have all been linked to perturbation in insulin/IGF signaling. We conclude that AD could be referred to as "type 3 diabetes". Moreover, owing to common pathophysiology with diabetes common therapeutic regime could be effective for AD patients.

  11. Can Alzheimer disease be a form of type 3 diabetes?

    PubMed

    Accardi, Giulia; Caruso, Calogero; Colonna-Romano, Giuseppina; Camarda, Cecilia; Monastero, Roberto; Candore, Giuseppina

    2012-04-01

    Alzheimer disease (AD) and metabolic syndrome are two highly prevalent pathological conditions of Western society due to incorrect diet, lifestyle, and vascular risk factors. Recent data have suggested metabolic syndrome as an independent risk factor for AD and pre-AD syndrome. Furthermore, biological plausibility for this relationship has been framed within the "metabolic cognitive syndrome" concept. Due to the increasing aging of populations, prevalence of AD in Western industrialized countries will rise in the near future. Thus, new knowledge in the area of molecular biology and epigenetics will probably help to make an early molecular diagnosis of dementia. An association between metabolic syndrome and specific single-nucleotide polymorphisms (SNPs) in the gene INPPL1, encoding for SHIP2, a SH2 domain-containing inositol 5-phosphatase involved in insulin signaling, has been described. According to recent data suggesting that Type 2 diabetes represents an independent risk factor for AD and pre-AD, preliminary results of a case-control study performed to test the putative association between three SNPs in the SHIP2 gene and AD show a trend toward association of these SNPs with AD.

  12. Segregation analysis of Alzheimer pedigrees: Rare Mendelian dominant mutation(s) explain a minority of early-onset cases

    SciTech Connect

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

    1996-02-16

    Segregation analysis of Alzheimer disease (AD) in 92 families ascertained through early-onset ({le}age 60 years) AD (EOAD) probands has been carried out, allowing for a mixture in AD inheritance among probands. The goal was to quantify the proportion of probands that could be explained by autosomal inheritance of a rare disease allele {open_quotes}a{close_quotes} at a Mendelian dominant gene (MDG). Our data provide strong evidence for a mixture of two distributions; AD transmission is fully explained by MDG inheritance in <20% of probands. Male and female age-of-onset distributions are significantly different for {open_quotes}AA{close_quote} but not for {open_quotes}aA{close_quote} subjects. For {open_quotes}aA{close_quote} subjects the estimated penetrance value was close to 1 by age 60. For {open_quotes}AA{close_quotes} subjects, it reaches, by age 90, 10% (males) and 30% (females). We show a clear cutoff in the posterior probability of being an MDG case. 10 refs., 1 tab.

  13. The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.

    PubMed

    Gerrish, Amy; Russo, Giancarlo; Richards, Alexander; Moskvina, Valentina; Ivanov, Dobril; Harold, Denise; Sims, Rebecca; Abraham, Richard; Hollingworth, Paul; Chapman, Jade; Hamshere, Marian; Pahwa, Jaspreet Singh; Dowzell, Kimberley; Williams, Amy; Jones, Nicola; Thomas, Charlene; Stretton, Alexandra; Morgan, Angharad R; Lovestone, Simon; Powell, John; Proitsi, Petroula; Lupton, Michelle K; Brayne, Carol; Rubinsztein, David C; Gill, Michael; Lawlor, Brian; Lynch, Aoibhinn; Morgan, Kevin; Brown, Kristelle S; Passmore, Peter A; Craig, David; McGuinness, Bernadette; Todd, Stephen; Johnston, Janet A; Holmes, Clive; Mann, David; Smith, A David; Love, Seth; Kehoe, Patrick G; Hardy, John; Mead, Simon; Fox, Nick; Rossor, Martin; Collinge, John; Maier, Wolfgang; Jessen, Frank; Kölsch, Heike; Heun, Reinhard; Schürmann, Britta; van den Bussche, Hendrik; Heuser, Isabella; Kornhuber, Johannes; Wiltfang, Jens; Dichgans, Martin; Frölich, Lutz; Hampel, Harald; Hüll, Michael; Rujescu, Dan; Goate, Alison M; Kauwe, John S K; Cruchaga, Carlos; Nowotny, Petra; Morris, John C; Mayo, Kevin; Livingston, Gill; Bass, Nicholas J; Gurling, Hugh; McQuillin, Andrew; Gwilliam, Rhian; Deloukas, Panagiotis; Davies, Gail; Harris, Sarah E; Starr, John M; Deary, Ian J; Al-Chalabi, Ammar; Shaw, Christopher E; Tsolaki, Magda; Singleton, Andrew B; Guerreiro, Rita; Mühleisen, Thomas W; Nöthen, Markus M; Moebus, Susanne; Jöckel, Karl-Heinz; Klopp, Norman; Wichmann, H-Erich; Carrasquillo, Minerva M; Pankratz, V Shane; Younkin, Steven G; Jones, Lesley; Holmans, Peter A; O'Donovan, Michael C; Owen, Michael J; Williams, Julie

    2012-01-01

    Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.

  14. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease.

    PubMed

    Keren-Shaul, Hadas; Spinrad, Amit; Weiner, Assaf; Matcovitch-Natan, Orit; Dvir-Szternfeld, Raz; Ulland, Tyler K; David, Eyal; Baruch, Kuti; Lara-Astaiso, David; Toth, Beata; Itzkovitz, Shalev; Colonna, Marco; Schwartz, Michal; Amit, Ido

    2017-06-15

    Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)(-/-) Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. VIDEO ABSTRACT. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Regulatable transgenic mouse models of Alzheimer disease: onset, reversibility and spreading of Tau pathology.

    PubMed

    Hochgräfe, Katja; Sydow, Astrid; Mandelkow, Eva-Maria

    2013-09-01

    Accumulation of amyloidogenic proteins such as Tau is a hallmark of neurodegenerative diseases including Alzheimer disease and fronto-temporal dementias. To link Tau pathology to cognitive impairments and defects in synaptic plasticity, we created four inducible Tau transgenic mouse models with expression of pro- and anti-aggregant variants of either full-length human Tau (hTau40/ΔK280 and hTau40/ΔK280/PP) or the truncated Tau repeat domain (Tau(RD)/ΔK280 and Tau(RD)/ΔK280/PP). Here we review the histopathological features caused by pro-aggregant Tau, and correlate them with behavioral deficits and impairments in synaptic transmission. Both pro-aggregant Tau variants cause Alzheimer-like features, including synapse loss, mis-localization of Tau into the somatodendritic compartment, conformational changes and hyperphosphorylation. However, there is a clear difference in the extent of Tau aggregation and neurotoxicity. While pro-aggregant full-length hTau40/ΔK280 leads to a 'pre-tangle' pathology, the repeat domain Tau(RD)/ΔK280 causes massive formation of neurofibrillary tangles and neuronal loss in the hippocampus. However, both Tau variants cause co-aggregation of human and mouse Tau and similar functional impairments. Thus, earlier Tau pathological stages and not necessarily neurofibrillary tangles are critical for the development of cognitive malfunctions. Most importantly, memory and synapses recover after switching off expression of pro-aggregant Tau. The rescue of functional impairments correlates with the rescue of most Tau pathological changes and most strikingly the recovery of synapses. This implies that tauopathies as such are reversible, provided that amyloidogenic Tau is removed. Therefore, our Tau transgenic mice may serve as model systems for in vivo validation of therapeutic strategies and drug candidates with regard to cognition and synaptic function. © 2013 The Authors Journal compilation © 2013 FEBS.

  16. Experimental induction of type 2 diabetes in aging-accelerated mice triggered Alzheimer-like pathology and memory deficits.

    PubMed

    Mehla, Jogender; Chauhan, Balwantsinh C; Chauhan, Neelima B

    2014-01-01

    Alzheimer's disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-β, dysregulated tau-phosphorylating glycogen synthase kinase 3β, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD.

  17. Serum irisin levels in new-onset type 2 diabetes.

    PubMed

    Choi, Yeon-Kyung; Kim, Mi-Kyung; Bae, Kwi Hyun; Seo, Hyun-Ae; Jeong, Ji-Yun; Lee, Won-Kee; Kim, Jung-Guk; Lee, In-Kyu; Park, Keun-Gyu

    2013-04-01

    Irisin has been identified as a novel myokine that drives brown-fat-like conversion of white adipose tissue. In this cross-sectional study, we investigated whether serum irisin levels are decreased in patients with type 2 diabetes (T2D) compared with control subjects with normal glucose tolerance (NGT), and assessed the association between serum irisin levels and various metabolic parameters. The study population was selected from a population-based study and included 104 subjects with NGT and 104 subjects with new-onset T2D. Serum irisin and adiponectin levels and metabolic parameters were measured. Multivariate logistic regression analysis was performed to assess the association between irisin levels and newly diagnosed T2D. Serum irisin levels were significantly decreased in the new-onset T2D group compared with the NGT control group (p=0.003). In a multivariable model adjusted for various metabolic parameters, increased irisin levels were associated with reduced odds (OR 0.64, 95% CI 0.47-0.88, p=0.006) of prevalent newly diagnosed T2D. Furthermore, multiple regression analysis showed that 2 h plasma glucose was an independent variable influencing serum irisin levels (p=0.004). In the present study, we found that serum irisin levels were decreased in T2D patients and inversely associated with newly diagnosed T2D, suggesting that irisin may play a crucial role in glucose intolerance and T2D. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  18. Characterization of human induced pluripotent stem cell (iPSC) line from a 72year old male patient with later onset Alzheimer's disease.

    PubMed

    Zhang, Shaokun; Lv, Zhenshan; Zhang, Songyuan; Liu, Lidi; Li, Qiao; Gong, Weiquan; Sha, Hui; Wu, Hong

    2017-03-01

    Peripheral blood was collected from a clinically diagnosed 72-year old male patient with later onset Alzheimer's disease. Peripheral blood mononuclear cells (PBMCs) were reprogrammed with the Yamanaka KMOS reprogramming factors using the Sendai-virus reprogramming system. The transgene-free iPSC line showed pluripotency verified by immunofluorescent staining for pluripotency markers, and the iPSC line was able to differentiate into the 3 germ layers in vivo. The iPSC line also showed normal karyotype. This in vitro cellular model will be useful for studying the pathological mechanism of Alzheimer's disease. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  19. [Late-onset Neurodegenerative Diseases Following Traumatic Brain Injury: Chronic Traumatic Encephalopathy (CTE) and Alzheimer's Disease Secondary to TBI (AD-TBI)].

    PubMed

    Takahata, Keisuke; Tabuchi, Hajime; Mimura, Masaru

    2016-07-01

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease, which is associated with mild repetitive traumatic brain injury (TBI). This long-term and progressive symptom due to TBI was initially called punch-drunk syndrome or dementia pugilistica, since it was believed to be associated with boxing. However, serial neuropathological studies of mild repetitive TBI in the last decade have revealed that CTE occurs not only in boxers but also in a wider population including American football players, wrestlers, and military personnel. CTE has gained large public interest owing to dramatic cases involving retired professional athletes wherein serious behavioral problems and tragic incidents were reported. Unlike mild repetitive TBI, a single episode of severe TBI can cause another type of late-onset neuropsychiatric disease including Alzheimer's disease (AD). Several epidemiological studies have shown that a single episode of severe TBI is one of the major risk factors of AD. Pathologically, both AD and CTE are characterized by abnormal accumulations of hyperphosphorylated tau proteins. However, recent neuropathological studies revealed that CTE demonstrates a unique pattern of tau pathology in neurons and astrocytes, and accumulation of other misfolded proteins such as TDP-43. Currently, no reliable biomarkers of late-onset neurodegenerative diseases following TBI are available, and a definitive diagnosis can be made only via postmortem neuropathological examination. Development in neuroimaging techniques such as tau and amyloid positron emission tomography imaging might not only enable early diagnosis of CTE, but also contribute to the interventions for prevention of late-onset neurodegenerative diseases following TBI. Further studies are necessary to elucidate the mechanisms of neurodegeneration in the living brain of patients with TBI.

  20. A preliminary study of the whole-genome expression profile of sporadic and monogenic early-onset Alzheimer's disease.

    PubMed

    Antonell, Anna; Lladó, Albert; Altirriba, Jordi; Botta-Orfila, Teresa; Balasa, Mircea; Fernández, Manel; Ferrer, Isidre; Sánchez-Valle, Raquel; Molinuevo, José Luis

    2013-07-01

    Alzheimer's disease (AD) is the most common neurodegenerative dementia. Approximately 10% of cases present at an age of onset before 65 years old, which in turn can be monogenic familial AD (FAD) or sporadic early-onset AD (sEOAD). Mutations in PSEN1, PSEN2, and APP genes have been linked with FAD. The aim of our study is to describe the brain whole-genome RNA expression profile of the posterior cingulate area in sEOAD and FAD caused by PSEN1 mutations (FAD-PSEN1). Fourteen patients (7 sEOAD and 7 FAD-PSEN1) and 7 neurologically healthy control subjects were selected and whole-genome expression was measured using Affymetrix Human Gene 1.1 microarrays. We identified statistically significant expression changes in sEOAD and FAD-PSEN1 brains with respect to control subjects (3183 and 3350 differentially expressed genes [DEG] respectively, false discovery rate-corrected p < 0.05). Of them, 1916 DEG were common between the 2 comparisons. We did not identify DEG between sEOAD and FAD-PSEN1. Microarray data were validated through real-time quantitative polymerase chain reaction. In silico analysis of DEG revealed an alteration in biological pathways related to intracellular signaling pathways (particularly calcium signaling), neuroactive ligand-receptor interactions, axon guidance, and long-term potentiation in both groups of patients. In conclusion, the altered biological final pathways in sEOAD and FAD-PSEN1 are mainly related with cell signaling cascades, synaptic plasticity, and learning and memory processes. We hypothesize that these 2 groups of early-onset AD with distinct etiologies and likely different could present a neurodegenerative process with potential different pathways that might converge in a common and similar final stage of the disease.

  1. Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease.

    PubMed

    Li, Yi-Ju; Oliveira, Sofia A; Xu, Puting; Martin, Eden R; Stenger, Judith E; Scherzer, Clemens R; Hauser, Michael A; Scott, William K; Small, Gary W; Nance, Martha A; Watts, Ray L; Hubble, Jean P; Koller, William C; Pahwa, Rajesh; Stern, Mathew B; Hiner, Bradley C; Jankovic, Joseph; Goetz, Christopher G; Mastaglia, Frank; Middleton, Lefkos T; Roses, Allen D; Saunders, Ann M; Schmechel, Donald E; Gullans, Steven R; Haines, Jonathan L; Gilbert, John R; Vance, Jeffery M; Pericak-Vance, Margaret A; Hulette, Christine; Welsh-Bohmer, Kathleen A

    2003-12-15

    We previously reported genetic linkage of loci controlling age-at-onset in Alzheimer disease (AD) and Parkinson's disease (PD) to a 15 cM region on chromosome 10q. Given the large number of genes in this initial starting region, we applied the process of 'genomic convergence' to prioritize and reduce the number of candidate genes for further analysis. As our second convergence factor we performed gene expression studies on hippocampus obtained from AD patients and controls. Analysis revealed that four of the genes [stearoyl-CoA desaturase; NADH-ubiquinone oxidoreductase 1 beta subcomplex 8; protease, serine 11; and glutathione S-transferase, omega-1 (GSTO1)] were significantly different in their expression between AD and controls and mapped to the 10q age-at-onset linkage region, the first convergence factor. Using 2814 samples from our AD dataset (1773 AD patients) and 1362 samples from our PD dataset (635 PD patients), allelic association studies for age-at-onset effects in AD and PD revealed no association for three of the candidates, but a significant association was found for GSTO1 (P=0.007) and a second transcribed member of the GST omega class, GSTO2 (P=0.005), located next to GSTO1. The functions of GSTO1 and GSTO2 are not well understood, but recent data suggest that GSTO1 maybe involved in the post-translational modification of the inflammatory cytokine interleukin-1beta. This is provocative given reports of the possible role of inflammation in these two neurodegenerative disorders.

  2. Influence of family history of dementia in the development and progression of late-onset Alzheimer's disease.

    PubMed

    Scarabino, Daniela; Gambina, Giuseppe; Broggio, Elisabetta; Pelliccia, Franca; Corbo, Rosa Maria

    2016-03-01

    Family history of dementia (FH) is a recognized risk factor for developing late-onset Alzheimer's disease (AD). We asked whether having FH increases AD risk and influences disease severity (age at onset and cognitive impairment) in 420 AD patients and 109 controls with (FH+) or without (FH-). The relationships of APOE and other AD risk genes with FH were analyzed as well. The proportion of APOE e4 allele carriers was higher among the FH+ than the FH- AD patients (49.6% vs. 38.9%; P = 0.04). The distribution of the risk genotypes of nine AD susceptibility genes previously examined (CHAT, CYP17, CYP19, ESR1, FSHR, P53, P73, P21, PPARG) did not differ between the FH+ and the FH- AD patients, indicating that none contributed significantly to familial clustering of disease. FH was associated with an increased AD risk (odds ratio [OR] 2.71, 95% confidence interval [CI] 1.44-5.09; P = 0.002) independent of carrying the APOE e4 allele (OR 2.61, 95%CI 1.53-4.44; P = 0.0004). Having a first-degree relative or a parent with dementia was significantly associated with AD risk (OR 2.9, 95%CI 1.3-6.4; P = 0.009 and OR 2.7, 95%CI 1.1-6.2; P = 0.02) but having a sibling with dementia was not (OR 1.7, 95%CI 0.2 to 14.7; P = 0.6). Among the FH+ AD patients, having one or both parents affected seemed to raise the risk of earlier onset age (P = 0.02) and greater cognitive impairment (P = 0.02) than having only an affected sibling, whereas having two or more affected relatives did not. © 2015 Wiley Periodicals, Inc.

  3. Variants in the ATP-Binding Cassette Transporter (ABCA7), Apolipoprotein E ε4, and the Risk of Late-Onset Alzheimer Disease in African Americans

    PubMed Central

    Reitz, Christiane; Jun, Gyungah; Naj, Adam; Rajbhandary, Ruchita; Vardarajan, Badri Narayan; Wang, Li-San; Valladares, Otto; Lin, Chiao-Feng; Larson, Eric B.; Graff-Radford, Neill R.; Evans, Denis; De Jager, Philip L.; Crane, Paul K.; Buxbaum, Joseph D.; Murrell, Jill R.; Raj, Towfique; Ertekin-Taner, Nilufer; Logue, Mark; Baldwin, Clinton T.; Green, Robert C.; Barnes, Lisa L.; Cantwell, Laura B.; Fallin, M. Daniele; Go, Rodney C. P.; Griffith, Patrick; Obisesan, Thomas O.; Manly, Jennifer J.; Lunetta, Kathryn L.; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Hendrie, Hugh; Hall, Kathleen S.; Goate, Alison M.; Byrd, Goldie S.; Kukull, Walter A.; Foroud, Tatiana M.; Haines, Jonathan L.; Farrer, Lindsay A.; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Mayeux, Richard

    2013-01-01

    Importance Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment. Objective To identify genetic loci associated with late-onset Alzheimer disease in African Americans. Design, Setting, and Participants The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance–weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci. Main Outcomes and Measures Presence of Alzheimer disease according to standardized criteria. Results Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10–9), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses

  4. Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans.

    PubMed

    Reitz, Christiane; Jun, Gyungah; Naj, Adam; Rajbhandary, Ruchita; Vardarajan, Badri Narayan; Wang, Li-San; Valladares, Otto; Lin, Chiao-Feng; Larson, Eric B; Graff-Radford, Neill R; Evans, Denis; De Jager, Philip L; Crane, Paul K; Buxbaum, Joseph D; Murrell, Jill R; Raj, Towfique; Ertekin-Taner, Nilufer; Logue, Mark; Baldwin, Clinton T; Green, Robert C; Barnes, Lisa L; Cantwell, Laura B; Fallin, M Daniele; Go, Rodney C P; Griffith, Patrick; Obisesan, Thomas O; Manly, Jennifer J; Lunetta, Kathryn L; Kamboh, M Ilyas; Lopez, Oscar L; Bennett, David A; Hendrie, Hugh; Hall, Kathleen S; Goate, Alison M; Byrd, Goldie S; Kukull, Walter A; Foroud, Tatiana M; Haines, Jonathan L; Farrer, Lindsay A; Pericak-Vance, Margaret A; Schellenberg, Gerard D; Mayeux, Richard

    2013-04-10

    Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment. To identify genetic loci associated with late-onset Alzheimer disease in African Americans. The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance-weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci. Presence of Alzheimer disease according to standardized criteria. Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10(-9)), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8 < D' < 0.9). The effect size for the SNP in ABCA7 was comparable with that of the APOE ϵ4-determining SNP rs429358 (allele = C; frequency, 0.30 cases and 0.18 controls; OR, 2.31 [95% CI, 2.19-2.42]; P = 5.5 × 10(-47)). Several loci previously associated with Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses accounting for linkage disequilibrium between markers and correcting for number of tests

  5. "Boomerang Neuropathology" of Late-Onset Alzheimer's Disease is Shrouded in Harmful "BDDS": Breathing, Diet, Drinking, and Sleep During Aging.

    PubMed

    Daulatzai, Mak Adam

    2015-07-01

    Brain damage begins years before substantial neurodegeneration and Alzheimer's dementia. Crucial fundamental activities of life are breathing, eating, drinking, and sleeping. When these pivotal functions are maligned over a prolonged period, they impart escalating dyshomeostasis. The latter may lead to disastrous consequences including cognitive dysfunction and Alzheimer's disease (AD). The current theme here is that multiple pathophysiological derangements are promoted over a prolonged period by the very fundamental activities of life-when "rendered unhealthy." They may converge on several regulating/modulating factors (e.g., mitochondrial energy production, oxidative stress, innate immunity, and vascular function) and promote insidious neuropathology that culminates in cognitive decline in the aged. This is of course associated with the accumulation of amyloid beta and phosphorylated tau in the brain. Epidemiological, biomarker, and neuroimaging studies have provided significant copious evidence on the presence of indolent prodromal AD neuropathology many years prior to symptomatic onset. Progressive oxidative damage to specific gene promoters may result in gene silencing. A mechanistic link may possibly exist between epigenomic state, DNA damage, and chronically unhealthy/dysfunctional body systems. This paper, therefore, addresses and delineates the deleterious pathophysiological impact triggered by dysfunctional breathing, harmful diet, excess of alcohol consumption, and sleep deprivation; indeed, their impact may alter epigenetic state. It is mandatory, therefore, to abrogate cognitive decline and attenuate AD pathology through adoption of a healthy lifestyle, in conjunction with combination therapy with known moderators of cognitive decline. This strategy may thwart multiple concurrent and synergistic pathologies, including epigenetic dysfunction. A multi-factorial therapeutic intervention is required to overcome wide ranging neuropathology and multi

  6. A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.

    PubMed

    Grupe, Andrew; Li, Yonghong; Rowland, Charles; Nowotny, Petra; Hinrichs, Anthony L; Smemo, Scott; Kauwe, John S K; Maxwell, Taylor J; Cherny, Sara; Doil, Lisa; Tacey, Kristina; van Luchene, Ryan; Myers, Amanda; Wavrant-De Vrièze, Fabienne; Kaleem, Mona; Hollingworth, Paul; Jehu, Luke; Foy, Catherine; Archer, Nicola; Hamilton, Gillian; Holmans, Peter; Morris, Chris M; Catanese, Joseph; Sninsky, John; White, Thomas J; Powell, John; Hardy, John; O'Donovan, Michael; Lovestone, Simon; Jones, Lesley; Morris, John C; Thal, Leon; Owen, Michael; Williams, Julie; Goate, Alison

    2006-01-01

    Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder.

  7. The onset of galactic winds in early-type galaxies

    NASA Technical Reports Server (NTRS)

    Forman, W.; Jones, C.; Tucker, W.; David, L. P.

    1990-01-01

    Researchers report on a program using Einstein x ray observations of the x ray spectra and surface brightness profiles (or extents) of a large sample of early-type (elliptical and SO) galaxies for which the goal is to determine the critical optical luminosity for which galactic winds are important. For galaxies in which the x ray emission is dominated by hydrostatic coronae, the x ray spectra will be relatively soft (characterized by a temperature of approx. 10 to the 7th power K), while for galaxies with a galactic wind, the emission will be dominated by the spectrally harder discrete sources (since the x ray emission from the wind is essentially negligible). In this new sample of 180 galaxies, there are 28 early type galaxies with sufficient counts to obtain a spectrum with the Einstein Image Proportional Counter (IPC). This sample more than doubles the total number of early-type galaxies in earlier compilations (Forman, Jones, and Tucker 1985; Canizares et al. 1987). The new spectral observations will help determine the critical optical luminosity for the onset of galactic winds which is important for understanding the chemical evolution of galaxies and of the intergalactic medium. The implications of galactic winds for the heavy element enrichment and energy content of the intracluster medium are discussed.

  8. In vivo type 1 cannabinoid receptor availability in Alzheimer's disease.

    PubMed

    Ahmad, Rawaha; Goffin, Karolien; Van den Stock, Jan; De Winter, François-Laurent; Cleeren, Evy; Bormans, Guy; Tournoy, Jos; Persoons, Philippe; Van Laere, Koen; Vandenbulcke, Mathieu

    2014-02-01

    The endocannabinoid system (ECS) is an important modulatory and potentially neuroprotective homeostatic system in the brain. In Alzheimer's disease (AD), the role of type 1 cannabinoid receptor (CB₁R) is unclear, with contradictory findings in post-mortem studies showing upregulation, downregulation or unchanged CB₁R status. We have investigated CB₁R availability in vivo in patients with AD, in relation to amyloid deposition, cognitive functioning and apolipoprotein E (ApoE) genotype. Eleven AD patients and 7 healthy volunteers (HV) underwent combined [¹⁸F]MK-9470 PET and [¹¹C]PIB PET scans to assess CB₁R availability and amyloid deposition, respectively, and T1 volumetric MRI for partial volume correction. We found no difference in CB₁R availability between AD and HV, VOI-based fractional uptake values (FUR) were 0.043±0.01 for AD and 0.045±0.01 for controls (p=0.9). CB₁R availability did not correlate with neuropsychological test scores and was not modulated by ApoE genotype. As expected, global [¹¹C]PIB SUVR (standardized uptake value ratio) was increased in AD (SUVR 1.9±0.3) compared to HV (1.2±0.1) with p<0.001, but no correlation was found between amyloid β (Aβ) deposition and CB₁R availability. In conclusion, we found no in vivo evidence for a difference in CB₁R availability in AD compared to age-matched controls. Taken together with recently reported in vivo CB₁R changes in Parkinson's and Huntington's disease, these data suggest that the CB₁R is differentially involved in neurodegenerative disorders. © 2013 Published by Elsevier B.V. and ECNP.

  9. Assessment of the genetic variance of late-onset Alzheimer's disease.

    PubMed

    Ridge, Perry G; Hoyt, Kaitlyn B; Boehme, Kevin; Mukherjee, Shubhabrata; Crane, Paul K; Haines, Jonathan L; Mayeux, Richard; Farrer, Lindsay A; Pericak-Vance, Margaret A; Schellenberg, Gerard D; Kauwe, John S K

    2016-05-01

    Alzheimer's disease (AD) is a complex genetic disorder with no effective treatments. More than 20 common markers have been identified, which are associated with AD. Recently, several rare variants have been identified in Amyloid Precursor Protein (APP), Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (UNC5C) that affect risk for AD. Despite the many successes, the genetic architecture of AD remains unsolved. We used Genome-wide Complex Trait Analysis to (1) estimate phenotypic variance explained by genetics; (2) calculate genetic variance explained by known AD single nucleotide polymorphisms (SNPs); and (3) identify the genomic locations of variation that explain the remaining unexplained genetic variance. In total, 53.24% of phenotypic variance is explained by genetics, but known AD SNPs only explain 30.62% of the genetic variance. Of the unexplained genetic variance, approximately 41% is explained by unknown SNPs in regions adjacent to known AD SNPs, and the remaining unexplained genetic variance outside these regions. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease

    PubMed Central

    Jacobsen, J. Steven; Wu, Chi-Cheng; Redwine, Jeffrey M.; Comery, Thomas A.; Arias, Robert; Bowlby, Mark; Martone, Robert; Morrison, John H.; Pangalos, Menelas N.; Reinhart, Peter H.; Bloom, Floyd E.

    2006-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. In both AD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of β-amyloid (Aβ)-containing plaques and neurodegeneration. Characterization of the timing and nature of preplaque dysfunction is important for understanding the progression of this disease and to identify pathways and molecular targets for therapeutic intervention. Hence, we have examined the progression of dysfunction at the morphological, functional, and behavioral levels in the Tg2576 mouse model of AD. Our data show that decreased dendritic spine density, impaired long-term potentiation (LTP), and behavioral deficits occurred months before plaque deposition, which was first detectable at 18 months of age. We detected a decrease in spine density in the outer molecular layer of the dentate gyrus (DG) beginning as early as 4 months of age. Furthermore, by 5 months, there was a decline in LTP in the DG after perforant path stimulation and impairment in contextual fear conditioning. Moreover, an increase in the Aβ42/Aβ40 ratio was first observed at these early ages. However, total amyloid levels did not significantly increase until ≈18 months of age, at which time significant increases in reactive astrocytes and microglia could be observed. Overall, these data show that the perforant path input from the entorhinal cortex to the DG is compromised both structurally and functionally, and this pathology is manifested in memory defects long before significant plaque deposition. PMID:16549764

  11. Association between Mitofusin 2 Gene Polymorphisms and Late-Onset Alzheimer's Disease in the Korean Population

    PubMed Central

    Kim, Young Jong; Park, Jin Kyung; Kang, Won Sub; Kim, Su Kang; Han, Changsu; Na, Hae Ri; Park, Hae Jeong; Kim, Jong Woo; Kim, Young Youl; Park, Moon Ho

    2017-01-01

    Objective Mitochondrial dysfunction is a prominent and early feature of Alzheimer's disease (AD). The morphologic changes observed in the AD brain could be caused by a failure of mitochondrial fusion mechanisms. The aim of this study was to investigate whether genetic polymorphisms of two genes involved in mitochondrial fusion mechanisms, optic atrophy 1 (OPA1) and mitofusin 2 (MFN2), were associated with AD in the Korean population by analyzing genotypes and allele frequencies. Methods One coding single nucleotide polymorphism (SNP) in the MFN2, rs1042837, and two coding SNPs in the OPA1, rs7624750 and rs9851685, were compared between 165 patients with AD (83 men and 82 women, mean age 72.3±4.41) and 186 healthy control subjects (82 men and 104 women, mean age 76.5±5.98). Results Among these three SNPs, rs1042837 showed statistically significant differences in allele frequency, and genotype frequency in the co-dominant 1 model and in the dominant model. Conclusion These results suggest that the rs1042837 polymorphism in MFN2 may be involved in the pathogenesis of AD. PMID:28096879

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

    PubMed

    Behl, Christian

    2012-08-01

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

  13. Therapeutic effect of mesenchymal multipotent stromal cells on memory in animals with Alzheimer-type neurodegeneration.

    PubMed

    Bobkova, N V; Poltavtseva, R A; Samokhin, A N; Sukhikh, G T

    2013-11-01

    Transplantation of human mesenchymal multipotent stromal cells improved spatial memory in bulbectomized mice with Alzheimer-type neurodegeneration. The positive effect was observed in 1 month after intracerebral transplantation and in 3 months after systemic injection of mesenchymal multipotent stromal cells. No cases of malignant transformation were noted. These findings indicate prospects of using mesenchymal multipotent stromal cells for the therapy of Alzheimer disease and the possibility of their systemic administration for attaining the therapeutic effect.

  14. Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease

    PubMed Central

    Grove, Megan L.; Naj, Adam; Vronskaya, Maria; DeStefano, Anita L.; Brody, Jennifer A.; Smith, Albert V.; Amin, Najaf; Sims, Rebecca; Ibrahim-Verbaas, Carla A.; Choi, Seung-Hoan; Lopez, Oscar L.; Beiser, Alexa; Ikram, M. Arfan; Garcia, Melissa E.; Hayward, Caroline; Ripatti, Samuli; Franks, Paul W.; Hallmans, Göran; Rolandsson, Olov; Jansson, Jan-Håkon; Porteous, David J.; Salomaa, Veikko; Eiriksdottir, Gudny; Rice, Kenneth M.; Bellen, Hugo J.; Levy, Daniel; Uitterlinden, Andre G.; Emilsson, Valur; Rotter, Jerome I.; Aspelund, Thor; O’Donnell, Christopher J.; Fitzpatrick, Annette L.; Launer, Lenore J.; Hofman, Albert; Wang, Li-San; Williams, Julie; Schellenberg, Gerard D.; Boerwinkle, Eric; Psaty, Bruce M.; Seshadri, Sudha; Shulman, Joshua M.; Gudnason, Vilmundur; van Duijn, Cornelia M.

    2016-01-01

    We performed an exome-wide association analysis in 1393 late-onset Alzheimer’s disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5–15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade. PMID:27764101

  15. A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease.

    PubMed

    Bertoli Avella, A M; Marcheco Teruel, B; Llibre Rodriguez, J J; Gomez Viera, N; Borrajero Martinez, I; Severijnen, E A; Joosse, M; van Duijn, C M; Heredero Baute, L; Heutink, P

    2002-10-01

    We studied a Cuban family with presenile dementia (autosomal dominant) consisting of 281 members within six generations, the proband descended from a Spanish founder. Mean age at onset was 59 years of age. Memory impairment was the main symptom in all patients, additionally, ischemic episodes were described in 4 (n = 18) patients. Neuropathological examination of brain material (1 patient) revealed neuronal loss, amyloid plaques, and neurofibrillary tangles. Thirty DNA samples were genotyped (regions on chromosome 1, 3, 10, 12, 14, 17, 19, 20, and 21). A maximum Lod score of 3.79 at theta = 0 was obtained for marker D14S43, located in a 9-cM interval in which all patients shared the same haplotype. Sequencing of the PSEN1 gene revealed a heterozygous base substitution, C520A (exon 6), which is predicted to cause an amino acid change from leucine to methionine in the TMIII of the presenilin 1 protein. The mutation was found to co-segregate with the disease phenotype and the associated disease haplotype. The C --> A change was not observed in 80 control chromosomes from the Cuban population. Leucine at position 174 is highly conserved among species and is identical in presenilin 1 and presenilin 2 proteins. We propose the L174 M mutation might lead to an abnormal N-terminal and probably C-terminal fragments and malfunction of the protein complex. In conclusion, we found a novel PSEN1 mutation in a large family with clinical and pathological diagnosis of early onset familial Alzheimer disease, which may be relevant for other Hispanic populations.

  16. A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease

    PubMed Central

    Vélez, Jorge I.; Rivera, Dora; Mastronardi, Claudio A.; Patel, Hardip R.; Tobón, Carlos; Villegas, Andrés; Cai, Yeping; Easteal, Simon; Arcos-Burgos, Mauricio

    2016-01-01

    We previously reported age of onset (AOO) modifier genes in the world's largest pedigree segregating early-onset Alzheimer's disease (AD), caused by the p.Glu280Ala (E280A) mutation in the PSEN1 gene. Here we report the results of a targeted analysis of functional exonic variants in those AOO modifier genes in sixty individuals with PSEN1 E280A AD who were whole-exome genotyped for ~250,000 variants. Standard quality control, filtering, and annotation for functional variants were applied, and common functional variants located in those previously reported as AOO modifier loci were selected. Multiloci linear mixed-effects models were used to test the association between these variants and AOO. An exonic missense mutation in the G72 (DAOA) gene (rs2391191, P = 1.94 × 10−4, P FDR = 9.34 × 10−3) was found to modify AOO in PSEN1 E280A AD. Nominal associations of missense mutations in the CLUAP1 (rs9790, P = 7.63 × 10−3, P FDR = 0.1832) and EXOC2 (rs17136239, P = 0.0325, P FDR = 0.391) genes were also found. Previous studies have linked polymorphisms in the DAOA gene with the occurrence of neuropsychiatric symptoms such as depression, apathy, aggression, delusions, hallucinations, and psychosis in AD. Our findings strongly suggest that this new conspicuous functional AOO modifier within the G72 (DAOA) gene could be pivotal for understanding the genetic basis of AD. PMID:26949549

  17. R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family

    PubMed Central

    Korvatska, Olena; Leverenz, James B.; Jayadev, Suman; McMillan, Pamela; Kurtz, Irina; Guo, Xindi; Rumbaugh, Malia; Matsushita, Mark; Girirajan, Santhosh; Dorschner, Michael O.; Kiianitsa, Kostantin; Yu, Chang-En; Brkanac, Zoran; Garden, Gwenn A.; Raskind, Wendy H.; Bird, Thomas D.

    2016-01-01

    Importance The R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders. Objective To investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases. Design, Setting, and Participants This study includes genetic and pathologic studies of families with LOAD from 1985 to 2014. A total of 131 families with LOAD (751 individuals) were included from the University of Washington Alzheimer Disease Research Center. To identify LOAD genes/risk factors in the LOAD123 family with 21 affected members and 12 autopsies, we sequenced 4 exomes. Candidate variants were tested for cosegregation with the disease. TREM2 R47H was genotyped in an additional 130 families with LOAD. We performed clinical and neuropathological assessments of patients with and without R47H and evaluated the variant's effect on brain pathology, cellular morphology, and expression of microglial markers. Main Outcomes and Measures We assessed the effect of TREM2 genotype on age at onset and disease duration. We compared Braak and Consortium to Establish a Registry for Alzheimer's Disease scores, presence of α-synuclein and TAR DNA-binding protein 43 aggregates, and additional vascular or Parkinson pathology in TREM2 R47H carriers vs noncarriers. Microglial activation was assessed by quantitative immunohistochemistry and morphometry. Results Twelve of 16 patients with AD in the LOAD123 family carried R47H. Eleven patients with dementia had apolipoprotein E 4 (ApoE4) and R47H genotypes. We also found a rare missense variant, D353N, in a nominated AD risk gene, unc-5 homolog C (UNC5C), in 5 affected individuals in the LOAD123 family. R47H carriers demonstrated a shortened disease duration (mean [SD], 6.7 [2.8] vs 11.1 [6.6] years; 2-tailed t test; P = .04) and more frequent α-synucleinopathy. The

  18. Increased frequency of T cells expressing IL-10 in Alzheimer disease but not in late-onset depression patients.

    PubMed

    Torres, Karen Cecília; Araújo Pereira, Patrícia; Lima, Giselle Sabrina; Bozzi, Isadora Cristina; Rezende, Vitor Bortolo; Bicalho, Maria Aparecida; Moraes, Edgar Nunes; Miranda, Débora Marques; Romano-Silva, Marco Aurélio

    2013-12-02

    Higher risk of dementia is expected for patients with late onset depression (LOD) history. The IL-10 polymorphisms are associated with Alzheimer disease (AD). On the other hand, there is no study associating IL-10 polymorphisms to LOD. This study aimed to investigate the -1082G/A polymorphism association in LOD, AD patients and controls and also the peripheral expression of IL-10 in CD4+ T cells. It was done in a case-control study comparing immune system phenotype and genetic polymorphism association among control individuals, LOD and AD patients. Participants were 569 subjects composed the genetics sample (249 AD, 222 LOD and 98 controls) from a tertiary medical center based on Belo Horizonte, Brazil. Flow cytometry analysis was performed in 55 people (22 AD patients, 11 LOD patients and 22 controls). A real time PCR for IL-10 SNP (rs 1800896) through genotyping analysis and flow cytometry evaluation of CD4+ T cells expressing IL-10 was done. An increased CD4+ T cells expressing IL-10 were detected only in the AD group. There was no difference detected in allele or genotype analysis for IL-10 polymorphism among LOD, AD patients or controls. IL-10 might have a role in the modulation of immune response in AD patients, however it is not presented in LOD population.

  19. Sequence variation in the proximity of IDE may impact age at onset of both Parkinson disease and Alzheimer disease.

    PubMed

    Blomqvist, Mia E-L; Silburn, Peter A; Buchanan, Daniel D; Andreasen, Niels; Blennow, Kaj; Pedersen, Nancy L; Brookes, Anthony J; Mellick, George D; Prince, Jonathan A

    2004-06-01

    We recently reported that a linkage disequilibrium (LD) block on chromosome 10q encompassing the gene encoding insulin-degrading enzyme ( IDE) harbors sequence variants that associate with Alzheimer disease (AD). Evidence also indicated effects upon a number of quantitative indices of AD severity, including age-at-onset (AAO). Since linkage of this immediate region to AAO has been shown in both AD and Parkinson disease (PD), we have explored the possibility that polymorphism within this LD block might also influence PD. Utilizing single nucleotide polymorphisms that delineate common haplotypes from this region, we observed significant evidence of association with AAO in an Australian PD case-control sample. Analyses were complemented with AAO data from two independent Swedish AD case samples, for which previously reported findings were replicated. Results were consistent between AD and PD, suggesting the presence of equivalent detrimental and protective alleles. These data highlight a genomic region in the proximity of IDE that may contribute to AD and PD in a similar manner.

  20. The PREVENT study: a prospective cohort study to identify mid-life biomarkers of late-onset Alzheimer's disease

    PubMed Central

    Ritchie, Craig W; Ritchie, Karen

    2012-01-01

    Introduction Epidemiological studies indicate that significant decreases in the incidence of Alzheimer's disease (AD) may be obtained by targeting multiple middle-age risk factors. However, as dementia is unlikely to be diagnosed for decades, short-term outcome measures are required. AD biomarker changes precede clinical symptoms by many years, but their sensitivity to mid-life change remains unknown. Methods and analysis PREVENT is a prospective cohort study examining biomarker status at mid-life in at least 150 individuals genetically at high, medium or low risk of late-onset AD. Participants are children of individuals with or without a diagnosed AD allocated to high, medium and low-risk groups according to parental clinical status and ApoE genotype. The biomarkers examined over 2 years are plasma and CSF Aβ42 amyloid, Tau and pTau, proinflammatory cytokines, acute-phase proteins, medial temporal-lobe atrophy, white matter lesion volume, cognitive performance related to transentorhinal and hippocampal functioning and hypothalamic−pituitary−adrenal and sympathetic axes regulation. Ethics and dissemination Detected pathologies are communicated to the participant's general practitioner with their permission. Risk status by genotype would not be revealed. The results of the study would be published in peer-reviewed journals and validated biomarkers used to construct a randomised controlled intervention study. PMID:23166135

  1. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease

    PubMed Central

    Zhang, Bin; Gaiteri, Chris; Bodea, Liviu-Gabriel; Wang, Zhi; McElwee, Joshua; Podtelezhnikov, Alexei A.; Zhang, Chunsheng; Xie, Tao; Tran, Linh; Dobrin, Radu; Fluder, Eugene; Clurman, Bruce; Melquist, Stacey; Narayanan, Manikandan; Suver, Christine; Shah, Hardik; Mahajan, Milind; Gillis, Tammy; Mysore, Jayalakshmi; MacDonald, Marcy E.; Lamb, John R.; Bennett, David A; Molony, Cliona; Stone, David J.; Gudnason, Vilmundur; Myers, Amanda J.; Schadt, Eric E.; Neumann, Harald; Zhu, Jun; Emilsson, Valur

    2013-01-01

    SUMMARY The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer’s disease (LOAD), we constructed gene regulatory networks in 1647 post-mortem brain tissues from LOAD patients and non-demented subjects, and demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune and microglia-specific module dominated by genes involved in pathogen phagocytosis, containing TYROBP as a key regulator and up-regulated in LOAD. Mouse microglia cells over-expressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a novel framework to test models of disease mechanisms underlying LOAD. PMID:23622250

  2. Longitudinal white matter change in frontotemporal dementia subtypes and sporadic late onset Alzheimer's disease.

    PubMed

    Elahi, Fanny M; Marx, Gabe; Cobigo, Yann; Staffaroni, Adam M; Kornak, John; Tosun, Duygu; Boxer, Adam L; Kramer, Joel H; Miller, Bruce L; Rosen, Howard J

    2017-01-01

    Degradation of white matter microstructure has been demonstrated in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). In preparation for clinical trials, ongoing studies are investigating the utility of longitudinal brain imaging for quantification of disease progression. To date only one study has examined sample size calculations based on longitudinal changes in white matter integrity in FTLD. To quantify longitudinal changes in white matter microstructural integrity in the three canonical subtypes of frontotemporal dementia (FTD) and AD using diffusion tensor imaging (DTI). 60 patients with clinical diagnoses of FTD, including 27 with behavioral variant frontotemporal dementia (bvFTD), 14 with non-fluent variant primary progressive aphasia (nfvPPA), and 19 with semantic variant PPA (svPPA), as well as 19 patients with AD and 69 healthy controls were studied. We used a voxel-wise approach to calculate annual rate of change in fractional anisotropy (FA) and mean diffusivity (MD) in each group using two time points approximately one year apart. Mean rates of change in FA and MD in 48 atlas-based regions-of-interest, as well as global measures of cognitive function were used to calculate sample sizes for clinical trials (80% power, alpha of 5%). All FTD groups showed statistically significant baseline and longitudinal white matter degeneration, with predominant involvement of frontal tracts in the bvFTD group, frontal and temporal tracts in the PPA groups and posterior tracts in the AD group. Longitudinal change in MD yielded a larger number of regions with sample sizes below 100 participants per therapeutic arm in comparison with FA. SvPPA had the smallest sample size based on change in MD in the fornix (n = 41 participants per study arm to detect a 40% effect of drug), and nfvPPA and AD had their smallest sample sizes based on rate of change in MD within the left superior longitudinal fasciculus (n = 49 for nfvPPA, and n = 23 for AD). Bv

  3. Systematic tissue-specific functional annotation of the human genome highlights immune-related DNA elements for late-onset Alzheimer's disease.

    PubMed

    Lu, Qiongshi; Powles, Ryan L; Abdallah, Sarah; Ou, Derek; Wang, Qian; Hu, Yiming; Lu, Yisi; Liu, Wei; Li, Boyang; Mukherjee, Shubhabrata; Crane, Paul K; Zhao, Hongyu

    2017-07-01

    Continuing efforts from large international consortia have made genome-wide epigenomic and transcriptomic annotation data publicly available for a variety of cell and tissue types. However, synthesis of these datasets into effective summary metrics to characterize the functional non-coding genome remains a challenge. Here, we present GenoSkyline-Plus, an extension of our previous work through integration of an expanded set of epigenomic and transcriptomic annotations to produce high-resolution, single tissue annotations. After validating our annotations with a catalog of tissue-specific non-coding elements previously identified in the literature, we apply our method using data from 127 different cell and tissue types to present an atlas of heritability enrichment across 45 different GWAS traits. We show that broader organ system categories (e.g. immune system) increase statistical power in identifying biologically relevant tissue types for complex diseases while annotations of individual cell types (e.g. monocytes or B-cells) provide deeper insights into disease etiology. Additionally, we use our GenoSkyline-Plus annotations in an in-depth case study of late-onset Alzheimer's disease (LOAD). Our analyses suggest a strong connection between LOAD heritability and genetic variants contained in regions of the genome functional in monocytes. Furthermore, we show that LOAD shares a similar localization of SNPs to monocyte-functional regions with Parkinson's disease. Overall, we demonstrate that integrated genome annotations at the single tissue level provide a valuable tool for understanding the etiology of complex human diseases. Our GenoSkyline-Plus annotations are freely available at http://genocanyon.med.yale.edu/GenoSkyline.

  4. Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study.

    PubMed

    Dean, Douglas C; Jerskey, Beth A; Chen, Kewei; Protas, Hillary; Thiyyagura, Pradeep; Roontiva, Auttawat; O'Muircheartaigh, Jonathan; Dirks, Holly; Waskiewicz, Nicole; Lehman, Katie; Siniard, Ashley L; Turk, Mari N; Hua, Xue; Madsen, Sarah K; Thompson, Paul M; Fleisher, Adam S; Huentelman, Matthew J; Deoni, Sean C L; Reiman, Eric M

    2014-01-01

    Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies. To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD. Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status. Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age. Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an

  5. Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease A Cross-sectional Imaging Study

    PubMed Central

    Dean, Douglas C.; Jerskey, Beth A.; Chen, Kewei; Protas, Hillary; Thiyyagura, Pradeep; Roontiva, Auttawat; O’Muircheartaigh, Jonathan; Dirks, Holly; Waskiewicz, Nicole; Lehman, Katie; Siniard, Ashley L.; Turk, Mari N.; Hua, Xue; Madsen, Sarah K.; Thompson, Paul M.; Fleisher, Adam S.; Huentelman, Matthew J.; Deoni, Sean C. L.; Reiman, Eric M.

    2014-01-01

    IMPORTANCE Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies. OBJECTIVE To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD. DESIGN, SETTING, AND PARTICIPANTS Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status. MAIN OUTCOMES AND MEASURES Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age. RESULTS Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001

  6. [Impact of facial emotional recognition alterations in Dementia of the Alzheimer type].

    PubMed

    Rubinstein, Wanda; Cossini, Florencia; Politis, Daniel

    2016-07-01

    Face recognition of basic emotions is independent of other deficits in dementia of the Alzheimer type. Among these deficits, there is disagreement about what emotions are more difficult to recognize. Our aim was to study the presence of alterations in the process of facial recognition of basic emotions, and to investigate if there were differences in the recognition of each type of emotion in Alzheimer's disease. With three tests of recognition of basic facial emotions we evaluated 29 patients who had been diagnosed with dementia of the Alzheimer type and 18 control subjects. Significant differences were obtained in tests of recognition of basic facial emotions and between each. Since the amygdala, one of the brain structures responsible for emotional reaction, is affected in the early stages of this disease, our findings become relevant to understand how this alteration of the process of emotional recognition impacts the difficulties these patients have in both interpersonal relations and behavioral disorders.

  7. Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset Alzheimer's disease in Mexican families.

    PubMed

    Yescas, Petra; Huertas-Vazquez, Adriana; Villarreal-Molina, María Teresa; Rasmussen, Astrid; Tusié-Luna, María Teresa; López, Marisol; Canizales-Quinteros, Samuel; Alonso, María Elisa

    2006-07-01

    The etiology of Alzheimer's disease (AD) is complex. To date, molecular genetic studies in several families affected with AD have identified three genes associated with highly penetrant early-onset AD: Presenilin 1 (PSEN1), Presenilin 2 (PSEN2) and beta-amyloid precursor protein (APP); and one gene (apolipoprotein E) associated with late-onset AD. Molecular analysis of the PSEN1 gene was performed by direct sequencing of genomic DNA. The possible founder effect was investigated analyzing two highly polymorphic microsatellite markers flanking the PSEN1 gene. Twelve unrelated Mexican families with early-onset AD were analyzed. The Ala431Glu mutation in exon 12 of PSEN1 was found in nine (75%) of these families, which segregated showing autosomal dominant inheritance. Because all families bearing the mutation are from the State of Jalisco (located in Western Mexico), a founder effect was hypothesized. Microsatellite haplotype analysis suggested a common ancestor in these nine kindreds. In conclusion, the Ala431Glu mutation is a prevalent cause of early-onset familial Alzheimer's disease in families from the State of Jalisco, Mexico. Genetic evidence supports that it is a founder mutation descending from a single common ancestor. These findings have important implications for prompt diagnosis and genetic counseling for Mexican patients with familial AD from Jalisco.

  8. Shared genetic etiology underlying Alzheimer's disease and type 2 diabetes.

    PubMed

    Hao, Ke; Di Narzo, Antonio Fabio; Ho, Lap; Luo, Wei; Li, Shuyu; Chen, Rong; Li, Tongbin; Dubner, Lauren; Pasinetti, Giulio Maria

    2015-01-01

    Epidemiological evidence supports the observation that subjects with type 2 diabetes (T2D) are at higher risk to develop Alzheimer's disease (AD). However, whether and how these two conditions are causally linked is unknown. Possible mechanisms include shared genetic risk factors, which were investigated in this study based on recent genome wide association study (GWAS) findings. In order to achieve our goal, we retrieved single nucleotide polymorphisms (SNPs) associated with T2D and AD from large-scale GWAS meta-analysis consortia and tested for overlap among the T2D- and AD-associated SNPs at various p-value thresholds. We then explored the function of the shared T2D/AD GWAS SNPs by leveraging expressional quantitative trait loci, pathways, gene ontology data, and co-expression networks. We found 927 SNPs associated with both AD and T2D with p-value ≤0.01, an overlap significantly larger than random chance (overlapping p-value of 6.93E-28). Among these, 395 of the shared GWAS SNPs have the same risk allele for AD and T2D, suggesting common pathogenic mechanisms underlying the development of both AD and T2D. Genes influenced by shared T2D/AD SNPs with the same risk allele were first identified using a SNP annotation variation (ANNOVAR) software, followed by using Association Protein-Protein Link Evaluator (DAPPLE) software to identify additional proteins that are known to physically interact with the ANNOVAR gene annotations. We found that gene annotations from ANNOVAR and DAPPLE significantly enriched specific KEGG pathways pertaining to immune responses, cell signaling and neuronal plasticity, cellular processes in which abnormalities are known to contribute to both T2D and AD pathogenesis. Thus, our observation suggests that among T2D subjects with common genetic predispositions (e.g., SNPs with consistent risk alleles for T2D and AD), dysregulation of these pathogenic pathways could contribute to the elevated risks for AD in subjects. Interestingly, we

  9. Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease

    PubMed Central

    Killick, Richard; Augustin, Hrvoje; Gandy, Carina; Allen, Marcus J.; Hardy, John; Lovestone, Simon; Partridge, Linda

    2010-01-01

    Aβ peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimer's disease (AD), with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3) is increasingly implicated as playing a pivotal role in this amyloid cascade. We have developed an adult-onset Drosophila model of AD, using an inducible gene expression system to express Arctic mutant Aβ42 specifically in adult neurons, to avoid developmental effects. Aβ42 accumulated with age in these flies and they displayed increased mortality together with progressive neuronal dysfunction, but in the apparent absence of neuronal loss. This fly model can thus be used to examine the role of events during adulthood and early AD aetiology. Expression of Aβ42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Aβ42 toxicity. Aβ42 pathogenesis was also reduced by removal of endogenous fly tau; but, within the limits of detection of available methods, tau phosphorylation did not appear to be altered in flies expressing Aβ42. The GSK-3–mediated effects on Aβ42 toxicity appear to be at least in part mediated by tau-independent mechanisms, because the protective effect of lithium alone was greater than that of the removal of tau alone. Finally, Aβ42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Aβ42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Aβ42 levels in the fly and to determine if similar mechanisms are present in mammals, and it supports the potential therapeutic use of GSK-3 inhibitors in AD. PMID:20824130

  10. Genome-wide association and linkage study in the Amish detects a novel candidate late-onset Alzheimer disease gene.

    PubMed

    Cummings, Anna C; Jiang, Lan; Velez Edwards, Digna R; McCauley, Jacob L; Laux, Renee; McFarland, Lynne L; Fuzzell, Denise; Knebusch, Clare; Caywood, Laura; Reinhart-Mercer, Lori; Nations, Laura; Gilbert, John R; Konidari, Ioanna; Tramontana, Michael; Cuccaro, Michael L; Scott, William K; Pericak-Vance, Margaret A; Haines, Jonathan L

    2012-09-01

    To identify novel late-onset Alzheimer disease (LOAD) risk genes, we have analysed Amish populations of Ohio and Indiana. We performed genome-wide SNP linkage and association studies on 798 individuals (109 with LOAD). We tested association using the Modified Quasi-Likelihood Score test and also performed two-point and multipoint linkage analyses. We found that LOAD was significantly associated with APOE (P= 9.0 × 10-6) in all our ascertainment regions except for the Adams County, Indiana, community (P= 0.55). Genome-wide, the most strongly associated SNP was rs12361953 (P= 7.92 × 10-7). A very strong, genome-wide significant multipoint peak [recessive heterogeneity multipoint LOD (HLOD) = 6.14, dominant HLOD = 6.05] was detected on 2p12. Three additional loci with multipoint HLOD scores >3 were detected on 3q26, 9q31 and 18p11. Converging linkage and association results, the most significantly associated SNP under the 2p12 peak was at rs2974151 (P= 1.29 × 10-4). This SNP is located in CTNNA2, which encodes catenin alpha 2, a neuronal-specific catenin known to have function in the developing brain. These results identify CTNNA2 as a novel candidate LOAD gene, and implicate three other regions of the genome as novel LOAD loci. These results underscore the utility of using family-based linkage and association analyses in isolated populations to identify novel loci for traits with complex genetic architecture. © 2012 The Authors Annals of Human Genetics © 2012 Blackwell Publishing Ltd/University College London.

  11. Strong association of lipid metabolism related microRNA binding sites polymorphisms with the risk of late onset Alzheimer's disease.

    PubMed

    Tan, Lin; Zhao, Da-Long; Sun, Fu-Rong; Tan, Meng-Shan; Wan, Yu; Tan, Chen-Chen; Zhang, Wei; Miao, Dan; Yu, Jin-Tai; Tan, Lan

    2016-10-27

    Although altered lipid metabolism has been extensively implicated in the pathogenesis of late onset Alzheimer's disease (LOAD) through cell biological and epidemiological studies, genetic studies linking lipid metabolism and LOAD are still not well understood. MicroRNAs (miRNAs) exert post-transcriptional down-regulation and their target sequence on the 3' untranslated regions (3'UTR) may be altered by single nucleotide polymorphisms (SNPs). We therefore explore whether the six loci in Clusterin gene (CLU) (rs9331949), Lipoprotein lipase gene (LPL) (rs1059507, rs3200218, rs3208305, rs3735964) and Low-density lipoprotein receptor related protein 6 (LRP6) (rs2160525) could modulate LOAD risk through the alteration of miRNA binding sites. We performed a case-control study of 2338 unrelated subjects (984 cases and 1354 age- and gender-matched controls) in Northern Han Chinese. We found that the minor C allele in rs9331949 was significantly increased the risk of LOAD (P&lt;0.001, OR=1.31, 95% CI=1.14-1.51), even after adjusting for multiple testing. Logistic analysis identified the rs9331949 polymorphism was still strongly associated with LOAD, even in Apolipoprotein E (APOE) ε4 allele noncarrier subgroups. However, the other five loci were not significantly associated with LOAD after Bonferroni adjustment. In conclusion, we have identified that the locus (rs9331949) located in the binding site of 3' UTR of CLU has a strong association with LOAD rather than loci in LPL and LRP6. However, additional independent replication is required for further validation.

  12. Genome-wide association and linkage study in the Amish detects a novel candidate late-onset Alzheimer disease gene

    PubMed Central

    Cummings, Anna C.; Jiang, Lan; Velez Edwards, Digna R.; McCauley, Jacob L.; Laux, Renee; McFarland, Lynne L.; Fuzzell, Denise; Knebusch, Clare; Caywood, Laura; Reinhart-Mercer, Lori; Nations, Laura; Gilbert, John R.; Konidari, Ioanna; Tramontana, Michael; Cuccaro, Michael L.; Scott, William K.; Pericak-Vance, Margaret A.; Haines, Jonathan L.

    2012-01-01

    Summary To identify novel late-onset Alzheimer disease (LOAD) risk genes, we have analyzed Amish populations of Ohio and Indiana. We performed genome-wide SNP linkage and association studies on 798 individuals (109 with LOAD). We tested association using the Modified Quasi-Likelihood Score (MQLS) test and also performed two-point and multipoint linkage analyses. We found that LOAD was significantly associated with APOE (P=9.0×10-6) in all our ascertainment regions except for the Adams County, Indiana, community (P=0.55). Genome-wide, the most strongly associated SNP was rs12361953 (P=7.92×10-7). A very strong, genome-wide significant multipoint peak (recessive HLOD=6.14, dominant HLOD=6.05) was detected on 2p12. Three additional loci with multipoint HLOD scores >3 were detected on 3q26, 9q31, and 18p11. Converging linkage and association results, the most significantly associated SNP under the 2p12 peak was at rs2974151 (P=1.29×10-4). This SNP is located in CTNNA2, which encodes catenin alpha 2, a neuronal-specific catenin known to have function in the developing brain. These results identify CTNNA2 as a novel candidate LOAD gene, and implicate three other regions of the genome as novel LOAD loci. These results underscore the utility of using family-based linkage and association analysis in isolated populations to identify novel loci for traits with complex genetic architecture. PMID:22881374

  13. Type-1 cannabinoid receptor activity during Alzheimer's disease progression.

    PubMed

    Manuel, Iván; González de San Román, Estíbaliz; Giralt, M Teresa; Ferrer, Isidro; Rodríguez-Puertas, Rafael

    2014-01-01

    The activity of CB1 cannabinoid receptors was studied in postmortem brain samples of Alzheimer's disease (AD) patients during clinical deterioration. CB1 activity was higher at earlier AD stages in limited hippocampal areas and internal layers of frontal cortex, but a decrease was observed at the advanced stages. The pattern of modification appears to indicate initial hyperactivity of the endocannabinoid system in brain areas that lack classical histopathological markers at earlier stages of AD, indicating an attempt to compensate for the initial synaptic impairment, which is then surpassed by disease progression. These results suggest that initial CB1 stimulation might have therapeutic relevance.

  14. Type 2 diabetes aggravates Alzheimer's disease-associated vascular alterations of the aorta in mice.

    PubMed

    Sena, Cristina M; Pereira, Ana M; Carvalho, Cristina; Fernandes, Rosa; Seiça, Raquel M; Oliveira, Catarina R; Moreira, Paula I

    2015-01-01

    Vascular risk factors are associated with a higher incidence of dementia. In fact, diabetes mellitus is considered a main risk factor for Alzheimer's disease (AD) and both diseases are characterized by vascular dysfunction. However, the underlying mechanisms remain largely unknown. Here, the effects of high-sucrose-induced type 2 diabetes (T2D) in the aorta of wild type (WT) and triple-transgenic AD (3xTg-AD) mice were investigated. 3xTg-AD mice showed a significant decrease in body weight and an increase in postprandial glycemia, glycated hemoglobin (HbA1c), and vascular nitrotyrosine, superoxide anion (O2•-), receptor for the advanced glycation end products (RAGE) protein, and monocyte chemoattractant protein-1 (MCP-1) levels when compared to WT mice. High-sucrose intake caused a significant increase in body weight, postprandial glycemia, HbA1c, triglycerides, plasma vascular cell adhesion molecule 1 (VCAM-1), and vascular nitrotyrosine, O2•-, RAGE, and MCP-1 levels in both WT and 3xTg-AD mice when compared to the respective control group. Also, a significant decrease in nitric oxide-dependent vasorelaxation was observed in 3xTg-AD and sucrose-treated WT mice. In conclusion, AD and T2D promote similar vascular dysfunction of the aorta, this effect being associated with elevated oxidative and nitrosative stress and inflammation. Also, AD-associated vascular alterations are potentiated by T2D. These findings support the idea that metabolic alterations predispose to the onset and progression of dementia.

  15. Prediction of psychosis onset in Alzheimer disease: the role of depression symptom severity and the HTR2A T102C polymorphism.

    PubMed

    Wilkosz, Patricia A; Kodavali, Chowdari; Weamer, Elise A; Miyahara, Sachiko; Lopez, Oscar L; Nimgaonkar, Vishwajit L; DeKosky, Steven T; Sweet, Robert A

    2007-12-05

    Psychotic symptoms in Alzheimer disease (AD + P) identify a heritable phenotype associated with a more severe course. We recently found an association of AD + P with depression symptom severity. Reports have shown an association of a serotonin-2A receptor (HTR2A) gene T102C polymorphism with AD + P and with depression during AD. We examined the interaction of this common genetic polymorphism with depression and increased psychosis risk. Subjects with possible or probable AD or mild cognitive impairment (MCI) without psychosis at study entry were genotyped for the HTR2A T102C polymorphism and reassessed every 6 months until psychosis onset. Psychotic and depressive symptoms were rated using the CERAD behavioral rating scale (CBRS). Cox proportional hazard models with time-dependent covariates were used to examine associations with psychosis onset. A total of 324 Caucasian subjects completed at least one follow-up exam. Depressive symptom severity was a strong predictor of psychosis onset. Neither psychosis onset nor depression severity was associated with the HTR2A genotype. Genotype interacted with depression severity to moderate the risk of AD + P onset. This did not result from an interaction of HTR2A genotype with antidepressant use. Psychosis onset in AD is strongly associated with severity of depressive symptoms, an association that may be modified by HTR2A genotype.

  16. Prediction of Psychosis Onset in Alzheimer Disease: The Role of Depression Symptom Severity and the HTR2A T102C Polymorphism

    PubMed Central

    Wilkosz, Patricia A.; Kodavali, Chowdari; Weamer, Elise A.; Miyahara, Sachiko; Lopez, Oscar L.; Nimgaonkar, Vishwajit L.; DeKosky, Steven T.; Sweet, Robert A.

    2009-01-01

    Background Psychotic symptoms in Alzheimer Disease (AD+P) identify a heritable phenotype associated with a more severe course. We recently found an association of AD+P with depression symptom severity. Reports have shown an association of a serotonin-2A receptor (HTR2A) gene T102C polymorphism with AD+P and with depression during AD. We examined the interaction of this common genetic polymorphism with depression and increased psychosis risk. Methods Subjects with possible or probable AD or Mild Cognitive Impairment (MCI) without psychosis at study entry were genotyped for the HTR2A T102C polymorphism and reassessed every 6 months until psychosis onset. Psychotic and depressive symptoms were rated using the CERAD Behavioral Rating Scale (CBRS). Cox proportional hazard models with time dependent covariates were used to examine associations with psychosis onset. Results A total of 324 Caucasian subjects completed at least one follow-up exam. Depressive symptom severity was a strong predictor of psychosis onset. Neither psychosis onset nor depression severity was associated with the HTR2A genotype. Genotype interacted with depression severity to moderate the risk of AD+P onset. This did not result from an interaction of HTR2A genotype with antidepressant use. Conclusion Psychosis onset in AD is strongly associated with severity of depressive symptoms, an association that may be modified by HTR2A genotype. PMID:17525976

  17. [Molecular basics of Alzheimer's disease].

    PubMed

    Grigorenko, A P; Rogaev, E I

    2007-01-01

    Studies of molecular mechanisms for Alzheimer's Disease have led to the two major achievements. First, genes with mutations causing Alzheimer's Disease (presenilin genes PSI, PS2 and APP) or bearing a risk factor polymorphism (ApoE) for Alzheimer's Disease were described. Second, the new type of proteases and mechanisms of regulation of cellular differentiation and development by processes of intramembrane proteolysis were identified. These mechanisms, apparently, are universal for various cell types and organisms. Presenilin is a catalytic component of tetra-protein complex (epsilon-/gamma-secretase) cleaving type I transmembrane proteins. Other recently discovered aspartate proteases, IMPAS/SPP, cleave type II transmembrane proteins. Processing of transmembrane proteins by cellular intramembrane proteases results in production of signal peptides, transcriptional factors and short hydrophobic proteins (fragments of transmembrane domains), which may have a physiological function or play a key role in patogenic events associated with ageing (e.g., beta-amyloid formation in Alzheimer's Disease). To date approximately 160 mutations in PSI gene, more than 10 mutations in PS2 gene and 21 mutations in APP gene were described. Early preclinical diagnostics of some early forms of Alzheimer's Disease became possible. Since patogeneses of early and late onset forms of Alzheimer's Disease are similar, identification of molecular or epigenetic factors affecting primary molecular mechanisms (intramembrane or membrane associated proteolysis) underlying the disease may ultimately contribute to development of rational therapy for Alzheimer's Disease.

  18. Affective false memories in Dementia of Alzheimer's Type.

    PubMed

    Fairfield, Beth; Colangelo, Mirco; Mammarella, Nicola; Di Domenico, Alberto; Cornoldi, Cesare

    2017-03-01

    This study examined the production of inferential false memories for complex pictorial stimuli and the implications of affective content in Alzheimer's disease (AD). A group of 24 AD patients and a group of 24 healthy older adults studied a sequence of pictures depicting stories that included positive, negative or neutral consequences of an unseen action, and then completed an old-new picture recognition test. The number of causal errors was higher in healthy older adults compared to AD patients but affective content attenuated the effect. Causal errors increased in AD patients when stories included affective (positive or negative) outcomes. In addition, negative content produced a larger number of errors than positive content across groups. This data confirms that although memory processing is poorer in AD, it is sensitive to affective content. Accordingly, the nature of affective false memory errors suggest the need to consider the use of affective information in the development of new cognitive training procedures.

  19. Order and Disorder in Conversation: Encounters with Dementia of the Alzheimer's Type

    ERIC Educational Resources Information Center

    Muller, Nicole; Guendouzi, Jacqueline A.

    2005-01-01

    After a brief introduction to Dementia of the Alzheimer's Type (DAT), its behavioral diagnostic symptom complex and a summary of communicative implications, we present data from two conversations involving participants with and without DAT. We discuss the concept of "order" in conversation, and the central importance of interactional monitoring.…

  20. Order and Disorder in Conversation: Encounters with Dementia of the Alzheimer's Type

    ERIC Educational Resources Information Center

    Muller, Nicole; Guendouzi, Jacqueline A.

    2005-01-01

    After a brief introduction to Dementia of the Alzheimer's Type (DAT), its behavioral diagnostic symptom complex and a summary of communicative implications, we present data from two conversations involving participants with and without DAT. We discuss the concept of "order" in conversation, and the central importance of interactional monitoring.…

  1. Impact of Alzheimer's-Type Dementia and Information Source on the Assessment of Depression.

    ERIC Educational Resources Information Center

    Gilley, David W.; And Others

    1995-01-01

    The level of agreement between the patient and a collateral source with regard to depressive symptomatology was compared for 185 patients with Alzheimer's-type dementia (AD), 57 patients with Parkinson's disease, and 54 nondemented geriatric referrals. Findings highlight the potential insensitivity of patient report in AD. (SLD)

  2. Utility of the Neurobehavioral Cognitive Status Examination (COGNISTAT) in differentiating between depressive states in late-life depression and late-onset Alzheimer's disease: a preliminary study.

    PubMed

    Tsuruoka, Yoshiaki; Takahashi, Michio; Suzuki, Masatoshi; Sato, Koichi; Shirayama, Yukihiko

    2016-01-01

    It is often difficult to differentiate between the depressive states seen in late-life depression and late-onset Alzheimer' disease (AD) in the clinical setting. Thirty-four outpatients were recruited, all fulfilling the criteria of aged 65 years or above, scores of 14 or more on the Hamilton depression rating scale (HAM-D), and 26 or less on the Mini-Mental State Examination (MMSE). At the initial visit, they were administered the Neurobehavioral Cognitive Status Examination (COGNISTAT). At 1 month, a diagnosis of either senile depression (n = 24) or Alzheimer' disease (n = 10) was made. The COGNISTAT revealed that the late-life depression group showed significantly higher scores in orientation and comprehension subtests compared with the AD group. At the study endpoint (6 months after treatment), MMSE detected significant improvements in the late-life depression group (n = 15), but no changes in the late-onset AD group (n = 7). Scores for memory, similarities, and judgment on the second COGNISTAT were significantly improved in the depressed group, whereas calculation scores deteriorated significantly in the AD group. The COGNISTAT could prove useful in differentiating late-life depression from late-onset AD, despite similar scores on MMSE.

  3. Does insulin therapy for type 1 diabetes mellitus protect against Alzheimer's disease?

    PubMed

    Rdzak, Grzegorz M; Abdelghany, Osama

    2014-12-01

    Alzheimer's disease is the most common cause of dementia in the United States. A better understanding of the disease's underlying pathways may provide novel treatment and/or prevention strategies for this progressive chronic neurodegenerative disorder. In recent years, there has been a growing interest in the possible links between insulin and Alzheimer's disease. Insulin-induced hypoglycemia causes adaptive changes in the brain, including an improved ability to use alternative fuels. Insulin has been shown to facilitate reduction of intracellular amyloid plaque and downregulation of amyloid-β-derived diffusible ligand-binding sites. Insulin also promotes tau hypophosphorylation, which stabilizes microtubules and promotes tubulin polymerization. Excess exogenous insulin may also play a role in overcoming the decreased utilization and transport of glucose in patients with Alzheimer's disease. Intranasal insulin therapy may have beneficial effects on cognition and function in patients with Alzheimer's disease, as well as having only minor adverse effects, and this route of administration been the focus in clinical trials. These data support the mechanistic pathways that might link excess exogenous insulin administered to patients with type 1 diabetes mellitus to possible protection from Alzheimer's disease and provide a rationale for using insulin to prevent the disease in high-risk patients.

  4. The role of ryanodine receptor type 3 in a mouse model of Alzheimer disease.

    PubMed

    Liu, Jie; Supnet, Charlene; Sun, Suya; Zhang, Hua; Good, Levi; Popugaeva, Elena; Bezprozvanny, Ilya

    2014-01-01

    Dysregulated endoplasmic reticulum (ER) calcium (Ca(2+)) signaling is reported to play an important role in Alzheimer disease (AD) pathogenesis. The role of ER Ca(2+) release channels, the ryanodine receptors (RyanRs), has been extensivelys tudied in AD models and RyanR expression and activity are upregulated in the brains of various familial AD (FAD) models.The objective of this study was to utilize a genetic approach to evaluate the importance of RyanR type 3 (RyanR3) in the context of AD pathology.The expression of RyanR3 was also elevated in hippocampus of APPPS1 mice (Thy1-APPKM670/671NL, Thy1-PS1L166P).In young (≤ 3 mo) APPPS1 mice, the deletion of RyanR3 increased hippocampal neuronal network excitability and accelerated AD pathology, leading to mushroom spine loss and increased amyloid accumulation. In contrast, deletion of RyanR3 in older APPPS1 mice (≥ 6 mo) rescued network excitability and mushroom spine loss, reduced amyloid plaque load and reduced spontaneous seizure occurrence.Our data suggests a dual role for RyanR3 in AD pathology. In young AD neurons, RyanR3 protects AD neurons from synaptic and network dysfunction. In older AD neurons, increased RyanR3 activity contributes to pathology. These results imply that blockade of RyanR3 may be beneficial for those in the later stages of the disease, but RyanR activators may be beneficial when used prior to disease onset or in its initial stages. Caffeine is an activator of RyanRs and our results may help to explain a complex epidemiological connection between coffee consumption in mid-life and risk of AD development in old age.

  5. Slowing of Hippocampal Activity Correlates with Cognitive Decline in Early Onset Alzheimer's Disease. An MEG Study with Virtual Electrodes.

    PubMed

    Engels, Marjolein M A; Hillebrand, Arjan; van der Flier, Wiesje M; Stam, Cornelis J; Scheltens, Philip; van Straaten, Elisabeth C W

    2016-01-01

    Pathology in Alzheimer's disease (AD) starts in the entorhinal cortex and hippocampus. Because of their deep location, activity from these areas is difficult to record with conventional electro- or magnetoencephalography (EEG/MEG). The purpose of this study was to explore hippocampal activity in AD patients and healthy controls using "virtual MEG electrodes". We used resting-state MEG recordings from 27 early onset AD patients [age 60.6 ± 5.4, 12 females, mini-mental state examination (MMSE) range: 19-28] and 26 cognitively healthy age- and gender-matched controls (age 61.8 ± 5.5, 14 females). Activity was reconstructed using beamformer-based virtual electrodes for 78 cortical regions and 6 hippocampal regions. Group differences in peak frequency and relative power in six frequency bands were identified using permutation testing. For the patients, spearman correlations between the MMSE scores and peak frequency or relative power were calculated. Moreover, receiver operator characteristic curves were plotted to estimate the diagnostic accuracy. We found a lower hippocampal peak frequency in AD compared to controls, which, in the patients, correlated positively with MMSE [r(25) = 0.61; p < 0.01] whereas hippocampal relative theta power correlated negatively with MMSE [r(25) = -0.54; p < 0.01]. Cortical peak frequency was also lower in AD in association areas. Furthermore, cortical peak frequency correlated positively with MMSE [r(25) = 0.43; p < 0.05]. In line with this finding, relative theta power was higher in AD across the cortex, and relative alpha and beta power was lower in more circumscribed areas. The average cortical relative theta power was the best discriminator between AD and controls (sensitivity 82%; specificity 81%). Using beamformer-based virtual electrodes, we were able to detect hippocampal activity in AD. In AD, this hippocampal activity is slowed, and correlates better with cognition than the (slowed) activity in cortical areas. On the other

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

    PubMed

    Hoyer, S

    2002-03-01

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

  7. Presenilin 1 Met146Leu variant due to an A --> T transversion in an early-onset familial Alzheimer's disease pedigree from Argentina.

    PubMed

    Morelli, L; Prat, M I; Levy, E; Mangone, C A; Castaño, E M

    1998-06-01

    Most of the cases of early-onset familial Alzheimer's disease (FAD) are related to missense mutations in the presenilin 1 (PS-1) gene on chromosome 14. Although PS-1 mutations are distributed throughout the entire open reading frame, most mutations are found in transmembrane region II and hydrophilic loop VI encoded by exons 5 and 8, respectively. These two groups of substitutions are associated with an age of onset of 40-43 years for exon 5 and 45-55 years for exon 8, respectively. We have previously described a South American pedigree from Argentina with early-onset FAD (mean age of onset 38.9 +/- 3.9 years) with no mutations in exons 16 and 17 of the beta-protein precursor gene (betaPP770 transcript). Here we report the identification of an A --> T transversion at the first position of codon 146 of PS-1 in these patients. This missense mutation results in a Met --> Leu substitution, as reported for the Italian pedigrees Tor1.1 and FAD4. The significant differences in ages of onset and death among members of generations II-III and IV suggest that other genetic and/or environmental factors may influence disease phenotype in this pedigree.

  8. Bender-Gestalt Test performance in senile dementia of the Alzheimer type.

    PubMed

    Storandt, M

    1990-12-01

    Bender-Gestalt Test performances of 144 persons with very mild, mild, or moderate senile dementia of the Alzheimer type (SDAT) and 96 healthy older adults ranging in age from 63 to 95 were compared. Total scores and error types according to the modified Hutt-Briskin scoring system are reported. The Bender-Gestalt Test does not appear to be useful in differentiating very mild or mild SDAT from normal aging.

  9. Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques.

    PubMed

    Wozniak, M A; Mee, A P; Itzhaki, R F

    2009-01-01

    The brains of Alzheimer's disease sufferers are characterized by amyloid plaques and neurofibrillary tangles. However, the cause(s) of these features and those of the disease are unknown, in sporadic cases. We previously showed that herpes simplex virus type 1 is a strong risk factor for Alzheimer's disease when in the brains of possessors of the type 4 allele of the apolipoprotein E gene (APOE-epsilon4), and that beta-amyloid, the main component of plaques, accumulates in herpes simplex virus type 1-infected cell cultures and mouse brain. The present study aimed to elucidate the relationship of the virus to plaques by determining their proximity in human brain sections. We used in situ polymerase chain reaction to detect herpes simplex virus type 1 DNA, and immunohistochemistry or thioflavin S staining to detect amyloid plaques. We discovered a striking localization of herpes simplex virus type 1 DNA within plaques: in Alzheimer's disease brains, 90% of the plaques contained the viral DNA and 72% of the DNA was associated with plaques; in aged normal brains, which contain amyloid plaques at a lower frequency, 80% of plaques contained herpes simplex virus type 1 DNA but only 24% of the viral DNA was plaque-associated (p < 0.001). We suggest that this is because in aged normal individuals, there is a lesser production and/or greater removal of beta-amyloid (Abeta), so that less of the viral DNA is seen to be associated with Abeta in the brain. Our present data, together with our finding of Abeta accumulation in herpes simplex virus type 1-infected cells and mouse brain, suggest that this virus is a major cause of amyloid plaques and hence probably a significant aetiological factor in Alzheimer's disease. They point to the usage of antiviral agents to treat the disease and possibly of vaccination to prevent it.

  10. Single-subject gray matter graph properties and their relationship with cognitive impairment in early- and late-onset Alzheimer's disease.

    PubMed

    Tijms, Betty M; Yeung, Hiu M; Sikkes, Sietske A M; Möller, Christiane; Smits, Lieke L; Stam, Cornelis J; Scheltens, Philip; van der Flier, Wiesje M; Barkhof, Frederik

    2014-06-01

    Abstract We investigated the relationships between gray matter graph properties and cognitive impairment in a sample of 215 patients with Alzheimer's disease (AD) and also whether age of disease onset modifies such relationships. We expected that more severe cognitive impairment in AD would be related to more random graph topologies. Single-subject gray matter graphs were constructed from T1-weighted magnetic resonance imaging scans. The following global and local graph properties were calculated: betweenness centrality, normalized clustering coefficient γ, and normalized path length λ. Local clustering, path length, and betweenness centrality measures were determined for 90 anatomically defined areas. Regression models with as interaction term age of onset (i.e., early onset when patients were ≤65 years old and late onset when they were >65 years old at the time of diagnosis)×graph property were used to assess the relationships between cognitive functioning in five domains (memory, language, visuospatial, attention, and executive). Worse cognitive impairment was associated with more random graphs, as indicated by low γ, λ, and betweenness centrality values. Three interaction effects for age of onset×global graph property were found: Low γ and λ values more strongly related to memory impairment in early-onset patients; low beta values were significantly related to impaired visuospatial functioning in late-onset patients. For the local graph properties, language impairment showed the strongest relationship with decreased clustering coefficient in the left superior temporal gyrus across the entire sample. Our study shows that single-subject gray matter graph properties are associated with individual differences in cognitive impairment.

  11. Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease.

    PubMed

    Sassi, Celeste; Guerreiro, Rita; Gibbs, Raphael; Ding, Jinhui; Lupton, Michelle K; Troakes, Claire; Lunnon, Katie; Al-Sarraj, Safa; Brown, Kristelle S; Medway, Chirstopher; Lord, Jenny; Turton, James; Mann, David; Snowden, Julie; Neary, David; Harris, Jeniffer; Bras, Jose; Morgan, Kevin; Powell, John F; Singleton, Andrew; Hardy, John

    2014-10-01

    Early-onset Alzheimer's disease (EOAD) represents 1%-2% of the Alzheimer's disease (AD) cases, and it is generally characterized by a positive family history and a rapidly progressive symptomatology. Rare coding and fully penetrant variants in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the only causative mutations reported for autosomal dominant AD. Thus, in this study we used exome sequencing data to rapidly screen rare coding variability in APP, PSEN1, and PSEN2, in a British cohort composed of 47 unrelated EOAD cases and 179 elderly controls, neuropathologically proven. We report 2 novel and likely pathogenic variants in PSEN1 (p.L166V and p.S230R). A comprehensive catalog of rare pathogenic variants in the AD Mendelian genes is pivotal for a premortem diagnosis of autosomal dominant EOAD and for the differential diagnosis with other early onset dementias such as frontotemporal dementia (FTD) and Creutzfeldt-Jakob disease (CJD).

  12. Microvascular changes in Down syndrome with Alzheimer-type pathology: Insights into a potential vascular mechanism for Down syndrome and Alzheimer's disease.

    PubMed

    Drachman, David A; Smith, Thomas W; Alkamachi, Bassam; Kane, Kevin

    2017-06-13

    The mechanism triggering degeneration in Alzheimer's disease (AD) remains uncertain. Therapeutic failure following amyloid β (Aβ) removal casts doubt on amyloid neurotoxicity per se as the primary cause of AD. Impaired microvascular function has been suggested as an alternative etiology. People with Down syndrome (DS) develop Alzheimer pathology, but whether microvascular impairment also occurs in DS (as in AD) is unknown. We examined brain microvasculature in five DS subjects with AD-type histopathology, seven AD cases, and seven controls without AD-type pathology. We counted microvessels in five anatomic regions and assessed endothelial integrity by CD31 immunohistochemistry. Microvascular numbers and endothelial integrity were significantly diminished in DS brains compared with controls and were similar to AD brains. People with DS and trisomy 21 produce a large amount of Aβ. If Alzheimer pathology occurred in DS without microvascular loss or endothelial impairment, a direct neurotoxic Aβ mechanism would be supported and microvascular impairment rejected. The observation of microvascular impairment in DS with Alzheimer changes fails to reject the microvascular hypothesis and provides some support for this potential mechanism of injury. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  13. Role of σ1 Receptors in Learning and Memory and Alzheimer's Disease-Type Dementia.

    PubMed

    Maurice, Tangui; Goguadze, Nino

    2017-01-01

    The present chapter will review the role of σ1 receptor in learning and memory and neuroprotection , against Alzheimer's type dementia. σ1 Receptor agonists have been tested in a variety of pharmacological and pathological models of learning impairments in rodents these last past 20 years. Their anti-amnesic effects have been explained by the wide-range modulatory role of σ1 receptors on Ca(2+) mobilizations, neurotransmitter responses, and particularly glutamate and acetylcholine systems, and neurotrophic factors. Recent observations from genetic and pharmacological studies have shown that σ1 receptor can also be targeted in neurodegenerative diseases, and particularly Alzheimer's disease . Several compounds, acting partly through the σ1 receptor, have showed effective neuroprotection in transgenic mouse models of Alzheimer's disease . We will review the data and discuss the possible mechanisms of action, particularly focusing on oxidative stress and mitochondrial integrity, trophic factors and a novel hypothesis suggesting a functional interaction between the σ1 receptor and α7 nicotinic acetylcholine receptor. Finally, we will discuss the pharmacological peculiarities of non-selective σ1 receptor ligands, now developed as neuroprotectants in Alzheimer's disease , and positive modulators, recently described and that showed efficacy against learning and memory deficits.

  14. C-338A polymorphism of the endothelin-converting enzyme (ECE-1) gene and the susceptibility to sporadic late-onset Alzheimer's disease and coronary artery disease.

    PubMed

    Scacchi, Renato; Gambina, Giuseppe; Broggio, Elisabetta; Ruggeri, Maria; Corbo, Rosa Maria

    2008-01-01

    The human endothelin-converting enzyme (ECE) is involved in beta-amyloid synthesis and regulation of the endothelin-1 (ET-1) vasoconstricting peptide. We investigated the distribution of the C-338A polymorphism of the ECE-1b gene in sporadic late-onset Alzheimer's disease (LOAD) and in coronary artery disease (CAD) to verify its role in the onset of these two complex diseases. Two cohorts of 458 Italian Caucasian LOAD patients and 165 CAD patients were examined for the C-338A polymorphism and compared with respective control samples (260 and 106 subjects, respectively) . The A allele was less present in LOAD patients than in controls, but an at limits statistically significant difference was achieved only in subjects aged less than 80 years, where only the AA genotypes appeared to have a protective role against the onset of the sporadic LOAD. For the overall CAD sample the pattern was similar and significant differences were observed only in subjects non carrying the apolipoprotein E (APOE) e*4 allele, where the A allele carrying genotypes had a protective role against the onset of the disease.

  15. Adeno-associated Virus Gene Therapy With Cholesterol 24-Hydroxylase Reduces the Amyloid Pathology Before or After the Onset of Amyloid Plaques in Mouse Models of Alzheimer's Disease

    PubMed Central

    Hudry, Eloise; Van Dam, Debby; Kulik, Wim; De Deyn, Peter P; Stet, Femke S; Ahouansou, Ornella; Benraiss, Abdellatif; Delacourte, André; Bougnères, Pierre; Aubourg, Patrick; Cartier, Nathalie

    2009-01-01

    The development of Alzheimer's disease (AD) is closely connected with cholesterol metabolism. Cholesterol increases the production and deposition of amyloid-β (Aβ) peptides that result in the formation of amyloid plaques, a hallmark of the pathology. In the brain, cholesterol is synthesized in situ but cannot be degraded nor cross the blood–brain barrier. The major exportable form of brain cholesterol is 24S-hydroxycholesterol, an oxysterol generated by the neuronal cholesterol 24-hydroxylase encoded by the CYP46A1 gene. We report that the injection of adeno-associated vector (AAV) encoding CYP46A1 in the cortex and hippocampus of APP23 mice before the onset of amyloid deposits markedly reduces Aβ peptides, amyloid deposits and trimeric oligomers at 12 months of age. The Morris water maze (MWM) procedure also demonstrated improvement of spatial memory at 6 months, before the onset of amyloid deposits. AAV5-wtCYP46A1 vector injection in the cortex and hippocampus of amyloid precursor protein/presenilin 1 (APP/PS) mice after the onset of amyloid deposits also reduced markedly the number of amyloid plaques in the hippocampus, and to a less extent in the cortex, 3 months after the injection. Our data demonstrate that neuronal overexpression of CYP46A1 before or after the onset of amyloid plaques significantly reduces Aβ pathology in mouse models of AD. PMID:19654569

  16. Age-specific incidence rates for dementia and Alzheimer disease in NIA-LOAD/NCRAD and EFIGA families: National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA).

    PubMed

    Vardarajan, Badri N; Faber, Kelley M; Bird, Thomas D; Bennett, David A; Rosenberg, Roger; Boeve, Bradley F; Graff-Radford, Neill R; Goate, Alison M; Farlow, Martin; Sweet, Robert A; Lantigua, Rafael; Medrano, Martin Z; Ottman, Ruth; Schaid, Daniel J; Foroud, Tatiana M; Mayeux, Richard

    2014-03-01

    Late-onset Alzheimer disease (LOAD), defined as onset of symptoms after age 65 years, is the most common form of dementia. Few reports investigate incidence rates in large family-based studies in which the participants were selected for family history of LOAD. To determine the incidence rates of dementia and LOAD in unaffected members in the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) family studies. Families with 2 or more affected siblings who had a clinical or pathological diagnosis of LOAD were recruited as a part of the NIA-LOAD/NCRAD Family Study. A cohort of Caribbean Hispanics with familial LOAD was recruited in a different study at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain in New York and from clinics in the Dominican Republic as part of the EFIGA study. Age-specific incidence rates of LOAD were estimated in the unaffected family members in the NIA-LOAD/NCRAD and EFIGA data sets. We restricted analyses to families with follow-up and complete phenotype information, including 396 NIA-LOAD/NCRAD and 242 EFIGA families. Among the 943 at-risk family members in the NIA-LOAD/NCRAD families, 126 (13.4%) developed dementia, of whom 109 (86.5%) met criteria for LOAD. Among 683 at-risk family members in the EFIGA families, 174 (25.5%) developed dementia during the study period, of whom 145 (83.3%) had LOAD. The annual incidence rates of dementia and LOAD in the NIA-LOAD/NCRAD families per person-year were 0.03 and 0.03, respectively, in participants aged 65 to 74 years; 0.07 and 0.06, respectively, in those aged 75 to 84 years; and 0.08 and 0.07, respectively, in those 85 years or older. Incidence rates in the EFIGA families were slightly higher, at 0.03 and 0.02, 0.06 and 0.05, 0.10 and 0.08, and 0.10 and 0.07, respectively, in the same age groups. Contrasting these

  17. Type-2 diabetes family history delays the onset of type-1 diabetes.

    PubMed

    Zalloua, P A; Shbaklo, H; Halaby, G; Terwedow, H; Xu, X; Azar, S T

    2002-07-01

    Type-1 diabetes (T1D) is an autoimmune disease leading to insulin deficiency. Its occurrence is influenced by genetic and environmental factors. The human leukocyte antigen (HLA) region on chromosome 6 accounts for 45% of the genetic susceptibility for the disease, mainly the HLA-DQB1*0201 and HLA-DQB1*0302 alleles. Among the environmental factors involved, early exposure to cow's milk seems to be a trigger. In this study, we investigated the occurrence of T1D in 253 Lebanese Caucasian patients, in relation to HLA-DQB1*0201, HLA-DQB1*0302, HLA-DQB1*0602, gender, and early exposure to cow's milk, as well as to family history of T1D and type-2 diabetes (T2D). Our genetic analysis results show that in the patients studied, 77% and 40% were positive for BQ1*0201 and BQ1*0302, respectively. As for BQ1*0602, only 0.8% of patients were positive for this T1D protective allele, compared with 24% among the controls. Furthermore, our results did not show any gender preference of the disease or any effects of early intake of cow's milk on the age at onset of T1D. When family history of T2D or T1D was studied, our results show a novel finding whereby an immediate family history of T2D, but not T1D, delays the age at onset of T1D.

  18. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases.

    PubMed

    Lanoiselée, Hélène-Marie; Nicolas, Gaël; Wallon, David; Rovelet-Lecrux, Anne; Lacour, Morgane; Rousseau, Stéphane; Richard, Anne-Claire; Pasquier, Florence; Rollin-Sillaire, Adeline; Martinaud, Olivier; Quillard-Muraine, Muriel; de la Sayette, Vincent; Boutoleau-Bretonniere, Claire; Etcharry-Bouyx, Frédérique; Chauviré, Valérie; Sarazin, Marie; le Ber, Isabelle; Epelbaum, Stéphane; Jonveaux, Thérèse; Rouaud, Olivier; Ceccaldi, Mathieu; Félician, Olivier; Godefroy, Olivier; Formaglio, Maite; Croisile, Bernard; Auriacombe, Sophie; Chamard, Ludivine; Vincent, Jean-Louis; Sauvée, Mathilde; Marelli-Tosi, Cecilia; Gabelle, Audrey; Ozsancak, Canan; Pariente, Jérémie; Paquet, Claire; Hannequin, Didier; Campion, Dominique

    2017-03-01

    Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series. We report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification. Our findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole

  19. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases

    PubMed Central

    Lanoiselée, Hélène-Marie; Nicolas, Gaël; Wallon, David; Rovelet-Lecrux, Anne; Lacour, Morgane; Rousseau, Stéphane; Richard, Anne-Claire; Pasquier, Florence; Rollin-Sillaire, Adeline; Martinaud, Olivier; Quillard-Muraine, Muriel; de la Sayette, Vincent; Boutoleau-Bretonniere, Claire; Etcharry-Bouyx, Frédérique; Chauviré, Valérie; Sarazin, Marie; le Ber, Isabelle; Epelbaum, Stéphane; Jonveaux, Thérèse; Rouaud, Olivier; Ceccaldi, Mathieu; Félician, Olivier; Godefroy, Olivier; Formaglio, Maite; Croisile, Bernard; Auriacombe, Sophie; Chamard, Ludivine; Vincent, Jean-Louis; Sauvée, Mathilde; Marelli-Tosi, Cecilia; Gabelle, Audrey; Ozsancak, Canan; Pariente, Jérémie; Paquet, Claire; Hannequin, Didier; Campion, Dominique

    2017-01-01

    Background Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series. Methods and findings We report here a novel update (2012–2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers—total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42—in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification. Conclusions Our findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only

  20. Breast-Feeding and Childhood-Onset Type 1 Diabetes

    PubMed Central

    Cardwell, Chris R.; Stene, Lars C.; Ludvigsson, Johnny; Rosenbauer, Joachim; Cinek, Ondrej; Svensson, Jannet; Perez-Bravo, Francisco; Memon, Anjum; Gimeno, Suely G.; Wadsworth, Emma J.K.; Strotmeyer, Elsa S.; Goldacre, Michael J.; Radon, Katja; Chuang, Lee-Ming; Parslow, Roger C.; Chetwynd, Amanda; Karavanaki, Kyriaki; Brigis, Girts; Pozzilli, Paolo; UrbonaitĖ, Brone; Schober, Edith; Devoti, Gabriele; Sipetic, Sandra; Joner, Geir; Ionescu-Tirgoviste, Constantin; de Beaufort, Carine E.; Harrild, Kirsten; Benson, Victoria; Savilahti, Erkki; Ponsonby, Anne-Louise; Salem, Mona; Rabiei, Samira; Patterson, Chris C.

    2012-01-01

    OBJECTIVE To investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders. RESEARCH DESIGN AND METHODS Relevant studies were identified from literature searches using MEDLINE, Web of Science, and EMBASE. Authors of relevant studies were asked to provide individual participant data or conduct prespecified analyses. Meta-analysis techniques were used to combine odds ratios (ORs) and investigate heterogeneity between studies. RESULTS Data were available from 43 studies including 9,874 patients with type 1 diabetes. Overall, there was a reduction in the risk of diabetes after exclusive breast-feeding for >2 weeks (20 studies; OR = 0.75, 95% CI 0.64–0.88), the association after exclusive breast-feeding for >3 months was weaker (30 studies; OR = 0.87, 95% CI 0.75–1.00), and no association was observed after (nonexclusive) breast-feeding for >2 weeks (28 studies; OR = 0.93, 95% CI 0.81–1.07) or >3 months (29 studies; OR = 0.88, 95% CI 0.78–1.00). These associations were all subject to marked heterogeneity (I2 = 58, 76, 54, and 68%, respectively). In studies with lower risk of bias, the reduced risk after exclusive breast-feeding for >2 weeks remained (12 studies; OR = 0.86, 95% CI 0.75–0.99), and heterogeneity was reduced (I2 = 0%). Adjustments for potential confounders altered these estimates very little. CONCLUSIONS The pooled analysis suggests weak protective associations between exclusive breast-feeding and type 1 diabetes risk. However, these findings are difficult to interpret because of the marked variation in effect and possible biases (particularly recall bias) inherent in the included studies. PMID:22837371

  1. The onset of galactic winds in early-type galaxies

    NASA Technical Reports Server (NTRS)

    Jones, Christine

    1992-01-01

    We completed the spectral analysis of 31 early-type galaxies to investigate whether their x-ray emission was predominantly due to thermal bremsstrahlung from a hot gaseous corona or emission from discrete, galactic sources such as x-ray binaries. If a corona dominates the x-ray emission, its spectra is expected to be relatively cool (0.5 - 1 keV) compared to the harder emission associated with x-ray binaries in our galaxy, the Magellanic Clouds and M31. While it is generally accepted that the x-ray emission in luminous E and S0 galaxies arises from hot coronae, the status of hot gas in lower luminosity (and hence lower mass) galaxies is less clear. Calculations show that, for a given supernova rate, a critical galaxy luminosity (mass) exists below which the gas cannot be gravitationally confined and a galactic wind is predicted to be effective in expelling gas from the galaxy. Since significant mass (a dark halo) is required to hold a hot, gaseous corona around a galaxy, we expect that the faintest, smallest galaxies will not have a hot corona, but their x-ray emission will be dominated by galactic sources or by an active galactic nuclei. In the sample we tested which spanned the absolute magnitude range from -21.5 to -19.5, we found that except for two galaxies whose x-ray emission was dominated by an active nucleus, that the others were consistent with emission from hot gas. We also found that there is a correlation between gas temperature and galaxy magnitude (mass), such that the brighter, more luminous galaxies have hotter gas temperatures. Thus even at relatively faint magnitudes, the dominant emission from early-type galaxies appears to be hot gas. We also carried out an investigation of the x-ray surface brightness distribution of the x-ray emission for about 100 early type galaxies to determine whether the x-ray emission from galaxies are extended. Extended x-ray emission is expected if the emission is due to a hot gaseous corona. We determined the ratio

  2. Fatty aspirin: a new perspective in the prevention of dementia of Alzheimer's type?

    PubMed

    Pomponi, M; Di Gioia, A; Bria, P; Pomponi, M F L

    2008-10-01

    Alzheimer's disease (AD) leads to a dramatic decline in cognitive abilities and memory. A more modest disruption of memory often occurs in normal aging and the same circuits that are devastated through degeneration in AD are vulnerable to sub-lethal age-related changes that alter synaptic transmission. There are numerous indications that aberrant plasticity is critically involved in Alzheimer's. Is ageing itself the major risk factor for AD? Is AD an acceleration of normal ageing? We assume that the ability of the brain is to modify its own structural organization and functioning which is liable to become impaired in ageing until it becomes dramatically impaired in Alzheimer's. Moreover, ageing can compromise the conversion of dietary alpha-linolenic acid (ALA) to docosahexaenoic acid (DHA). DHA regulates synaptogenesis and affects the synaptic structure, and synapse density is reduced in ageing. DHA and newly identified DHA-derived messenger, neuroprotecting D1 (NPD1), protect synapses and decrease the number of activated microglia in the hippocampal system. Delaying AD onset by a few years would reduce the number of the cases of dementia in the community. DHA (and NPD1?) and aspirin induce brain-derived neurotrophic factor (BDNF) protein expression and this protein has a crucial role in neuronal survival. The authors--in view of the increased neuroinflammatory reaction frequently observed during normal brain ageing--suggest the long-term use of "fatty aspirin", an association of DHA and/or NPD1 and aspirin (or nitroaspirin), to postpone, or prevent, the structural neurodegeneration of the brain.

  3. [Diabetes type 2 and Alzheimer disease - one or two diseases? Mechanisms of association].

    PubMed

    Marszałek, Małgorzata

    2013-07-23

    Some epidemiological data and pathophysiological evidence suggest similarities and connection of two amyloidoses: diabetes mellitus type 2, (DM2) (non-insulin dependent diabetes mellitus, NIDDM) and Alzheimer's disease (AD). What they have in common is insulin resistance, neurodegeneration, development and progression of dementia, and the fact that in the course of both diseases fibrillar aggregates of specific proteins are accumulated in affected organs. What is more, experimental evidence also supports the hypothesis that small prefibrillar aggregates that emerge prior to the appearance of mature fibrils are responsible for a key step in development and cytotoxicity of both diseases. They also have similar pathogenic effects. Both peptides possess the common receptor AMY3. More and more evidence is accumulating that key cell regulation processes are similar for both diseases as well. The question is raised: can Alzheimer be a new form of diabetes disease?

  4. Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a Peruvian family with early-onset Alzheimer's disease.

    PubMed

    Cornejo-Olivas, Mario R; Yu, Chang-En; Mazzetti, Pilar; Mata, Ignacio F; Meza, Maria; Lindo-Samanamud, Saul; Leverenz, James B; Bird, Thomas D

    2014-03-20

    Presenilin 1 (PSEN1) gene mutations are found in 30-70% of familial early-onset Alzheimer disease (EOAD) cases (onset <60 years). Prevalence of these mutations is highly variable including ethnic differences worldwide. No Peruvian kindred with familial AD (FAD) have been described. Standardized clinical evaluation and cognitive assessment were completed in a Peruvian family with severe EOAD. Clinical course was characterized by very early onset (before age 35 years), progressive cognitive impairment with early memory loss, spatial disorientation and executive dysfunction. We sequenced all exons of PSEN1 in the proband and identified a c.475C>G DNA change resulting in a p.L153V missense mutation in the transmembrane domain 2 of the gene. This mutation is also present in the three additional affected siblings but not in a non-affected family member consistent with segregation of this mutation with the disease. This is the first report of a Peruvian family affected with EOAD associated with a PSEN1 mutation. This same mutation has been reported previously in English and French families, but a novel variants very close to the mutation and ancestry informative markers analysis suggests the mutation might be of Amerindian or African origin in this Peruvian family.

  5. Clinical and Molecular Studies Reveal a PSEN1 Mutation (L153V) in a Peruvian Family with Early-Onset Alzheimer's Disease

    PubMed Central

    Cornejo-Olivas, Mario R.; Yu, Chang-En; Mazzetti, Pilar; Mata, Ignacio F.; Meza, Maria; Lindo-Samanamud, Saul; Leverenz, James B.; Bird, Thomas D.

    2014-01-01

    Presenilin 1 (PSEN1) gene mutations are found in 30 to 70% of familial early onset Alzheimer disease (EOAD) cases (onset <60 years). Prevalence of these mutations is highly variable including ethnic differences worldwide. No Peruvian kindred with familial AD (FAD) have been described. Standardized clinical evaluation and cognitive assessment was completed in a Peruvian family with severe EOAD. Clinical course was characterized by very early onset (before age 35 years), progressive cognitive impairment with early memory loss, spatial disorientation and executive dysfunction. We sequenced all exons of PSEN1 in the proband and identified a c.475C>G DNA change resulting in a p.L153V missense mutation in the transmembrane domain 2 of the gene. This mutation is also present in the three additional affected siblings but not in a non-affected family member consistent with segregation of this mutation with the disease. This is the first report of a Peruvian family affected with EOAD associated with a PSEN1 mutation. This same mutation has been reported previously in English and French families, but a novel variants very close to the mutation and ancestry informative markers analysis suggests the mutation might be of Amerindian or African origin in this Peruvian family. PMID:24495933

  6. Contrasts Between Patients With Lewy Body Dementia Syndromes and APOE-ε3/ε3 Patients With Late-onset Alzheimer Disease Dementia.

    PubMed

    Oliveira, Fabricio F; Machado, Fernando C; Sampaio, Gustavo; Marin, Sheilla M C; Chen, Elizabeth S; Smith, Marilia C; Bertolucci, Paulo H F

    2015-08-01

    Neuropsychiatric and epidemiological patterns may compensate for insufficient specificity of diagnostic criteria of Lewy body dementia (LBD) syndromes in differential analysis with Alzheimer disease (AD) dementia. We aimed to compare and distinguish demographic and neuropsychiatric features between LBD and APOE-ε3/ε3 late-onset AD. A total of 39 consecutive patients with Parkinson disease dementia or dementia with Lewy bodies were matched with 39 APOE-ε3/ε3 patients with late-onset AD according to sex and Mini-Mental State Examination scores, and evaluated for education, age at disease onset, lifetime sanitary conditions, anthropometric measures, alcohol use, smoking, history of head trauma or bacterial infections, family history of neurodegenerative diseases, caregiver burden, functional independence, cognitive decline, neuropsychiatric symptoms, and pharmacological treatment. Family history of parkinsonism and worse motor performance were more prevalent in Parkinson disease dementia, also impacting sleep satisfaction and physical self-maintenance. Patients with AD had higher systolic blood pressure, were more independent, and had better performance in visuospatial tasks and calculations, whereas patients with LBD were more oriented and previously lived longer in rural areas without sanitation. Among neuropsychiatric symptoms, hallucinations, apathy, dysphoria, anxiety, and aberrant motor behavior were the most significant for discrimination amidst dementia diagnoses. Functional performance, visuospatial skills, and behavioral symptoms are helpful for differential diagnoses between LBD and AD. Cerebrovascular risk might be more important for AD pathogenesis, whereas environmental factors might impact development of LBD.

  7. Elevations in Circulating Methylated and Unmethylated Preproinsulin DNA in New-Onset Type 1 Diabetes

    PubMed Central

    Fisher, Marisa M.; Watkins, Renecia A.; Blum, Janice; Evans-Molina, Carmella; Chalasani, Naga; DiMeglio, Linda A.; Mather, Kieren J.; Tersey, Sarah A.

    2015-01-01

    Elevated ratios of circulating unmethylated to methylated preproinsulin (INS) DNA have been suggested to reflect β-cell death in type 1 diabetes (T1D). We tested the hypothesis that absolute levels (rather than ratios) of unmethylated and methylated INS DNA differ between subjects with new-onset T1D and control subjects and assessed longitudinal changes in these parameters. We used droplet digital PCR to measure levels of unmethylated and methylated INS DNA in serum from subjects at T1D onset and at 8 weeks and 1 year post-onset. Compared with control subjects, levels of both unmethylated and methylated INS DNA were elevated at T1D onset. At 8 weeks post-onset, methylated INS DNA remained elevated, but unmethylated INS DNA fell. At 1 year postonset, both unmethylated and methylated INS DNA returned to control levels. Subjects with obesity, type 2 diabetes, and autoimmune hepatitis exhibited lower levels of unmethylated and methylated INS compared with subjects with T1D at onset and no differences compared with control subjects. Our study shows that elevations in both unmethylated and methylated INS DNA occurs in new-onset T1D and that levels of these DNA species change during T1D evolution. Our work emphasizes the need to consider absolute levels of differentially methylated DNA species as potential biomarkers of disease. PMID:26216854

  8. Is obsessive-compulsive symptomatology a risk factor for Alzheimer-type dementia?

    PubMed

    Dondu, Ayse; Sevincoka, Levent; Akyol, Ali; Tataroglu, Cengiz

    2015-02-28

    In the present study, we hypothesized that lifetime Obsessive-Compulsive (OC) symptomatology would be risk factors for the development of Alzheimer׳s disease (AD). For this aim, first we compared 39 patients with AD and 30 age and gender matched control subjects. We have found that lifetime and current OC symptoms (OCs) and comorbid diagnosis of Obsessive-Compulsive Personality Disorder in AD patients were significantly more prevalent than in control group. AD patients had more likely to have lifetime and current hoarding, and checking obsessions compared to controls. The rate of lifetime and current hoarding, and checking compulsions also appeared to be higher in AD patients in comparison to control subjects. Hoarding and checking obsessions, and compulsions seemed to proceed through the dementia in contrast to other OCs. The mean number of lifetime compulsions seemed to predict the diagnosis of AD. When we compared AD patients with and without OCs, we have found that OC symptomatology prior to AD did not cause an earlier onset of dementia and more severe cognitive impairment. Further longitudinal clinical, genetic and neuroimaging investigations are required to determine if lifetime presence of OCs would predispose to the development of later AD.

  9. Molecular misreading of genes in Down syndrome as a model for the Alzheimer type of neurodegeneration.

    PubMed

    van Leeuwen, F W; Hol, E M

    1999-01-01

    The occurrence of +1 frameshifted proteins, such as amyloid precursor protein (APP+1) and ubiquitin-B (UBB+1) in Down syndrome (DS) has been linked to the onset of Alzheimer's disease (AD). In DS and AD patients, but also in elderly non-demented persons, these co-called +1 proteins accumulate in the neuropathological hallmarks (neurofibrillary tangles, dystrophic neurites of the neuritic plaques and neuropil threads) and may have deleterious effects on neuronal function. Frameshifts are caused by dinucleotide deletions in GAGAG motifs in messenger RNA and are now thought to be the result of unfaithful transcription of normal DNA by a novel process termed "molecular misreading". In the present review some of the critical events in molecular misreading are discussed, the emphasis being on DS.

  10. Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease

    PubMed Central

    Sassi, Celeste; Guerreiro, Rita; Gibbs, Raphael; Ding, Jinhui; Lupton, Michelle K.; Troakes, Claire; Al-Sarraj, Safa; Niblock, Michael; Gallo, Jean-Marc; Adnan, Jihad; Killick, Richard; Brown, Kristelle S.; Medway, Christopher; Lord, Jenny; Turton, James; Bras, Jose; Morgan, Kevin; Powell, John F.; Singleton, Andrew; Hardy, John

    2014-01-01

    The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raise the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias. PMID:25104557

  11. [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.

  12. Physical mapping of the major early-onset familial Alzheimer`s disease locus on chromosome 14 and analysis of candidate gene sequences

    SciTech Connect

    Tanzi, R.E.; Romano, D.M.; Crowley, A.C.

    1994-09-01

    Genetic studies of kindreds displaying evidence for familial AD (FAD) have led to the localization of gene defects responsible for this disorder on chromosomes 14, 19, and 21. A minor early-onset FAD gene on chromosome 21 has been identified to enode the amyloid precursor protein (APP), and the late-onset FAD susceptibility locus on chromosome 19 has been shown to be in linkage disequilibrium with the E4 allele of the APOE gene. Meanwhile, the locus responsible for the major form of early-onset FAD on chromosome 14q24 has not yet been identified. By recombinational analysis, we have refined the minimal candidate region containing the gene defect to approximately 3 megabases in 14q24. We will describe our laboratory`s progress on attempts to finely localize this locus, as well as test known candidate genes from this region for either inclusion in the minimal candidate region or the presence of pathogenic mutations. Candidate genes that have been tested so far include cFOS, heat shock protein 70 member (HSF2A), transforming growth factor beta (TGFB3), the trifunctional protein C1-THF synthase (MTHFD), bradykinin receptor (BR), and the E2k component of a-ketoglutarate dehydrogenase. HSP2A, E2k, MTHFD, and BR do not map to the current defined minimal candidate region; however, sequence analysis must be performed to confirm exclusion of these genes as true candidates. Meanwhile, no pathogenic mutations have yet been found in cFOS or TGFB3. We have also isolated a large number of novel transcribed sequences from the minimal candidate region in the form of {open_quotes}trapped exons{close_quotes} from cosmids identified by hybridization to select YAC clones; we are currently in the process of searching for pathogenic mutations in these exons in affected individuals from FAD families.

  13. Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from Type 1 diabetes.

    PubMed

    McDonald, T J; Colclough, K; Brown, R; Shields, B; Shepherd, M; Bingley, P; Williams, A; Hattersley, A T; Ellard, Sian

    2011-09-01

    Maturity-onset diabetes of the young is a monogenic form of familial, young-onset diabetes. It is rare (∼1% diabetes) and may be misdiagnosed as Type 1 diabetes and inappropriately treated with insulin. Type 1 diabetes is characterized by the presence of islet autoantibodies, including glutamate decarboxylase (GAD) and islet antigen-2 (IA-2) antibodies. The prevalence of islet autoantibodies is unknown in maturity-onset diabetes of the young and may have the potential to differentiate this form of diabetes from Type 1 diabetes. The aim of this study was to determine the prevalence of GAD and IA-2 antibodies in patients with maturity-onset diabetes of the young and Type 1 diabetes. We measured plasma GAD and IA-2 antibodies in 508 patients with the most common forms of maturity-onset diabetes of the young (GCK: n = 227; HNF1A: n = 229; HNF4A: n = 52) and 98 patients with newly diagnosed Type 1 diabetes (diagnosed < 6 months). Autoantibodies were considered positive if ≥ 99th centile of 500 adult control subjects. GAD and/or IA-2 antibodies were present in 80/98 (82%) patients with Type 1 diabetes and 5/508 (< 1%) patients with maturity-onset diabetes of the young. In the cohort with Type 1 diabetes, both GAD and IA-2 antibodies were detected in 37.8% of patients, GAD only in 24.5% and IA-2 only in 19.4%. All five patients with maturity-onset diabetes of the young with detectable antibodies had GAD antibodies and none had detectable IA-2 antibodies. The prevalence of GAD and IA-2 antibodies in maturity-onset diabetes of the young is the same as in control subjects (< 1%). The finding of islet autoantibodies, especially IA-2 antibodies, makes the diagnosis of maturity-onset diabetes of the young very unlikely and genetic testing should only be performed if other clinical characteristics strongly suggest this form of diabetes rather than Type 1 diabetes. This supports routine islet autoantibody testing before proceeding to more expensive molecular genetic testing

  14. Genetic Modifiers of Age at Onset in Carriers of the G206A Mutation in PSEN1 With Familial Alzheimer Disease Among Caribbean Hispanics

    PubMed Central

    Lee, Joseph H.; Cheng, Rong; Vardarajan, Badri; Lantigua, Rafael; Reyes-Dumeyer, Dolly; Ortmann, Ward; Graham, Robert R.; Bhangale, Tushar; Behrens, Timothy W.; Medrano, Martin; Jiménez-Velázquez, Ivonne Z.; Mayeux, Richard

    2016-01-01

    Importance The present study identified potential genetic modifiers that may delay or accelerate age at onset of familial Alzheimer disease (AD) by examining age at onset in PSEN1 mutation carrier families, and further investigation of these modifiers may provide insight into the pathobiology of AD and potential therapeutic measures. Objective To identify genetic variants that modify age at onset of AD. Design, Setting, And Participants Using a subset of Caribbean Hispanic families that carry the PSEN1 p.G206A mutation, we performed a 2-stage genome study. The mutation carrier families from an ongoing genetic study served as a discovery set, and the cohort of those with LOAD served as a confirmation set. To identify candidate loci, we performed linkage analysis using 5 p.G206A carrier families (n = 56), and we also performed whole-exome association analysis using 31 p.G206A carriers from 26 families. To confirm the genetic modifiers identified from the p.G206A carrier families, we analyzed the GWAS data for 2888 elderly individuals with LOAD. All study participants were Caribbean Hispanics. Main Outcomes and Measures Age at onset of AD. Results Linkage analysis of AD identified the strongest linkage support at 4q35 (LOD [logarithm of odds] score, 3.69), and the GWAS of age at onset identified variants on 1p13.1, 2q13, 4q25, and 17p11. In the confirmation stage, genewise analysis identified SNX25, PDLIM3, and 3 SH3 domain genes (SORBS2, SH3RF3, and NPHP1) to be significantly associated with LOAD. Subsequent allelic association analysis confirmed SNX25, PDLIM3, and SORBS2 as genetic modifiers of age at onset of EOAD and LOAD and provided modest support for SH3RF3 and NPHP1. Conclusions and Relevance Our 2-stage analysis revealed that SNX25, PDLIM3, and SORBS2 may serve as genetic modifiers of age at onset in both EOAD and LOAD. PMID:26214276

  15. BACE1 elevation is involved in amyloid plaque development in the triple transgenic model of Alzheimer's disease: differential Aβ antibody labeling of early-onset axon terminal pathology.

    PubMed

    Cai, Yan; Zhang, Xue-Mei; Macklin, Lauren N; Cai, Huaibin; Luo, Xue-Gang; Oddo, Salvatore; Laferla, Frank M; Struble, Robert G; Rose, Gregory M; Patrylo, Peter R; Yan, Xiao-Xin

    2012-02-01

    β-amyloid precursor protein (APP) and presenilins mutations cause early-onset familial Alzheimer's disease (FAD). Some FAD-based mouse models produce amyloid plaques, others do not. β-Amyloid (Aβ) deposition can manifest as compact and diffuse plaques; it is unclear why the same Aβ molecules aggregate in different patterns. Is there a basic cellular process governing Aβ plaque pathogenesis? We showed in some FAD mouse models that compact plaque formation is associated with a progressive axonal pathology inherent with increased expression of β-secretase (BACE1), the enzyme initiating the amyloidogenic processing of APP. A monoclonal Aβ antibody, 3D6, visualized distinct axon terminal labeling before plaque onset. The present study was set to understand BACE1 and axonal changes relative to diffuse plaque development and to further characterize the novel axonal Aβ antibody immunoreactivity (IR), using triple transgenic AD (3xTg-AD) mice as experimental model. Diffuse-like plaques existed in the forebrain in aged transgenics and were regionally associated with increased BACE1 labeled swollen/sprouting axon terminals. Increased BACE1/3D6 IR at axon terminals occurred in young animals before plaque onset. These axonal elements were also co-labeled by other antibodies targeting the N-terminal and mid-region of Aβ domain and the C-terminal of APP, but not co-labeled by antibodies against the Aβ C-terminal and APP N-terminal. The results suggest that amyloidogenic axonal pathology precedes diffuse plaque formation in the 3xTg-AD mice, and that the early-onset axonal Aβ antibody IR in transgenic models of AD might relate to a cross-reactivity of putative APP β-carboxyl terminal fragments.

  16. Genome-Wide Association of Familial Late-Onset Alzheimer's Disease Replicates BIN1 and CLU and Nominates CUGBP2 in Interaction with APOE

    PubMed Central

    Wijsman, Ellen M.; Pankratz, Nathan D.; Choi, Yoonha; Rothstein, Joseph H.; Faber, Kelley M.; Cheng, Rong; Lee, Joseph H.; Bird, Thomas D.; Bennett, David A.; Diaz-Arrastia, Ramon; Goate, Alison M.; Farlow, Martin; Ghetti, Bernardino; Sweet, Robert A.; Foroud, Tatiana M.; Mayeux, Richard

    2011-01-01

    Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10−81), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10−8). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false

  17. Do adolescent drug users fare the worst? Onset type, juvenile delinquency, and criminal careers.

    PubMed

    DeLisi, Matt; Angton, Alexia; Behnken, Monic P; Kusow, Abdi M

    2015-02-01

    Although substance abuse often accompanies delinquency and other forms of antisocial behavior, there is less scholarly agreement about the timing of substance use vis-à-vis an individual's antisocial trajectory. Similarly, although there is extraordinary evidence that onset is inversely related to the severity of the criminal career, there is surprisingly little research on the offense type of onset or the type of antisocial behavior that was displayed when an individual initiated his or her offending career. Drawing on data from a sample of serious adult criminal offenders (N = 500), the current study examined 12 forms of juvenile delinquency (murder, rape, robbery, aggravated assault, burglary, larceny, auto theft, arson, weapons, sexual offense, drug sales, and drug use) in addition to age at arrest onset, age, sex, race to explore their association with chronicity (total arrests), extreme chronicity (1 SD above the mean which was equivalent to 90 career arrests), and lambda (offending per year). The only onset offense type that was significantly associated with all criminal career outcomes was juvenile drug use. Additional research on the offense type of delinquent onset is needed to understand launching points of serious antisocial careers.

  18. Adult-Onset Type 1 Diabetes: A Qualitative Study of Decision-Making Needs.

    PubMed

    Jull, Janet; Witteman, Holly O; Ferne, Judi; Yoganathan, Manosila; Stacey, Dawn

    2016-04-01

    Type 1 diabetes is an autoimmune disease resulting from insulin deficiency and must be carefully managed to prevent serious health complications. Diabetes education and management strategies usually focus on meeting the decision-making needs of children and their families, but little is known about the decisional needs of people with adult-onset type 1 diabetes. The aim of this study was to explore the diabetes-related decision-making needs of people diagnosed with adult-onset type 1 diabetes. An interpretive descriptive qualitative study was conducted. Participants who self-identified as having adult-onset type 1 diabetes were interviewed using a semistructured interview guide. Transcripts were coded to identify needs, supports and barriers using thematic analysis. Participating in the study were 8 adults (2 men, 6 women), ages 33 to 57, with type 1 diabetes for durations of 1 to 20 or more years. Their decision-making needs are summarized in 6 broad themes: 1) people diagnosed with type 1 diabetes are launched into a process of decision-making; 2) being diagnosed with type 1 diabetes means you will always have to make decisions; 3) knowledge is crucial; 4) personal preferences matter; 5) support is critical for decisions about self-care in type 1 diabetes; 6) living with type 1 diabetes means making very individualized decisions about daily life. The findings describe the sudden and ubiquitous nature of type 1 diabetes decision-making and the need to tailor approaches for making care decisions in type 1 diabetes. People diagnosed with adult-onset type 1 diabetes require access to reliable information, support and opportunities for participation in decision-making. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  19. Tension-type headache in Parma's adult general population: a focus on age of onset.

    PubMed

    Taga, Arens; Russo, Marco; Manzoni, Gian C; Torelli, Paola

    2015-01-01

    In the present paper, we focus on the age of onset for tension-type headache in a population-based sample in the Parma, distinguishing its different subtypes and considering definite and probable diagnoses. Age of headache onset is a useful clinical feature for differential diagnosis between primary headaches and between primary and secondary headache forms. A total of 904 subjects representative of the Parma's adult general population were interviewed face to face by a physician from the Parma Headache Centre, using a validated questionnaire specially designed for the diagnosis of primary headaches according to the ICHD-II criteria. In the majority of subjects diagnosed with definite tension-type headache, age of onset was 39 years or less, while mean age of onset was 29.7 years (SD 16.3 years, range 5-79 years), the median being 25 years. Both infrequent and frequent episodic definite tension-type headache first occurred in the majority of cases in the second, third and fourth decades. Subjects with chronic definite tension-type headache reported a later onset in life (i.e. fourth, fifth and sixth decades). In our study, mean age of onset for probable tension-type headache was 23.7 years (SD 9.2 years, range 10-40 years) and the median was 22 years. In no case did we find significant gender differences. Our study results are similar to most of those reported in the literature. Further research needs to be done in the Italian epidemiological context, given the lack of literature reports on this topic.

  20. The role of ryanodine receptor type 3 in a mouse model of Alzheimer disease

    PubMed Central

    Liu, Jie; Supnet, Charlene; Sun, Suya; Zhang, Hua; Good, Levi; Popugaeva, Elena; Bezprozvanny, Ilya

    2014-01-01

    Dysregulated endoplasmic reticulum (ER) calcium (Ca2+) signaling is reported to play an important role in Alzheimer disease (AD) pathogenesis. The role of ER Ca2+ release channels, the ryanodine receptors (RyanRs), has been extensively studied in AD models and RyanR expression and activity are upregulated in the brains of various familial AD (FAD) models. The objective of this study was to utilize a genetic approach to evaluate the importance of RyanR type 3 (RyanR3) in the context of AD pathology. PMID:24476841

  1. Emotional recognition from face, voice, and music in dementia of the Alzheimer type.

    PubMed

    Drapeau, Joanie; Gosselin, Nathalie; Gagnon, Lise; Peretz, Isabelle; Lorrain, Dominique

    2009-07-01

    Persons with dementia of the Alzheimer type (DAT) are impaired in recognizing emotions from face and voice. Yet clinical practitioners use these mediums to communicate with DAT patients. Music is also used in clinical practice, but little is known about emotional processing from music in DAT. This study aims to assess emotional recognition in mild DAT. Seven patients with DAT and 16 healthy elderly adults were given three tasks of emotional recognition for face, prosody, and music. DAT participants were only impaired in the emotional recognition from the face. These preliminary results suggest that dynamic auditory emotions are preserved in DAT.

  2. Focal cerebral hypoperfusion and selective cognitive deficit in dementia of the Alzheimer type.

    PubMed Central

    Celsis, P; Agniel, A; Puel, M; Rascol, A; Marc-Vergnes, J P

    1987-01-01

    Regional cerebral blood flow was investigated using single photon emission computed tomography and xenon-133 intravenous injection in six patients with dementia of the Alzheimer type (DAT) with atypical focal clinical presentation, and in 20 age-matched healthy volunteers. The patients had a progressive and preponderant cognitive deficit and a focal hypoperfusion that correlated with the neuropsychological findings, whereas the average flow did not significantly differ from that of controls. The assessment of concordant haemodynamic and neuropsychological focal abnormalities could be useful in the diagnosis of atypical cases of DAT. Images PMID:3501801

  3. Cognitive performance in senile dementia of the Alzheimer's type: the Kitchen Task Assessment.

    PubMed

    Baum, C; Edwards, D F

    1993-05-01

    The Kitchen Task Assessment (KTA) is a functional measure that records the level of cognitive support required by a person with Senile Dementia of the Alzheimer's Type (SDAT) to complete a cooking task successfully. The results allow the clinician to help caregivers understand the level of support the impaired person needs to perform daily living tasks. This paper presents the validity and internal consistency of the KTA. Data were collected from 106 persons diagnosed with SDAT. Construct validity was established by examining the relationship between subjects' performance on the KTA and standard neuropsychological measures.

  4. Association of the 3' UTR transcription factor LBP-1c/CP2/LSF polymorphism with late-onset Alzheimer's disease.

    PubMed

    Luedecking-Zimmer, Erin; DeKosky, Steven T; Nebes, Robert; Kamboh, M Ilyas

    2003-02-01

    Alzheimer's disease (AD) is a genetically heterogeneous neurodegenerative disorder. To date, apolipoprotein E (apoE) is the only established susceptibility gene for late-onset AD. ApoE accounts for less than 50% of the risk of AD, indicating the presence of other unknown susceptibility loci. Linkage studies have indicated chromosome 12 as the most likely location for another late-onset AD locus. We examined seven polymorphisms in five candidate genes located in and around the linkage peaks on chromosome 12 in 564 cases and 523 controls. The genes included complement component 1R (C1R), vitamin D receptor (VDR), scavenger-receptor B1 (SR-B1), low-density lipoprotein receptor related protein 1 (LRP1), and transcription factor LBP-1c/CP2/LSF. We found no association with C1R, VDR, SR-B1, and LRP1 polymorphisms. However, the frequency of the A allele of the 3' (untranslated region) UTR LBP-1c/CP2/LSF polymorphism was higher in controls than cases (0.071 vs. 0.051; P = 0.042) with an adjusted odds ratio (OR) of 0.65 (95% confidence interval [CI]: 0.43-0.96; P = 0.0498). Our data suggest that the LBP-1c/CP2/LSF polymorphism may have a moderate protective effect against the risk of AD.

  5. Youth-onset type 2 diabetes among american indians and alaska natives.

    PubMed

    Moore, Kelly

    2010-01-01

    Youth-onset type 2 diabetes has emerged as a significant public health concern for American Indians and Alaska Natives. Data from the National Institutes of Health longitudinal epidemiological study among the Pima Indians of southern Arizona and the Indian Health Service continue to document a rising incidence and prevalence of type 2 diabetes among American Indian and Alaska Native youth. Although national trends related to lack of physical activity and to unhealthy nutrition behaviors have contributed to the epidemic, the adverse conditions created by poverty, social injustice, trauma, and cultural disruption are also important in understanding the underlying causes for this public health crisis. This adverse environment is likely to provide little support for healthy nutrition and physical activity behaviors as well as other diabetes self-care behaviors. Known risk factors from the Pima Indian studies, such as intrauterine exposure to diabetes, bottle-feeding, and obesity, provide a basis for worthwhile intervention strategies. In this article, the author will review the current literature on the epidemiology of youth-onset type 2 diabetes among American Indians and Alaska Natives, discuss causes for the diabetes epidemic among American Indians and Alaska Natives, review risk factors for youth-onset type 2 diabetes in this population, and share promising youth physical activity promotion programs created and implemented specifically for American Indian and Alaska Native youth. However, more research on interventions to address the Native communities' psychosocial issues and concerns around youth-onset type 2 diabetes is urgently needed.

  6. Type II diabetes of early onset: a distinct clinical and genetic syndrome?

    PubMed Central

    O'Rahilly, S; Spivey, R S; Holman, R R; Nugent, Z; Clark, A; Turner, R C

    1987-01-01

    The inheritance of non-insulin-dependent (type II) diabetes was studied by a continuous infusion of glucose test in all available first degree relatives of 48 diabetic probands of various ages and with differing severity of disease. In an initial study of 38 type II diabetic subjects and their first degree relatives six islet cell antibody negative patients with early onset disease (aged 25-40 at diagnosis) were found to have a particularly high familial prevalence of diabetes or glucose intolerance. Nine of 10 parents available for study either had type II diabetes or were glucose intolerant. A high prevalence of diabetes or glucose intolerance was also found in their siblings (11/16;69%). In a second study of the families of a further 10 young diabetic probands (presenting age 25-40) whose islet cell antibody state was unknown a similar high prevalence of diabetes or glucose intolerance was found among parents of the five islet cell antibody negative probands (8/9; 89%) but not among parents of the five islet cell antibody positive probands (3/8;38%). Islet cell antibody negative diabetics with early onset type II disease may have inherited a diabetogenic gene or genes from both parents. They commonly need insulin to maintain adequate glycaemic control and may develop severe diabetic complications. Early onset type II diabetes may represent a syndrome in which characteristic pedigrees, clinical severity, and absence of islet autoimmunity make it distinct from either type I diabetes, maturity onset diabetes of the young, or late onset type II diabetes. PMID:3107658

  7. Herpes simplex virus type 1 and Alzheimer's disease: possible mechanisms and signposts.

    PubMed

    Itzhaki, Ruth F

    2017-08-01

    Support for the concept that herpes simplex virus type 1 (HSV1), when present in the brains of apolipoprotein E-ε4 carriers, is a major risk for Alzheimer's disease (AD) is increasing steadily, with over 120 publications providing direct or indirect evidence relevant to the hypothesis. No articles have contested the concept, apart from 3 published 13-18 yr ago. This review describes very recent studies on the role of HSV1 but refers also to older studies that provide background for some lesser-known related topics not covered in other recent reviews; these include the relevance of herpes simplex encephalitis and of epilepsy to AD, the action of IFN, and the possible relevance of the different types of DNA damage to AD-in particular, those caused by HSV1-and mechanisms of repair of damage. New epidemiologic data supporting previous studies on mild cognitive impairment and progression to AD are reviewed, as are those examining the relationship between total infectious burden (additive seropositivity to various microbes) and cognition/AD. The latter indicates the involvement of HSV1 and cytomegalovirus (and the necessity of taking into account any marked differences in sensitivity of antibody detection). Recent studies that provide further support for the occurrence of repeated reactivation of latent HSV1 in the brain in AD pathogenesis are also discussed.-Itzhaki, R. F. Herpes simplex virus type 1 and Alzheimer's disease: possible mechanisms and signposts. © FASEB.

  8. Peripheral blood mononuclear cell-converted induced pluripotent stem cells (iPSCs) from an early onset Alzheimer's patient.

    PubMed

    Lee, Han-Kyu; Morin, Peter; Xia, Weiming

    2016-03-01

    Improvement in transduction efficiency makes it possible to convert blood cells into induced pluripotent stem cells (iPSC). In this study, we generated an iPSC line from peripheral blood mononuclear cells (PBMC) donated by a patient who exhibited memory deficit at age 59; outcome of positron emission tomography scan is consistent with a diagnosis of Alzheimer's disease. Integration-free CytoTune-iPS Sendai Reprogramming factors which include Sendai virus particles of the four Yamanaka factors Oct4, Sox2, Klf4, and c-Myc were introduced to PBMC to convert them to iPSCs without retention of virus. Three germ layer differentiation was induced to demonstrate the pluripotency of these iPSCs. Published by Elsevier B.V.

  9. Neuroethics, confidentiality, and a cultural imperative in early onset Alzheimer disease: a case study with a First Nation population.

    PubMed

    Stevenson, Shaun; Beattie, B Lynn; Vedan, Richard; Dwosh, Emily; Bruce, Lindsey; Illes, Judy

    2013-10-16

    The meaningful consideration of cultural practices, values and beliefs is a necessary component in the effective translation of advancements in neuroscience to clinical practice and public discourse. Society's immense investment in biomedical science and technology, in conjunction with an increasingly diverse socio-cultural landscape, necessitates the study of how potential discoveries in neurodegenerative diseases such as Alzheimer disease are perceived and utilized across cultures. Building on the work of neuroscientists, ethicists and philosophers, we argue that the growing field of neuroethics provides a pragmatic and constructive pathway to guide advancements in neuroscience in a manner that is culturally nuanced and relevant. Here we review a case study of one issue in culturally oriented neuroscience research where it is evident that traditional research ethics must be broadened and the values and needs of diverse populations considered for meaningful and relevant research practices. A global approach to neuroethics has the potential to furnish critical engagement with cultural considerations of advancements in neuroscience.

  10. Seasonality at the clinical onset of type 1 diabetes-Lessons from the SWEET database.

    PubMed

    Gerasimidi Vazeou, A; Kordonouri, O; Witsch, M; Hermann, J M; Forsander, G; de Beaufort, C; Veeze, H J; Maffeis, C; Cherubini, V; Cinek, O; Piccini, B; Holl, R W; Danne, T

    2016-10-01

    Seasonality at the clinical onset of type 1 diabetes (T1D) has been suggested by different studies, however, the results are conflicting. This study aimed to evaluate the presence of seasonality at clinical onset of T1D based on the SWEET database comprising data from 32 different countries. The study cohort included 23 603 patients (52% males) recorded in the international multicenter SWEET database (48 centers), with T1D onset ≤20 years, year of onset between 1980 and 2015, gender, year and month of birth and T1D-diagnosis documented. Data were stratified according to four age groups (<5, 5-<10, 10-<15, 15-20 years) at T1D onset, the latitude of European center (Northern ≥50°N and Southern Europe <50°N) and the year of onset ≤ or >2009. Analysis by month revealed significant seasonality with January being the month with the highest and June with the lowest percentage of incident cases (P < .001). Winter, early spring and late autumn months had higher percentage of incident cases compared with late spring and summer months. Stratification by age showed similar seasonality patterns in all four age groups (P ≤ .003 each), but not in children <24 months of age. There was no gender or latitude effect on seasonality pattern, however, the pattern differed by the year of onset (P < .001). Seasonality of diagnosis conformed to a sinusoidal model for all cases, females and males, age groups, northern and southern European countries. Seasonality at T1D clinical onset is documented by the large SWEET database with no gender or latitude (Europe only) effect except from the year of manifestation. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Influence of the Pro12Ala polymorphism of PPAR-gamma on age at onset and sRAGE levels in Alzheimer's disease.

    PubMed

    Yao, Lifen; Li, Keshen; Zhang, Liming; Yao, Songpo; Piao, Zhongyuan; Song, Lin

    2009-09-29

    Peroxisome proliferator-activated receptor gamma (PPAR-gamma) has been described to have a role in the modulation of various genes involved in Abeta homeostasis, inflammation, and energy metabolism, making it a candidate gene for risk of Alzheimer's disease (AD). A functional polymorphism in exon 2 of the PPAR-gamma gene has been related to AD, but the effects are inconsistent across studies. To determine the role of PPAR-gamma in genetic susceptibility to AD in a representative Chinese sample, we genotyped 362 AD patients and 370 healthy controls for PPAR-gamma Pro12Ala polymorphism by polymerase chain reaction-restriction fragment length polymorphism method. We also examined the potential impact of this polymorphism on plasma level of soluble receptor for advanced glycation end products (sRAGE), a decoy receptor whose reduction has been associated with a higher risk of AD. Our results suggest that PPAR-gamma Pro12Ala polymorphism was not associated with an increased risk of AD in the overall sample. Stratification analysis revealed that the PPAR-gamma Pro/Ala genotype may be associated with the development of early-onset AD in the individuals without APOE epsilon4 allele (OR=3.76, 95% CI=1.10-12.84; p=0.03), but this association became insignificant after Bonferroni correction (p (corr)=0.10). Moreover, in the subgroup of APOE epsilon4 noncarriers, Kaplan-Meier survival analyses indicated that AD patients with the Pro/Ala genotype presented with disease onset 4.6 years earlier than carriers of Pro/Pro genotype. Further investigation revealed that AD patients carrying Pro/Ala genotype had significantly lower plasma sRAGE levels than patients with Pro/Pro genotype. These findings suggest that the functional PPAR-gamma Pro12Ala polymorphism may modify the age at onset of AD.

  12. [A Japanese family with familial Alzheimer's disease associated with presenilin 1 mutation: relationship between younger age of onset and ApoE gene polymorphism].

    PubMed

    Marui, Wami; Iseki, Eizo; Sugiyama, Naoya; Matsumura, Takehiko; Suzuki, Kyoko; Odawara, Toshinari; Hino, Hiroaki; Kosaka, Kenji

    2003-04-01

    We previously reported a Japanese family with early-onset familial Alzheimer's disease associated with G 209 R presenilin 1(PS 1) mutation. There have been six patients across three generations in this family. In the present report, we described the clinical course, findings with neuroimaging and results of genetic examination of PS 1 and apolipoprotein E(ApoE) in three of six patients(II-1, III-1 and 2). The clinical course was common to all three patients. Memory disturbance, disorientation, amnestic aphasia, personality changes and perseveration appeared at early stages, whereas Gerstmann's syndrome, myoclonus and general convulsion were recognized at advanced stages. CT disclosed mild brain atrophy in the temporal lobes at early stages and diffuse brain atrophy predominantly in the fronto--temporal lobes at advanced stages. SPECT exhibited hypoperfusion in the fronto-temporal areas at early stages and hypoperfusion in the fronto-temporal and parieto-occipital areas at advanced stages. The age of onset in six patients demonstrated two clusters at age 53-55(I-1, II-1, 2 and 5) and age 46-48(III-1 and 2). PS 1 genotyping demonstrated that the heterozygous exonic missense mutation G 209 R was confirmed in all three patients. Regarding the ApoE genotyping, II-1(mother) was epsilon 3/epsilon 3, whereas III-1 and 2(children) were epsilon 3/epsilon 4. These findings suggest the possibility that there might be a gene dose effect, since the age of onset ranged from 5 to 7 years younger in patients who received epsilon 4 alleles from the father.

  13. Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families

    PubMed Central

    Cruchaga, Carlos; Chakraverty, Sumitra; Mayo, Kevin; Vallania, Francesco L. M.; Mitra, Robi D.; Faber, Kelley; Williamson, Jennifer; Bird, Tom; Diaz-Arrastia, Ramon; Foroud, Tatiana M.; Boeve, Bradley F.; Graff-Radford, Neill R.; St. Jean, Pamela; Lawson, Michael; Ehm, Margaret G.; Mayeux, Richard; Goate, Alison M.

    2012-01-01

    Pathogenic mutations in APP, PSEN1, PSEN2, MAPT and GRN have previously been linked to familial early onset forms of dementia. Mutation screening in these genes has been performed in either very small series or in single families with late onset AD (LOAD). Similarly, studies in single families have reported mutations in MAPT and GRN associated with clinical AD but no systematic screen of a large dataset has been performed to determine how frequently this occurs. We report sequence data for 439 probands from late-onset AD families with a history of four or more affected individuals. Sixty sequenced individuals (13.7%) carried a novel or pathogenic mutation. Eight pathogenic variants, (one each in APP and MAPT, two in PSEN1 and four in GRN) three of which are novel, were found in 14 samples. Thirteen additional variants, present in 23 families, did not segregate with disease, but the frequency of these variants is higher in AD cases than controls, indicating that these variants may also modify risk for disease. The frequency of rare variants in these genes in this series is significantly higher than in the 1,000 genome project (p = 5.09×10−5; OR = 2.21; 95%CI = 1.49–3.28) or an unselected population of 12,481 samples (p = 6.82×10−5; OR = 2.19; 95%CI = 1.347–3.26). Rare coding variants in APP, PSEN1 and PSEN2, increase risk for or cause late onset AD. The presence of variants in these genes in LOAD and early-onset AD demonstrates that factors other than the mutation can impact the age at onset and penetrance of at least some variants associated with AD. MAPT and GRN mutations can be found in clinical series of AD most likely due to misdiagnosis. This study clearly demonstrates that rare variants in these genes could explain an important proportion of genetic heritability of AD, which is not detected by GWAS. PMID:22312439

  14. Late onset glycogen storage disease type II with reducing body-like inclusions.

    PubMed

    Gayathri, N; Yasha, T C; Vani, S; Taly, A B; Nalini, A; Shankar, S K

    2010-01-01

    Skeletal muscle tissue from 3 patients with clinical diagnosis of limb girdle muscular dystrophy revealed a vacuolar myopathy with glycogen storage and lysosomal activity. A diagnosis of late onset GSD Type II was considered. An interesting finding was the presence of round to oval eosinophilic inclusions which reduced on menadione linked a-glycerophosphate dehydrogenase (MAG). There are only two reports in the literature describing similar inclusions in late onset GSD II. We report morphological findings of this rare disorder and compare the findings with earlier two reports.

  15. Amplification of Herpes simplex type 1 and Human Herpes type 5 viral DNA from formalin-fixed Alzheimer brain tissue.

    PubMed

    Rodriguez, John D; Royall, Donald; Daum, Luke T; Kagan-Hallet, Kathleen; Chambers, James P

    2005-12-16

    It is known that nucleic acids from formalin-fixed tissues are not nearly as good templates for DNA amplification as those extracted from fresh tissues. However, specimens stored in most pathologic archives are initially fixed in formalin. The possibility of an infectious etiology of several diseases including Alzheimer's underscores the usefulness of archived tissue in assessing the association of infectious agents with specific pathology. In this report, we describe in detail a method resulting in robust amplification of HSV1 and Human Herpes type (HHV) 5 viral DNA targets using formalin-fixed Alzheimer brain frontal and temporal tissue as source of amplification template. Herpes simplex type 2 viral DNA was not detected in the limited samples examined in this study. Amplicons were verified by sequence analysis. Brain tissue stored in formalin longer than 1 year prior to post-formalin-fixation analysis gave rise to significantly shorter amplicons consistent with the observation that template DNA integrity decreases significantly with increasing time of storage in formalin. Thus, this report should be useful in PCR-based investigations assessing the regional presence of viral DNAs in formalin-fixed brain tissue.

  16. A Novel AβPP M722K Mutation Affects Amyloid-β Secretion and Tau Phosphorylation and May Cause Early-Onset Familial Alzheimer's Disease in Chinese Individuals.

    PubMed

    Wang, Qianqian; Jia, Jianping; Qin, Wei; Wu, Liyong; Li, Dan; Wang, Qi; Li, Hanzhi

    2015-01-01

    Mutations within exons 16 and 17 of the amyloid-β protein precursor (AβPP) gene were the first known causes of early-onset familial Alzheimer's disease (EOFAD). Since the first AβPP mutation was reported, 39 different AβPP variations have been discovered in EOFAD. We described a novel AβPP M722K mutation found in a Chinese familial Alzheimer's disease pedigree and confirmed its effects on amyloid-β (Aβ) secretion and tau phosphorylation. We performed direct sequencing of exons 16 and 17 of the AβPP gene and coding exons 3-12 of the PSEN1 and PSEN2 genes for genetic analysis. N2a cells were transfected with wild-type AβPP, AβPP constructs harboring the M722K mutation, or AβPP constructs harboring the Swedish mutation to demonstrate the effects of the AβPP M722K mutation on Aβ secretion and tau phosphorylation. Different phenotypes of patients carrying the AβPP M722K mutation maybe were related to different apolipoprotein E genotypes. The expression of AβPP M722K in mouse neuroblastoma N2a cells induced a 1.7-fold increased ratio of Aβ 42 to Aβ 40 without changes in sAβPPα and sAβPPβ. Tau phosphorylation at the AT8 sites was also increased. Maybe the AβPP M722K mutation contributed to the cause of EOFAD in this Chinese pedigree mediated by increased Aβ 42/Aβ 40. Further studies should be conducted to validate the pathogenicity of AβPP M722K and the interactions among γ-secretase, APOE, and AβPP.

  17. Neuroethics, confidentiality, and a cultural imperative in early onset Alzheimer disease: a case study with a First Nation population

    PubMed Central

    2013-01-01

    The meaningful consideration of cultural practices, values and beliefs is a necessary component in the effective translation of advancements in neuroscience to clinical practice and public discourse. Society’s immense investment in biomedical science and technology, in conjunction with an increasingly diverse socio-cultural landscape, necessitates the study of how potential discoveries in neurodegenerative diseases such as Alzheimer disease are perceived and utilized across cultures. Building on the work of neuroscientists, ethicists and philosophers, we argue that the growing field of neuroethics provides a pragmatic and constructive pathway to guide advancements in neuroscience in a manner that is culturally nuanced and relevant. Here we review a case study of one issue in culturally oriented neuroscience research where it is evident that traditional research ethics must be broadened and the values and needs of diverse populations considered for meaningful and relevant research practices. A global approach to neuroethics has the potential to furnish critical engagement with cultural considerations of advancements in neuroscience. PMID:24131854

  18. Acute-Onset Type 1 Diabetes that Developed During the Administration of Olanzapine

    PubMed Central

    Iwaku, Kenji; Otuka, Fumiko; Taniyama, Matsuo

    2017-01-01

    The patient was 32-year-old man, who received olanzapine for schizophrenia and developed polyuria and thirst without drinking soft-drinks after 4 months. Five months after the initiation of treatment, he developed diabetic ketoacidosis (blood glucose: 490 mg/dL, HbA1c: 15.5%). He was diagnosed with type 1 diabetes (glutamic acid decarboxylase (GAD)-Ab: 5.6 U/mL, IA-2 Ab: 5.9 U/mL, fasting C-peptide: 0.12 ng/mL) and was put on intensive insulin therapy. At four months after the onset of 1A diabetes, he experienced a honeymoon phase that was sustained until the 40th month of treatment. We hypothesize that the administration of olanzapine to a patient with pre-type 1A diabetes induced marked hyperglycemia and accelerated the onset of type 1A diabetes. PMID:28154279

  19. Herpes simplex virus type 1 and Alzheimer's disease: the autophagy connection.

    PubMed

    Itzhaki, Ruth F; Cosby, S Louise; Wozniak, Matthew A

    2008-01-01

    The causes of Alzheimer's disease (AD) and of the characteristic pathological features - amyloid plaques and neurofibrillary tangles - of AD brain are unknown, despite the enormous resources provided over the years for their investigation. Indeed, the only generally accepted risk factors are age, Down syndrome, carriage of the type 4 allele of the apolipoprotein E gene (APOE-epsilon 4), and possibly brain injury. Following the authors' previous studies implicating herpes simplex virus type 1 (HSV1) in brain of APOE-epsilon 4 carriers as a major cause of AD, the authors propose here, on the basis of their and others' recent studies, that not only does HSV1 generate the main components of amyloid plaques and neurofibrillary tangles (NFTs) - beta-amyloid (A beta) and abnormally phosphorylated tau but also, by disrupting autophagy, it prevents degradation of these aberrant proteins, leading to their accumulation and deposition, and eventually to AD.

  20. Bayer-activities of daily living scale in mild and moderate dementia of the Alzheimer type.

    PubMed

    Nagaratnam, Nages; Nagaratnam, Kujan; O'Mara, Deborah

    2013-12-01

    The main purpose of this study is to examine the reliability of the Bayer-Activities of Daily Living (B-ADL) scale when used as a cognitive screening instrument for mild and moderate dementia of the Alzheimer type. This is a retrospective study of 66 patients with dementia. The B-ADL scale was completed by the caregiver or the family member at the first encounter. The internal consistency was found to be 0.94 for the 27 patients that completed all 25 questions in the scale. Significant correlation and receiver-operating characteristic curve analysis were found for the B-ADL total score and subscale 1 (tasks requiring short- and long-term memory) for Clinical Dementia Rating scale. Severity of dementia by the B-ADL scale is statistically similar but not the same as Mini-Mental State Examination. Our findings confirm that B-ADL scale is a valid indicator of the cognitive status of patients with Alzheimer's disease.

  1. Does study partner type impact the rate of Alzheimer's disease progression?

    PubMed

    Grill, Joshua D; Zhou, Yan; Karlawish, Jason; Elashoff, David

    2014-01-01

    Most patients with Alzheimer's disease (AD) do not have a spouse. Despite this, the majority of AD research participants enroll with a spouse study partner. It remains unclear if differences between AD patients who do and do not have a spouse may bias study results. In this study, we examined whether AD patients with different study partner types (spouse versus adult child) demonstrate different rates of disease progression over two years on three outcome measures commonly used in AD research, including clinical trials. We used data from the National Alzheimer's Coordinating Center Uniform Data Set to examine disease progression in participants age 55-90 with probable AD dementia. We examined disease progression as measured by the Clinical Dementia Rating Scale-Sum of the Boxes score, the Mini Mental Status Examination, and the Functional Assessment Questionnaire. Analyses were performed on data for all available eligible participants from the NACC UDS and after performing a propensity-matching model to better account for inherent differences between the populations of interest. Propensity matching was successful only when models did not include age and gender. For both propensity-matched analyses and those of all available data, we did not observe any differences between the study partner populations for any outcome measure. These results suggest that if investigators can improve in recruiting AD patients with adult child caregivers to research, the implications to study results may be minimal.

  2. Raman spectroscopy of blood serum for Alzheimer's disease diagnostics: specificity relative to other types of dementia.

    PubMed

    Ryzhikova, Elena; Kazakov, Oleksandr; Halamkova, Lenka; Celmins, Dzintra; Malone, Paula; Molho, Eric; Zimmerman, Earl A; Lednev, Igor K

    2015-07-01

    The key moment for efficiently and accurately diagnosing dementia occurs during the early stages. This is particularly true for Alzheimer's disease (AD). In this proof-of-concept study, we applied near infrared (NIR) Raman microspectroscopy of blood serum together with advanced multivariate statistics for the selective identification of AD. We analyzed data from 20 AD patients, 18 patients with other neurodegenerative dementias (OD) and 10 healthy control (HC) subjects. NIR Raman microspectroscopy differentiated patients with more than 95% sensitivity and specificity. We demonstrated the high discriminative power of artificial neural network (ANN) classification models, thus revealing the high potential of this developed methodology for the differential diagnosis of AD. Raman spectroscopic, blood-based tests may aid clinical assessments for the effective and accurate differential diagnosis of AD, decrease the labor, time and cost of diagnosis, and be useful for screening patient populations for AD development and progression. Multivariate data analysis of blood serum Raman spectra allows for the differentiation between patients with Alzheimer's disease, other types of dementia and healthy individuals.

  3. AVP-786 for the treatment of agitation in dementia of the Alzheimer's type.

    PubMed

    Garay, Ricardo P; Grossberg, George T

    2017-01-01

    Agitation is common and distressing in patients with Alzheimer-type dementia, but safe, effective treatments remain elusive. Psychological treatments are first-line options, but they have limited efficacy. Off-label psychotropic medications are frequently used, but they also have limited effectiveness, and their use may have harmful side effects, including death. Areas covered: This review discusses the history leading to the conception of AVP-786 (deuterated (d6)-dextromethorphan/quinidine), its pharmacokinetic and pharmacodynamic profiles and safety issues, together with an overview of recent clinical trials. Data were found in the medical literature, in US and EU clinical trial registries and in information provided by the manufacturer. Expert opinion: AVP-786 is one of six investigational compounds in recent phase III clinical development for agitation in Alzheimer disease (AD). Quinidine and deuteration appear to prolong dextromethorphan's plasma half-life and facilitate brain penetration. The FDA granted fast-track designation to AVP-786 and allowed use of data generated on dextromethorphan-quinidine (AVP-923, Nuedexta®) for regulatory filings. AVP-923 reduced agitation in AD and was well tolerated in a phase II RCT that included more than 200 patients. A phase III clinical development program of AVP-786 for AD agitation was recently initiated. This program is expected to start generating results in July 2018.

  4. Early onset type 2 diabetes in Jamaica and in Mexico. Opportunities derived from an interethnic study.

    PubMed

    Irving, Rachael; Tusié-Luna, Ma Teresa; Mills, James; Wright-Pascoe, Rosemarie; McLaughlin, Wayne; Aguilar-Salinas, Carlos A

    2011-01-01

    Populations with Amerindian or African heritages are the one with the highest prevalence of diabetes worldwide. A large percentage of these individuals survived famine. However, the survival effect has become detrimental to their descendents living in an environment of caloric surplus. In countries, like Mexico and Jamaica, in which diabetes is highly prevalent, the onset of the disease happens at earlier ages. Our objective is to summarize diabetes data from Mexico and Jamaica and to discuss the opportunities that can result from an interethnic study. On one hand, the prevalence of diabetes in Jamaica is 17.9% in the 15+ age group. Jamaican researchers have built a cohort of families with early onset type 2 diabetes. In this population, this form of the disease is unrelated to MODY genes. On the other hand, the prevalence of diabetes in adult Mexicans is 14.4%. The group in which the greater percentual changes have occurred is the adults who are below the age of 40. More than two thirds of the early onset cases studied have a body mass index that is >25 kg/m2 and the clinical characteristics of metabolic syndrome. A minority of them has mutations in the MODY genes. The joint study of Mexican and Jamaican cohorts of early onset type 2 diabetes cases will be useful to identify new genetic and environmental players in the pathogenesis of this entity.

  5. Preparing for presymptomatic DNA testing for early onset Alzheimer's disease/cerebral haemorrhage and hereditary Pick disease.

    PubMed Central

    Tibben, A; Stevens, M; de Wert, G M; Niermeijer, M F; van Duijn, C M; van Swieten, J C

    1997-01-01

    The acceptability of presymptomatic testing in 21 people at 50% risk for the APP-692 mutation causing presenile Alzheimer's disease or cerebral haemorrhage resulting from cerebral amyloid angiopathy (FAD-CH), and in 43 people at 50% risk for hereditary Pick disease (HPD) was assessed. Neither group differed in demographic variables. Thirty-nine people (64%) in the whole group would request presymptomatic testing if it were clinically available, although two-thirds did not yet feel ready to take it. The most important reasons in the HPD and FAD-CH group for taking the test were: to further basic research (42% and 47%, respectively), informing children (47% and 50%, respectively), future planning (29% and 47%, respectively), and relieving uncertainty (46% and 27%, respectively). The most commonly cited effect of an unfavourable test result concerned increasing problems for spouses (75% and 76%, respectively) and children (61% and 57%, respectively). Most respondents denied that an unfavourable result would have adverse effects on personal mood or relationship. One-third of all respondents favoured prenatal testing where one of the parents had an increased risk for HPD or FAD-CH. Participants would encourage their offspring to have the test before starting a relationship (35%) and before family planning (44%). Thirty-seven percent of the respondents would encourage their children to opt for prenatal diagnosis. People at risk for HPD were significantly more preoccupied with the occurrence of potential symptoms in themselves, compared with those at risk for FAD-CH, reflecting the devastating impact that disinhibition in the affected patient has on the family. Our findings underline the need for adequate counselling and the availability of professional and community resources to deal with the impact of test results in subjects and their relatives. PMID:9032652

  6. Molecular basis for increased risk for late-onset Alzheimer disease due to the naturally occurring L28P mutation in apolipoprotein E4.

    PubMed

    Argyri, Letta; Dafnis, Ioannis; Theodossiou, Theodossis A; Gantz, Donald; Stratikos, Efstratios; Chroni, Angeliki

    2014-05-02

    The apolipoprotein (apo) E4 isoform has consistently emerged as a susceptibility factor for late-onset Alzheimer disease (AD), although the exact mechanism is not clear. A rare apoE4 mutant, apoE4[L28P] Pittsburgh, burdens carriers with an added risk for late-onset AD and may be a useful tool for gaining insights into the role of apoE4 in disease pathogenesis. Toward this end, we evaluated the effect of the L28P mutation on the structural and functional properties of apoE4. ApoE4[L28P] was found to have significantly perturbed thermodynamic properties, to have reduced helical content, and to expose a larger portion of the hydrophobic surface to the solvent. Furthermore, this mutant is thermodynamically destabilized and more prone to proteolysis. When interacting with lipids, apoE4[L28P] formed populations of lipoprotein particles with structural defects. The structural perturbations brought about by the mutation were accompanied by aberrant functions associated with the pathogenesis of AD. Specifically, apoE4[L28P] promoted the cellular uptake of extracellular amyloid β peptide 42 (Aβ42) by human neuroblastoma SK-N-SH cells as well as by primary mouse neuronal cells and led to increased formation of intracellular reactive oxygen species that persisted for at least 24 h. Furthermore, lipoprotein particles containing apoE4[L28P] induced intracellular reactive oxygen species formation and reduced SK-N-SH cell viability. Overall, our findings suggest that the L28P mutation leads to significant structural and conformational perturbations in apoE4 and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress. We propose that these structural and functional changes underlie the observed added risk for AD development in carriers of apoE4[L28P].

  7. Pooling/bootstrap-based GWAS (pbGWAS) identifies new loci modifying the age of onset in PSEN1 p.Glu280Ala Alzheimer's disease

    PubMed Central

    Vélez, J I; Chandrasekharappa, S C; Henao, E; Martinez, A F; Harper, U; Jones, M; Solomon, B D; Lopez, L; Garcia, G; Aguirre-Acevedo, D C; Acosta-Baena, N; Correa, J C; Lopera-Gómez, C M; Jaramillo-Elorza, M C; Rivera, D; Kosik, K S; Schork, N J; Swanson, J M; Lopera, F; Arcos-Burgos, M

    2013-01-01

    The literature on GWAS (genome-wide association studies) data suggests that very large sample sizes (for example, 50,000 cases and 50,000 controls) may be required to detect significant associations of genomic regions for complex disorders such as Alzheimer's disease (AD). Because of the challenges of obtaining such large cohorts, we describe here a novel sequential strategy that combines pooling of DNA and bootstrapping (pbGWAS) in order to significantly increase the statistical power and exponentially reduce expenses. We applied this method to a very homogeneous sample of patients belonging to a unique and clinically well-characterized multigenerational pedigree with one of the most severe forms of early onset AD, carrying the PSEN1 p.Glu280Ala mutation (often referred to as E280A mutation), which originated as a consequence of a founder effect. In this cohort, we identified novel loci genome-wide significantly associated as modifiers of the age of onset of AD (CD44, rs187116, P=1.29 × 10−12; NPHP1, rs10173717, P=1.74 × 10−12; CADPS2, rs3757536, P=1.54 × 10−10; GREM2, rs12129547, P=1.69 × 10−13, among others) as well as other loci known to be associated with AD. Regions identified by pbGWAS were confirmed by subsequent individual genotyping. The pbGWAS methodology and the genes it targeted could provide important insights in determining the genetic causes of AD and other complex conditions. PMID:22710270

  8. From 'needing to know' to 'needing not to know more': an interpretative phenomenological analysis of couples' experiences with early-onset Alzheimer's disease.

    PubMed

    Wawrziczny, Emilie; Pasquier, Florence; Ducharme, Francine; Kergoat, Marie-Jeanne; Antoine, Pascal

    2016-12-01

    To explore the experiences and adjustment modes of couples during the period between the initial signs of the Alzheimer's disease (AD) and the years following diagnosis, particularly in the case of early-onset AD. A dyadic interpretative phenomenological analysis was conducted with married couples in which one member of each couple received a diagnosis of probable early-onset AD (before 65 years of age). Sixteen young couples, followed by the National Reference Centre for Young Persons with AD, agreed to participate. For seven of the couples, the caregiver was a woman. The mean age was 57.4 (SD = 4.2) for the caregivers and 57.3 (SD = 4.1) for the persons with AD. The semi-structured interviews were conducted in the couples' homes. Each interview was conducted with both spouses to capture their interactions in the context of individual and shared experiences. Two higher-order themes emerged from the analyses: the 'need to know' and, after the diagnosis, the 'need not to know more'. Indeed, the first signs mark the beginning of a period of doubt and a search for understanding. This pursuit of knowledge progresses to the recognition of more intense and severe signs that encourage couples to seek medical attention. Both reassuring and destabilising, the diagnosis is a breaking point that modifies how the changes and painful effects associated with disease are experienced. Couples employ strategies to minimise their suffering and consequently their knowledge about the disease. These results show that the couples oscillate between the need to know and the fear of knowing. To protect themselves, they use strategies to reduce their suffering and to distance the disease. The use of these avoidance strategies indicates that certain times in the course of disease management are less appropriate for couples to accept the assistance offered by formal caregivers. © 2015 Nordic College of Caring Science.

  9. Type-specific capsular antigen is associated with virulence in late-onset group B Streptococcal type III disease.

    PubMed Central

    Klegerman, M E; Boyer, K M; Papierniak, C K; Levine, L; Gotoff, S P

    1984-01-01

    Strain differences have been postulated to explain the observation that group B Streptococcus type III (GBS III) late-onset disease occurs in only a fraction of colonized infants. To determine the distribution of type-specific polysaccharide antigen (Ag) in GBS III, Ag was measured by rocket immunoelectrophoresis in both supernatant fluids and EDTA extracts and by radial immunodiffusion in multiple HCl extracts of the pellet from cultures of 10 strains of GBS III. Capsular Ag was defined as the sum of Ag in EDTA extracts + Ag in multiple HCl extracts. Both Ag in EDTA extracts and Ag in supernatant fluids correlated with capsular Ag (r = 0.94). GBS III strains were obtained from the blood of 19 infants with late-onset sepsis, from the cerebrospinal fluid or blood of 22 infants with late-onset meningitis, and from mucosal surfaces of both 18 infants and 12 mothers of infants with low levels of type-specific antibody and asymptomatic colonization. Mean values of Ag in supernatant fluids in strains from infants with late-onset sepsis (1.50 +/- 0.08 micrograms/ml) and late-onset meningitis (1.67 +/- 0.09 micrograms/ml) were significantly greater than those in asymptomatic colonization strains (1.14 +/- 0.05 micrograms/ml; P less than 0.001). The number of organisms required for a 50% lethal dose in the chick embryo, determined in 29 strains, was inversely related to Ag in supernatant fluids (r = -0.60). The demonstration that the quantity of capsular Ag produced by GBS III strains is related to their virulence in chick embryos and to their invasiveness in susceptible infants supports the hypothesis that Ag is a virulence factor in humans. Images PMID:6423540

  10. R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study.

    PubMed

    Korvatska, Olena; Leverenz, James B; Jayadev, Suman; McMillan, Pamela; Kurtz, Irina; Guo, Xindi; Rumbaugh, Malia; Matsushita, Mark; Girirajan, Santhosh; Dorschner, Michael O; Kiianitsa, Kostantin; Yu, Chang-En; Brkanac, Zoran; Garden, Gwenn A; Raskind, Wendy H; Bird, Thomas D

    2015-08-01

    The R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders. To investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases. This study includes genetic and pathologic studies of families with LOAD from 1985 to 2014. A total of 131 families with LOAD (751 individuals) were included from the University of Washington Alzheimer Disease Research Center. To identify LOAD genes/risk factors in the LOAD123 family with 21 affected members and 12 autopsies, we sequenced 4 exomes. Candidate variants were tested for cosegregation with the disease. TREM2 R47H was genotyped in an additional 130 families with LOAD. We performed clinical and neuropathological assessments of patients with and without R47H and evaluated the variant's effect on brain pathology, cellular morphology, and expression of microglial markers. We assessed the effect of TREM2 genotype on age at onset and disease duration. We compared Braak and Consortium to Establish a Registry for Alzheimer's Disease scores, presence of α-synuclein and TAR DNA-binding protein 43 aggregates, and additional vascular or Parkinson pathology in TREM2 R47H carriers vs noncarriers. Microglial activation was assessed by quantitative immunohistochemistry and morphometry. Twelve of 16 patients with AD in the LOAD123 family carried R47H. Eleven patients with dementia had apolipoprotein E 4 (ApoE4) and R47H genotypes. We also found a rare missense variant, D353N, in a nominated AD risk gene, unc-5 homolog C (UNC5C), in 5 affected individuals in the LOAD123 family. R47H carriers demonstrated a shortened disease duration (mean [SD], 6.7 [2.8] vs 11.1 [6.6] years; 2-tailed t test; P = .04) and more frequent α-synucleinopathy. The panmicroglial marker ionized calcium-binding adapter molecule 1 was decreased in all AD

  11. Age of Childhood Onset in Type 1 Diabetes and Functional Brain Connectivity in Midlife.

    PubMed

    Ryan, John P; Aizenstein, Howard J; Orchard, Trevor J; Ryan, Christopher M; Saxton, Judith A; Fine, David F; Nunley, Karen A; Rosano, Caterina

    2015-01-01

    The development of Type 1 diabetes mellitus (T1DM) within the first 7 years of life has been linked to poorer cognitive performance. Adults with T1DM have altered functional brain connectivity, but no studies have examined whether earlier age of T1DM onset is associated with functional connectivity later in life. Accordingly, we tested the relationship between age of onset and resting state functional connectivity in a cohort of middle-aged adults with childhood-onset T1DM. Participants were from a subsample of the Pittsburgh Epidemiology of Diabetes Complications cohort and included 66 adults (mean age = 47.54 years, 32 men). Resting state blood oxygen level-dependent activity was used to calculate mean connectivity for eight functional brain networks. A multivariate analysis of variance examined associations between age of onset and network connectivity. Diffusion tensor and fluid-attenuated inversion recovery images were analyzed to identify microstructural alterations and white-matter hyperintensity volumes. Later childhood onset of T1DM was associated with lower connectivity (F(8,57) = 2.40, p = .026). A significant interaction was present for current age such that an inverse association with age of onset for functional connectivity was present in older individuals (F(8,55) = 2.88, p = .035). Lower connectivity was associated with older age, increased white-matter hyperintensity volume, and lower microstructural integrity. Diagnosis of T1DM later in childhood may be associated with lower brain functional connectivity, particularly in those surviving into older ages. These alterations may be an early marker for subsequent cognitive decrements. Future studies are warranted to understand the pathways underlying these associations.

  12. Age of Childhood Onset in Type 1 Diabetes and Functional Brain Connectivity in Midlife

    PubMed Central

    Ryan, John P.; Aizenstein, Howard J.; Orchard, Trevor J.; Ryan, Christopher M.; Saxton, Judith A.; Fine, David F.; Nunley, Karen A.; Rosano, Caterina

    2015-01-01

    Objective The development of type 1 diabetes (T1DM) within the first 7 years of life has been linked to poorer cognitive performance. Adults with T1DM have altered functional brain connectivity, but no studies have examined whether earlier age of T1DM onset is associated with functional connectivity later in life. Accordingly, we tested the relationship between age of onset and resting state functional connectivity in a cohort of middle-aged adults with childhood-onset T1DM. Methods Subjects were from a subsample of the Pittsburgh Epidemiology of Diabetes Complications cohort and included 66 adults (mean age = 47.54 years; 32 Male). Resting state blood oxygen level dependent activity was used to calculate mean connectivity for eight functional brain networks. A multivariate analysis of variance examined associations between age of onset and network connectivity. Diffusion tensor and fluid attenuated inversion recovery images were analyzed to identify microstructural alterations and white matter hyperintensity volumes. Results Later childhood onset of T1DM was associated with lower connectivity (F (8,57) = 2.40, p = .026). A significant interaction was present for current age such that an inverse association with age of onset for functional connectivity was present in older individuals (F (8,55) = 2.88, p = .035). Lower connectivity was associated with older age, increased white matter hyperintensity volume, and lower microstructural integrity. Conclusions Diagnosis of T1DM later in childhood may be associated with lower brain functional connectivity, particularly in those surviving into older ages. These alterations may be an early marker for subsequent cognitive decrements. Future studies are warranted to understand the pathways underlying these associations. PMID:26163816

  13. Association between the SORL1 rs2070045 polymorphism and late-onset Alzheimer's disease: interaction with the ApoE genotype in the Chinese Han population.

    PubMed

    Xue, Xiaofan; Zhang, Milan; Lin, Yicong; Xu, Erhe; Jia, Jianping

    2014-01-24

    Late-onset Alzheimer's Disease (LOAD) is a common neurodegenerative disease [1], and the two well identified pathological hallmarks of LOAD are senile plaques formed from amyloid β peptides (Aβ) and neurofibrillary tangles (NFTs) consisting of hyperphorylated tau protein [2]. The neuronal Sortilin-related receptor (SORL1) is involved in the processing and trafficking of amyloid precursor protein (APP) into recycling pathways, thus influencing Aβ generation and by this AD pathology [3]. To explore the relationship between the single nucleotide polymorphism (SNP) of the SORL1 SNP 19 rs2070045 and LOAD, a case-control study was conducted in a Chinese Han cohort including 77 LOAD patients and 100 control participants. This SNP 19 rs2070045 was genotyped with a polymerase chain reaction-restriction fragment length polymorphism, (PCR-RFLP) method. The association was revealed between the polymorphism of SNP 19 rs2070045 (T/T, T/G, G/G) and the risk of LOAD. The results of this study indicated that the T allele (T/G+T/T) of SNP 19 rs2070045 was successful in exerting obvious influence in LOAD patients (χ(2)=4.884, P=0.027<0.05). However, there is no sufficient evidence to prove that the T allele of SNP 19 rs2070045 is associated with ɛ4 allele of ApoE gene in LOAD patients (χ(2)=0.771, P=0.380>0.05). Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  14. Communication of brain network core connections altered in behavioral variant frontotemporal dementia but possibly preserved in early-onset Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Daianu, Madelaine; Jahanshad, Neda; Mendez, Mario F.; Bartzokis, George; Jimenez, Elvira E.; Thompson, Paul M.

    2015-03-01

    Diffusion imaging and brain connectivity analyses can assess white matter deterioration in the brain, revealing the underlying patterns of how brain structure declines. Fiber tractography methods can infer neural pathways and connectivity patterns, yielding sensitive mathematical metrics of network integrity. Here, we analyzed 1.5-Tesla wholebrain diffusion-weighted images from 64 participants - 15 patients with behavioral variant frontotemporal dementia (bvFTD), 19 with early-onset Alzheimer's disease (EOAD), and 30 healthy elderly controls. Using whole-brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We evaluated the brain's networks focusing on the most highly central and connected regions, also known as hubs, in each diagnostic group - specifically the "high-cost" structural backbone used in global and regional communication. The high-cost backbone of the brain, predicted by fiber density and minimally short pathways between brain regions, accounted for 81-92% of the overall brain communication metric in all diagnostic groups. Furthermore, we found that the set of pathways interconnecting high-cost and high-capacity regions of the brain's communication network are globally and regionally altered in bvFTD, compared to healthy participants; however, the overall organization of the high-cost and high-capacity networks were relatively preserved in EOAD participants, relative to controls. Disruption of the major central hubs that transfer information between brain regions may impair neural communication and functional integrity in characteristic ways typical of each subtype of dementia.

  15. A case of possibly pathogenic PSEN2 R62C mutation in a patient with probable early-onset Alzheimer's dementia supported by structure prediction.

    PubMed

    Park, Kyung Won; An, Seong Soo; Bagyinszky, Eva; Kim, SangYun

    2017-01-01

    A 49-year-old Korean male patient with dementia was diagnosed with probable early-onset Alzheimer's disease (AD). He presented with memory problems, personality changes, and disorientation. His family history of dementia was probably negative, since no family member with dementia was found or mentioned. Mild cortical atrophy was observed upon magnetic resonance imaging analyses of his brain, and the single-photon emission computed tomography analysis revealed hypoperfusion in the frontal, temporal, and limbic lobes. The patient was tested for mutations in APP, PSEN1, PSEN2, PGRN, MAPT, and PRNP genes. Genetic analysis revealed R62C mutation in PSEN2 gene. PSEN2 R62C mutation was previously reported in European populations, including Dutch and Belgian families with AD. Herein, we present the first case report of PSEN2 R62C mutation in Asia. PolyPhen-2 and SIFT software analyses predicted this mutation as "possibly damaging", suggesting its potential involvement with AD. In silico protein structural prediction analyses of PSEN2 R62 and C62 revealed two divergent structures, suggesting that large perturbations of R62C mutation might cause dysfunctions of PSEN2, which may alter the normal amyloid production.

  16. Vascular dysfunction associated with type 2 diabetes and Alzheimer's disease: a potential etiological linkage.

    PubMed

    Wang, Fuzhou; Guo, Xirong; Shen, Xiaofeng; Kream, Richard M; Mantione, Kirk J; Stefano, George B

    2014-08-01

    The endothelium performs a crucial role in maintaining vascular integrity leading to whole organ metabolic homeostasis. Endothelial dysfunction represents a key etiological factor leading to moderate to severe vasculopathies observed in both Type 2 diabetic and Alzheimer's Disease (AD) patients. Accordingly, evidence-based epidemiological factors support a compelling hypothesis stating that metabolic rundown encountered in Type 2 diabetes engenders severe cerebral vascular insufficiencies that are causally linked to long term neural degenerative processes in AD. Of mechanistic importance, Type 2 diabetes engenders an immunologically mediated chronic pro-inflammatory state involving interactive deleterious effects of leukocyte-derived cytokines and endothelial-derived chemotactic agents leading to vascular and whole organ dysfunction. The long term negative consequences of vascular pro-inflammatory processes on the integrity of CNS basal forebrain neuronal populations mediating complex cognitive functions establish a striking temporal comorbidity of AD with Type 2 diabetes. Extensive biomedical evidence supports the pivotal multi-functional role of constitutive nitric oxide (NO) production and release as a critical vasodilatory, anti-inflammatory, and anti-oxidant, mechanism within the vascular endothelium. Within this context, we currently review the functional contributions of dysregulated endothelial NO expression to the etiology and persistence of Type 2 diabetes-related and co morbid AD-related vasculopathies. Additionally, we provide up-to-date perspectives on critical areas of AD research with special reference to common NO-related etiological factors linking Type 2 diabetes to the pathogenesis of AD.

  17. Type-1 interferon signaling mediates neuro-inflammatory events in models of Alzheimer's disease.

    PubMed

    Taylor, Juliet M; Minter, Myles R; Newman, Andrew G; Zhang, Moses; Adlard, Paul A; Crack, Peter J

    2014-05-01

    A neuro-inflammatory response has been implicated in human patients and animal models of Alzheimer's disease (AD). Type-1 interferons are pleiotropic cytokines involved in the initiation and regulation of the pro-inflammatory response; however, their role in AD is unknown. This study investigated the contribution of type-1 IFN signaling in the neuro-inflammatory response to amyloid-beta (Aβ) in vitro and in the APP/PS1 transgenic mouse model of AD. Enzyme-linked immunosorbent assay confirmed a 2-fold increase in IFNα in APP/PS1 brains compared with control brains. Quantitative polymerase chain reaction also identified increased IFNα and IFNβ expression in human pre-frontal cortex from AD patients. In vitro studies in primary neurons demonstrated Aβ-induced type-1 IFN expression preceded that of other classical pro-inflammatory cytokines, IL1-β, and IL-6. Significantly, ablation of type-1 interferon-α receptor 1 expression in BE(2)M17 neuroblastoma cells and primary neurons afforded protection against Aβ-induced toxicity. This study supports a role for type-1 interferons in the pro-inflammatory response and neuronal cell death in AD and suggests that blocking type-1 interferon-α receptor 1 maybe a therapeutic target to limit the disease progression.

  18. Initiating Characteristics of Early-onset Type 2 Diabetes Mellitus in Chinese Patients.

    PubMed

    Yu, Hui; Xie, Li-Fang; Chen, Kang; Yang, Gang-Yi; Xing, Xiao-Yan; Zhao, Jia-Jun; Hong, Tian-Pei; Shan, Zhong-Yan; Li, Hong-Mei; Chen, Bing; Tang, Xu-Lei; Qi, Ling; Yang, Jing; Fang, Yuan; Li, Ting; Wang, Shuang-Shuang; Liang, Xue; Yin, Ya-Qi; Mu, Yi-Ming

    2016-04-05

    Type 2 diabetes mellitus (T2DM) has traditionally been considered to affect mainly the elderly; however, the age at diagnosis has gradually reduced in recent years. Although the incidence of young-onset T2DM is increasing, it is still not fully clear the onset characteristics and risk factors of early-onset T2DM. The aim of this study was to describe the initiating characteristics of early-onset T2DM in Chinese patients and evaluate the risk factors for diabetes mellitus. This cross-sectional controlled study was performed using a questionnaire survey method in outpatients of multiple centers in China. A total of 1545 patients with T2DM with an age at onset of <40 years were included, and the control group consisted of subjects aged <40 years with normal blood glucose level. In patients with young-onset T2DM, the mean age and initial hemoglobin 1Ac at diagnosis were 32.96 ± 5.40 years and 9.59 ± 2.71%, respectively. Most of the patients were obese, followed irregular diet pattern and sedentary lifestyle, had life or work pressure, and had a family history of diabetes mellitus. Compared with subjects with normal blood glucose level, logistic regression analysis showed that waist-to-hip ratio (odds ratio [OR] 446.99, 95% confidence interval [CI] 42.37-4714.87), family history of diabetes mellitus (OR 23.46, CI 14.47-38.03), dyslipidemia (OR 2.65, CI 1.54-4.56), diastolic blood pressure (OR 1.02, CI 1.00-1.04), and body mass index (OR 0.95, CI 0.92-0.99) are independent factors for early-onset T2DM. We observed that abdominal obesity, family history of diabetes mellitus, and medical history of hypertension and dyslipidemia are independent risk factors for early-onset T2DM. It is, therefore, necessary to apply early lifestyle intervention in young people with risk of diabetes mellitus.

  19. Initiating Characteristics of Early-onset Type 2 Diabetes Mellitus in Chinese Patients

    PubMed Central

    Yu, Hui; Xie, Li-Fang; Chen, Kang; Yang, Gang-Yi; Xing, Xiao-Yan; Zhao, Jia-Jun; Hong, Tian-Pei; Shan, Zhong-Yan; Li, Hong-Mei; Chen, Bing; Tang, Xu-Lei; Qi, Ling; Yang, Jing; Fang, Yuan; Li, Ting; Wang, Shuang-Shuang; Liang, Xue; Yin, Ya-Qi; Mu, Yi-Ming

    2016-01-01

    Background: Type 2 diabetes mellitus (T2DM) has traditionally been considered to affect mainly the elderly; however, the age at diagnosis has gradually reduced in recent years. Although the incidence of young-onset T2DM is increasing, it is still not fully clear the onset characteristics and risk factors of early-onset T2DM. The aim of this study was to describe the initiating characteristics of early-onset T2DM in Chinese patients and evaluate the risk factors for diabetes mellitus. Methods: This cross-sectional controlled study was performed using a questionnaire survey method in outpatients of multiple centers in China. A total of 1545 patients with T2DM with an age at onset of <40 years were included, and the control group consisted of subjects aged <40 years with normal blood glucose level. Results: In patients with young-onset T2DM, the mean age and initial hemoglobin 1Ac at diagnosis were 32.96 ± 5.40 years and 9.59 ± 2.71%, respectively. Most of the patients were obese, followed irregular diet pattern and sedentary lifestyle, had life or work pressure, and had a family history of diabetes mellitus. Compared with subjects with normal blood glucose level, logistic regression analysis showed that waist-to-hip ratio (odds ratio [OR] 446.99, 95% confidence interval [CI] 42.37–4714.87), family history of diabetes mellitus (OR 23.46, CI 14.47–38.03), dyslipidemia (OR 2.65, CI 1.54–4.56), diastolic blood pressure (OR 1.02, CI 1.00–1.04), and body mass index (OR 0.95, CI 0.92–0.99) are independent factors for early-onset T2DM. Conclusions: We observed that abdominal obesity, family history of diabetes mellitus, and medical history of hypertension and dyslipidemia are independent risk factors for early-onset T2DM. It is, therefore, necessary to apply early lifestyle intervention in young people with risk of diabetes mellitus. PMID:26996471

  20. Social Network Data Validity: The Example of the Social Network of Caregivers of Older Persons with Alzheimer-Type Dementia

    ERIC Educational Resources Information Center

    Carpentier, Normand

    2007-01-01

    This article offers reflection on the validity of relational data such as used in social network analysis. Ongoing research on the transformation of the support network of caregivers of persons with an Alzheimer-type disease provides the data to fuel the debate on the validity of participant report. More specifically, we sought to understand the…

  1. Shared Neuropathological Characteristics of Obesity, Type 2 Diabetes and Alzheimer's Disease: Impacts on Cognitive Decline.

    PubMed

    Walker, Jennifer M; Harrison, Fiona E

    2015-09-01

    In the past few decades, the prevalence of obesity and type 2 diabetes mellitus (T2DM), as well as older individuals at risk for Alzheimer's disease (AD), has increased. While the consumption of diets high in fat (total and saturated) have been linked to increased risk of AD, diets rich in antioxidants, polyunsaturated fats, and omega-3 fatty acids are associated with decreased risk. Additionally, AD patients are at increased risk for developing T2DM. Recent research suggests that there are stronger similarities between AD and T2DM than have previously been considered. Here we review the neurocognitive and inflammatory effects of high-fat diet consumption, its relationship to AD, and the treatment potential of dietary interventions that may decrease risk of cognitive decline and other associated neuropathological changes, such as insulin resistance, oxidative stress, and chronic inflammatory processes.

  2. Auditory and Visual Cues for Topic Maintenance with Persons Who Exhibit Dementia of Alzheimer's Type

    PubMed Central

    Teten, Amy F.; Dagenais, Paul A.; Friehe, Mary J.

    2015-01-01

    This study compared the effectiveness of auditory and visual redirections in facilitating topic coherence for persons with Dementia of Alzheimer's Type (DAT). Five persons with moderate stage DAT engaged in conversation with the first author. Three topics related to activities of daily living, recreational activities, food, and grooming, were broached. Each topic was presented three times to each participant: once as a baseline condition, once with auditory redirection to topic, and once with visual redirection to topic. Transcripts of the interactions were scored for overall coherence. Condition was a significant factor in that the DAT participants exhibited better topic maintenance under visual and auditory conditions as opposed to baseline. In general, the performance of the participants was not affected by the topic, except for significantly higher overall coherence ratings for the visually redirected interactions dealing with the topic of food. PMID:26171273

  3. Disclosing a disability: Do strategy type and onset controllability make a difference?

    PubMed

    Lyons, Brent J; Volpone, Sabrina D; Wessel, Jennifer L; Alonso, Natalya M

    2017-09-01

    In hiring contexts, individuals with concealable disabilities make decisions about how they should disclose their disability to overcome observers' biases. Previous research has investigated the effectiveness of binary disclosure decisions-that is, to disclose or conceal a disability-but we know little about how, why, or under what conditions different types of disclosure strategies impact observers' hiring intentions. In this article, we examine disability onset controllability (i.e., whether the applicant is seen as responsible for their disability onset) as a boundary condition for how disclosure strategy type influences the affective reactions (i.e., pity, admiration) that underlie observers' hiring intentions. Across 2 experiments, we found that when applicants are seen as responsible for their disability, strategies that de-emphasize the disability (rather than embrace it) lower observers' hiring intentions by elevating their pity reactions. Thus, the effectiveness of different types of disability disclosure strategies differs as a function of onset controllability. We discuss implications for theory and practice for individuals with disabilities and organizations. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  4. Maternal and neonatal outcomes by labor onset type and gestational age.

    PubMed

    Bailit, Jennifer L; Gregory, Kimberly D; Reddy, Uma M; Gonzalez-Quintero, Victor H; Hibbard, Judith U; Ramirez, Mildred M; Branch, D Ware; Burkman, Ronald; Haberman, Shoshana; Hatjis, Christos G; Hoffman, Matthew K; Kominiarek, Michelle; Landy, Helain J; Learman, Lee A; Troendle, James; Van Veldhuisen, Paul; Wilkins, Isabelle; Sun, Liping; Zhang, Jun

    2010-03-01

    We sought to determine maternal and neonatal outcomes by labor onset type and gestational age. We used electronic medical records data from 10 US institutions in the Consortium on Safe Labor on 115,528 deliveries from 2002 through 2008. Deliveries were divided by labor onset type (spontaneous, elective induction, indicated induction, unlabored cesarean). Neonatal and maternal outcomes were calculated by labor onset type and gestational age. Neonatal intensive care unit admissions and sepsis improved with each week of gestational age until 39 weeks (P < .001). After adjusting for complications, elective induction of labor was associated with a lower risk of ventilator use (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.28-0.53), sepsis (OR, 0.36; 95% CI, 0.26-0.49), and neonatal intensive care unit admissions (OR, 0.52; 95% CI, 0.48-0.57) compared to spontaneous labor. The relative risk of hysterectomy at term was 3.21 (95% CI, 1.08-9.54) with elective induction, 1.16 (95% CI, 0.24-5.58) with indicated induction, and 6.57 (95% CI, 1.78-24.30) with cesarean without labor compared to spontaneous labor. Some neonatal outcomes improved until 39 weeks. Babies born with elective induction are associated with better neonatal outcomes compared to spontaneous labor. Elective induction may be associated with an increased hysterectomy risk. Copyright 2010 Mosby, Inc. All rights reserved.

  5. Maternal and neonatal outcomes by labor onset type and gestational age

    PubMed Central

    Bailit, Jennifer L.; Gregory, Kimberly D.; Reddy, Uma M.; Gonzalez-Quintero, Victor H.; Hibbard, Judith U.; Ramirez, Mildred M.; Branch, D. Ware; Burkman, Ronald; Haberman, Shoshana; Hatjis, Christos G.; Hoffman, Matthew K.; Kominiarek, Michelle; Landy, Helain J.; Learman, Lee A.; Troendle, James; Van Veldhuisen, Paul; Wilkins, Isabelle; Sun, Liping; Zhang, Jun

    2010-01-01

    OBJECTIVE We sought to determine maternal and neonatal outcomes by labor onset type and gestational age. STUDY DESIGN We used electronic medical records data from 10 US institutions in the Consortium on Safe Labor on 115,528 deliveries from 2002 through 2008. Deliveries were divided by labor onset type (spontaneous, elective induction, indicated induction, unlabored cesarean). Neonatal and maternal outcomes were calculated by labor onset type and gestational age. RESULTS Neonatal intensive care unit admissions and sepsis improved with each week of gestational age until 39 weeks (P < .001). After adjusting for complications, elective induction of labor was associated with a lower risk of ventilator use (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.28 – 0.53), sepsis (OR, 0.36; 95% CI, 0.26 – 0.49), and neonatal intensive care unit admissions (OR, 0.52; 95% CI, 0.48 – 0.57) compared to spontaneous labor. The relative risk of hysterectomy at term was 3.21 (95% CI, 1.08 – 9.54) with elective induction, 1.16 (95% CI, 0.24 – 5.58) with indicated induction, and 6.57 (95% CI, 1.78 – 24.30) with cesarean without labor compared to spontaneous labor. CONCLUSION Some neonatal outcomes improved until 39 weeks. Babies born with elective induction are associated with better neonatal outcomes compared to spontaneous labor. Elective induction may be associated with an increased hysterectomy risk. PMID:20207242

  6. Enhanced levels of mitochondrial enzyme 17beta-hydroxysteroid dehydrogenase type 10 in patients with Alzheimer disease and multiple sclerosis.

    PubMed

    Kristofiková, Zdena; Bocková, Markéta; Hegnerová, Katerina; Bartos, Ales; Klaschka, Jan; Rícný, Jan; Rípová, Daniela; Homola, Jirí

    2009-10-01

    The multifunctional mitochondrial enzyme 17beta-hydroxysteroid dehydrogenase type 10 might play a role in the development of Alzheimer disease via its high-affinity binding to amyloid beta peptides and its neuronal over-expression. It is suggested that the cerebrospinal fluid levels of the enzyme, free or bound to amyloid beta peptides, are a potential specific biomarker of Alzheimer disease. However, mitochondrial dysfunction seems to play a role in many neurological diseases including multiple sclerosis. In this study, the specificity of changes in relation to the enzyme over-expression was evaluated using enzyme-linked immunosorbent and surface plasmon resonance sensors. The data indicated pronounced increases in the enzyme levels, specifically to 179% in multiple sclerosis and to 573% in Alzheimer disease when compared to the age-matched controls. Although the differences between both diseases were statistically significant, enzyme levels do not appear to be a highly specific biomarker of Alzheimer disease. On the other hand, enhancement in levels of the enzyme bound to amyloid beta peptides was only observed in people with Alzheimer disease, which suggests that the complex should be further considered as a possible biomarker. In patients with multiple sclerosis, our results are the first to demonstrate significant changes in enzyme expression and to suggest possible alterations in amyloid beta peptides.

  7. Pre-pubertal onset of type 1 diabetes and appearance of retinopathy.

    PubMed

    Porta, M; Dalmasso, P; Grassi, G; Marena, S; Maurino, M; Passera, P; Trento, M

    2004-06-01

    It was suggested that the years of diabetes preceding puberty may not contribute to the development of retinopathy but evidence for this is conflicting. To verify the influence of pre-pubertal diabetes, we compared the correlations between prevalence of retinopathy and diabetes duration in patients who developed type 1 diabetes before and after puberty. Six hundred and twenty-eight patients with diabetes onset at age< or =29, on insulin treatment and aged< or =60 at the time of screening for retinopathy were considered retrospectively. Pre-pubertal age was defined as 0-12 in males and 0-11 in females. Two hundred patients had developed diabetes before puberty and 428 after puberty. Screening was by ophthalmoscopy + 35 mm photography or digital photography. Prevalence of retinopathy was lower among patients with pre-pubertal onset and diabetes durations 10-14 and 15-19 years (p=0.006 and p=0.003, respectively) but prevalence rates became similar after 20 yrs duration. That retinopathy is infrequent and mild during childhood, is probably due to the short duration of diabetes rather than a specific protective effect of pre-puberty. After 20 years' duration, however, the prevalence of retinopathy is no longer influenced by age at onset, suggesting that, in the longer term, pre-pubertal years do contribute to the onset of retinopathy.

  8. A Deeper Look into Type 1 Diabetes – Imaging Immune Responses during Onset of Disease

    PubMed Central

    Christoffersson, Gustaf; von Herrath, Matthias G.

    2016-01-01

    Cytotoxic T lymphocytes execute the killing of insulin-producing beta cells during onset of type 1 diabetes mellitus (T1D). The research community has come far in dissecting the major events in the development of this disease, but still the trigger and high-resolved information of the immunological events leading up to beta cell loss are missing. During the past decades, intravital imaging of immune responses has led to significant scientific breakthroughs in diverse models of disease, including T1D. Dynamic imaging of immune cells at the pancreatic islets during T1D onset has been made possible through the development of both advanced microscopes, and animal models that allow long-term immobilization of the pancreas. The use of these modalities has revealed a milling microenvironment at the pancreatic islets during disease onset with a plethora of active players. Clues to answering the remaining questions in this disease may lie in intravital imaging, including how key immune cells traffic to and from the pancreas, and how cells interact at this target tissue. This review highlights and discusses recent studies, models, and techniques focused to understand the immune responses during T1D onset through intravital imaging. PMID:27574523

  9. Alzheimer-type neuropathology in a 28 year old patient with iatrogenic Creutzfeldt-Jakob disease after dural grafting.

    PubMed

    Preusser, M; Ströbel, T; Gelpi, E; Eiler, M; Broessner, G; Schmutzhard, E; Budka, H

    2006-03-01

    We report the case of a 28 year old man who had received a cadaverous dura mater graft after a traumatic open skull fracture with tearing of the dura at the age of 5 years. A clinical suspicion of Creutzfeldt-Jakob disease (CJD) was confirmed by a brain biopsy 5 months prior to death and by autopsy, thus warranting the diagnosis of iatrogenic CJD (iCJD) according to WHO criteria. Immunohistochemistry showed widespread cortical depositions of disease associated prion protein (PrP(sc)) in a synaptic pattern, and western blot analysis identified PrP(sc) of type 2A according to Parchi et al. Surprisingly, we found Alzheimer-type senile plaques and cerebral amyloid angiopathy in widespread areas of the brain. Plaque-type and vascular amyloid was immunohistochemically identified as deposits of beta-A4 peptide. CERAD criteria for diagnosis of definite Alzheimer's disease (AD) were met in the absence of neurofibrillar tangles or alpha-synuclein immunoreactive inclusions. There was no family history of AD, CJD, or any other neurological disease, and genetic analysis showed no disease specific mutations of the prion protein, presenilin 1 and 2, or amyloid precursor protein genes. This case represents (a) the iCJD case with the longest incubation time after dural grafting reported so far, (b) the youngest documented patient with concomitant CJD and Alzheimer-type neuropathology to date, (c) the first description of Alzheimer-type changes in iCJD, and (d) the second case of iCJD in Austria. Despite the young patient age, the Alzheimer-type changes may be an incidental finding, possibly related to the childhood trauma.

  10. Taste detection and recognition thresholds in Japanese patients with Alzheimer-type dementia.

    PubMed

    Ogawa, Takao; Irikawa, Naoya; Yanagisawa, Daijiro; Shiino, Akihiko; Tooyama, Ikuo; Shimizu, Takeshi

    2017-04-01

    Alzheimer-type dementia (AD) is pathologically characterized by massive neuronal loss in the brain, and the taste cortex is thought to be affected. However, there are only a few reports regarding the gustatory function of AD patients, and the conclusions of this research are inconsistent. This prospective study enrolled 22 consecutive patients with mild to moderately severe Alzheimer-type dementia (AD) with mean age of 84.0 years, and 49 elderly volunteers without dementia with mean age of 71.0 years as control subjects. The control subjects were divided into two groups according to age: a younger group (N=28, mean age: 68.5) and an older group (N=21, mean age: 83.0). The gustatory function was investigated using the filter paper disc method (FPD) and electrogustometry (EGM). The gustatory function as measured by the FPD was significantly impaired in patients with AD as compared with age-matched control subjects; no such difference was found between the younger and the older control groups. On the other hand, as for the EGM thresholds, there were no differences between the AD patient group and the age-matched controls. The FPD method demonstrated decreased gustatory function in AD patients beyond that of aging. On the other hand, EGM thresholds did not differ between the AD patient group and the age-matched controls. These results suggest that failure of taste processing in the brain, but not taste transmission in the peripheral taste system, occurs in patients with AD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. 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…

  12. Alzheimer - resources

    MedlinePlus

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

  13. Altered Kv3.3 channel gating in early-onset spinocerebellar ataxia type 13.

    PubMed

    Minassian, Natali A; Lin, Meng-Chin A; Papazian, Diane M

    2012-04-01

    Mutations in Kv3.3 cause spinocerebellar ataxia type 13 (SCA13). Depending on the causative mutation, SCA13 is either a neurodevelopmental disorder that is evident in infancy or a progressive neurodegenerative disease that emerges during adulthood. Previous studies did not clarify the relationship between these distinct clinical phenotypes and the effects of SCA13 mutations on Kv3.3 function. The F448L mutation alters channel gating and causes early-onset SCA13. R420H and R423H suppress Kv3 current amplitude by a dominant negative mechanism. However, R420H results in the adult form of the disease whereas R423H produces the early-onset, neurodevelopmental form with significant clinical overlap with F448L. Since individuals with SCA13 have one wild type and one mutant allele of the Kv3.3 gene, we analysed the properties of tetrameric channels formed by mixtures of wild type and mutant subunits. We report that one R420H subunit and at least one R423H subunit can co-assemble with the wild type protein to form active channels. The functional properties of channels containing R420H and wild type subunits strongly resemble those of wild type alone. In contrast, channels containing R423H and wild type subunits show significantly altered gating, including a hyperpolarized shift in the voltage dependence of activation, slower activation, and modestly slower deactivation. Notably, these effects resemble the modified gating seen in channels containing a mixture of F448L and wild type subunits, although the F448L subunit slows deactivation more dramatically than the R423H subunit. Our results suggest that the clinical severity of R423H reflects its dual dominant negative and dominant gain of function effects. However, as shown by R420H, reducing current amplitude without altering gating does not result in infant onset disease. Therefore, our data strongly suggest that changes in Kv3.3 gating contribute significantly to an early age of onset in SCA13.

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

    NASA Astrophysics Data System (ADS)

    Khademi, April; Hosseinzadeh, Danoush

    2014-03-01

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

  15. Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study.

    PubMed

    Acosta-Baena, Natalia; Sepulveda-Falla, Diego; Lopera-Gómez, Carlos Mario; Jaramillo-Elorza, Mario César; Moreno, Sonia; Aguirre-Acevedo, Daniel Camilo; Saldarriaga, Amanda; Lopera, Francisco

    2011-03-01

    Mild cognitive impairment (MCI) and pre-MCI have been proposed as stages preceding Alzheimer's disease (AD) dementia. We assessed descendants of individuals with a mutation in presenilin 1 (PSEN1) that causes familial AD, with the aim of identifying distinct stages of clinical progression to AD dementia. We retrospectively studied a cohort of descendants of carriers of the PSEN1 E280A mutation. Pre-dementia cognitive impairment was defined by a score 2 SD away from normal values in objective cognitive tests, and was subdivided as follows: asymptomatic pre-MCI was defined by an absence of memory complaints and no effect on activities of daily living; symptomatic pre-MCI was defined by a score on the subjective memory complaints checklist higher than the mean and no effect on activities of daily living; and MCI was defined by a score on the subjective memory complaints checklist higher than the mean, with no effect on basic activities of daily living and little or no effect on complex daily activities. Dementia was defined according to the diagnostic and statistical manual of mental disorders, fourth edition. Reference mean scores were those of participants who did not carry the PSEN1 E280A mutation. We used the Turnbull survival analysis method to identify ages at onset of each stage of the disease. We measured the time from birth until onset of the three pre-dementia stages, dementia, and death, and assessed decline in cognitive domains for each stage. Follow-up was from Jan 1, 1995, to Jan 27, 2010. 1784 patients were initially identified, 449 of whom were PSEN1 E280A carriers who had complete clinical follow-up. Median age at onset was 35 years (95% CI 30-36) for asymptomatic pre-MCI, 38 years (37-40) for symptomatic pre-MCI, 44 years (43-45) for MCI, and 49 years (49-50) for dementia. The median age at death was 59 years (95% CI 58-61). The median time of progression from asymptomatic to symptomatic pre-MCI was 4 years (95% CI 2-8), from symptomatic pre-MCI to

  16. Early-onset facioscapulohumeral muscular dystrophy type 1 with some atypical features.

    PubMed

    Dorobek, Małgorzata; van der Maarel, Silvère M; Lemmers, Richard J L F; Ryniewicz, Barbara; Kabzińska, Dagmara; Frants, Rune R; Gawel, Malgorzata; Walecki, Jerzy; Hausmanowa-Petrusewicz, Irena

    2015-04-01

    Facioscapulohumeral muscular dystrophy cases with facial weakness before the age of 5 and signs of shoulder weakness by the age of 10 are defined as early onset. Contraction of the D4Z4 repeat on chromosome 4q35 is causally related to facioscapulohumeral muscular dystrophy type 1, and the residual size of the D4Z4 repeat shows a roughly inverse correlation with the severity of the disease. Contraction of the D4Z4 repeat on chromosome 4q35 is believed to induce a local change in chromatin structure and consequent transcriptional deregulation of 4qter genes. We present early-onset cases in the Polish population that amounted to 21% of our total population with facioscapulohumeral muscular dystrophy. More than 27% of them presented with severe phenotypes (wheelchair dependency). The residual D4Z4 repeat sizes ranged from 1 to 4 units. In addition, even within early-onset facioscapulohumeral muscular dystrophy type 1 phenotypes, some cases had uncommon features (head drop, early disabling contractures, progressive ptosis, and respiratory insufficiency and cardiomyopathy).

  17. Youth-onset type 2 diabetes mellitus: lessons learned from the TODAY study.

    PubMed

    Narasimhan, Sumana; Weinstock, Ruth S

    2014-06-01

    Type 2 diabetes mellitus is increasingly diagnosed in obese children and adolescents. Evidence suggests that this disease commonly progresses more rapidly in youth compared with adults and is associated with high rates of early microalbuminuria, hypertension, and dyslipidemia. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study was the first multiethnic, multicenter randomized trial in the United States to compare 3 treatment approaches in obese youth with new-onset type 2 diabetes (n=699; ages 10-17 years): monotherapy with metformin, metformin with rosiglitazone, and metformin with an intensive lifestyle intervention. The primary outcome was glycemic control. Diabetes-related complications and cardiovascular risk factors were also examined. Approximately half of the participants could not maintain glycemic control by using metformin alone. Combination therapy with metformin and rosiglitazone resulted in better durability of glycemic control, and metformin plus intensive lifestyle intervention was intermediate but not superior to metformin alone. Deterioration in glycemic control was associated with rapid loss of beta cell function, not worsened insulin sensitivity, and could not be explained by differences in adherence or body mass index. After 3.9 years, 236 (33.8%) of participants had hypertension and 116 participants (16.6%) had microalbuminuria. Only 55.9% of participants had a low-density lipoprotein cholesterol level less than 100 mg/dL (to convert to mmol/L, multiply by 0.0259) after 3 years, and 71 of 517 participants (13.7%) had retinopathy. The significance of the findings from this important trial for the management of youth and young adults with youth-onset type 2 diabetes and its complications is discussed. An aggressive multifaceted approach is needed to prevent or forestall premature microvascular and macrovascular complications in youth-onset type 2 diabetes.

  18. Comparison of Age of Onset and Frequency of Diabetic Complications in the Very Elderly Patients with Type 2 Diabetes

    PubMed Central

    2016-01-01

    Background The prevalence of type 2 diabetes in elderly people has increased dramatically in the last few decades. This study was designed to clarify the clinical characteristics of type 2 diabetes in patients aged ≥80 years according to age of onset. Methods We reviewed the medical records of 289 patients aged ≥80 years with type 2 diabetes at the outpatient diabetes clinics of Kangwon National University Hospital from September 2010 to June 2014. We divided the patients into middle-age-onset diabetes (onset before 65 years of age) and elderly-onset diabetes (onset at 65+ years of age). Results There were 141 male and 148 female patients. The patients had a mean age of 83.2±2.9 years and the mean duration of diabetes was 14.3±10.4 years. One hundred and ninety-nine patients had elderly-onset diabetes. The patients with elderly-onset diabetes had a significantly lower frequency of diabetic retinopathy and nephropathy, lower serum creatinine levels, lower glycated hemoglobin (HbA1c) levels, and similar coronary revascularization and cerebral infarction rates compared to those with middle-age-onset diabetes. There was no frequency difference in coronary revascularization and cerebral infarction and HbA1c levels between three subgroups (<5, 5 to 15, and ≥15 years) of diabetes duration in elderly onset diabetes. However, both in the elderly onset diabetes and middle-age-onset diabetes, the cumulative incidence of retinopathy was increasing rapidly according to the duration of diabetes. Conclusion We report that individuals with elderly-onset diabetes have a lower frequency of diabetic retinopathy and nephropathy and similar cardiovascular complications compared to those with middle-age-onset diabetes. PMID:27586451

  19. Reduced beta cell function in offspring of mothers with young-onset type 2 diabetes.

    PubMed

    Singh, R; Pearson, E; Avery, P J; McCarthy, M I; Levy, J C; Hitman, G A; Sampson, M; Walker, M; Hattersley, A T

    2006-08-01

    Animal models indicate that even exposure to mild maternal hyperglycaemia in utero is detrimental to the beta cell function of the offspring, but evidence of this in humans is limited. In Europids who are diagnosed with type 2 diabetes before the age of 50 years, the risk of diabetes in the offspring of the diabetic mothers is greatly increased compared with the risk in those born to diabetic fathers. We hypothesised that offspring born to mothers with young-onset type 2 diabetes would have been exposed to mild hyperglycaemia in utero, so we studied the impact of this on their beta cell function. We measured beta cell function using early insulin response (EIR) after oral glucose; insulin resistance using HOMA; and HbA(1c) in 568 non-diabetic adult offspring born to parents with type 2 diabetes (mean age 55.8 years), split according to which parent was affected (in 327 it was the mother) and parental age of diagnosis: <50 years (n=117) or > or =50 years. To reduce the impact of genetic susceptibility, the offspring of affected fathers were used as control subjects. Offspring of mothers with young-onset type 2 diabetes had lower EIR (log EIR 4.32, 95% CI [4.14-4.51] vs 4.63 [4.43-4.83] p=0.02) and higher HbA(1c) (4.89% [4.79-4.99] vs 4.68% [4.57-4.79] p=0.02) than the offspring of fathers with young-onset type 2 diabetes. Insulin sensitivity was similar in the two groups. There were no differences in EIR or HbA(1c) between the offspring born to mothers and fathers who were diagnosed after the age of 50 years. We conclude that the offspring of mothers with young-onset type 2 diabetes have a reduction in beta cell function. This is consistent with exposure to mild maternal hyperglycaemia programming beta cell function.

  20. Plasma oxidative stress parameters in men and women with early stage Alzheimer type dementia.

    PubMed

    Puertas, M C; Martínez-Martos, J M; Cobo, M P; Carrera, M P; Mayas, M D; Ramírez-Expósito, M J

    2012-08-01

    It is well known that oxidative stress is one of the earliest events in Alzheimer's disease pathogenesis, indicating that may play a key role in this disease. In our study, we measured the levels of oxidative stress indicators (TBARS and protein carbonyls content) and the non-enzymatic (glutathione (GSH) and oxidized glutathione (GSSG)) and enzymatic (glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD)) defense systems in the plasma of 46 patients diagnosed of ATD and 46 age-matched controls. We found decreased levels in total GSH in ATD patients, although healthy control women showed lower levels of total GSH than healthy control men. On the contrary, we found increased levels of TBARS and carbonyl groups content in ATD patients in both genders. The activity of the plasma antioxidant enzymes showed no changes for SOD activity in ATD patients, independently of the gender, although western blot analysis showed an increase in SOD-1 protein. CAT activity was also decreased in ATD patients, although this decrease is mainly due to the decrease found in men but not in women. However, western blot analysis did not show differences in CAT protein between controls and ATD patients. Finally, a decrease of GPx activity was found in ATD patients in both genders. However, as with CAT protein, western blot analysis did not show differences in GPx protein between controls and ATD patients. Our results suggest that there is a defect in the antioxidant defense system that is incapable of responding to increased free radical production, which may lead to oxidative damage and the development of the pathological alterations that characterize the neurodegenerative disorder of patients with ATD. Thus, oxidative damage could be one important aspect for the onset of ATD and oxidative stress markers could be useful to diagnose the illness in their earliest stages through both non-invasive, reliable and cost-affordable methods. Copyright © 2012 Elsevier Inc. All

  1. Clinicopathological features of familial Alzheimer's disease associated with the M139V mutation in the presenilin 1 gene. Pedigree but not mutation specific age at onset provides evidence for a further genetic factor.

    PubMed

    Fox, N C; Kennedy, A M; Harvey, R J; Lantos, P L; Roques, P K; Collinge, J; Hardy, J; Hutton, M; Stevens, J M; Warrington, E K; Rossor, M N

    1997-03-01

    Sixteen affected individuals are described from two families with early onset autosomal dominant familial Alzheimer's disease. A mutation at codon 139 in the presenilin 1 gene on chromosome 14 results in a methionine to valine substitution which cosegregates with the disease in these families. Onset of dementia was before the age of 50 years in all individuals. The ages at onset within each family were tightly clustered but were significantly different between the families; this difference could not be accounted for by apolipoprotein E status and suggests the existence of a further genetic factor that modifies age at disease onset. The pattern of cognitive decline was similar in both families: early memory loss (initially selective for verbal memory in some individuals) was followed soon after by loss of arithmetic skills while naming and object perception skills were relatively preserved. A speech production deficit was observed in three members of one family but not in the other. Seizures were common and usually predated by myoclonic jerks by a number of years. Serial MRIs showed progressive cortical atrophy with periventricular white matter change appearing 3-4 years into the disease. PET revealed parieto-temporal hypometabolism in all individuals scanned. The diagnosis of Alzheimer's disease was confirmed with typical histopathology in one individual from each family.

  2. Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, caucasians, and hispanics in New York City

    SciTech Connect

    Tang, M.X.; Liu, X.H.; Stern, Y.

    1996-03-01

    Apolipoprotein-E {epsilon}4 (APOE-{epsilon}4) has been consistently associated with Alzheimer disease (AD) and may be responsible for an earlier age at onset. We have previously reported a diminished association between APOE-{epsilon}4 and AD in African Americans. Using a new method, which allows inclusion of censored information, we compared relative risks by APOE genotypes in an expanded collection of cases and controls from three ethnic groups in a New York community. The relative risk for AD associated with APOE-{epsilon}4 homozygosity was increased in all ethnic groups (African American relative risk [RR] = 3.0; 95% confidence interval [CI] = 1.5-5.9; Caucasian RR = 7.3, 95% CI = 2.5-21.6; and Hispanic RR = 2.5, 95% CI = 1.1-5.7), compared with those with APOE-{epsilon}3/{epsilon}3 genotypes. The risk was also increased for APOE-{epsilon}4 heterozygous Caucasians (RR = 2.9, 95% CI = 1.7-5.1) and Hispanics (RR = 1.6,95% CI = 1.1-2.3), but not for African Americans (RR = 0.6, 95% CI = 0.4-0.9). The age distribution of the proportion of Caucasians and Hispanics without AD was consistently lower for APOE-{epsilon}4 homozygous and APOE-{epsilon}4 heterozygous individuals than for those with other APOE genotypes. In African Americans this relationship was observed only in APOE-{epsilon}4 homozygotes. These results confirm that APOE genotypes influence the RR of AD in Caucasians and Hispanics. Differences in risk among APOE-{epsilon}4 heterozygote African Americans suggest that other genetic or environmental factors may modify the effect of APOE-{epsilon}4 in some populations. 58 refs., 3 figs., 4 tabs.

  3. Early-onset Alzheimer’s Disease: Nonamnestic Subtypes and Type 2 AD

    PubMed Central

    Mendez, Mario F.

    2012-01-01

    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 E ε4 (APOE ε4) 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. PMID:23178565

  4. Reversal of new-onset type 1 diabetes in mice by syngeneic bone marrow transplantation.

    PubMed

    Wen, Yanting; Ouyang, Jian; Yang, Rong; Chen, Junhao; Liu, Yong; Zhou, Xiaojun; Burt, Richard K

    2008-09-19

    Autologous hematopoietic stem cell transplantation (HSCT) has recently been performed as a novel strategy to treat patients with new-onset type 1 diabetes (T1D). However, the mechanism of autologous HSCT-induced remission of diabetes remains unknown. In order to help clarify the mechanism of remission-induction following autologous HSCT in patients with T1D, mice treated with multiple low doses of streptozotocin to induce diabetes were used as both donors (n=20) and recipients (n=20). Compared to streptozocin-treated mice not receiving transplantation, syngeneic bone marrow transplantation (syn-BMT) from a streptozocin-treated diabetic donor, if applied during new-onset T1D (day 10 after diabetes onset), can reverse hyperglycemia without relapse (P<0.001), maintain normal blood insulin levels (P<0.001), and preserve islet cell mass. Compared to diabetic mice not undergoing HSCT, syn-BMT, results in restoration of Tregs in spleens (P<0.01), increased Foxp3 mRNA expression (P<0.01) and increased Foxp3 protein expression (P<0.05). This diabetic-remission-inducing effect occurred in mice receiving bone marrow from either streptozocin-treated diabetic or non-diabetic normal donors. We conclude that autologous HSCT remission of diabetes is more than transient immune suppression, and is capable of prolonged remission-induction via regeneration of CD4+CD25+FoxP3+ Tregs.

  5. A novel mouse model that recapitulates adult-onset glycogenosis type 4

    PubMed Central

    Orhan Akman, H.; Emmanuele, Valentina; Kurt, Yasemin Gülcan; Kurt, Bülent; Sheiko, Tatiana; DiMauro, Salvatore; Craigen, William J.

    2015-01-01

    Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by deficiency of the glycogen-branching enzyme (GBE). The diagnostic hallmark of the disease is the accumulation of a poorly branched form of glycogen known as polyglucosan (PG). The disease is clinically heterogeneous, with variable tissue involvement and age at onset. Complete loss of enzyme activity is lethal in utero or in infancy and affects primarily the muscle and the liver. However, residual enzyme activity as low as 5–20% leads to juvenile or adult onset of a disorder that primarily affects the central and peripheral nervous system and muscles and in the latter is termed adult polyglucosan body disease (APBD). Here, we describe a mouse model of GSD IV that reflects this spectrum of disease. Homologous recombination was used to knock in the most common GBE1 mutation p.Y329S c.986A > C found in APBD patients of Ashkenazi Jewish decent. Mice homozygous for this allele (Gbe1ys/ys) exhibit a phenotype similar to APBD, with widespread accumulation of PG. Adult mice exhibit progressive neuromuscular dysfunction and die prematurely. While the onset of symptoms is limited to adult mice, PG accumulates in tissues of newborn mice but is initially absent from the cerebral cortex and heart muscle. Thus, PG is well tolerated in most tissues, but the eventual accumulation in neurons and their axons causes neuropathy that leads to hind limb spasticity and premature death. This mouse model mimics the pathology and pathophysiologic features of human adult-onset branching enzyme deficiency. PMID:26385640

  6. Increased urinary angiotensinogen precedes the onset of albuminuria in normotensive type 2 diabetic patients

    PubMed Central

    Zhuang, Zhen; Bai, Qiong; A, Lata; Liang, Yaoxian; Zheng, Danxia; Wang, Yue

    2015-01-01

    It was previously reported that intrarenal renin angiotensin system (RAS) plays a pivotal role in the onset and progression of diabetic nephropathy (DN). Urinary angiotensinogen (UAGT) was employed as a special index of the intrarenal RAS status and enhanced significantly at a very early stage of chronic kidney disease and type 1 diabetes. On the basis of these findings, the present study was performed to test the hypothesis that UAGT levels are increase even before the development of DN in type 2 diabetic patients without hypertension. 102 patients with type 2 diabetes mellitus (T2DM) and 18 healthy volunteers were studied cross-sectionally. Clinical data were collected and morning spot urine samples were obtained from all participants. UAGT levels were detected by an enzyme-linked immunosorbent assay (ELISA). As a result, UAGT to creatinine ratio (UAGT/Cr) was significantly enhanced in T2DM patients before the appearance of urinary albumin (UALB) and further increased to a greater degree in albuminuric patients. UAGT/Cr levels were positively correlated with Log (UALB to creatinine ratio) and diastolic blood pressure, but negatively correlated with estimated glomerular filtration rate. These data indicate that elevated UAGT levels precede the onset of albuminuria in normotensive T2DM patients. UAGT might potentially serve as an early marker to determine intrarenal RAS activity and predict progressive kidney disease in T2DM patients without hypertension. PMID:26617876

  7. Peripheral blood monocyte gene expression profile clinically stratifies patients with recent-onset type 1 diabetes.

    PubMed

    Irvine, Katharine M; Gallego, Patricia; An, Xiaoyu; Best, Shannon E; Thomas, Gethin; Wells, Christine; Harris, Mark; Cotterill, Andrew; Thomas, Ranjeny

    2012-05-01

    Novel biomarkers of disease progression after type 1 diabetes onset are needed. We profiled peripheral blood (PB) monocyte gene expression in six healthy subjects and 16 children with type 1 diabetes diagnosed ∼3 months previously and analyzed clinical features from diagnosis to 1 year. Monocyte expression profiles clustered into two distinct subgroups, representing mild and severe deviation from healthy control subjects, along the same continuum. Patients with strongly divergent monocyte gene expression had significantly higher insulin dose-adjusted HbA(1c) levels during the first year, compared with patients with mild deviation. The diabetes-associated expression signature identified multiple perturbations in pathways controlling cellular metabolism and survival, including endoplasmic reticulum and oxidative stress (e.g., induction of HIF1A, DDIT3, DDIT4, and GRP78). Quantitative PCR (qPCR) of a 9-gene panel correlated with glycemic control in 12 additional recent-onset patients. The qPCR signature was also detected in PB from healthy first-degree relatives. A PB gene expression signature correlates with glycemic control in the first year after diabetes diagnosis and is present in at-risk subjects. These findings implicate monocyte phenotype as a candidate biomarker for disease progression pre- and postonset and systemic stresses as contributors to innate immune function in type 1 diabetes.

  8. Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer's type.

    PubMed

    Popp, Julius; Wolfsgruber, Steffen; Heuser, Isabella; Peters, Oliver; Hüll, Michael; Schröder, Johannes; Möller, Hans-Jürgen; Lewczuk, Piotr; Schneider, Anja; Jahn, Holger; Luckhaus, Christian; Perneczky, Robert; Frölich, Lutz; Wagner, Michael; Maier, Wolfgang; Wiltfang, Jens; Kornhuber, Johannes; Jessen, Frank

    2015-02-01

    Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1-42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline.

  9. Heterogeneity in red wine polyphenolic contents differentially influences Alzheimer's disease-type neuropathology and cognitive deterioration.

    PubMed

    Ho, Lap; Chen, Ling Hong; Wang, Jun; Zhao, Wei; Talcott, Stephen T; Ono, Kenjiro; Teplow, David; Humala, Nelson; Cheng, Alice; Percival, Susan S; Ferruzzi, Mario; Janle, Elsa; Dickstein, Dara L; Pasinetti, Giulio Maria

    2009-01-01

    We recently found that moderate consumption of two unrelated red wines generate from different grape species, a Cabernet Sauvignon and a muscadine wine that are characterized by distinct component composition of polyphenolic compounds, significantly attenuated the development of Alzheimer's disease (AD)-type brain pathology and memory deterioration in a transgenic AD mouse model. Interestingly, our evidence suggests that the two red wines attenuated AD phenotypes through independent mechanisms. In particular, we previously found that treatment with Cabernet Sauvignon reduced the generation of AD-type amyloid-beta (Abeta) peptides. In contrast, evidence from our present study suggests that muscadine treatment attenuates Abeta neuropathology and Abeta-related cognitive deterioration in Tg2576 mice by interfering with the oligomerization of Abeta molecules to soluble high-molecular-weight Abeta oligomer species that are responsible for initiating a cascade of cellular events resulting in cognitive decline. Collectively, our observations suggest that distinct polyphenolic compounds from red wines may be bioavailable at the organism level and beneficially modulate AD phenotypes through multiple Abeta-related mechanisms. Results from these studies suggest the possibility of developing a "combination" of dietary polyphenolic compounds for AD prevention and/or therapy by modulating multiple Abeta-related mechanisms.

  10. Heterogeneity in Red Wine Polyphenolic Contents Differentially Influences Alzheimer's Disease-type Neuropathology and Cognitive Deterioration

    PubMed Central

    Ho, Lap; Chen, Ling Hong; Wang, Jun; Zhao, Wei; Talcott, Stephen T.; Ono, Kenjiro; Teplow, David; Humala, Nelson; Cheng, Alice; Percival, Susan S.; Ferruzzi, Mario; Janle, Elsa; Dickstein, Dara L.; Pasinetti, Giulio Maria

    2009-01-01

    We recently found that moderate consumption of two unrelated red wines generate from different grape species, a Cabernet Sauvignon and a muscadine wine that are characterized by distinct component composition of polyphenolic compounds, significantly attenuated the development of Alzheimer's disease (AD)-type brain pathology and memory deterioration in a transgenic AD mouse model. Interestingly, our evidence suggests that the two red wines attenuated AD phenotypes through independent mechanisms. In particular, we previously found that treatment with Cabernet Sauvignon reduced the generation of AD-type amyloid-β (Aβ) peptides. In contrast, evidence from our present study suggests that muscadine treatment attenuates Aβ neuropathology and Aβ-related cognitive deterioration in Tg2576 mice by interfering with the oligomerization of Aβ molecules to soluble high-molecular-weight Aβ oligomer species that are responsible for initiating a cascade of cellular events resulting in cognitive decline. Collectively, our observations suggest that distinct polyphenolic compounds from red wines may be bioavailable at the organism level and beneficially modulate AD phenotypes through multiple Aβ-related mechanisms. Results from these studies suggest the possibility of developing a “combination” of dietary polyphenolic compounds for AD prevention and/or therapy by modulating multiple Aβ-related mechanisms. PMID:19158422

  11. Diabetes type II: a risk factor for depression-Parkinson-Alzheimer?

    PubMed

    Riederer, Peter; Bartl, Jasmin; Laux, Gerd; Grünblatt, Edna

    2011-02-01

    There is ample evidence that impairments in the hypothalamic-pituitary-adrenal (HPA) axis are of etiopathobiochemical importance in a subgroup of patients with "depression", causing hypercortisolaemia as major metabolic effect. Chronic hypercortisolaemia causes insulin resistance. Therefore, it is not surprising that epidemiological studies demonstrate an association of "depression" with diabetes type II and vice versa. Chronic stress and hypercortisolaemia are conditions, which have been suggested to be causal for Alzheimer's disease (AD) as brain insulin resistance is associated with β-Amyloid-accumulation and hyperphosphorylation of tau-protein. Depression is one of the significant symptomatology preceding AD. It is however, not known whether "depression" associated with hypercortisolaemia is the subgroup at risk for AD. In contrast to a subgroup of "depression" and to AD, in Parkinson's disease (PD) there is only weak evidence for an association with diabetes type II and insulin resistance. As "depression" is preceding PD in up to half of such patients, it remains to be elucidated whether this is a subgroup of depressed patients, which is not associated with disturbances of the HPA axis and hypercortisolaemia. Improved clinical and biochemical/molecular knowledge about "depression" associated with AD and PD in comparison to "pure" depression might lead to improved therapeutic strategies and even drug development focusing subtypes of "depression".

  12. Regional cerebral metabolic alterations in dementia of the Alzheimer type: positron emission tomography with (/sup 18/F)fluorodeoxyglucose

    SciTech Connect

    Friedland, R.P.; Budinger, T.F.; Ganz, E.; Yano, Y.; Mathis, C.A.; Koss, B.; Ober, B.A.; Huesman, R.H.; Derenzo, S.E.

    1983-08-01

    Alzheimer disease is the most common cause of dementia in adults. Despite recent advances in our understanding of its anatomy and chemistry, we remain largely ignorant of its pathogenesis, physiology, diagnosis, and treatment. Dynamic positron emission tomography using (/sup 18/F)fluorodeoxyglucose (FDG) was performed on the Donner 280-crystal ring in 10 subjects with dementia of the Alzheimer type and six healthy age-matched controls. Ratios comparing mean counts per resolution element in frontal, temporoparietal, and entire cortex regions in brain sections 10 mm thick obtained 40-70 min following FDG injection showed relatively less FDG uptake in the temporoparietal cortex bilaterally in all the Alzheimer subjects (p less than 0.01). Left-right alterations were less prominent than the anteroposterior changes. This diminished uptake was due to lowered rates of FDG use and suggests that the metabolic effects of Alzheimer disease are most concentrated in the temporoparietal cortex. Positron emission tomography is a most powerful tool for the noninvasive in vivo assessment of cerebral pathophysiology in dementia.

  13. Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset

    PubMed Central

    Kornum, Birgitte Rahbek; Pizza, Fabio; Knudsen, Stine; Plazzi, Giuseppe; Jennum, Poul; Mignot, Emmanuel

    2015-01-01

    Type 1 Narcolepsy is caused by a loss of hypocretin (orexin) signaling in the brain. Genetic data suggests the disorder is caused by an autoimmune attack on hypocretin producing neurons in hypothalamus. This hypothesis has however not yet been confirmed by consistent findings of autoreactive antibodies or T-cells in patient samples. One explanation for these negative results may be that the autoimmune process is no longer active when patients present to the clinic. With increasing awareness in recent years, more and more patients have been diagnosed closer and closer to disease onset. In this study, we tested whether an active immune process in the brain could be detected in these patients, as reflected by increased cytokine levels in the cerebrospinal fluid (CSF). Using multiplex analysis, we measured the levels of 51 cytokines and chemokines in the CSF of 40 Type 1 Narcolepsy patients having varying disease duration. For comparison, we used samples from 9 healthy controls and 9 patients with other central hypersomnia. Cytokine levels did not differ significantly between controls and patients, even in 5 patients with disease onset less than a month prior to CSF sampling. PMID:25771509

  14. Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset.

    PubMed

    Kornum, Birgitte Rahbek; Pizza, Fabio; Knudsen, Stine; Plazzi, Giuseppe; Jennum, Poul; Mignot, Emmanuel

    2015-10-01

    Type 1 narcolepsy is caused by a loss of hypocretin (orexin) signaling in the brain. Genetic data suggests the disorder is caused by an autoimmune attack on hypocretin producing neurons in hypothalamus. This hypothesis has however not yet been confirmed by consistent findings of autoreactive antibodies or T-cells in patient samples. One explanation for these negative results may be that the autoimmune process is no longer active when patients present to the clinic. With increasing awareness in recent years, more and more patients have been diagnosed closer and closer to disease onset. In this study, we tested whether an active immune process in the brain could be detected in these patients, as reflected by increased cytokine levels in the cerebrospinal fluid (CSF). Using multiplex analysis, we measured the levels of 51 cytokines and chemokines in the CSF of 40 type 1 narcolepsy patients having varying disease duration. For comparison, we used samples from 9 healthy controls and 9 patients with other central hypersomnia. Cytokine levels did not differ significantly between controls and patients, even in 5 patients with disease onset less than a month prior to CSF sampling.

  15. 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.

  16. Topographic maps of brain electrical activity in primary degenerative dementia of the Alzheimer type and multiinfarct dementia.

    PubMed

    Martin-Loeches, M; Gil, P; Jimenez, F; Exposito, F J; Miguel, F; Cacabelos, R; Rubia, F J

    1991-02-01

    The topography of the electroencephalographic (EEG) pattern of ten patients with primary degenerative dementia of the Alzheimer type, ten multiinfarct dementia patients, and ten age-matched controls was compared during three different behavioral conditions: resting condition with eyes open (EO), memorizing a list of words (M), and recalling the same list of words (R). Results indicate that the alpha frequency band does not show significant changes. On the other hand, the theta band could be considered an important factor in the differential diagnosis of the primary degenerative dementia of the Alzheimer type, showing a higher power over right posterior regions in this group of patients compared with the multiinfarct dementia patients under different behavioral conditions.

  17. Onset of autoimmune type 1 diabetes during pregnancy: Prevalence and outcomes.

    PubMed

    Wucher, Hélène; Lepercq, Jacques; Timsit, José

    2010-08-01

    Although this has been recently challenged, gestational diabetes mellitus (gestational diabetes) is still defined as an "impairment of glucose tolerance with onset or first recognition during pregnancy". According to this definition, all pathophysiological conditions leading to beta cell deficiency may reveal as gestational diabetes, due to the physiological insulin resistance associated with pregnancy. In rare patients, gestational diabetes is associated with the presence of islet autoantibodies and with a high risk of progression to overt type 1 diabetes after delivery. This condition has often been compared to the Latent Autoimmune Diabetes in Adults. The frequency of islet autoantibodies in gestational diabetes has been assessed in many studies, but data about the clinical presentation of this subtype and about its prognosis are few. We review these studies and discuss the links of autoimmune gestational diabetes with type 1 diabetes mellitus.

  18. Hepatocyte nuclear factor 1-alpha mutation in normal glucose-tolerant subjects and early-onset type 2 diabetic patients.

    PubMed

    Lim, Dong Mee; Huh, Nam; Park, Keun Yong

    2008-12-01

    The prevalence of diabetes in Korea is reported to be approximately 10%, but cases of maturity-onset diabetes of the young (MODY) are rare in Korea. A diagnostic technique for autosomal dominant MODY is being actively sought. In this regard, we used a DNA chip to investigate the frequency of mutations of the MODY3 gene (hepatocyte nuclear factor-1alpha) in Korean patients with early-onset type 2 diabetes. The genomic DNA of 30 normal individuals [age, 24.9+/-8.6 years] and 25 patients with early-onset type 2 diabetes (age, 27+/-5.9 years) was extracted, and the MODY3 gene was amplified. The amplified DNA was hybridized onto a MODY3 chip, which has oligonucleotides of 15-25 bases, representing wild-type and mutant MODY3 sequences in both forward and reverse orientations, immobilized on its surface. Among the normal subjects, there was no mutation of MODY3. Among those with early-onset type 2 diabetes, there was one case of MODY3 mutation. Our results indicate that MODY3 mutations are not rare in Korean early-onset type 2 diabetes patients in Korea and suggest that MODY3 mutations in patients with early-onset type 2 diabetes need to be further evaluated.

  19. ICF-Based Analysis of Communication Disorders in Dementia of Alzheimer's Type

    PubMed Central

    Badarunisa, Mohamad Basheer; Sebastian, Daly; Rangasayee, Raghunath Rao; Kala, Baby

    2015-01-01

    Purpose Dementia of Alzheimer's type (DAT) is a major cognitive communication disorder. The present study attempted to analyse communication disorders in DAT in the International Classification of Functions (ICF) framework. The study investigated the impact of the severity of communication disorders in persons with DAT on activity participation and environment components of the ICF. Method Thirty bilingual individuals with DAT in the age range of 65-88 years were classified into three groups of mild, moderate and severe degree of dementia. Forty-three items of the American Speech-Language-Hearing Association Functional Assessment of Communication Skills for Adults (ASHA FACS) were linked to the ICF framework. A few additional items were also added for a complete profiling of DAT. A total of 50 (ASHA FACS + ICF) items were rated and administered for the purpose of the study. Results The study revealed a disproportionate impact of the severity of DAT on activity participation and environment components of the ICF. Conclusion The present study investigated the utility of the ICF framework for profiling the functionality of persons with DAT. This profiling highlighted the need for ensuring effective communication and quality of life in the DAT population. PMID:26955380

  20. Selegiline versus L-acetylcarnitine in the treatment of Alzheimer-type dementia.

    PubMed

    Campi, N; Todeschini, G P; Scarzella, L

    1990-01-01

    Forty elderly patients (13 men and 27 women, aged 56 to 80 years) were enrolled in a single-blind, randomized, parallel study to assess the efficacy and safety of selegiline (10 mg, once daily) and that of L-acetylcarnitine (500 mg, twice daily) in the treatment of patients with mild-to-moderate Alzheimer-type disorders. The treatments lasted 90 days, after a run-in period of 15 days. An extensive psychometric examination, carried out at baseline and subsequently at every 30 days of treatment, was used for evaluation of efficacy. Drug safety was assessed by noting any adverse effects that occurred during treatment and by performing laboratory tests at the beginning and end of treatment. According to the resulting data, selegiline therapy led to a global improvement in the capacity for the processing, storage, and retrieval of given information. Improvements in verbal fluency and visuospatial abilities were also noted. The marked between-group differences demonstrate that, at the dosage used, selegiline was far more effective than L-acetylcarnitine with respect to the degree of improvement. Finally, tolerability of both drugs was excellent, inasmuch as neither the monitoring for adverse drug reactions nor laboratory tests revealed any abnormalities resulting from therapy.

  1. Impaired information sampling in mild dementia of Alzheimer's type but not in healthy aging.

    PubMed

    Zamarian, Laura; Benke, Thomas; Brand, Matthias; Djamshidian, Atbin; Delazer, Margarete

    2015-05-01

    It is unknown whether aging affects predecisional processing, that is, gathering information and evaluating options before making a decision. Here, we investigated information sampling in mild Dementia of Alzheimer's type (DAT) and healthy aging by using the Information Sampling Task (IST). In a first investigation, we compared patients with mild DAT (n = 20) with healthy controls (n = 20) on the IST and several neuropsychological background tests. In a second investigation, healthy older adults (n = 30) were compared with younger adults (n = 30) on the IST and executive-function tasks. Results of the first investigation demonstrated that, in the IST, patients gathered significantly less information, made riskier and less accurate decisions, and showed less reward sensitivity relative to controls. We found a significant correlation between performance on the IST and performance on tests of verbal fluency, working memory, and recognition in patients but not in controls. Results of the second investigation indicated a largely similar performance pattern between healthy older adults and younger adults. There were no significant correlations for both groups between the IST and executive-function tasks. There are no relevant changes with healthy aging in predecisional processing. In contrast, mild DAT significantly affects predecisional information sampling. Thus, the problems shown in patients with mild DAT in decision making might be related to the patients' difficulties in predecisional processing. Decision-making performance in mild DAT might be improved by helping the patients at a predecisional stage to gather sufficient information and evaluate options more accurately. (c) 2015 APA, all rights reserved).

  2. Thyroid medication use and subsequent development of dementia of the Alzheimer type

    PubMed Central

    Roe, Catherine M.

    2009-01-01

    Associations between medication use and the development of Alzheimer’s disease have been investigated since the late 1900s. Thyroid hormone supplementation is rarely a studied medication class in this area of research. We examined data from participants enrolled in longitudinal studies at the Washington University Alzheimer’s Disease Research Center for associations between thyroid disease, thyroid hormone supplementation therapy, and subsequent development of dementia of the Alzheimer type (DAT). Data collected between April 1992 and June 2008 from 499 participants, 184 men and 315 women, were analyzed. Mean age was 76.9 years (S.D. = 9.2). At baseline, 61 participants reported thyroid medication use and 87 were identified as having a history of thyroid dysfunction. These participants progressed to a DAT diagnosis more rapidly than individuals not taking thyroid medication (HR: 1.67, 95% CI: 0.99–2.78, p = 0.054). While an interesting trend was seen, baseline thyroid disease was not significantly (p=.093) associated with time to DAT diagnosis. Our findings suggest that utilization of thyroid medication may be associated with the development of DAT. PMID:19666883

  3. Oligomerization of beta-amyloid of the Alzheimer's and the Dutch-cerebral-haemorrhage types.

    PubMed Central

    Sian, A K; Frears, E R; El-Agnaf, O M; Patel, B P; Manca, M F; Siligardi, G; Hussain, R; Austen, B M

    2000-01-01

    A novel ELISA has been developed which detects oligomerization of beta-amyloid (A beta). Oligomerization, fibrillization and neurotoxicity of native A beta associated with Alzheimer's disease (AD) type has been compared with E22Q A beta (amyloid beta-protein containing residues 1--40 with the native Glu at residue 22 changed to Gln) implicated in Dutch cerebral haemorrhage disease. Solutions of A beta rapidly yield soluble oligomers in a concentration-dependent manner, which are detected by the ELISA, and by size-exclusion gel chromatography. Conformational changes from disordered to beta-sheet occur more slowly than oligomerization, and fibrils are produced after prolonged incubation. The E22Q A beta oligomerizes, changes conformation and fibrillizes more rapidly than the native form and produces shorter stubbier fibrils. Aged fibrillar preparations of E22Q A beta are more potent than aged fibrils of native A beta in inducing apoptotic changes and toxic responses in human neuroblastoma cell lines, whereas low-molecular-mass oligomers in briefly incubated solutions are much less potent. The differences in the rates of oligomerization of the two A beta forms, their conformational behaviour over a range of pH values, and NMR data reported elsewhere, are consistent with a molecular model of oligomerization in which strands of A beta monomers initially overcome charge repulsion to form dimers in parallel beta-sheet arrangement, stabilized by intramolecular hydrophobic interactions, with amino acids of adjacent chains in register. PMID:10861242

  4. Oral reading in Chinese: evidence from dementia of the Alzheimer's type.

    PubMed

    Weekes, B

    2000-01-01

    The traditional view of oral reading ability in patients with dementia holds that it is a preserved skill even if there is a general impairment to lexico-semantic processing ability. Recently, this view has been challenged by studies showing that the oral reading ability of patients with dementia can deteriorate over the course of the disease. These studies have found that the oral reading of irregular English words is more prone to error than the oral reading of regular words by patients with dementia suggesting that the oral reading of irregular words depends upon support from semantic memory. Relatively little is known about the oral reading abilities of Chinese-speaking dementia patients. This paper reports on the results of a study of the language processing and the oral reading ability of Chinese speakers with probable dementia of the Alzheimer's type (DAT). DAT patients displayed impairment on tests of oral reading as well as impairment on tests of semantic memory, confrontation naming and word comprehension. The results also show significant effects of regularity, frequency and imageability on the oral reading of DAT patients. It is argued that Chinese-speaking DAT patients display a pattern of language impairment similar to their English-speaking counterparts and, moreover, that normal oral reading of Chinese characters may depend critically upon the integrity of semantic memory.

  5. Musical structural determinants of emotional judgments in dementia of the Alzheimer type.

    PubMed

    Gagnon, Lise; Peretz, Isabelle; Fülöp, Tamàs

    2009-01-01

    People with dementia of the Alzheimer type (DAT) may well be emotionally soothed by listening to music. However, very few systematic studies have been conducted to support the anecdotal evidence. DAT does damage certain cerebral structures that subsume emotional processing, and some studies have demonstrated deficits affecting emotional judgments of facial expression and prosody in DAT. Accordingly, this study addressed the question of whether DAT might leave musical emotional judgment intact. Twelve early DAT participants and 12 healthy elderly participants took part in this study. Emotional judgments were examined in relation to mode and tempo, two important structural properties that contribute to the happy-sad distinction in music. Their respective contributions were assessed in four different experimental conditions. The DAT participants' responses were similar to those of healthy elderly participants, showing spared ability to employ tempo and mode as cues for emotional interpretation. The DAT participants' performance was not correlated with their global cognitive functioning. These results constitute a preliminary empirical demonstration that, in early DAT, musical emotional judgments appear to be based on normal structural analysis of musical input.

  6. Increased cortical atrophy in patients with Alzheimer's disease and type 2 diabetes mellitus

    PubMed Central

    Biessels, G J; De Leeuw, F‐E; Lindeboom, J; Barkhof, F; Scheltens, P

    2006-01-01

    Background The risk of Alzheimer's disease (AD) is increased in type 2 diabetes (DM2). This increased risk has been attributed to vascular comorbidity, but other mechanisms, such as accelerated ageing of the brain, have also been implicated. Objective To determine whether AD in patients with DM2 is associated with an increased occurrence of vascular lesions in the brain, by increased cerebral atrophy, or a combination of both. Methods In total, 29 patients with AD and DM2 and 58 patients with AD and without DM2 were included in the study. Clinical characteristics were recorded, and a neuropsychological examination and magnetic resonance imaging (MRI) scan were performed. MRI scans were rated for cortical and subcortical atrophy, medial temporal lobe atrophy, white matter lesions, and infarcts. Results The neuropsychological profiles of the two groups were identical. Patients with AD and DM2 had increased cortical atrophy on MRI (p<0.05) compared with the non‐DM2 group. In addition, infarcts were more common (odds ratio 2.4; 95% CI 0.8 to 7.8), but this effect did not account for the increased atrophy. The other MR measures did not differ between the groups. Conclusion The results suggest that non‐vascular mechanisms, leading to increased cortical atrophy, are also involved in the increased risk of AD in DM2. PMID:16484636

  7. Theory of mind and cognitive processes in aging and Alzheimer type dementia: a systematic review.

    PubMed

    Sandoz, Mélanie; Démonet, Jean-François; Fossard, Marion

    2014-09-01

    Theory of mind (ToM) performance in aging and dementia of the Alzheimer type (DAT) has been a growing interest of researchers and recently, theoretical trends in ToM development have led to a focus on determining the cognitive skills involved in ToM performance. The aim of the present review is to answer three main questions: How is ToM assessed in aging and DAT? How does ToM performance evolve in aging and DAT? Do cognitive processes influence ToM performance in aging and DAT? A systematic review was conducted to provide a targeted overview of recent studies relating ToM performance with cognitive processes in aging and DAT. RESULTS suggest a decrease in ToM performance, more pronounced in complex ToM tasks. Moreover, the review points up the strong involvement of executive functions, especially inhibition, and reasoning skills in ToM task achievement. Current data suggest that the structure of ToM tasks itself could lead to poor performance, especially in populations with reduced cognitive abilities.

  8. Role of gut microbiota in obesity, type 2 diabetes and Alzheimer's disease.

    PubMed

    Naseer, Muhammad I; Bibi, Fehmida; Alqahtani, Mohammed H; Chaudhary, Adeel G; Azhar, Esam I; Kamal, Mohammad A; Yasir, Muhammad

    2014-03-01

    In recent years, there is a growing interest in research to investigate the importance of gut microbiome in health and diseases. This opens a new area of research for the role of microbial flora of the human gut in inflammation, energy homeostasis, pathogenesis of obesity and other associated disorders. Recent studies propose association of the gut microbiome with development of obesity and metabolic syndromes, such as type 2 diabetes mellitus (T2DM). The T2DM is a metabolic disease that is mainly caused by obesity-linked insulin resistance. The vascular effects of obesity appears to play a role in the development of Alzheimer's disease (AD) that is one of the rapidly growing diseases of a late stage of life all over the world. Studies from both humans and mice models have been demonstrated the engagement of gut microbial flora in the pathogenesis of obesity and host metabolism. The aim of this review is to discuss the current findings that may explain the cascade of gut microbial flora participation in the development of obesity, T2DM and further initiation of AD. In addition, the available data regarding the mechanisms that have been proposed to elucidate the role of gut microbiota in weight gain and possible cause of T2DM and AD have been examined.

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

    PubMed

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

    2014-01-01

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

  10. Effect of fever-management strategy on the progression of dementia of the Alzheimer type.

    PubMed

    Hurley, A C; Volicer, B J; Volicer, L

    1996-01-01

    This study was undertaken to determine if the progression of dementia of the Alzheimer type (DAT) is accelerated by an intercurrent infection and if management strategy (aggressive or palliative care) would modify this effect. A prospective cohort study compared the progression of DAT in patients in three 25-bed dementia special care units that provide a hospice option for care. There were three groups of patients, as follows: (a) developed a fever and received aggressive care (FAC, n = 30), (b) developed a fever and received palliative care (FPC, n = 19), and (c) did not develop a fever (NF, n = 46). The presence of a fever episode did not have an effect of its own on DAT progression. Over a 3-month period, DAT severity increased in most patients, but more so in FAC patients. Thus aggressive medical treatment of infections did not affect the underlying disease process and was associated with an acceleration of the progression of severity of DAT. Providing palliative care is recommended because it prevents patients from undergoing invasive diagnostic workups and treatments, does not accelerate the progression of DAT, and conserves scarce health care resources.

  11. Linking Alzheimer's disease and type 2 diabetes mellitus via aberrant insulin signaling and inflammation.

    PubMed

    Kamal, Mohammad A; Priyamvada, Shubha; Anbazhagan, Arivarasu N; Jabir, Nasimudeen R; Tabrez, Shams; Greig, Nigel H

    2014-03-01

    Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two progressive and devastating health disorders afflicting millions of people worldwide. The probability and incidence of both have increased considerably in recent years consequent to increased longevity and population growth. Progressively more links are being continuously found between inflammation and central nervous system disorders like AD, Parkinson's disease, Huntington's disease, motor neuron disease, multiple sclerosis, stroke, traumatic brain injury and even cancers of the nervous tissue. The depth of the relationship depends on the timing and extent of anti- or pro-inflammatory gene expression. Inflammation has also been implicated in T2DM. Misfolding and fibrillization (of tissue specific and/or non-specific proteins) are features common to both AD and T2DM and are induced by as well as contribute to inflammation and stress (oxidative/ glycation). This review appraises the roles of inflammation and abnormalities in the insulin signaling system as important shared features of T2DM and AD. The capacity of anti-cholinesterases in reducing the level of certain common inflammatory markers in particular if they may provide therapeutic potential to mitigate awry mechanisms leading to AD.

  12. Evidence for a dissociation of structural and semantic knowledge in dementia of the Alzheimer type (DAT).

    PubMed

    Hajilou, B Bruce; Done, D John

    2007-03-02

    Object recognition and naming deficits in dementia of the Alzheimer type (DAT) have typically been attributed to deficits in semantic processing, with only a few studies proposing loci of deficits other than semantic. One possible cause of DAT object recognition impairments could involve deficits in processing structural aspects of visually presented items. In this paper, we assess the performance of a group of mild DAT patients on two tasks of structural access, object decision, and the complete/incomplete task (based on part-whole matching task), as well as on a semantic probes task, designed to assess the patients' semantic knowledge of the same items for which structural knowledge had earlier been assessed. The DAT patients were substantially impaired in their performance on tasks of structural access. Further, no evidence for item-to-item consistency in the DAT patients' errors for the structural and semantic tasks was found, raising the possibility that structural and semantic knowledge may become differentially impaired in DAT.

  13. Brain local and regional neuroglial alterations in Alzheimer's Disease: cell types, responses and implications.

    PubMed

    Toledano, Adolfo; Álvarez, María-Isabel; Toledano-Díaz, Adolfo; Merino, José-Joaquín; Rodríguez, José Julio

    2016-01-01

    From birth to death, neurons are dynamically accompanied by neuroglial cells in a very close morphological and functional relationship. Three families have been classically considered within the CNS: astroglia, oligodendroglia and microglia. Many types/subtypes (including NGR2+ cells), with a wide variety of physiological and pathological effects on neurons, have been described using morphological and immunocytochemical criteria. Glio-glial, glio-neuronal and neuro-glial cell signaling and gliotransmission are phenomena that are essential to support brain functions. Morphofunctional changes resulting from the plasticity of all the glial cell types parallel the plastic neuronal changes that optimize the functionality of neuronal circuits. Moreover, neuroglia possesses the ability to adopt a reactive status (gliosis) in which, generally, new functions arise to improve and restore if needed the neural functionality. All these features make neuroglial cells elements of paramount importance when attempting to explain any physiological or pathological processes in the CNS, because they are involved in both, neuroprotection/neurorepair and neurodegeneration. There exist diverse and profound, regional and local, neuroglial changes in all involutive processes (physiological and pathological aging; neurodegenerative disorders, including Alzheimer ´s disease -AD-), but today, the exact meaning of such modifications (the modifications of the different neuroglial types, in time and place), is not well understood. In this review we consider the different neuroglial cells and their responses in order to understand the possible role they fulfill in pathogenesis, diagnosis and treatment (preventive or palliative) of AD. The existence of differentiated and/or concurrent pathogenic and neuro-protective/neuro-restorative astroglial and microglial responses is highlighted.

  14. [Longitudinal study of procedural memory in patients with Alzheimer-type dementia].

    PubMed

    Kawai, Hiroko; Kawamura, Mitsuru; Mochizuki, Satoshi; Yamanaka, Katsuo; Arakaki, Hiroshi; Tanaka, Kuniaki; Kawachi, Juro

    2002-04-01

    We never forget how to ride a bicycle, and it is thought that procedural memories are retained for a long time. Recently, it was reported that patients with dementia of the Alzheimer type(DAT) could not only acquire, but also retain, long-lasting procedural memories. Previous group studies had shown procedural memory retention times of only 1 month in DAT patients, while amnesic patients and healthy people could retain such memories for 12 months. The relationship between the ability to retain procedural memory and the stage of the disease is not clear, as to date there has been no longitudinal study of procedural memory retention in DAT patients. Thus, we examined DAT patients' ability to retain long-term procedural memories (after 1, 5 and 20 months), and analyzed the relationship between procedural memory ability and the progress of disease. Motor-type procedural memory was examined using the mirror tracing task and the bi-manual coordinated tracing task. All three of the DAT patients showed improvement in their performance. The time required for the tracing was reduced between trials, and the improvement did not disappear between sessions, or rather, their times further decreased in subsequent sessions. Even the most severe DAT patient (Mini Mental State Examination(MMSE) score of 4) was able to acquire the procedural memory and retain it for at least 3 months. Furthermore, one of the subjects showed retention of the procedural memory at 20 months. Our results suggest that DAT patients can retain procedural memories for extended periods, with no relationship between retention ability and disease progression. It is possible for even severely demented patients to acquire and retain motor-type procedural memories. Cognitive rehabilitation in DAT appears to be effective, and it is possible for DAT patients to learn new things. It may be that DAT patients can ameliorate their quality of life by using retained procedural memory.

  15. Sensorineural hearing loss--a common finding in early-onset type 2 diabetes mellitus.

    PubMed

    Lerman-Garber, Israel; Cuevas-Ramos, Daniel; Valdés, Samantha; Enríquez, Lorena; Lobato, Marlette; Osornio, Melannie; Escobedo, Ana Rosa; Pascual-Ramos, Virginia; Mehta, Roopa; Ramírez-Anguiano, Jacqueline; Gómez-Pérez, Francisco J

    2012-01-01

    To evaluate the prevalence and potential associations of hearing impairment in patients 30 to 50 years old with diabetes diagnosed before age 40 years-early-onset type 2 diabetes mellitus (T2DM). The study cohorts consisted of 46 consecutive patients with early-onset T2DM and 47 age-matched control subjects with rheumatoid arthritis. All study subjects completed clinical, serologic, and auditory assessments. The patients with T2DM had a mean age of 42 ± 6 years and a mean disease duration of 11 ± 6 years. Microalbuminuria was present in 26.1%, proliferative retinopathy in 26.1%, and symptomatic peripheral neuropathy in 23.9%. The prevalence of unilateral or bilateral hearing loss was significantly higher in the patients with T2DM than in the patients with rheumatoid arthritis (21.7% versus 6.4%, respectively; P = .01). Most cases of hearing loss were mild and involved high or acute tones. After multivariate analysis with adjustment for age, there was a significant association between hearing loss and hemoglobin A1c (odds ratio, 1.3; 95% confidence interval, 1.02 to 1.81; P = .035). In the patients with T2DM, the lengthening of the brainstem response was not significantly increased; however, the wave morphologic features were abnormal and the reproducibility was poor in both ears in 11 patients (24%). Patients with early-onset T2DM and poor glycemic control have an increased prevalence of subclinical hearing loss and impaired auditory brainstem responses. Hearing impairment may be an underrecognized complication of diabetes.

  16. Association between clusterin gene polymorphism rs11136000 and late-onset Alzheimer's disease susceptibility: A review and meta-analysis of case-control studies

    PubMed Central

    Du, Wenjin; Tan, Jiping; Xu, Wei; Chen, Jinwen; Wang, Luning

    2016-01-01

    The present study aimed to evaluate the association between rs11136000 in clusterin (CLU) and late-onset Alzheimer's disease (LOAD) by meta-analysis. Several databases including PubMed, EMbase, CBMdisc and CMCC were searched for relevant case-control studies based on defined selection criteria. Odds ratios (OR) and 95% confidence interval (CI) of the rs11136000 genotype and allele distribution were analyzed with RevMan and Stata software. The control population and heterogeneity between populations were examined in the selected studies using the Hardy-Weinberg equilibrium. Overall OR among the frequencies of the genotype and allele in both patients with AD and controls was estimated using fixed or random effect models. The summary of the OR and 95% CI were then analyzed to obtain the effects across the studies. Publication bias was examined using a funnel plot, Egger's test and Begg's test, and a Fail-safe Number (Nfs). A total of 20 reports were used. The summary OR for studies in the Caucasian population with a frequency of TT+TC/CC genotype and T/C allele at rs11136000 locus in CLU were 0.79 (95% CI, 0.73–0.86; P<0.00001) and 0.87 (95% CI, 0.85–0.90; P<0.00001). The summary OR for the studies conducted in the Asian population were 0.90 (95% CI, 0.81–0.99; P=0.04) and 0.87 (95% CI, 0.81–0.93; P<0.0001). The summary OR in other mixed ethnic groups with regards to the frequency of T/C allele was 0.82 (95% CI, 0.68–0.99; P=0.04). These results demonstrated the presence of a statistically significant difference in LOAD susceptibility between individuals with the T allele CLU rs11136000 polymorphism and those without. The studies conducted in populations of African descent or Hispanics showed no statistically significant difference. Negligible publication bias was present, with Nfs being 750.604. In summary, polymorphism rs11136000 in the CLU gene may contribute to susceptibility to LOAD, and the presence of the T allele may reduce the risk of LOAD in

  17. Association between clusterin gene polymorphism rs11136000 and late-onset Alzheimer's disease susceptibility: A review and meta-analysis of case-control studies.

    PubMed

    Du, Wenjin; Tan, Jiping; Xu, Wei; Chen, Jinwen; Wang, Luning

    2016-11-01

    The present study aimed to evaluate the association between rs11136000 in clusterin (CLU) and late-onset Alzheimer's disease (LOAD) by meta-analysis. Several databases including PubMed, EMbase, CBMdisc and CMCC were searched for relevant case-control studies based on defined selection criteria. Odds ratios (OR) and 95% confidence interval (CI) of the rs11136000 genotype and allele distribution were analyzed with RevMan and Stata software. The control population and heterogeneity between populations were examined in the selected studies using the Hardy-Weinberg equilibrium. Overall OR among the frequencies of the genotype and allele in both patients with AD and controls was estimated using fixed or random effect models. The summary of the OR and 95% CI were then analyzed to obtain the effects across the studies. Publication bias was examined using a funnel plot, Egger's test and Begg's test, and a Fail-safe Number (Nfs). A total of 20 reports were used. The summary OR for studies in the Caucasian population with a frequency of TT+TC/CC genotype and T/C allele at rs11136000 locus in CLU were 0.79 (95% CI, 0.73-0.86; P<0.00001) and 0.87 (95% CI, 0.85-0.90; P<0.00001). The summary OR for the studies conducted in the Asian population were 0.90 (95% CI, 0.81-0.99; P=0.04) and 0.87 (95% CI, 0.81-0.93; P<0.0001). The summary OR in other mixed ethnic groups with regards to the frequency of T/C allele was 0.82 (95% CI, 0.68-0.99; P=0.04). These results demonstrated the presence of a statistically significant difference in LOAD susceptibility between individuals with the T allele CLU rs11136000 polymorphism and those without. The studies conducted in populations of African descent or Hispanics showed no statistically significant difference. Negligible publication bias was present, with Nfs being 750.604. In summary, polymorphism rs11136000 in the CLU gene may contribute to susceptibility to LOAD, and the presence of the T allele may reduce the risk of LOAD in Caucasian and

  18. White Matter Tract Integrity in Alzheimer's Disease vs. Late Onset Bipolar Disorder and Its Correlation with Systemic Inflammation and Oxidative Stress Biomarkers.

    PubMed

    Besga, Ariadna; Chyzhyk, Darya; Gonzalez-Ortega, Itxaso; Echeveste, Jon; Graña-Lecuona, Marina; Graña, Manuel; Gonzalez-Pinto, Ana

    2017-01-01

    Background: Late Onset Bipolar Disorder (LOBD) is the development of Bipolar Disorder (BD) at an age above 50 years old. It is often difficult to differentiate from other aging dementias, such as Alzheimer's Disease (AD), because they share cognitive and behavioral impairment symptoms. Objectives: We look for WM tract voxel clusters showing significant differences when comparing of AD vs. LOBD, and its correlations with systemic blood plasma biomarkers (inflammatory, neurotrophic factors, and oxidative stress). Materials: A sample of healthy controls (HC) (n = 19), AD patients (n = 35), and LOBD patients (n = 24) was recruited at the Alava University Hospital. Blood plasma samples were obtained at recruitment time and analyzed to extract the inflammatory, oxidative stress, and neurotrophic factors. Several modalities of MRI were acquired for each subject, Methods: Fractional anisotropy (FA) coefficients are obtained from diffusion weighted imaging (DWI). Tract based spatial statistics (TBSS) finds FA skeleton clusters of WM tract voxels showing significant differences for all possible contrasts between HC, AD, and LOBD. An ANOVA F-test over all contrasts is carried out. Results of F-test are used to mask TBSS detected clusters for the AD > LOBD and LOBD > AD contrast to select the image clusters used for correlation analysis. Finally, Pearson's correlation coefficients between FA values at cluster sites and systemic blood plasma biomarker values are computed. Results: The TBSS contrasts with by ANOVA F-test has identified strongly significant clusters in the forceps minor, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and cingulum gyrus. The correlation analysis of these tract clusters found strong negative correlation of AD with the nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) blood biomarkers. Negative correlation of AD and positive correlation of LOBD with inflammation biomarker IL6 was also found. Conclusion

  19. Amyloid-β-related genes SORL1 and ACE are genetically associated with risk for late-onset Alzheimer disease in the Chinese population.

    PubMed

    Ning, Mei; Yang, Yifeng; Zhang, Zhou; Chen, Zhuo; Zhao, Teng; Zhang, Di; Zhou, Daizhan; Xu, Jie; Liu, Zhe; Wang, Yabing; Liu, Yun; Zhao, Xinzhi; Li, Weidong; Li, Sheng; He, Lin

    2010-01-01

    Late-onset Alzheimer Disease (LOAD) is a common neurodegenerative disease, and one of its major pathologic characteristics is senile plaques. Proteins encoded by SORL1 and ACE have been shown to be related to the processing, trafficking, and degradation of Amyloid-β, the principal component of senile plaques. In this paper, we investigated whether SORL1 and ACE are associated with LOAD. We recruited 144 LOAD patients and 476 controls from Shanghai, China and conducted a case-control study on 9 single-nucleotide polymorphisms (SNPs): 6 in SORL1 (rs2070045, rs661057, rs668387, rs689021, rs3824968, rs2282649) and 3 in ACE (rs1800764, rs4343, rs1799752). Despite the small case sample size (144), we observed that rs1800764, rs4343, rs1799752 in ACE, and rs2070045, rs3824968, rs2282649 in SORL1 showed significantly different allele frequencies between patients and controls (P=4.57×10, 5.24×10, 1.95×10, 1.77×10, 6.44×10, and 3.11×10, respectively). Moreover, haplotypes on ACE and on SORL1 were significantly associated with LOAD (all P-value<0.009 in ACE and all P-value <0.003 in SORL1). In ACE, we found the most significant protective haplotype encompasses SNPs rs2070045, rs3824968, and rs2282649 (C-G-D: OR=0.20, P=8.96×10). In SORL1, we detected a "complementary" haplotype (G-A-T: OR=1.54, P=2.67×10; T-T-C: OR=0.63, P=2.36×10) composed of SNPs rs2070045, rs3824968, and rs2282649. In addition, we carried out meta-analysis with 3 other Asian populations on 3 SNPs in SORL1 (rs2070045, rs3824968, and rs2282649). Results supported our initial finding that these 3 SNPs were associated with LOAD. Our data suggested that SORL1 and ACE might play a role in LOAD susceptibility among Han Chinese.

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

    PubMed

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

    2015-08-01

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

  1. Molecular interaction between type 2 diabetes and Alzheimer's disease through cross-seeding of protein misfolding.

    PubMed

    Moreno-Gonzalez, I; Edwards Iii, G; Salvadores, N; Shahnawaz, M; Diaz-Espinoza, R; Soto, C

    2017-09-01

    Numerous epidemiological studies have shown a significantly higher risk for development of Alzheimer's disease (AD) in patients affected by type 2 diabetes (T2D), but the molecular mechanism responsible for this association is presently unknown. Both diseases are considered protein misfolding disorders associated with the accumulation of protein aggregates; amyloid-beta (Aβ) and tau in the brain during AD, and islet amyloid polypeptide (IAPP) in pancreatic islets in T2D. Formation and accumulation of these proteins follows a seeding-nucleation model, where a misfolded aggregate or 'seed' promotes the rapid misfolding and aggregation of the native protein. Our underlying hypothesis is that misfolded IAPP produced in T2D potentiates AD pathology by cross-seeding Aβ, providing a molecular explanation for the link between these diseases. Here, we examined how misfolded IAPP affects Aβ aggregation and AD pathology in vitro and in vivo. We observed that addition of IAPP seeds accelerates Aβ aggregation in vitro in a seeding-like manner and the resulting fibrils are composed of both peptides. Transgenic animals expressing both human proteins exhibited exacerbated AD-like pathology compared with AD transgenic mice or AD transgenic animals with type 1 diabetes (T1D). Remarkably, IAPP colocalized with amyloid plaques in brain parenchymal deposits, suggesting that these peptides may directly interact and aggravate the disease. Furthermore, inoculation of pancreatic IAPP aggregates into the brains of AD transgenic mice resulted in more severe AD pathology and significantly greater memory impairments than untreated animals. These data provide a proof-of-concept for a new disease mechanism involving the interaction of misfolded proteins through cross-seeding events which may contribute to accelerate or exacerbate disease pathogenesis. Our findings could shed light on understanding the linkage between T2D and AD, two of the most prevalent protein misfolding disorders.

  2. Predictability and Risk Factors for Development of New-Onset Type 2 Diabetes Mellitus After Transplant in the Saudi Population.

    PubMed

    Alshamsi, Shaikha; Basri, Nawal; Flaiw, Ahmed; Ghamdi, Ghormullah; Hejaili, Fayez; Shaheen, Faissal A M; Sheayria, Foud; Jaradat, Maha; Al Sayyari, Abdulla

    2016-06-01

    The study objective was to investigate the predictability and risk factors for the development of new-onset type 2 diabetes mellitus after transplant in the Saudi population. This was a retrospective observational cohort study in adult kidney transplant recipients who developed new-onset type 2 diabetes mellitus after transplant. Patients with and without new-onset type 2 diabetes mellitus after transplant were compared for demographic factors, blood glucose levels at 4-hour intervals for 24 hours after transplant, and serum creatinine levels at 6 and 12 months after transplant. Of 279 patients included in our study, 15.5% developed new-onset type 2 diabetes mellitus after a mean follow-up of 4.6 ± 2.1 years after transplant. Patients with new-onset type 2 diabetes mellitus after transplant were significant older (P = .001), had a higher body mass index (P = .001), and had higher fasting blood glucose levels 24 hours after transplant (P = .03). No significant differences were observed regarding sex, transplant type, or serum creatinine levels at 6 and 12 months. Risk factors for new-onset type 2 diabetes mellitus after transplant are body mass index (P = .001; relative risk of 1.26), fasting blood glucose at 24 hours (P = .001; relative risk of 1.3), age (P = .001; relative risk of 1.44), and family history of diabetes mellitus (P = .001; relative risk of 31.3). Risk factors for developing new-onset type 2 diabetes mellitus were age, heavier weight, body mass index, family history of diabetes mellitus, and having higher fasting blood glucose levels 24 hours after transplant, with family history of diabetes mellitus being an especially very high significant risk factor.

  3. Delaying the onset of type 2 diabetes mellitus in patients with prediabetes.

    PubMed

    Irons, Brian K; Mazzolini, Timothy A; Greene, Ronald Shane

    2004-03-01

    The frequency of type 2 diabetes mellitus is increasing at an alarming rate. Prediabetes, also referred to as impaired glucose tolerance (IGT) and/or impaired fasting glucose, is a major risk factor for development of type 2 diabetes mellitus. In addition, IGT has been associated with an increased risk of cardiovascular disease and mortality. Several studies have measured the effects of various interventions in patients with IGT on the development of type 2 diabetes mellitus. Intensive lifestyle modifications through alterations in diet and improvement in exercise have delayed the development of type 2 diabetes mellitus by 58% in patients with IGT. Therapy with metformin, troglitazone, or acarbose also has reduced the progression of IGT to diabetes mellitus by 31%, 49% and 25%, respectively. The mechanisms by which lifestyle interventions and drugs reduce the progression may be through alterations in insulin sensitivity. The American Diabetes Association recommends screening for prediabetes in patients who are 45 years or older and those with a body mass index of 25 kg/m2 or greater who have additional diabetes mellitus risk factors. Pharmacists can promote awareness, counsel patients on intervention strategies to delay the onset of diabetes mellitus, and screen high-risk patients.

  4. Pyridoxal 5'-phosphate (PLP) deficiency might contribute to the onset of type I diabetes.

    PubMed

    Rubí, B

    2012-01-01

    The incidence of type I diabetes is rising worldwide, particularly in young children. Type I diabetes is considered a multifactorial disease with genetic predisposition and environmental factors participating. Currently, despite years of research, there is no consensus regarding the factors that initiate the autoimmune response. Type I diabetes is preceded by autoimmunity to islet antigens, among them the protein glutamic acid decarboxylase, GAD-65. Pyridoxal 5'-phosphate (PLP) is formed from vitamin B6 by the action of pyridoxal kinase. Interaction of GAD65 with PLP is necessary for GAD65-mediated synthesis of the neurotransmitter γ-aminobutyric acid (GABA). PLP is also a required cofactor for dopamine synthesis by L-aromatic decarboxylase (L-AADC). Both GAD65 and L-AADC are expressed in pancreatic islets. Here it is proposed that lack of the vitamin B6 derivative pyridoxal 5'-phosphate might contribute to the appearance of pancreatic islet autoimmunity and type I diabetes onset. Copyright © 2011 Elsevier Ltd. All rights reserved.

  5. A search for the primary abnormality in adult-onset type II citrullinemia

    SciTech Connect

    Kobayashi, Keiko; Shaheen, Nazma; Saheki, Takeyori ); Kumashiro, Ryukichi; Tanikawa, Kyuichi ); O'Brien, W.E.; Beaudet, A.L. )

    1993-11-01

    Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia in human beings. Type II citrullinemia is found in most patients with adult-onset citrullinemia in Japan, and ASS deficiency is found specifically in the liver. Previous studies have shown that the decrease of hepatic ASS activity is caused by a decrease in enzyme protein with normal kinetic properties and that there were no apparent abnormalities in the amount, translational activity, and gross structure of hepatic ASS mRNA. In the present work, the authors show by sequencing analysis that there was no mutation in the ASS mRNA from two patients with type II citrullinemia. The authors also report RFLP analysis of a consanguineous family with type II citrullinemia, by using three DNA polymorphisms located within the ASS gene locus. In spite of having consanguineous parents, the patient was not a homozygous haplotype for the ASS gene. The RFLP analysis of 16 affected patients from consanguineous parents showed that 5 of 16 patients had the heterozygous pattern for one of the three DNA probes and that the frequency of the heterozygous haplotype was not different from the control frequency. These results suggest that the primary defect of type II citrullinemia is not within the ASS gene locus. 29 refs., 1 fig., 3 tabs.

  6. The onset of chromospheric activity among the A- and F- type stars

    NASA Technical Reports Server (NTRS)

    Simon, Theodore; Landsman, Wayne

    1987-01-01

    IUE observations of C II lambda1335 and C IV lambda1549 and ground-based observations of He I lambda5876 have previously discovered intense levels of chromospheric activity among early F type stars. Virtually all F dwarfs show stronger chromospheric and transition region emission than do the cooler and more deeply convective dwarf stars like the Sun. The IUE spectra and those of He lambda5876 place the onset of stellar activity along the main sequence near a color B - V = 0.28, which corresponds approximately to spectral type FO and an effective temperature of 7300 K. However, existing X-ray observations of A and F stars suggest that coronal activity may reach a peak blueward of this high temperature boundary at B - V = 0.28 before vanishing among the early and mid A-type stars. Discussed are preliminary results of a new effort to refine the location of the high temperature boundary to chromospheric activity among A- and F- type stars, making use of low dispersion short-wavelength spectra from the IUE archives from which the strengths of C IV, C II, and Lyman alpha emission have been measured.

  7. Young stellar populations in type II quasars: timing the onset of star formation and nuclear activity

    NASA Astrophysics Data System (ADS)

    Bessiere, P. S.; Tadhunter, C. N.; Ramos Almeida, C.; Villar Martín, M.; Cabrera-Lavers, A.

    2017-04-01

    Despite the emerging morphological evidence that luminous quasar-like active galactic nuclei (AGN) are triggered in galaxy mergers, the natures of the triggering mergers and the order of events in the triggering sequence remain uncertain. In this work, we present a detailed study of the stellar populations of the host galaxies of 21 type II quasars, with the aim of understanding the sequence of events between the onset of the merger, the triggering of the associated starburst and the initiation of the quasar activity. To this end, we model high-quality, wide spectral coverage, intermediate-resolution optical spectra of the type II quasars. We find that of the 21 objects, the higher order Balmer absorption lines, characteristic of young stellar populations (YSPs), are directly detected in ˜62 per cent of the sample. We also fit these spectra using a number of combinations of stellar and/or power-law components, representative of viable formation histories, as well as including the possibility of scattered AGN light. We find that ˜90 per cent of the type II quasar host galaxies require the inclusion of a YSP to adequately model their spectra, whilst 71 per cent of the sample require the inclusion of a YSP with age <100 Myr. Since the ages of the YSP in most type II quasar host galaxies are comparable with the expected lifetimes of the AGN activity, these results provide strong evidence that the quasars are triggered close to the peaks of the merger-induced starbursts.

  8. Cytosolic proteins lose solubility as amyloid deposits in a transgenic mouse model of Alzheimer-type amyloidosis

    PubMed Central

    Xu, Guilian; Stevens, Stanley M.; Moore, Brenda D.; McClung, Scott; Borchelt, David R.

    2013-01-01

    The extracellular accumulation of β-amyloid peptide is a key trigger in the pathogenesis of Alzheimer's disease (AD). In humans, amyloid deposition precedes the appearance of intracellular inclusion pathology formed by cytosolic proteins such as Tau, α-synuclein and TDP-43. These secondary pathologies have not been observed in mice that model Alzheimer-type amyloidosis by expressing mutant amyloid precursor protein, with or without mutant presenilin 1. The lack of secondary pathology in these models has made it difficult to establish how amyloid deposition initiates the cascade of events that leads to secondary intracellular pathology that characterizes human AD. In transgenic mice that model Alzheimer-type amyloidosis, we sought to determine whether there is evidence of altered cytosolic protein folding by assessing whether amyloid deposition causes normally soluble proteins to misfold. Using a method that involved detergent extraction and sedimentation coupled with proteomic approaches, we identified numerous cytosolic proteins that show specific losses in solubility as amyloid accumulates. The proteins identified included glycolytic enzymes and members of the 14-3-3 chaperone family. A substantial accumulation of lysine 48-linked polyubiquitin was also detected. Overall, the data demonstrate that the accumulation of amyloid by some manner causes the loss of solubility intracellular cytosolic proteins. PMID:23512986

  9. Spinocerebellar ataxia type 13 mutation that is associated with disease onset in infancy disrupts axonal pathfinding during neuronal development.

    PubMed

    Issa, Fadi A; Mock, Allan F; Sagasti, Alvaro; Papazian, Diane M

    2012-11-01

    Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominant disease caused by mutations in the Kv3.3 voltage-gated potassium (K(+)) channel. SCA13 exists in two forms: infant onset is characterized by severe cerebellar atrophy, persistent motor deficits and intellectual disability, whereas adult onset is characterized by progressive ataxia and progressive cerebellar degeneration. To test the hypothesis that infant- and adult-onset mutations have differential effects on neuronal development that contribute to the age at which SCA13 emerges, we expressed wild-type Kv3.3 or infant- or adult-onset mutant proteins in motor neurons in the zebrafish spinal cord. We characterized the development of CaP (caudal primary) motor neurons at ∼36 and ∼48 hours post-fertilization using confocal microscopy and 3D digital reconstruction. Exogenous expression of wild-type Kv3.3 had no significant effect on CaP development. In contrast, CaP neurons expressing the infant-onset mutation made frequent pathfinding errors, sending long, abnormal axon collaterals into muscle territories that are normally innervated exclusively by RoP (rostral primary) or MiP (middle primary) motor neurons. This phenotype might be directly relevant to infant-onset SCA13 because interaction with inappropriate synaptic partners might trigger cell death during brain development. Importantly, pathfinding errors were not detected in CaP neurons expressing the adult-onset mutation. However, the adult-onset mutation tended to increase the complexity of the distal axonal arbor. From these results, we speculate that infant-onset SCA13 is associated with marked changes in the development of Kv3.3-expressing cerebellar neurons, reducing their health and viability early in life and resulting in the withered cerebellum seen in affected children.

  10. Breakout character of islet amyloid polypeptide hydrophobic mutations at the onset of type-2 diabetes

    NASA Astrophysics Data System (ADS)

    Frigori, Rafael B.

    2014-11-01

    Toxic fibrillar aggregates of islet amyloid polypeptide (IAPP) appear as the physical outcome of a peptidic phase transition signaling the onset of type-2 diabetes mellitus in different mammalian species. In particular, experimentally verified mutations on the amyloidogenic segment 20-29 in humans, cats, and rats are highly correlated with the molecular aggregation propensities. Through a microcanonical analysis of the aggregation of IAPP20 -29 isoforms, we show that a minimalist one-bead hydrophobic-polar continuum model for protein interactions properly quantifies those propensities from free-energy barriers. Our results highlight the central role of sequence-dependent hydrophobic mutations on hot spots for stabilization, and thus for the engineering, of such biological peptides.

  11. Early onset symptomatic neuropathy in a child with Type 1 Diabetes mellitus.

    PubMed

    Shafi, Obeid Mohammad; Latief, Muzamil

    2017-04-05

    Diabetic neuropathy (DN) is a major complication of Type 1 Diabetes Mellitus (T1DM). It is usually subclinical in childhood, but can cause significant impairment with its progression through to adulthood. Current guidelines vary in their recommendation regarding screening for DN in children with T1DM, with some advocating starting screening 5 years after the diagnosis of T1DM. Clinical assessment comprising of history and neurological examination is the most commonly used method for screening, though Nerve Conduction Studies (NCS) provide better sensitivity in picking up early subclinical diabetic neuropathy. We describe an adolescent female with poorly controlled T1DM, presenting with symptomatic diabetic neuropathy within 2 years of disease onset and as the initial long term complication. Thus, guidelines regarding screening for DN may need revision, to start screening earlier than presently recommended, and NCS could play a prominent role in screening children with significant risk factors for developing DN.

  12. Case report: An adult-onset type II citrin deficiency patient in the emergency department.

    PubMed

    Tang, Lujia; Chen, Liang; Wang, Hairong; Dai, Lihua; Pan, Shuming

    2016-07-01

    Mutations in the solute carrier family 25 (SLC25A13) gene may result in neonatal intrahepatic cholestasis caused by citrin deficiency and/or adult-onset type II citrullinemia. These conditions are inherited in an autosomal recessive manner. The current case report describes a 43-year-old man who presented with sudden delirium and upper limb weakness. Upon admission, the patient was fully conscious and alert but later lost consciousness subsequent to a sudden convulsive seizure. Hyperammonemia was detected and analysis of the SLC25A13 gene identified an 851del4 mutation. Thus, the possibility of genetic disease should be considered as a potential cause of the symptoms of patients with altered states of consciousness, such as delirium and loss of consciousness, in cases where the cause of the disturbance is unknown.

  13. [A case of adult-onset type II citrullinemia in an elderly patient].

    PubMed

    Kitaoka, Mayuko; Sakaeda, Hiroshi; Suzuki, Mika; Miki, Toshifumi; Saito, Junko; Chikamori, Masayasu; Tomita, Hideharu; Ichikawa, Hiromoto; Yoshimoto, Kaori; Takamatsu, Masahiro; Okada, Mitsuo; Aono, Rei; Enzan, Hideaki; Miyamoto, Takako

    2013-03-01

    A 72-year-old man presented with consciousness disturbance. The results of brain magnetic resonance imaging and cerebrospinal fluid examination were normal, but triphasic waves were noted on electroencephalography. His plasma ammonia level was elevated due to which encephalopathy secondary to hyperammonemia was suspected. However, his liver function was normal, and no evidence of cirrhosis or portal-systemic shunt was noted. The patient's medical history revealed that he had a tendency to excessively consume pulse products since childhood, and an amino acid analysis showed elevation of citrulline and arginine levels. Thus, we diagnosed the patient with an extremely rare case of adult-onset type II citrullinemia, which was triggered by cessation of the intake of pulse foods (soybeans and peanuts) due to dental problems.

  14. Case report: An adult-onset type II citrin deficiency patient in the emergency department

    PubMed Central

    TANG, LUJIA; CHEN, LIANG; WANG, HAIRONG; DAI, LIHUA; PAN, SHUMING

    2016-01-01

    Mutations in the solute carrier family 25 (SLC25A13) gene may result in neonatal intrahepatic cholestasis caused by citrin deficiency and/or adult-onset type II citrullinemia. These conditions are inherited in an autosomal recessive manner. The current case report describes a 43-year-old man who presented with sudden delirium and upper limb weakness. Upon admission, the patient was fully conscious and alert but later lost consciousness subsequent to a sudden convulsive seizure. Hyperammonemia was detected and analysis of the SLC25A13 gene identified an 851del4 mutation. Thus, the possibility of genetic disease should be considered as a potential cause of the symptoms of patients with altered states of consciousness, such as delirium and loss of consciousness, in cases where the cause of the disturbance is unknown. PMID:27347070

  15. Alzheimer disease and cognitive impairment associated with diabetes mellitus type 2: associations and a hypothesis.

    PubMed

    Domínguez, R O; Pagano, M A; Marschoff, E R; González, S E; Repetto, M G; Serra, J A

    2014-01-01

    Epidemiological studies have demonstrated that patients with diabetes mellitus have an increased risk of developing Alzheimer disease, but the relationship between the 2 entities is not clear. Both diseases exhibit similar metabolic abnormalities: disordered glucose metabolism, abnormal insulin receptor signalling and insulin resistance, oxidative stress, and structural abnormalities in proteins and β-amyloid deposits. Different hypotheses have emerged from experimental work in the last two decades. One of the most comprehensive relates the microvascular damage in diabetic polyneuritis with the central nervous system changes occurring in Alzheimer disease. Another hypothesis considers that cognitive impairment in both diabetes and Alzheimer disease is linked to a state of systemic oxidative stress. Recently, attenuation of cognitive impairment and normalisation of values in biochemical markers for oxidative stress were found in patients with Alzheimer disease and concomitant diabetes. Antidiabetic drugs may have a beneficial effect on glycolysis and its end products, and on other metabolic alterations. Diabetic patients are at increased risk for developing Alzheimer disease, but paradoxically, their biochemical alterations and cognitive impairment are less pronounced than in groups of dementia patients without diabetes. A deeper understanding of interactions between the pathogenic processes of both entities may lead to new therapeutic strategies that would slow or halt the progression of impairment. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  16. An autopsy case of Creutzfeldt-Jakob disease with a V180I mutation of the PrP gene and Alzheimer-type pathology.

    PubMed

    Yoshida, Hidenori; Terada, Seishi; Ishizu, Hideki; Ikeda, Kenji; Hayabara, Toshiyuki; Ikeda, Kazuyo; Deguchi, Kazushi; Touge, Tetsuo; Kitamoto, Tetsuyuki; Kuroda, Shigetoshi

    2010-04-01

    We report an autopsy case of Creutzfeldt-Jakob disease with a codon 180 point mutation of the prion protein gene (PRNP). A 77-year-old woman developed gait instability, followed by dementia and limb/truncal ataxia. She became akinetic and mute 18 months and died of pneumonia 26 months after the disease onset. Analysis of the PRNP gene revealed a codon 180 point mutation. Post-mortem examination revealed marked spongiosis, neuronal loss, and astrocytic gliosis in the cerebral cortex. Mild to moderate spongiosis and neuronal loss were observed in the limbic cortex and basal ganglia. There was no spongiform change in the hippocampus, brain stem or cerebellum. Many senile plaques and neurofibrillary tangles were found, and the Braak stages were stage C and stage IV, respectively. Immunostaining for prion protein (PrP) revealed granular (synaptic-type) and patchy PrP deposition in the cerebral cortex and especially in the hippocampus. Most patchy PrP deposits were colocalized with amyloid beta plaques, but some of them were isolated. The relatively strong PrP deposition and coexistence of Alzheimer-type pathology of this case are remarkable. We suppose that amyloid beta plaques might act as a facilitating factor for PrP deposition.

  17. Exercise testing in late-onset glycogen storage disease type II patients undergoing enzyme replacement therapy.

    PubMed

    Marzorati, Mauro; Porcelli, Simone; Bellistri, Giuseppe; Morandi, Lucia; Grassi, Bruno

    2012-12-01

    Enzyme replacement therapy (ERT) has recently became available for patients with glycogen storage disease type II. Previous studies have demonstrated clinical efficacy of enzyme replacement therapy, however, data on physiological variables related to exercise tolerance are scarce. Four glycogen storage disease type II late-onset patients (45 ± 6 years) performed an incremental exercise on a cycle ergometer, up to voluntary exhaustion, before (BEFORE) and after 12 months of ERT (AFTER). Peak workload, oxygen uptake, heart rate, cardiac output (by impedance cardiography) and vastus lateralis oxygenation indices (by continuous-wave near-infrared spectroscopy, NIRS) were determined. Peak workload and oxygen uptake values significantly increased during ERT (54 ± 30 vs. 63 ± 31 watt, and 17.2 ± 4.4 vs. 19.7 ± 3.5 ml/kg/min, respectively, in BEFORE vs. AFTER). On the other hand, for both peak cardiac output (12.3 ± 5.3 vs. 14.8 ± 4.5L/min) and the NIRS-determined peak skeletal muscle fractional O(2) extraction, expressed as a percentage of the maximal values during a transient limb ischemia (30 ± 39% vs. 38 ± 28%), the observed increases were not statistically significant. Our findings suggest that in glycogen storage disease type II patients enzyme replacement therapy is associated with a mild improvement of exercise tolerance. The findings need to be validated during a longer follow-up on a larger group of patients.

  18. Anthocyanins restore behavioral and biochemical changes caused by streptozotocin-induced sporadic dementia of Alzheimer's type.

    PubMed

    Gutierres, Jessié M; Carvalho, Fabiano B; Schetinger, Maria Rosa C; Marisco, Patrícia; Agostinho, Paula; Rodrigues, Marília; Rubin, Maribel A; Schmatz, Roberta; da Silva, Cassia R; de P Cognato, Giana; Farias, Julia G; Signor, Cristiane; Morsch, Vera M; Mazzanti, Cinthia M; Bogo, Mauricio; Bonan, Carla D; Spanevello, Roselia

    2014-02-06

    The aim of this study was to analyze if the pre-administration of anthocyanin on memory and anxiety prevented the effects caused by intracerebroventricular streptozotocin (icv-STZ) administration-induced sporadic dementia of Alzheimer's type (SDAT) in rats. Moreover, we evaluated whether the levels of nitrite/nitrate (NOx), Na(+),K(+)-ATPase, Ca(2+)-ATPase and acethylcholinesterase (AChE) activities in the cerebral cortex (CC) and hippocampus (HC) are altered in this experimental SDAT. Male Wistar rats were divided in 4 different groups: control (CTRL), anthocyanin (ANT), streptozotocin (STZ) and streptozotocin+anthocyanin (STZ+ANT). After seven days of treatment with ANT (200mg/kg; oral), the rats were icv-STZ injected (3mg/kg), and four days later the behavior parameters were performed and the animals submitted to euthanasia. A memory deficit was found in the STZ group, but ANT treatment showed that it prevents this impairment of memory (P<0.05). Our results showed a higher anxiety in the icv-STZ group, but treatment with ANT showed a per se effect and prevented the anxiogenic behavior induced by STZ. Our results reveal that the ANT treatment (100μM) tested displaces the specific binding of [(3)H] flunitrazepam to the benzodiazepinic site of GABAA receptors. AChE, Ca(+)-ATPase activities and NOx levels were found to be increased in HC and CC in the STZ group, which was attenuated by ANT (P<0.05). STZ decreased Na(+),K(+)-ATPase activity and ANT was able to prevent these effects (P<0.05). In conclusion, these findings demonstrated that ANT is able to regulate ion pump activity and cholinergic neurotransmission, as well as being able to enhance memory and act as an anxiolytic compound in animals with SDAT. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Autoantibodies Toward the Angiotensin 2 Type 1 Receptor: A Novel Autoantibody in Alzheimer's Disease.

    PubMed

    Giil, Lasse M; Kristoffersen, Einar K; Vedeler, Christian A; Aarsland, Dag; Nordrehaug, Jan Erik; Winblad, Bengt; Cedazo-Minguez, Angel; Lund, Anders; Reksten, Tove Ragna

    2015-01-01

    Autoantibodies with agonist function are described in cardiovascular disorders. Since vascular risk factors are associated with an increased risk for Alzheimer's disease (AD), we investigated a potential association between antibodies to the angiotensin 2 type 1 receptor (anti-AT1R) and AD. The primary objective of this study was to investigate the association between anti-AT1R and AD. The secondary objective was to investigate the association between clinical or biomarker features of AD and anti-AT1R. Samples from patients with mild AD participating in a longitudinal study in Western Norway (n = 92, 65 [71%] females, mean age 74.8 [range 50-89]) and age- and gender-matched healthy controls (n = 102) were included. Cerebrospinal fluid (CSF) AD biomarkers were assessed in a subgroup of patients. Patients were examined annually, including Mini-Mental State Examination. ELISA was used to measure anti-AT1R in serum. Non-parametric tests were used for statistical calculations and a p <  0.05 was considered significant. AD patients had significantly higher levels of anti-AT1R compared with healthy controls (10.2 U/mL versus 8.1 U/mL, p = 0.04). This difference was found only in patients without hypertension and diabetes. Anti-AT1R levels correlated with CSF total tau (p = 0.03) and phosphorylated tau (p = 0.03) levels, and inversely with blood pressure in AD (Spearman R -0.277, p = 0.008). AD is associated with increased levels of anti-AT1R, and the antibodies correlated with CSF total, and phosphorylated tau levels. Further research is needed to understand the blood pressure response in AD without hypertension and a potential link between tau and anti-AT1R in AD.

  20. Pharmacological benefits of selective modulation of cannabinoid receptor type 2 (CB2) in experimental Alzheimer's disease.

    PubMed

    Jayant, Shalini; Sharma, Brij Mohan; Bansal, Rani; Sharma, Bhupesh

    2016-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder that pervasively affects the population across the world. Currently, there is no effective treatment available for this and existing drugs merely slow the progression of cognitive function decline. Thus, massive effort is required to find an intended therapeutic target to overcome this condition. The present study has been framed to investigate the ameliorative role of selective modulator of cannabinoid receptor type 2 (CB2), 1-phenylisatin in experimental AD condition. We have induced experimental AD in mice by using two induction models viz., intracerebroventricular (i.c.v.) administration of streptozotocin (STZ) and aluminum trichloride (AlCl3)+d-galactose. Morris water maze (MWM) and attentional set shifting test (ASST) were used to assess learning and memory. Hematoxylin-eosin and Congo red staining were used to examine the structural variation in brain. Brain oxidative stress (thiobarbituric acid reactive substance and glutathione), nitric oxide levels (nitrites/nitrates), acetyl cholinesterase activity, myeloperoxidase and calcium levels were also estimated. i.c.v. STZ as well as AlCl3+d-galactose have impaired spatial and reversal learning with executive functioning, increased brain oxidative and nitrosative stress, cholinergic activity, inflammation and calcium levels. Furthermore, these agents have also enhanced the burden of Aβ plaque in the brain. Treatment with 1-phenylisatin and donepezil attenuated i.c.v. STZ as well as AlCl3+d-galactose induced impairment of learning-memory, brain biochemistry and brain damage. Hence, this study concludes that CB2 receptor modulation can be a potential therapeutic target for the management of AD. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. A nanotechnological approach to the management of Alzheimer disease and type 2 diabetes.

    PubMed

    Alam, Qamre; ZubairAlam, Mohammad; Karim, Sajjad; Gan, Siew H; Kamal, Mohammad A; Jiman-Fatani, Asif; Damanhouri, Ghazi A; Abuzenadah, Adel M; Chaudhary, Adeel G; Haque, Absarul

    2014-04-01

    Alzheimer's disease (AD) and type 2 diabetes (T2D) are both prevalent in older individuals and have gained significant attention due to alarming rates of increase. The high incidences of these diseases pose a great socioeconomic burden and cause major public health concerns worldwide. A number of studies have established potential links between AD and T2D, supporting the hypothesis that T2D is linked with an increased risk of AD and that controlling diabetes could have a positive impact on the prevention of AD. At present, both diseases lack precise diagnostic approaches for early intervention and effective cure. Further, the currently available diagnostic tools for AD screening are insufficiently sensitive and robust for preventive measures. Although several drugs are used for the treatment of both these diseases, none of these drugs offers complete remission of the disease, merely symptomatic relief. Moreover, these drugs have limited efficacy because of problems such as conventional drug delivery systems beyond the blood brain barrier, a lack of target specificity and diminished potency. From this perspective, the emerging field of nanotechnology has offered new techniques and tools to overcome these challenges. In this review, we discuss the direct and indirect limitations of existing therapies and describe alternative potential nanotechnological approaches that could be utilized to overcome these limitations. New insight in the field of nanomedicine is necessary for early diagnosis, the development of novel drug therapies, the action of drugs and prevention, as well as for gaining an in-depth understanding of the complex biology of both diseases.

  2. Protein misfolding and aggregation in Alzheimer's disease and type 2 diabetes mellitus.

    PubMed

    Ashraf, Ghulam M; Greig, Nigel H; Khan, Taqi A; Hassan, Iftekhar; Tabrez, Shams; Shakil, Shazi; Sheikh, Ishfaq A; Zaidi, Syed K; Akram, Mohammad; Jabir, Nasimudeen R; Firoz, Chelaprom K; Naeem, Aabgeena; Alhazza, Ibrahim M; Damanhouri, Ghazi A; Kamal, Mohammad A

    2014-01-01

    In general, proteins can only execute their various biological functions when they are appropriately folded. Their amino acid sequence encodes the relevant information required for correct three-dimensional folding, with or without the assistance of chaperones. The challenge associated with understanding protein folding is currently one of the most important aspects of the biological sciences. Misfolded protein intermediates form large polymers of unwanted aggregates and are involved in the pathogenesis of many human diseases, including Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM). AD is one of the most prevalent neurological disorders and has worldwide impact; whereas T2DM is considered a metabolic disease that detrementally influences numerous organs, afflicts some 8% of the adult population, and shares many risk factors with AD. Research data indicates that there is a widespread conformational change in the proteins involved in AD and T2DM that form β-sheet like motifs. Although conformation of these β-sheets is common to many functional proteins, the transition from α-helix to β-sheet is a typical characteristic of amyloid deposits. Any abnormality in this transition results in protein aggregation and generation of insoluble fibrils. The abnormal and toxic proteins can interact with other native proteins and consequently catalyze their transition into the toxic state. Both AD and T2DM are prevalent in the aged population. AD is characterized by the accumulation of amyloid-β (Aβ) in brain, while T2DM is characterized by the deposition of islet amyloid polypeptide (IAPP, also known as amylin) within beta-cells of the pancreas. T2DM increases pathological angiogenesis and immature vascularisation. This also leads to chronic cerebral hypoperfusion, which results in dysfunction and degeneration of neuroglial cells. With an abundance of common mechanisms underpinning both disorders, a significant question that can be posed is whether T2DM leads

  3. Multiple patterns of writing disorders in dementia of the Alzheimer type and their evolution.

    PubMed

    Luzzatti, Claudio; Laiacona, Marcella; Agazzi, Daniela

    2003-01-01

    This paper reports the results obtained from a writing task given to 23 Italian patients suffering from mild to moderate dementia of the Alzheimer's type (DAT). Spelling performance was tested with a task that taps the sub-word-level (spelling of regular words and nonwords), and the lexical route (spelling of regular and irregular words), in line with contemporary models of writing. Each patient's performance was classified according to the emergence of dissociated patterns of damage between regular words and nonwords and between regular and irregular words. The 23 DAT patients span the whole spectrum of dysgraphic taxonomy; five showed the characteristic pattern of impairment of surface dysgraphia, two showed the characteristics of phonological dysgraphia, while a mixed pattern (i.e. better performance on regular words compared to irregular words and regular nonwords) emerged in seven cases. Three patients presented undifferentiated writing disorders, two were completely agraphic, while four patients showed only minimal or no writing defects. The rate of dissociated impairments in the lexical and the sub-word-level routine is very similar to that observed after acute focal brain damage, which contradicts the hypothesis that degenerative brain damage selectively impairs writing performance along the lexical-semantic route. To test the hypothesis that surface sub-word-level processing abilities are affected only during the evolution of the disease, nine patients were tested longitudinally after an interval of 6-12 months. Once again, the data showed high variability across subjects, and do not seem to support involvement of the sub-word-level spelling routine only at a late stage in the development of the disease.

  4. Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors in Sporadic Alzheimer's Disease.

    PubMed

    Harris, Steven A; Harris, Elizabeth A

    2015-01-01

    This review focuses on research in epidemiology, neuropathology, molecular biology, and genetics regarding the hypothesis that pathogens interact with susceptibility genes and are causative in sporadic Alzheimer's disease (AD). Sporadic AD is a complex multifactorial neurodegenerative disease with evidence indicating coexisting multi-pathogen and inflammatory etiologies. There are significant associations between AD and various pathogens, including Herpes simplex virus type 1 (HSV-1), Cytomegalovirus, and other Herpesviridae, Chlamydophila pneumoniae, spirochetes, Helicobacter pylori, and various periodontal pathogens. These pathogens are able to evade destruction by the host immune system, leading to persistent infection. Bacterial and viral DNA and RNA and bacterial ligands increase the expression of pro-inflammatory molecules and activate the innate and adaptive immune systems. Evidence demonstrates that pathogens directly and indirectly induce AD pathology, including amyloid-β (Aβ) accumulation, phosphorylation of tau protein, neuronal injury, and apoptosis. Chronic brain infection with HSV-1, Chlamydophila pneumoniae, and spirochetes results in complex processes that interact to cause a vicious cycle of uncontrolled neuroinflammation and neurodegeneration. Infections such as Cytomegalovirus, Helicobacter pylori, and periodontal pathogens induce production of systemic pro-inflammatory cytokines that may cross the blood-brain barrier to promote neurodegeneration. Pathogen-induced inflammation and central nervous system accumulation of Aβ damages the blood-brain barrier, which contributes to the pathophysiology of AD. Apolipoprotein E4 (ApoE4) enhances brain infiltration by pathogens including HSV-1 and Chlamydophila pneumoniae. ApoE4 is also associated with an increased pro-inflammatory response by the immune system. Potential antimicrobial treatments for AD are discussed, including the rationale for antiviral and antibiotic clinical trials.

  5. [Multi-infarct dementia clinically simulating dementia of Alzheimer type. A comparison with angular gyrus syndrome].

    PubMed

    Nitta, E; Ohkawa, Y; Kuzuhara, S; Yamanouchi, H; Toyokura, Y

    1989-01-01

    A 74-year-old right-handed man with multiple cerebral infarction who presented with dementia simulating dementia of Alzheimer type (DAT) is reported. He had been well until April 20, 1987 when he developed transient right hand palsy lasting overnight. Eleven days later, he became confused, disorientated, and amnestic. He was admitted to this hospital on June 8. Physical examination revealed hypertension (170/90mmHg). On neurological examination, his consciousness was clear but he was demented. He showed disorientation, amnesia, and urinary incontinence. His most prominent symptom was disturbance of speech, including fluent aphasia and alexia with agraphia. Additionally, he showed ideomotor apraxia, construction apraxia, right-left agnosia, finger agnosia, and acalculia. On July 9, he had a transient attack of right hemiplegia with confusion. The brain CT scan performed on admission was unremarkable except for cavum septi pellucidum and a small low density area in the right basal ganglia. However, single photon emission computed tomography (SPECT) by 123I-labeled N-isopropyl-p-iodoamphetamine disclosed hypoperfusion of the cerebral blood flow in the border zones of the temporoparietal and frontal lobes on the left. A follow-up brain CT scan taken one month later demonstrated low density in the new areas corresponding to hypoperfusion shown by SPECT. Although the clinical features of the present case resembled those of DAT, dementia in this case was regarded as the result of multiple cerebral infarction since it occurred acutely with mild motor deficits, and brain CT scans and SPECT showed lesions indicating focal cerebral ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology.

    PubMed

    Nagy, Z; Esiri, M M; LeGris, M; Matthews, P M

    1999-04-01

    Recent reports have suggested that mitochondrial dysfunction may contribute to the progression of the pathology of Alzheimer's disease (AD). However, both increases and decreases in the activity of cytochrome oxidase have been described in the hippocampi of AD patients. In this study we used immunohistochemistry and quantitative autoradiographic methods to study the expression pattern of two cytochrome oxidase subunit proteins (nuclear-encoded COX IV and mitochondrial-encoded COX I) in the hippocampus in relation to the development of AD-type pathology. We found heterogeneous expression of both COX subunits in AD with an increased expression of both subunit proteins in healthy, non-tangle-bearing, neurones but absence of both subunit proteins in tangle-bearing neurones. Levels of COX IV but not of COX I were related to the amount of hyperphosphorylated tau accumulated in the same hippocampal region but not to the amount of amyloid deposited in sporadic AD. In Down's syndrome COX I and COX IV were similarly increased in the presence of AD pathology in non-tangle-bearing neurones. However, in these cases levels of enzyme expression were correlated to the amount of amyloid accumulation but not the amount of hyperphosphorylated tau in the hippocampus. We believe that heterogeneity of expression of mitochondrial enzyme proteins between neurones may contribute to the conflicting conclusions in previous reports regarding relative levels of cytochrome oxidase activity in the hippocampus in AD. We hypothesise that the increased mitochondrial enzyme expression in healthy-appearing neurones of AD brains may represent a physiological response to increased functional demand on surviving neurones as a consequence of AD-related neuronal pathology.

  7. Differential alterations of cortical glutamatergic binding sites in senile dementia of the Alzheimer type

    SciTech Connect

    Chalmers, D.T.; Dewar, D.; Graham, D.I.; Brooks, D.N.; McCulloch, J. )

    1990-02-01

    Involvement of cortical glutamatergic mechanisms in senile dementia of the Alzheimer type (SDAT) has been investigated with quantitative ligand-binding autoradiography. The distribution and density of Na(+)-dependent glutamate uptake sites and glutamate receptor subtypes--kainate, quisqualate, and N-methyl-D-aspartate--were measured in adjacent sections of frontal cortex obtained postmortem from six patients with SDAT and six age-matched controls. The number of senile plaques was determined in the same brain region. Binding of D-(3H)aspartate to Na(+)-dependent uptake sites was reduced by approximately 40% throughout SDAT frontal cortex relative to controls, indicating a general loss of glutamatergic presynaptic terminals. (3H)Kainate receptor binding was significantly increased by approximately 70% in deep layers of SDAT frontal cortex compared with controls, whereas this binding was unaltered in superficial laminae. There was a positive correlation (r = 0.914) between kainate binding and senile plaque number in deep cortical layers. Quisqualate receptors, as assessed by 2-amino-3-hydroxy-5-(3H)methylisoxazole-4-propionic acid binding, were unaltered in SDAT frontal cortex compared with controls. There was a small reduction (25%) in N-methyl-D-aspartate-sensitive (3H)glutamate binding only in superficial cortical layers of SDAT brains relative to control subjects. (3H)Glutamate binding in SDAT subjects was unrelated to senile plaque number in superficial cortical layers (r = 0.104). These results indicate that in the presence of cortical glutamatergic terminal loss in SDAT plastic alterations occur in some glutamate receptor subtypes but not in others.

  8. Non-cognitive psychopathological symptoms associated with incident mild cognitive impairment and dementia, Alzheimer's type.

    PubMed

    Lobo, Antonio; López-Antón, Raúl; de-la-Cámara, Concepción; Quintanilla, Miguel Angel; Campayo, Antonio; Saz, Pedro

    2008-10-01

    To test the hypothesis that specific psychopathological non-cognitive symptoms are associated with incident mild cognitive impairment (MCI), while different symptoms are associated with incident dementia of Alzheimer's type (DAT). A representative community sample of 4,803 individuals aged 55+ years was interviewed in a two-phase screening, in Wave I or ZARADEMP I. This is the baseline, cross-sectional study of the ZARADEMP Project, a longitudinal study to document incidence and risk factors of dementia. The main instrument for assessment of participants was the ZARADEMP Interview, which includes standardized Spanish versions of instruments such as the Mini-Mental Status Examination and the Geriatric Mental State GMS-AGECAT. Two years later, in Wave II or ZARADEMP II, the cognitively non-deteriorated elderly were reassessed in a similar, two-phase procedure. "Incident cases" of both dementia and DAT (DSM-IV-TR criteria), as well as MCI (operationally defined Petersen's criteria) were diagnosed by a panel of psychiatrists. Statistical, logistic regression models, adjusted by age, sex and education were used to test the hypothesized association. "Irritability", "neurovegetative symptoms", "sleep problems", "concentration difficulties", "loneliness" and "subjective slowing" documented at baseline were associated with incident MCI (odds ratio, OR range 1.71-2.67). A different profile of non-cognitive symptoms was associated with incident DAT, specifically "tension" (OR= 2.45), "sleep problems" (OR= 2.81), and "observed slowing" (OR= 4.35). On the contrary, "subjective restriction of activities" seemed to be negatively associated with DAT (OR= 0.12). To our knowledge, this is the first report about some specific psychopathological, non-cognitive symptoms associated with incident MCI and/ or incident DAT, when controlling by each other. The psychopathological profile associated with MCI is different from the profile preceding DAT.

  9. Association of polymorphisms of peroxisome proliferator activated receptors in early and late onset of type 2 diabetes mellitus.

    PubMed

    Raj, Resal; Bhatti, Jasvinder Singh; Bhadada, Sanjay Kumar; Ramteke, Pramod W

    2017-03-06

    Genetic variation of disease susceptible genes is different in different ethnic groups and there is an evidence of association of polymorphisms of Peroxisome Proliferator Activated Receptors (PPARs) in Type 2 Diabetes Mellitus (T2DM). This research analyses the association of PPARs in early and late onset of T2DM in North Indian Population (NIP). Total of 703 subjects were recruited from north of India and subjects were further divided into subjects of early onset (less than 25 years of onset, 26 T2DM and 26 controls) and late onset (more than 25 years of onset, 326 T2DM and 325 controls). The onset of T2DM begins from 15 years and continues further to maximum T2DM subjects to the age of 50 (76% of T2DM). High BMI and WHR, high blood pressure leading to early onset of hypertension, early mortality due to T2DM (7% of T2DM is above 75 years and 3% of T2DM has 20 years duration of onset) and high hyperglycemic NIP were the few outcomes of this research. There is a strong association of PPAR γ, PPAR α and PPAR δ genes on the susceptibility of T2DM in late onset but not with the early onset of T2DM subjects in North Indian Population: Dual association of PPAR γ was observed with its genotype G/G (Ala/Ala) favoring protection against T2DM and genotype C/C (Pro/Pro) favoring susceptibility to T2DM. Association of intron7 polymorphism of PPAR α and +T294C polymorphism of PPAR δ on the susceptibility to T2DM requires further analysis. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  10. Molecular and phenotypic characteristics of maturity-onset diabetes of the young compared with early onset type 2 diabetes in China.

    PubMed

    Zhang, Manna; Zhou, Jiao Jiao; Cui, Wenjie; Li, Yan; Yang, Peng; Chen, Xiaoyun; Sheng, Chunjun; Li, Hong; Qu, Shen

    2015-11-01

    The aim of the present study was to investigate the contribution of maturity-onset diabetes of the young (MODY) genes to the etiology of 14 Chinese MODY families and to assess phenotypic differences between patients with MODY but without a known genetic cause of diabetes (MODYX) and those with early onset type 2 diabetes (T2D). The study included 14 MODY probands from unrelated families and 59 patients (age of onset ≤35 years) diagnosed as early onset T2D. A standard meal test and metabolic studies were performed to characterize the clinical features of all patients. All probands with MODY were analyzed for nucleotide variations in promoters, exons, and exon-intron boundaries of 13 known MODY genes by direct DNA sequencing. Mutations in 13 known MODY genes were not present in the 14 Chinese families and they were classified as MODYX. However, different polymorphisms were identified, with I27L (42.9%; 12/28) and S487N (46.4%; 13/28) of hepatocyte nuclear factor 4α (HNF1α/MODY3) being two most frequent polymorphisms. Two new polymorphisms, namely T412I and D504H, were detected in carboxyl ester lipase (CEL/MODY8). Compared with patients with early onset T2D, patients with MODYX were diagnosed with diabetes at a younger age (28.3 ± 6.5 vs 24.3 ± 6.5 years; P < 0.05) and had a lower body mass index (BMI; 28.3 ± 6.1 vs 24.1 ± 4.3 kg/m(2) ; P < 0.01) and homeostatic model assessment of β-cell function (47.6 [22.2-89.4] vs 18.5 [6.5-33.7]; P < 0.05). Herein we report on 14 Chinese families with MODYX and describe its phenotype. Compared with early onset T2D, MODYX is characterized by lower BMI and decreased insulin-secreting capacity. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  11. Profiling of circulating microRNAs in children with recent onset of type 1 diabetes

    PubMed Central

    Erener, Suheda; Marwaha, Ashish; Tan, Rusung; Kieffer, Timothy J.

    2017-01-01

    Type 1 diabetes (T1D) is an autoimmune disease that is clinically silent until the majority of β cells are destroyed. There is an unmet need for reliable and cost-effective biomarkers to predict and diagnose diabetes at an early stage. A number of stable microRNAs (miRNAs) have been reported in serum and plasma and are now being investigated as biomarkers of different diseases. We measured the levels of 745 miRNAs in sera of children with recent-onset T1D and age-matched controls using locked nucleic acid–enhanced (LNA-enhanced) quantitative PCR profiling. Thirty-five miRNAs were significantly different between the groups, and 27 miRNAs were elevated in T1D. Good discriminating power was obtained for 6 miRNAs (miR-454-3p, miR-222-3p, miR-144-5p, miR-345-5p, miR-24-3p, and miR-140-5p), which were not elevated at later stages of diabetes. In silico pathway analysis, based on inferred miRNA target genes, associated glycosaminoglycan biosynthesis as well as PI3K/Akt, MAPK, and Wnt signaling pathways with early stages of T1D. Among the 27 upregulated miRNAs in T1D, 2 miRNAs significantly correlated with hemoglobin A1c (HbA1c), as did 5 of 8 downregulated miRNAs. A total of 134 miRNAs significantly correlated with HbA1c when stratifying hyperglycemia-induced miRNAs from T1D-specific miRNAs. In conclusion, we have identified a serum miRNA pattern of recent-onset T1D and signaling pathways that may be involved in its pathogenesis. PMID:28239651

  12. Reactivation of latent viruses in individuals receiving rituximab for new onset type 1 diabetes.

    PubMed

    Kroll, Jing Lu; Beam, Craig; Li, Shaobing; Viscidi, Raphael; Dighero, Bonnie; Cho, Alice; Boulware, David; Pescovitz, Mark; Weinberg, Adriana

    2013-06-01

    Rituximab has been successfully used as an experimental therapy in different autoimmune diseases. Recently, a double-blind placebo-controlled phase-2 study in early onset type 1 diabetes showed that rituximab delayed progression of the disease. However, like with any immunosuppressive therapy, there is a concern of opportunistic viral reactivations with the use of rituximab, including herpes and polyomaviruses. To study the incidence of new infections and reactivations with BK, JC, Epstein-Barr and cytomegalovirus (BKV, JCV, EBV and CMV) in T1D participants in the phase-2 rituximab study. Subjects received 4 weekly doses of rituximab (N = 57) or placebo (N = 30) during the first month of study. Blood samples obtained at weeks 0, 12, 26, 56 and 78 were assayed for CMV, EBV, BKV and JCV by real-time DNA PCR and serology. EBV reactivations were diagnosed by PCR in 25% of placebo, but none of rituximab recipients (p < 0.01). There were no episodes of CMV viremia in either treatment group. BKV viremias were significantly more common in the rituximab recipients (9%) compared with placebo controls (0, p < 0.01). No JCV reactivations were detected in this study, but among 6 rituximab and 2 placebo recipients who seroconverted for JCV during the study, only one rituximab recipient had detectable viremia. All infections were asymptomatic. Four doses of rituximab administered to individuals with early onset T1D decreased the incidence of asymptomatic EBV reactivations, as predicted by the rituximab-mediated elimination of memory B-cells, but increased the frequency of asymptomatic viremias caused by polyomaviruses. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Rapid Deterioration of Insulin Secretion in Obese Adolescents Preceding the Onset of Type 2 Diabetes

    PubMed Central

    Elder, Deborah A.; Hornung, Lindsey N.; Herbers, Patricia M.; Prigeon, Ron; Woo, Jessica G.; D'Alessio, David A.

    2014-01-01

    Objective To identify pathophysiologic changes that lead to the onset of type 2 diabetes (T2DM) in adolescents. Study design Obese adolescents with NGT (n=41) were studied longitudinally over 4 years with serial measure of the acute insulin response to IV glucose (AIRg) as well as proinsulin (PI) concentrations. Insulin resistance was estimated with HOMA modeling, the disposition index (DI) computed as AIRg × 1/HOMA-IR, and IV glucose tolerance estimated as the glucose disappearance constant (kg). Results Four adolescents developed diabetes during the study (DM), and the rest of the cohort remained non-diabetic (NDM). Baseline PI exceeded the interquartile range of the NDM group in 3 of 4 subjects with DM and all had > 85% reduction from baseline AIRg, and DI, within 6 months of diagnosis. All the subjects with DM gained weight over the course of the study but these changes paralleled those for the NDM group. HOMA-IR increased substantially in 1 of the subjects with DM at the time of diagnosis, but was comparable with baseline in the other 3. The DI and kg of the subjects with DM was below the 10th percentile of the NDM group before and after diagnosis. Conclusion Conversion from NGT to T2DM in adolescents can occur rapidly, and T2DM onset is heralded by a substantial decline in AIRg and DI, as well as increased release of PI. These results support loss of beta-cell function as the proximate step in the development of T2DM in this age group. PMID:25557969

  14. [Nutritional condition in patients with Alzheimer-type dementia from the neurosciences' group, Medellín 2004].

    PubMed

    Muñoz, Angélica María; Agudelo, Gloria María; Lopera, Francisco Javier

    2006-03-01

    Patients suffering clinical dementia caused by Alzheimer's disease have a high risk of developing malnutrition caused by all the physiological, socio-economic and psychological changes related to the disease, together with the ageing process. To describe the nutritional condition of a group of patients with Alzheimer's dementia according to the degree of disease severity. Patients were selected from the University of Antioquia Neurosciences Group. Descriptive cross sectional study. Patients were assessed and information was collected about their body composition, food consumption behaviour, clinical, and psychosocial variables. 77 patients were studied; their mean age was 65, 5 +/- 12.8 years. 48 had a family history of Alzheimer's disease; 39 were diagnosed more than 60 months before the study started; the most frequently found degree of severity was moderate, the most common type of dementia was the early family form. 26 began the disease process before they were 50 years old. Significant differences for Body Mass Index, brachial adipose area and brachial lean area were found (p = 0.001, p = 0.000, p = 0.000, respectively) between patients with the different degrees of disease severity. These parameters measures were lowest in patients with severe disease. The intake of calcium and folate was the lowest amongst the nutrients studied. The nutritional state is impaired in patients suffering Alzheimer's dementia from the early stages of the disease. The most important nutritional and clinical abnormalities found were depletion of the lean and fat stores, low intake of calcium and folate and clinical signs of the disease. Changes in these parameters worsen as the disease progresses.

  15. Genetic aspects of Alzheimer disease.

    PubMed

    Bird, Thomas D

    2008-04-01

    Alzheimer disease is the most common cause of dementia and represents a major public health problem. The neuropathologic findings of amyloid-beta plaques and tau containing neurofibrillary tangles represent important molecular clues to the underlying pathogenesis. Genetic factors are well recognized, but complicated. Three rare forms of autosomal-dominant early-onset familial Alzheimer disease have been identified and are associated with mutations in amyloid precursor protein, presenilin 1, and presenilin 2 genes. The more common late-onset form of Alzheimer disease is assumed to be polygenic/multifactorial. However, thus far the only clearly identified genetic risk factor for Alzheimer disease is Apo lipoprotein E. The epsilon4 allele of Apo lipoprotein E influences age at onset of Alzheimer disease, but is neither necessary nor sufficient for the disease. The search continues for the discovery of additional genetic influences.

  16. Averting Dementia of the Alzheimer's Type in Women: Can Counselors Help?

    ERIC Educational Resources Information Center

    Douthit, Kathryn Z.

    2007-01-01

    Alzheimer's disease (AD) is the most common cause of dementia in late life, taking its greatest toll on women over age 80. This article provides an overview of AD, including risk factors and counseling strategies targeting risk. Counseling strategies address stress, cardiovascular health, social integration, depression, and holistic wellness.

  17. Counseling Patients with Senile Dementia of the Alzheimer Type and Their Families.

    ERIC Educational Resources Information Center

    LaBarge, Emily

    1981-01-01

    Discusses symptoms of Alzheimer Disease and suggests client-centered counseling techniques to use with patients and family. Considers the disease's effect on family relationships relative to stage of family development. Examines the adjustment of the caregiving spouse. Offers practical suggestions for coping. (RC)

  18. Effects of Attention on Dichotic Listening in Elderly and Patients with Dementia of the Alzheimer Type

    ERIC Educational Resources Information Center

    Bouma, Anke; Gootjes, Liselotte

    2011-01-01

    This article presents an overview of our studies in elderly and Alzheimer patients employing Kimura's dichotic digits paradigm as a measure for left hemispheric predominance for processing language stimuli. In addition to structural brain mechanisms, we demonstrated that attention modulates the direction and degree of ear asymmetry in dichotic…

  19. Averting Dementia of the Alzheimer's Type in Women: Can Counselors Help?

    ERIC Educational Resources Information Center

    Douthit, Kathryn Z.

    2007-01-01

    Alzheimer's disease (AD) is the most common cause of dementia in late life, taking its greatest toll on women over age 80. This article provides an overview of AD, including risk factors and counseling strategies targeting risk. Counseling strategies address stress, cardiovascular health, social integration, depression, and holistic wellness.

  20. Driving and Dementia of the Alzheimer Type: Beliefs and Cessation Strategies among Stakeholders

    ERIC Educational Resources Information Center

    Perkinson, Margaret A.; Berg-Weger, Marla L.; Carr, David B.; Meuser, Thomas M.; Palmer, Janice L.; Buckles, Virginia D.; Powlishta, Kimberly K.; Foley, Daniel J.; Morris, John C.

    2005-01-01

    Purpose: Although driving by persons with Alzheimer's disease (AD) is an important public health concern, we know little about the attitudes and perceptions of key stakeholders regarding driving safety in these individuals or the factors that precipitate and influence driving assessment and cessation decisions. Design and Methods: We convened 10…

  1. Counseling Patients with Senile Dementia of the Alzheimer Type and Their Families.

    ERIC Educational Resources Information Center

    LaBarge, Emily

    1981-01-01

    Discusses symptoms of Alzheimer Disease and suggests client-centered counseling techniques to use with patients and family. Considers the disease's effect on family relationships relative to stage of family development. Examines the adjustment of the caregiving spouse. Offers practical suggestions for coping. (RC)

  2. Effects of Attention on Dichotic Listening in Elderly and Patients with Dementia of the Alzheimer Type

    ERIC Educational Resources Information Center

    Bouma, Anke; Gootjes, Liselotte

    2011-01-01

    This article presents an overview of our studies in elderly and Alzheimer patients employing Kimura's dichotic digits paradigm as a measure for left hemispheric predominance for processing language stimuli. In addition to structural brain mechanisms, we demonstrated that attention modulates the direction and degree of ear asymmetry in dichotic…

  3. Alzheimer's Genes: Are You at Risk?

    MedlinePlus

    ... development of Alzheimer's disease. As research on the genetics of Alzheimer's progresses, researchers are uncovering links between late-onset ... Neuron. 2014;83:11. Sherva R, et al. Genetics of Alzheimer disease. http://www.uptodate.com/home. Accessed Nov. ...

  4. Germinal centre frequency is decreased in pancreatic lymph nodes from individuals with recent-onset type 1 diabetes.

    PubMed

    Willcox, Abby; Richardson, Sarah J; Walker, Lucy S K; Kent, Sally C; Morgan, Noel G; Gillespie, Kathleen M

    2017-07-01

    Pancreatic lymph nodes (PLNs) are critical sites for the initial interaction between islet autoantigens and autoreactive lymphocytes, but the histology of PLNs in tissue from individuals with type 1 diabetes has not been analysed in detail. The aim of this study was to examine PLN tissue sections from healthy donors compared with those at risk of, or with recent-onset and longer-duration type 1 diabetes. Immunofluorescence staining was used to examine PLN sections from the following donor groups: non-diabetic (n=15), non-diabetic islet autoantibody-positive (n=5), recent-onset (≤1.5 years duration) type 1 diabetes (n=13), and longer-duration type 1 diabetes (n=15). Staining for CD3, CD20 and Ki67 was used to detect primary and secondary (germinal centre-containing) follicles and CD21 and CD35 to detect follicular dendritic cell networks. The frequency of secondary follicles was lower in the recent-onset type 1 diabetes group compared with the non-diabetic control group. The presence of insulitis (as evidence of ongoing beta cell destruction) and diagnosis of type 1 diabetes at a younger age, however, did not appear to be associated with a lower frequency of secondary follicles. A higher proportion of primary B cell follicles were observed to lack follicular dendritic cell networks in the recent-onset type 1 diabetes group. Histological analysis of rare PLNs from individuals with type 1 diabetes suggests a previously unrecognised phenotype comprising decreased primary B cell follicle frequency and fewer follicular dendritic cell networks in recent-onset type 1 diabetes.

  5. Inadequate supply of vitamins and DHA in the elderly: implications for brain aging and Alzheimer-type dementia.

    PubMed

    Mohajeri, M Hasan; Troesch, Barbara; Weber, Peter

    2015-02-01

    Alzheimer's disease (AD) is the most prevalent, severe, and disabling cause of dementia worldwide. To date, AD therapy is primarily targeted toward palliative treatment of symptoms rather than prevention of disease progression. So far, no pharmacologic interventions have changed the onset or progression of AD and their use is accompanied by side effects. The major obstacle in managing AD and designing therapeutic strategies is the difficulty in retarding neuronal loss in the diseased brain once the pathologic events leading to neuronal death have started. Therefore, a promising alternative strategy is to maintain a healthy neuronal population in the aging brain for as long as possible. One factor evidently important for neuronal health and function is the optimal supply of nutrients necessary for maintaining normal functioning of the brain. Mechanistic studies, epidemiologic analyses, and randomized controlled intervention trials provide insight to the positive effects of docosahexaenoic acid (DHA) and micronutrients such as the vitamin B family, and vitamins E, C, and D, in helping neurons to cope with aging. These nutrients are inexpensive in use, have virtually no side effects when used at recommended doses, are essential for life, have established modes of action, and are broadly accepted by the general public. This review provides some evidence that the use of vitamins and DHA for the aging population in general, and for individuals at risk in particular, is a viable alternative approach to delaying brain aging and for protecting against the onset of AD pathology. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Determinants of Long-Term Durable Glycemic Control in New-Onset Type 2 Diabetes Mellitus.

    PubMed

    Kim, Kyoung Jin; Choi, Ju Hee; Kim, Kyeong Jin; An, Jee Hyun; Kim, Hee Young; Kim, Sin Gon; Kim, Nam Hoon

    2017-08-01

    Long-term durable glycemic control is a difficult goal in the management of type 2 diabetes mellitus (T2DM). We evaluated the factors associated with durable glycemic control in a real clinical setting. We retrospectively reviewed the medical records of 194 new-onset, drug-naïve patients with T2DM who were diagnosed between January 2011 and March 2013, and were followed up for >2 years. Glycemic durability was defined as the maintenance of optimal glycemic control (glycosylated hemoglobin [HbA1c] <7.0%) for 2 years without substitution or adding other glucose-lowering agents. Clinical factors and glycemic markers associated with glycemic durability were compared between two groups: a durability group and a non-durability group. Patients in the durability group had a higher baseline body mass index (26.1 kg/m² vs. 24.9 kg/m²) and lower HbA1c (8.6% vs. 9.7%) than the non-durability group. The initial choice of glucose-lowering agents was similar in both groups, except for insulin and sulfonylureas, which were more frequently prescribed in the non-durability group. In multiple logistic regression analyses, higher levels of education, physical activity, and homeostasis model assessment of β-cell function (HOMA-β) were associated with glycemic durability. Notably, lower HbA1c (<7.0%) at baseline and first follow-up were significantly associated with glycemic durability (adjusted odds ratio [OR], 7.48; 95% confidence interval [CI], 2.51 to 22.3) (adjusted OR, 9.27; 95% CI, 1.62 to 53.1, respectively), after adjusting for confounding variables including the types of glucose-lowering agents. Early achievement of HbA1c level within the glycemic target was a determinant of long-term glycemic durability in new-onset T2DM, as were higher levels of education, physical activity, and HOMA-β.

  7. Determinants of Long-Term Durable Glycemic Control in New-Onset Type 2 Diabetes Mellitus

    PubMed Central

    Kim, Kyoung Jin; Choi, Ju Hee; Kim, Kyeong Jin; An, Jee Hyun; Kim, Hee Young; Kim, Sin Gon

    2017-01-01

    Background Long-term durable glycemic control is a difficult goal in the management of type 2 diabetes mellitus (T2DM). We evaluated the factors associated with durable glycemic control in a real clinical setting. Methods We retrospectively reviewed the medical records of 194 new-onset, drug-naïve patients with T2DM who were diagnosed between January 2011 and March 2013, and were followed up for >2 years. Glycemic durability was defined as the maintenance of optimal glycemic control (glycosylated hemoglobin [HbA1c] <7.0%) for 2 years without substitution or adding other glucose-lowering agents. Clinical factors and glycemic markers associated with glycemic durability were compared between two groups: a durability group and a non-durability group. Results Patients in the durability group had a higher baseline body mass index (26.1 kg/m2 vs. 24.9 kg/m2) and lower HbA1c (8.6% vs. 9.7%) than the non-durability group. The initial choice of glucose-lowering agents was similar in both groups, except for insulin and sulfonylureas, which were more frequently prescribed in the non-durability group. In multiple logistic regression analyses, higher levels of education, physical activity, and homeostasis model assessment of β-cell function (HOMA-β) were associated with glycemic durability. Notably, lower HbA1c (<7.0%) at baseline and first follow-up were significantly associated with glycemic durability (adjusted odds ratio [OR], 7.48; 95% confidence interval [CI], 2.51 to 22.3) (adjusted OR, 9.27; 95% CI, 1.62 to 53.1, respectively), after adjusting for confounding variables including the types of glucose-lowering agents. Conclusion Early achievement of HbA1c level within the glycemic target was a determinant of long-term glycemic durability in new-onset T2DM, as were higher levels of education, physical activity, and HOMA-β. PMID:28868826

  8. Immunohistochemical screening for antibodies in recent onset type 1 narcolepsy and after H1N1 vaccination.

    PubMed

    van der Heide, Astrid; Hegeman-Kleinn, Ingrid M; Peeters, Els; Lammers, Gert J; Fronczek, Rolf

    2015-06-15

    Narcolepsy type 1 patients typically have undetectable hypocretin-1 levels in the cerebrospinal fluid (CSF), as a result of a selective loss of the hypocretin containing neurons in the hypothalamus. An autoimmune attack targeting hypothalamic hypocretin (orexin) neurons is hypothesised. So far, no direct evidence for an autoimmune attack was found. One of the major limitations of previous studies was that none included patients close to disease onset. We screened serum of 21 narcolepsy type 1 patients close to disease onset (median 11 months), including 8 H1N1 vaccinated patients, for antibodies against hypocretin neurons using immunohistochemistry. No autoantibodies against hypocretin neurons could be detected.

  9. Exercise testing in late-onset glycogen storage disease type II patients undergoing enzyme replacement therapy

    PubMed Central

    Marzorati, Mauro; Porcelli, Simone; Bellistri, Giuseppe; Morandi, Lucia; Grassi, Bruno

    2012-01-01

    Enzyme replacement therapy (ERT) has recently became available for patients with glycogen storage disease type II. Previous studies have demonstrated clinical efficacy of enzyme replacement therapy, however, data on physiological variables related to exercise tolerance are scarce. Four glycogen storage disease type II late-onset patients (45 ± 6 years) performed an incremental exercise on a cycle ergometer, up to voluntary exhaustion, before (BEFORE) and after 12 months of ERT (AFTER). Peak workload, oxygen uptake, heart rate, cardiac output (by impedance cardiography) and vastus lateralis oxygenation indices (by continuous-wave near-infrared spectroscopy, NIRS) were determined. Peak workload and oxygen uptake values significantly increased during ERT (54 ± 30 vs. 63 ± 31 watt, and 17.2 ± 4.4 vs. 19.7 ± 3.5 ml/kg/min, respectively, in BEFORE vs. AFTER). On the other hand, for both peak cardiac output (12.3 ± 5.3 vs. 14.8 ± 4.5 L/min) and the NIRS-determined peak skeletal muscle fractional O2 extraction, expressed as a percentage of the maximal values during a transient limb ischemia (30 ± 39% vs. 38 ± 28%), the observed increases were not statistically significant. Our findings suggest that in glycogen storage disease type II patients enzyme replacement therapy is associated with a mild improvement of exercise tolerance. The findings need to be validated during a longer follow-up on a larger group of patients. PMID:23182645

  10. Factors affecting recall of different types of personal genetic information about Alzheimer's disease risk: the REVEAL study.

    PubMed

    Besser, Andria G; Sanderson, Saskia C; Roberts, J Scott; Chen, Clara A; Christensen, Kurt D; Lautenbach, Denise M; Cupples, L Adrienne; Green, Robert C

    2015-01-01

    Data were obtained through a multisite clinical trial in which different types of genetic risk-related information were disclosed to individuals (n = 246) seeking a risk assessment for Alzheimer's disease. Six weeks after disclosure, 83% of participants correctly recalled the number of risk-increasing APOE alleles they possessed, and 74% correctly recalled their APOE genotype. While 84% of participants recalled their lifetime risk estimate to within 5 percentage points, only 51% correctly recalled their lifetime risk estimate exactly. Correct recall of the number of APOE risk-increasing alleles was independently associated with higher education (p < 0.001), greater numeracy (p < 0.05) and stronger family history of Alzheimer's disease (p < 0.05). Before adjustments for confounding, correct recall of APOE genotype was also associated with higher education, greater numeracy and stronger family history of Alzheimer's disease, as well as with higher comfort with numbers and European American ethnicity (all p < 0.05). Correct recall of the lifetime risk estimate was independently associated only with younger age (p < 0.05). Recall of genotype-specific information is high, but recall of exact risk estimates is lower. Incorrect recall of numeric risk may lead to distortions in understanding risk. Further research is needed to determine how best to communicate different types of genetic risk information to patients, particularly to those with lower educational levels and lower numeracy. Health-care professionals should be aware that each type of genetic risk information may be differentially interpreted and retained by patients and that some patient subgroups may have more problems with recall than others. © 2015 S. Karger AG, Basel.

  11. Analyzing gene expression from whole tissue vs. different cell types reveals the central role of neurons in predicting severity of Alzheimer's disease.

    PubMed

    Stempler, Shiri; Ruppin, Eytan

    2012-01-01

    Alterations in gene expression resulting from Alzheimer's disease have received considerable attention in recent years. Although expression has been investigated separately in whole brain tissue, in astrocytes and in neurons, a rigorous comparative study quantifying the relative utility of these sources in predicting the progression of Alzheimer's disease has been lacking. Here we analyze gene expression from neurons, astrocytes and whole tissues across different brain regions, and compare their ability to predict Alzheimer's disease progression by building pertaining classification models based on gene expression sets annotated to different biological processes. Remarkably, we find that predictions based on neuronal gene expression are significantly more accurate than those based on astrocyte or whole tissue expression. The findings explicate the central role of neurons, particularly as compared to glial cells, in the pathogenesis of Alzheimer's disease, and emphasize the importance of measuring gene expression in the most relevant (pathogenically 'proximal') single cell types.

  12. Inhibitory Activities of Antioxidant Flavonoids from Tamarix gallica on Amyloid Aggregation Related to Alzheimer's and Type 2 Diabetes Diseases.

    PubMed

    Ben Hmidene, Asma; Hanaki, Mizuho; Murakami, Kazuma; Irie, Kazuhiro; Isoda, Hiroko; Shigemori, Hideyuki

    2017-01-01

    The prevention of amyloid aggregation is promising for the treatment of age-related diseases such as Alzheimer's (AD) and type 2 diabetes (T2D). Ten antioxidant flavonoids isolated from the medicinal halophyte Tamarix gallica were tested for their amyloid aggregation inhibition potential. Glucuronosylated flavonoids show relatively strong inhibitory activity of Amyloid β (Aβ) and human islet amyloid polypeptide (hIAPP) aggregation compared to their aglycone analogs. Structure-activity relationship of the flavonoids suggests that the catechol moiety is important for amyloid aggregation inhibition, while the methylation of the carboxyl group in the glucuronide moiety and of the hydroxyl group in the aglycone flavonoids decreased it.

  13. Up-regulation of E2F-1 in Down's syndrome brain exhibiting neuropathological features of Alzheimer-type dementia.

    PubMed

    Motonaga, K; Itoh, M; Hirayama, A; Hirano, S; Becker, L E; Goto, Y; Takashima, S

    2001-06-29

    We studied the expression of the apoptosis-related protein, E2F-1, in Down's syndrome (DS) brains. The immunoreactivity for E2F-1 was detected in the pyramidal neurons of the cerebral cortex from DS brains exhibiting the neuropathological features of dementia of Alzheimer type (DAT), in accordance with the amyloid beta protein (A beta) deposition in the neuron. Therefore, the implication is that A beta deposition may trigger E2F-1-mediated neuronal apoptosis in DS brains with DAT.

  14. Capsaicin reduces Alzheimer-associated tau changes in the hippocampus of type 2 diabetes rats.

    PubMed

    Xu, Weijie; Liu, Juanhong; Ma, Delin; Yuan, Gang; Lu, Yan; Yang, Yan

    2017-01-01

    Type 2 diabetes (T2D) is a high-risk factor for Alzheimer's disease (AD) due to impaired insulin signaling pathway in brain. Capsaicin is a specific transient receptor potential vanilloid 1 (TRPV1) agonist which was proved to ameliorate insulin resistance. In this study, we investigated whether dietary capsaicin could reduce the risk of AD in T2D. T2D rats were fed with capsaicin-containing high fat (HF) diet for 10 consecutive days (T2D+CAP). Pair-fed T2D rats (T2D+PF) fed with the HF-diet of average dose of T2D+CAP group were included to control for the effects of reduced food intake and body weight. Capsaicin-containing standard chow was also introduced to non-diabetic rats (NC+CAP). Blood glucose and insulin were monitored. The phosphorylation level of tau at individual sites, the activities of phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) and glycogen synthase kinase-3β (GSK-3β) were analyzed by Western blots. The results revealed that the levels of phosphorylated tau protein at sites Ser199, Ser202 and Ser396 in hippocampus of T2D+CAP group were decreased significantly, but these phospho-sites in T2D+PF group didn't show such improvements compared with T2D group. There were almost no changes in non-diabetic rats on capsaicin diet (NC+CAP) compared with the non-diabetic rats with normal chow (NC). Increased activity of PI3K/AKT and decreased activity of GSK-3β were detected in hippocampus of T2D+CAP group compared with T2D group, and these changes did not show in T2D+PF group either. These results demonstrated that dietary capsaicin appears to prevent the hyperphosphorylation of AD-associated tau protein by increasing the activity of PI3K/AKT and inhibiting GSK-3β in hippocampus of T2D rats, which supported that dietary capsaicin might have a potential use for the prevention of AD in T2D.

  15. Verbal and Academic Skills in Children with Early-Onset Type 1 Diabetes

    ERIC Educational Resources Information Center

    Hannonen, Riitta; Komulainen, Jorma; Eklund, Kenneth; Tolvanen, Asko; Riikonen, Raili; Ahonen, Timo

    2010-01-01

    Aim: Basic verbal and academic skills can be adversely affected by early-onset diabetes, although these skills have been studied less than other cognitive functions. This study aimed to explore the mechanism of learning deficits in children with diabetes by assessing basic verbal and academic skills in children with early-onset diabetes and in…

  16. Verbal and Academic Skills in Children with Early-Onset Type 1 Diabetes

    ERIC Educational Resources Information Center

    Hannonen, Riitta; Komulainen, Jorma; Eklund, Kenneth; Tolvanen, Asko; Riikonen, Raili; Ahonen, Timo

    2010-01-01

    Aim: Basic verbal and academic skills can be adversely affected by early-onset diabetes, although these skills have been studied less than other cognitive functions. This study aimed to explore the mechanism of learning deficits in children with diabetes by assessing basic verbal and academic skills in children with early-onset diabetes and in…

  17. The time of onset of abnormal calcification in spondylometaepiphyseal dysplasia, short limb-abnormal calcification type.

    PubMed

    Tüysüz, Beyhan; Gazioğlu, Nurperi; Ungür, Savaş; Aji, Dolly Yafet; Türkmen, Seval

    2009-01-01

    A 1-month-old boy with shortness of extremities on prenatal US was referred to our department with a provisional diagnosis of achondroplasia. His height was normal but he had short extremities and platyspondyly, premature carpal epiphyses on both hands, and short tubular bones with irregular metaphyses on radiographs. Re-evaluation of the patient at the age of 1 year revealed very short height and premature calcification of the costal cartilages and epiphyses. Spondylometaepiphyseal dysplasia (SMED), short limb-abnormal calcification type was diagnosed. This condition is a very rare autosomal recessively inherited disorder, and most of the patients die in early childhood due to neurological involvement. At the age of 2 years and 5 months, a CT scan showed narrowing of the cervical spinal canal. One month later he died suddenly because of spinal cord injury. In conclusion early diagnosis is very important because the recurrence risk is high and patients may die due to early neurological complications. The time of onset of abnormal calcifications, a diagnostic finding of the disease, is at the age of around 1 year in most patients. When abnormal calcifications are not yet present, but radiological changes associated with SMED are present, this rare disease must be considered.

  18. Outcomes of preterm children according to type of delivery onset: a nationwide population-based study.

    PubMed

    Morken, Nils-Halvdan; Källen, Karin; Jacobsson, Bo

    2007-09-01

    The objective of the study was to investigate whether spontaneous and iatrogenic preterm births are associated with different paediatric outcomes. A nationwide population-based study comprising 1 010 487 singletons used data from 1991 to 2001 from the Swedish Medical Birth Register and the Swedish Hospital Discharge Register. Intrauterine fetal deaths, unknown type of delivery onset and congenital malformations were excluded. Neonatal, perinatal and long-term neurological outcomes were studied. Spontaneous preterm births were compared with iatrogenic preterm births. Odds ratios (OR) and hazard ratios (HR) for outcome variables were obtained using the Mantel-Haenszel technique and Cox analyses respectively. Adjustments were made for gestational age at birth, maternal age, parity and smoking. The preterm population consisted of 34 215 (73.2%) spontaneous preterm infants and 12 511 (26.8%) iatrogenic preterm infants. Spontaneous preterm infants were at increased risk of cerebral palsy at gestational age 28-31 weeks (HR: 1.86 [95% CI: 1.12, 3.10]), and of sepsis at gestational age 32-33 weeks (HR: 1.58 [95% CI: 1.28, 1.96]). Other outcome variables were associated with iatrogenic preterm birth, especially respiratory and gastrointestinal diagnoses. In conclusion, spontaneous preterm birth and iatrogenic preterm birth are associated with different paediatric outcomes.

  19. Teplizumab Preserves C-Peptide in Recent-Onset Type 1 Diabetes

    PubMed Central

    Hagopian, William; Ferry, Robert J.; Sherry, Nicole; Carlin, David; Bonvini, Ezio; Johnson, Syd; Stein, Kathryn E.; Koenig, Scott; Daifotis, Anastasia G.; Herold, Kevan C.; Ludvigsson, Johnny

    2013-01-01

    Protégé was a phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study of three intravenous teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes. We sought to determine efficacy and safety of teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response. Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up. Teplizumab (14-day full-dose) reduced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo. In analyses of prespecified and post hoc subsets at entry, U.S. residents, patients with C-peptide mean AUC >0.2 nmol/L, those randomized ≤6 weeks after diagnosis, HbA1c <7.5% (58 mmol/mol), insulin use <0.4 units/kg/day, and 8–17 years of age each had greater teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be reduced versus placebo. Antidrug antibodies developed in some patients, without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. In summary, anti-CD3 therapy reduced C-peptide loss 2 years after diagnosis using a tolerable dose. PMID:23801579

  20. Immunoproteomic Profiling of Antiviral Antibodies in New-Onset Type 1 Diabetes Using Protein Arrays

    PubMed Central

    Bian, Xiaofang; Wallstrom, Garrick; Davis, Amy; Wang, Jie; Park, Jin; Throop, Andrea; Steel, Jason; Yu, Xiaobo; Wasserfall, Clive; Schatz, Desmond; Atkinson, Mark

    2016-01-01

    The rapid rise in the incidence of type 1 diabetes (T1D) suggests the involvement of environmental factors including viral infections. We evaluated the association between viral infections and T1D by profiling antiviral antibodies using a high-throughput immunoproteomics approach in patients with new-onset T1D. We constructed a viral protein array comprising the complete proteomes of seven viruses associated with T1D and open reading frames from other common viruses. Antibody responses to 646 viral antigens were assessed in 42 patients with T1D and 42 age- and sex-matched healthy control subjects (mean age 12.7 years, 50% males). Prevalence of antiviral antibodies agreed with known infection rates for the corresponding virus based on epidemiological studies. Antibody responses to Epstein-Barr virus (EBV) were significantly higher in case than control subjects (odds ratio 6.6; 95% CI 2.0–25.7), whereas the other viruses showed no differences. The EBV and T1D association was significant in both sex and age subgroups (≤12 and >12 years), and there was a trend toward early EBV infections among the case subjects. These results suggest a potential role for EBV in T1D development. We believe our innovative immunoproteomics platform is useful for understanding the role of viral infections in T1D and other disorders where associations between viral infection and disease are unclear. PMID:26450993

  1. Late onset pityriasis rubra pilaris type IV treated with low-dose acitretin.

    PubMed

    Mota, Fernando; Carvalho, Sandrina; Sanches, Madalena; Selores, Manuela

    2016-01-01

    Pityriasis rubra pilaris is a chronic inflammatory dermatosis of unknown etiology and great clinical variability. It has been divided into six categories. Types III, IV, and V occur in childhood and are distinguished by their clinical presentation, age of onset, and course. We report a 19-year-old male patient with a 2-week history of pruritic, scaling dermatosis of the hands, feet, elbows, and knees. He had no family history of skin disease. On physical examination, we observed circumscribed, reddish-orange, scaling plaques affecting the elbows and knees and a waxy palmoplantar keratoderma. The skin biopsy showed acanthosis, alternating orthokeratosis, parakeratosis, and follicular plugging suggestive of pityriasis rubra pilaris. The patient started treatment with oral acitretin, 25 mg every other day. The treatment was tolerated well, and after 6 months the lesions had resolved completely. Pityriasis rubra pilaris is a chronic papulosquamous disorder of unknown pathogenesis, characterized by reddish-orange scaly plaques, palmoplantar keratoderma, and keratotic follicular papules. There is still no consensus regarding the treatment, but therapeutic options include systemic retinoids, particularly acitretin in the recommended dose of 0.5 to 0.75 mg/kg/day. In our case, the patient was treated with a low-dose regimen of acitretin, which was effective and well tolerated.

  2. ILAE focal cortical dysplasia type IIIc in the ictal onset zone in epileptic patients with solitary meningioangiomatosis.

    PubMed

    Mukae, Nobutaka; Suzuki, Satoshi O; Morioka, Takato; Murakami, Nobuya; Hashiguchi, Kimiaki; Shigeto, Hiroshi; Sakata, Ayumi; Iihara, Koji

    2014-12-01

    "Solitary" meningioangiomatosis (MA) is a rare, benign, hamartomatous lesion of the cerebral cortex and frequently leads to epilepsy. However, the source of the epileptogenicity in meningioangiomatosis remains controversial. We report two surgically-treated meningioangiomatosis cases with medically intractable epilepsy. In both cases, chronic subdural electrocorticogram (ECoG) recordings identified the ictal onset zone on apparently normal cortex, adjacent to and/or above the meningioangiomatosis lesion, not on the meningioangiomatosis lesion itself. The ictal onset zone was resected, along with the MA lesion, and good seizure outcome was achieved. Histological examination of the ictal onset zone revealed the presence of ILAE focal cortical dysplasia (FCD) type IIIc. Our case studies suggest that in the surgical management of epilepsy with meningioangiomatosis, it is important to identify undetected, but epileptogenic, ILAE FCD Type IIIc, using preoperative multimodal examinations, including chronic ECoG recordings.

  3. Fluid snacks to help persons with type 1 diabetes avoid late onset postexercise hypoglycemia.

    PubMed

    Hernandez, J M; Moccia, T; Fluckey, J D; Ulbrecht, J S; Farrell, P A

    2000-05-01

    The present study assessed whether whole milk, skim milk, or two commercially available sports drinks are effective in preventing late onset postexercise hypoglycemia (LOPEH) in persons with type 1 diabetes mellitus. Subjects ingested water, whole milk, skim milk, sport drink A (carbohydrate and electrolytes), or sport drink B (carbohydrate, fat, and protein) before, during, and after 1 h of bicycle exercise at 60% VO2max in the late afternoon. Drinks were isocaloric (470 +/- 150 kcal) and the number of calories consumed was based on individual energy expenditure. No adjustment in insulinization was allowed in anticipation of exercise. During water trials all subjects became hypoglycemic. Most drinks lead to a moderate hyperglycemia (range of mean values = 200-280 mg x dL(-1)) during the period between the end of exercise and dinner, but this was not the case for whole milk (range 80-120 mg x dL(-1)). Glycemia peaked about 1.5 h after dinner and declined over the next 90 min. Persistent hyperglycemia (range of means = 200-310 mg x dL(-1)) from after exercise to about 4 h postexercise was observed with sports drink B. A decline in glycemia in the evening was greatest during the skim milk trial and required subjects to ingest more carbohydrate as a late evening snack. The least decline during this period occurred during the whole milk trial. Subjects experienced pre-bed and early morning (0300 h) hypoglycemia in 7 of the 28 trials. These data show that whole milk and sports drinks that are designed for both quick (sport drink A) and long lasting (sport drink B) nutrient replenishment can be used by persons with type 1 diabetes in an effort to avoid LOPEH.

  4. Clinically Relevant Cognitive Impairment in Middle-Aged Adults With Childhood-Onset Type 1 Diabetes

    PubMed Central

    Nunley, Karen A.; Ryan, Christopher M.; Jennings, J. Richard; Aizenstein, Howard J.; Zgibor, Janice C.; Costacou, Tina; Boudreau, Robert M.; Miller, Rachel; Orchard, Trevor J.; Saxton, Judith A.

    2015-01-01

    OBJECTIVE The aim of this study was to investigate the presence and correlates of clinically relevant cognitive impairment in middle-aged adults with childhood-onset type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS During 2010–2013, 97 adults diagnosed with T1D and aged <18 years (age and duration 49 ± 7 and 41 ± 6 years, respectively; 51% female) and 138 similarly aged adults without T1D (age 49 ± 7 years; 55% female) completed extensive neuropsychological testing. Biomedical data on participants with T1D were collected periodically since 1986–1988. Cognitive impairment status was based on the number of test scores ≥1.5 SD worse than demographically appropriate published norms: none, mild (only one test), or clinically relevant (two or more tests). RESULTS The prevalence of clinically relevant cognitive impairment was five times higher among participants with than without T1D (28% vs. 5%; P < 0.0001), independent of education, age, or blood pressure. Effect sizes were large (Cohen d 0.6–0.9; P < 0.0001) for psychomotor speed and visuoconstruction tasks and were modest (d 0.3–0.6; P < 0.05) for measures of executive function. Among participants with T1D, prevalent cognitive impairment was related to 14-year average A1c >7.5% (58 mmol/mol) (odds ratio [OR] 3.0; P = 0.009), proliferative retinopathy (OR 2.8; P = 0.01), and distal symmetric polyneuropathy (OR 2.6; P = 0.03) measured 5 years earlier; higher BMI (OR 1.1; P = 0.03); and ankle-brachial index ≥1.3 (OR 4.2; P = 0.01) measured 20 years earlier, independent of education. CONCLUSIONS Clinically relevant cognitive impairment is highly prevalent among these middle-aged adults with childhood-onset T1D. In this aging cohort, chronic hyperglycemia and prevalent microvascular disease were associated with cognitive impairment, relationships shown previously in younger populations with T1D. Two additional potentially modifiable risk factors for T1D-related cognitive impairment, vascular health and BMI

  5. Visual association test to detect early dementia of the Alzheimer type

    PubMed Central

    Lindeboom, J; Schmand, B; Tulner, L; Walstra, G; Jonker, C

    2002-01-01

    Background: The visual association test (VAT) is a brief learning task based on imagery mnemonics. The test materials consist of six line drawings of pairs of interacting objects or animals—for example, an ape holding an umbrella. The person is asked to name each object and, later, is presented with one object from the pair and asked to name the other. Objective: To verify that the task induces robust incidental or effortless learning (study 1), and to study the efficiency of the test as a discriminator between early dementia of the Alzheimer type (DAT) and non-demented people (study 2) and non-DAT types of dement