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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. 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.

  3. Early-Onset Alzheimer's

    MedlinePlus

    MENU Return to Web version Early-Onset Alzheimer’s What is early-onset Alzheimer’s disease? Early-onset Alzheimer’s disease is when Alzheimer’s affects a person younger than 65 years of age. People ...

  4. First episodes of behavioral symptoms in Alzheimer's disease patients at age 90 and over, and early-onset Alzheimer's disease: comparison with senile dementia of Alzheimer's type.

    PubMed

    Hori, Koji; Oda, Tatsuro; Asaoka, Toshiyasu; Yoshida, Masahiro; Watanabe, Shoichi; Oyamada, Reiko; Tominaga, Itaru; Inada, Toshiya

    2005-12-01

    We evaluated dementia symptoms to clarify the character of dementia with Alzheimer's disease (AD) observed in the oldest old patients and that of dementia with early-onset AD. Subjects were consecutive AD inpatients admitted for the first time at age of 90 years and over because of behavioral symptoms (demented nonagenarian group: D90G; n=18) and those with 24 consecutive inpatients with AD with early-onset (EOG). The Gottfries, Brane and Steen's scale and the Dementia Behavior Disturbance scale were used to evaluate the symptoms and troublesome behaviors. The scores of these scales in D90G and in EOG were compared with those of 26 sex distribution-, severity of dementia-, and disease duration-matched inpatients with AD with late-onset (LOG). Compared with LOG, wakefulness was more impaired and waking up at night was more frequent in D90G, while memory, orientation and inappropriate behaviors were more severe in EOG. These results suggest that the clinical features of dementia in EOG were quantitatively different from those of LOG. In contrast, the clinical feature of dementia of D90G were sleep-wake pattern disturbance and were qualitatively different from those of LOG. PMID:16401251

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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.

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

    PubMed

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

    2015-06-01

    Given the lack of effective treatments for late-onset Alzheimer's disease (LOAD) and the substantial burden on patients, families, health care systems, and economies, finding an effective therapy is one of the highest medical priorities. The past few years have seen a growing interest in the medicinal uses of cannabinoids, the bioactive components of the cannabis plant, including the treatment of LOAD and other physical conditions that are common in older people. Several in vitro and in vivo studies have demonstrated that cannabinoids can reduce oxidative stress, neuroinflammation, and the formation of amyloid plaques and neurofibrillary tangles, the key hallmarks of LOAD. In addition, in population-based studies, cannabinoids reduced dementia-related symptoms (e.g., behavioral disturbances). The current article provides an overview of the potential of cannabinoids in the treatment of LOAD and related neuropsychiatric symptoms in older people. We also discuss the efficacy, safety, and pharmacokinetics of cannabinoid-based drugs in older people with dementia. PMID:25788394

  13. 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.

  14. 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…

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. 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

  3. 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

  4. Therapeutic Approaches to Delay the Onset of Alzheimer's Disease

    PubMed Central

    Kumar, Raj; Atamna, Hani

    2011-01-01

    The key cytopathologies in the brains of Alzheimer's disease (AD) patients include mitochondrial dysfunction and energy hypometabolism, which are likely caused by the accumulation of small aggregates of amyloid-β (Aβ) peptides. Thus, targeting these two abnormalities of the AD brain may hold promising therapeutic value for delaying the onset of AD. In his paper, we discuss two potential approaches to delay the onset of AD. The first is the use of low dose of diaminophenothiazins (redox active agents) to prevent mitochondrial dysfunction and to attenuate energy hypometabolism. Diaminophenothiazines enhance mitochondrial metabolic activity and heme synthesis, both key factors in intermediary metabolism of the AD brain.The second is to use the naturally occurring osmolytes to prevent the formation of toxic forms of Aβ and prevent oxidative stress. Scientific evidence suggests that both approaches may change course of the basic mechanism of neurodegeneration in AD. Osmolytes are brain metabolites which accumulate in tissues at relatively high concentrations following stress conditions. Osmolytes enhance thermodynamic stability of proteins by stabilizing natively-folded protein conformation, thus preventing aggregation without perturbing other cellular processes. Osmolytes may inhibit the formation of Aβ oligomers in vivo, thus preventing the formation of soluble oligomers. The potential significance of combining diaminophenothiazins and osmolytes to treat AD is discussed. PMID:21423548

  5. 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.

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

    PubMed Central

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

    2015-01-01

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

  7. 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.

  8. 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.

  9. [Late onset type I tyrosinemia].

    PubMed

    Klujber, V; Sallai, A; Kálmánchey, R; Szönyi, L; Hosszú, E

    1997-07-13

    The authors present a case of tyrosinemia type 1, 3 years old girl at the time of diagnosis. The presenting symptoms were 3 times colic, obstipation, acute encephalopathy, hypertension, hyponatremia, according to the porphyric crisis. Her kidney function tests gave normal results during illness, only once an increased calcium turnover was observed. She has no singe of rachitis. Cirrhosis of the liver was proved by biopsy because of progressively rising gammaGT and alfa-fetoprotein levels. A new ensime-blocker (NTBC) treatment was started in an international collaboration. The authors compare the history of this case to that of others published in the literature. They summarize the pathomechanism of the disease.

  10. Biological mechanisms linking Alzheimer's disease and type-2 diabetes mellitus.

    PubMed

    Mushtaq, Gohar; Khan, Jalaluddin A; Kamal, Mohammad A

    2014-01-01

    The emerging data suggest that type 2 diabetes mellitus (T2DM) can contribute significantly to the onset or progression of Alzheimer's disease (AD) either directly or as a cofactor. Various in vitro and in vivo animal and human clinical studies have provided evidence that T2DM is a major risk factor in the pathology of AD and the two diseases share common biological mechanisms at the molecular level. The biological mechanisms that are common in the pathology of both T2DM and AD include insulin resistance, impaired glucose metabolism, β-amyloid formation, oxidative stress, and the presence of advanced glycation end products. With better understanding of the degree of association between AD and T2DM and the underlying molecular mechanisms explaining this relationship, it is hoped that researchers will be able to develop effective therapeutic interventions to treat or control T2DM and, as a consequence, delay the onset or progression of AD.

  11. 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.

  12. Microcephaly genes and risk of late-onset Alzheimer disease.

    PubMed

    Erten-Lyons, Deniz; Wilmot, Beth; Anur, Pavana; McWeeney, Shannon; Westaway, Shawn K; Silbert, Lisa; Kramer, Patricia; Kaye, Jeffrey

    2011-01-01

    Brain development in the early stages of life has been suggested to be one of the factors that may influence an individual's risk of Alzheimer disease (AD) later in life. Four microcephaly genes, which regulate brain development in utero and have been suggested to play a role in the evolution of the human brain, were selected as candidate genes that may modulate the risk of AD. We examined the association between single nucleotide polymorphisms tagging common sequence variations in these genes and risk of AD in two case-control samples. We found that the G allele of rs2442607 in microcephalin 1 was associated with an increased risk of AD (under an additive genetic model, P=0.01; odds ratio=3.41; confidence interval, 1.77-6.57). However, this association was not replicated using another case-control sample research participants from the Alzheimer Disease Neuroimaging Initiative. We conclude that the common variations we measured in the 4 microcephaly genes do not affect the risk of AD or that their effect size is small. PMID:21297427

  13. Exome sequencing in a consanguineous family clinically diagnosed with early-onset Alzheimer's disease identifies a homozygous CTSF mutation.

    PubMed

    Bras, Jose; Djaldetti, Ruth; Alves, Ana Margarida; Mead, Simon; Darwent, Lee; Lleo, Alberto; Molinuevo, Jose Luis; Blesa, Rafael; Singleton, Andrew; Hardy, John; Clarimon, Jordi; Guerreiro, Rita

    2016-10-01

    We have previously reported the whole genome genotyping analysis of 2 consanguineous siblings clinically diagnosed with early onset Alzheimer's disease (AD). In this analysis, we identified several large regions of homozygosity shared between both affected siblings, which we suggested could be candidate loci for a recessive genetic lesion underlying the early onset AD in these cases. We have now performed exome sequencing in one of these siblings and identified the potential cause of disease: the CTSF c.1243G>A:p.Gly415Arg mutation in homozygosity. Biallelic mutations in this gene have been shown to cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis with some cases resembling the impairment seen in AD. PMID:27524508

  14. 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.

  15. 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…

  16. 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…

  17. Exploratory Data from Complete Genomes of Familial Alzheimer Disease Age-at-Onset Outliers

    PubMed Central

    Lalli, Matthew A.; Garcia, Gloria; Madrigal, Lucia; Arcos-Burgos, Mauricio; Arcila, Mary Luz; Kosik, Kenneth S.; Lopera, Francisco

    2012-01-01

    Identifying genes that modify the age-at-onset (AAO) of Alzheimer disease and targeting them pharmacologically represent a potential treatment strategy. In this exploratory study, we sequenced the complete genomes of six individuals with familial Alzheimer disease due to the autosomal dominant mutation p.Glu280Ala in PSEN1 (MIM# 104311; NM_000021.3:c.839A>C). The disease and its age-at-onset are highly heritable, motivating our search for genetic variants that modulate AAO. The median AAO of dementia in carriers of the mutant allele is 49 years. Extreme phenotypic outliers for AAO in this genetically isolated population with limited environmental variance are likely to harbor onset-modifying genetic variants. A narrow distribution of AAO in this kindred suggests large effect sizes of genetic determinants of AAO in these outliers. Identity by Descent (IBD) analysis and a combination of bioinformatics filters have suggested several candidate variants for AAO modifiers. Future work and replication studies on these variants may provide mechanistic insights into the etiopathology of Alzheimer disease. PMID:22829467

  18. Increased risk of type 2 diabetes in Alzheimer disease.

    PubMed

    Janson, Juliette; Laedtke, Thomas; Parisi, Joseph E; O'Brien, Peter; Petersen, Ronald C; Butler, Peter C

    2004-02-01

    Alzheimer disease and type 2 diabetes are characterized by increased prevalence with aging, a genetic predisposition, and comparable pathological features in the islet and brain (amyloid derived from amyloid beta protein in the brain in Alzheimer disease and islet amyloid derived from islet amyloid polypeptide in the pancreas in type 2 diabetes). Evidence is growing to link precursors of amyloid deposition in the brain and pancreas with the pathogenesis of Alzheimer disease and type 2 diabetes, respectively. Given these similarities, we questioned whether there may be a common underlying mechanism predisposing to islet and cerebral amyloid. To address this, we first examined the prevalence of type 2 diabetes in a community-based controlled study, the Mayo Clinic Alzheimer Disease Patient Registry (ADPR), which follows patients with Alzheimer disease versus control subjects without Alzheimer disease. In addition to this clinical study, we performed a pathological study of autopsy cases from this same community to determine whether there is an increased prevalence of islet amyloid in patients with Alzheimer disease and increased prevalence of cerebral amyloid in patients with type 2 diabetes. Patients who were enrolled in the ADPR (Alzheimer disease n = 100, non-Alzheimer disease control subjects n = 138) were classified according to fasting glucose concentration (FPG) as nondiabetic (FPG <110 mg/dl), impaired fasting glucose (IFG, FPG 110-125 mg/dl), and type 2 diabetes (FPG >126 mg/dl). The mean slope of FPG over 10 years in each case was also compared between Alzheimer disease and non-Alzheimer disease control subjects. Pancreas and brain were examined from autopsy specimens obtained from 105 humans (first, 28 cases of Alzheimer disease disease vs. 21 non-Alzheimer disease control subjects and, second, 35 subjects with type 2 diabetes vs. 21 non-type 2 diabetes control subjects) for the presence of islet and brain amyloid. Both type 2 diabetes (35% vs. 18%; P < 0

  19. [Genetics of late-onset Alzheimer's disease: vascular risk and beta-amyloid metabolism].

    PubMed

    Panza, Francesco; Solfrizzi, Vincenzo; D'Introno, Alessia; Capurso, Cristiano; Colacicco, Anna Maria; Torres, Francesco; Altomare, Emanuele; Capurso, Antonio

    2002-09-01

    Progress in clinical and basic research of Alzheimer's disease (AD) suggested theoretical models of possible pathogenetic mechanisms, with a primary role of the genetic factors that have been implicated in AD. These can be divided into two main categories. First, the three genes in which mutations are known to result in early onset autosomal dominant familial AD (presenilins 1 and 2, and amyloid beta protein precursor [APP]): well characterized but that account for only a small proportion of AD cases. Secondly, late onset, sporadic AD is more common and evidence suggests that there is a genetic component to this type of disease. A number of genetic risk factors have been implicated that might increase the risk of developing sporadic disease: particularly, apolipoprotein E (apo E) polymorphism and many others suggested by linkage studies [alpha-macroglobulin, low density receptor protein (LRP1), bleomycin hydrolase], with a precise role in beta-amyloid metabolism and deposition. Many of these are controversial and studies have shown conflicting results, but apoE polymorphism seems to be only one of the possible genetic factors suggested to play a role in the multifactoral pathogenesis of AD. Regional and ethnic differences may affect the strength of association between apoE epsilon 4 allele and the disease, and we reported evidences of the decreasing frequency of epsilon 4 allele in AD patients and centenarians from Northern to Southern European regions. Finally, several genetic risk factors of vascular origin (angiotensin converting enzyme, methyltetrahydropholate-reductase, and NOS3 gene polymorphisms) have been implicated in the development of both vascular dementia and AD with conflicting results.

  20. Mediterranean diet and dementia of the Alzheimer type.

    PubMed

    Vassallo, Neville; Scerri, Charles

    2013-07-01

    Dementia of the Alzheimer type is the most common form of dementia affecting mostly the elderly population. It is a progressive and fatal neurodegenerative disorder with characteristic neuropathology and clinical symptomology. In the coming years, the number of individuals with Alzheimer's disease (AD) will increase as the elderly population worldwide is expected to grow significantly thus putting an added strain on national health care systems as well as caregivers who will inevitably carry most of the care burden. Thus it has been suggested that early intervention strategies which delay or halt the disease progression will have a strong impact on clinical outcomes. Changes in lifestyle habits such as diet modification or supplementation have been indicated as probable protective factors for a number of chronic conditions including AD. Particular attention has recently been devoted to the Mediterranean diet which is rich in the antioxidants Vitamins C and E, polyunsaturated fatty acids and polyphenolic compounds. Several in vitro, animal and population-based studies reported a positive effect between adherence to a Mediterranean diet and AD prevention, although contrasting views remain. This review will focus on the latest developments and findings in the ongoing research investigating the relationship between Mediterranean diet and its major constituents in AD onset and progression.

  1. ERα Variants Affect Age at Onset of Alzheimer's Disease in a Multiethnic Female Cohort

    PubMed Central

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

    2014-01-01

    Background/Aims 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 investigated the influence of ESR1 polymorphisms on age at onset of AD in a multiethnic cohort of women. Methods Among 1,436 women participating in the Washington Heights Inwood Columbia Aging Project (WHICAP), 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 (BMI). Results 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 (RFLPs) 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. Conclusions ESR1 polymorphisms affect age of onset for 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 SNP effect on risk for AD. PMID:24732579

  2. Exploring the service and support needs of families with early-onset Alzheimer's disease.

    PubMed

    Gibson, Allison K; Anderson, Keith A; Acocks, Sara

    2014-11-01

    Although often cast as a disease of later life, a growing number of people are being diagnosed with Alzheimer's disease in their 50s and 60s. Early-onset Alzheimer's disease (EOAD) poses special challenges and needs for individuals and their caregivers, such as employment and access to services. In this cross-sectional study, the researchers surveyed 81 (N = 81) family caregivers to individuals with EOAD to identify service and support usage and need. Descriptive analyses revealed that families utilized a range of formal services (eg, adult day) and informal support from family and friends. In terms of challenges and needs, participants indicated that they struggled most with employment, benefits, and financial issues. Although most caregivers felt that they were coping well, they also indicated that their needs were not well understood by service providers and the public. These findings highlight the need to better understand and respond to the specific issues surrounding EOAD. PMID:25392308

  3. 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.

  4. Type 2 diabetes mellitus and Alzheimer's disease.

    PubMed

    Barbagallo, Mario; Dominguez, Ligia J

    2014-12-15

    Epidemiological and biological evidences support a link between type 2 diabetes mellitus (DM2) and Alzheimer's disease (AD). Persons with diabetes have a higher incidence of cognitive decline and an increased risk of developing all types of dementia. Cognitive deficits in persons with diabetes mainly affect the areas of psychomotor efficiency, attention, learning and memory, mental flexibility and speed, and executive function. The strong epidemiological association has suggested the existence of a physiopathological link. The determinants of the accelerated cognitive decline in DM2, however, are less clear. Increased cortical and subcortical atrophy have been evidenced after controlling for diabetic vascular disease and inadequate cerebral circulation. Most recent studies have focused on the role of insulin and insulin resistance as possible links between diabetes and AD. Disturbances in brain insulin signaling mechanisms may contribute to the molecular, biochemical, and histopathological lesions in AD. Hyperglycemia itself is a risk factor for cognitive dysfunction and dementia. Hypoglycemia may also have deleterious effects on cognitive function. Recurrent symptomatic and asymptomatic hypoglycemic episodes have been suggested to cause sub-clinical brain damage, and permanent cognitive impairment. Future trials are required to clarify the mechanistic link, to address the question whether cognitive decline may be prevented by an adequate metabolic control, and to elucidate the role of drugs that may cause hypoglycemic episodes.

  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. PMID:27445249

  6. Amyloid beta protein levels in cerebrospinal fluid are elevated in early-onset Alzheimer's disease.

    PubMed

    Nakamura, T; Shoji, M; Harigaya, Y; Watanabe, M; Hosoda, K; Cheung, T T; Shaffer, L M; Golde, T E; Younkin, L H; Younkin, S G

    1994-12-01

    The 4-kd amyloid beta protein (A beta) deposited as amyloid in Alzheimer's disease (AD) is produced and released by normal proteolytic processing of the amyloid beta protein precursor (beta APP) and is readily detected in cerebrospinal fluid (CSF). Here, we present the levels of A beta in CSF from a total of 95 subjects, including 38 patients with AD, 14 with early-onset AD and 24 with late-onset AD, 25 normal control subjects, and 32 patients with other neurological diseases. The level of A beta decreased with normal aging, and there was a significant elevation in the level of A beta in the CSF of early-onset AD patients (4.14 +/- 1.37 pmol/ml, p < 0.01). Neither Mini-Mental State nor Functional Assessment Staging were correlated with the amount of A beta in the CSF. The A beta/secreted form of beta APP ratio was elevated, but the level of alpha 1-antichymotrypsin in the CSF did not correlate with the level of CSF A beta in early-onset AD patients. Thus, the level of A beta in the CSF is elevated in early-onset AD patients and is suggested to be correlated with the pathology in the brain that characterizes AD. PMID:7998778

  7. 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.

  8. Senile dementia of the Alzheimer type.

    PubMed

    Erwin, W G

    1984-01-01

    The etiology, pathophysiology, neurochemistry, diagnosis, clinical presentation, and management of senile dementia of the Alzheimer type (SDAT) are discussed. The etiology of SDAT is unclear. The pathophysiologic changes in the brain tissue of patients with SDAT are quantitative rather than qualitative in comparison to normal age-matched controls. The number of neuritic plaques and neurofibrillary tangles are positively correlated to the severity of clinical symptoms and cognitive impairment. There is overwhelming evidence that SDAT is associated with a loss of cholinergic function. Reduction of choline acetyltransferase activity, a cholinergic marker, has been significantly correlated to the severity of dementia. The diagnosis of SDAT is one of exclusion and is based upon clinical presentation and neurological, psychological, and laboratory testing. The clinical presentation of SDAT involves the progressive deterioration of intellectual capabilities. Management of SDAT primarily involves supportive care and symptom control. Attempts to treat the disease with cerebral vasodilators, metabolic enhancers, and neurotransmitter manipulation have been largely unsuccessful. Drug therapy aimed at reversing or retarding the progression of the disease is not recommended. Behavioral disturbances represent the main indication for drug use in patients with SDAT. The antipsychotic agents are considered the drugs of choice. SDAT remains an enigma. The successes in the treatment of the disease are few, but as more information is gathered on the neurochemical abnormalities involved, there is hope that early detection can prevent the disease or at least slow its progression.

  9. 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.

  10. 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.

  11. 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

  12. [Risk factors for dementia of the Alzheimer type].

    PubMed

    Bidzan, L; Ussorowska, D

    1995-01-01

    A case-control study was conducted on 90 cases of "probable" Alzheimer's disease and 97 controls at the same age as patients with dementia of the Alzheimer type. The patients were diagnosed according to the DSM IIIR criteria. Information was obtained on birth and childhood, medical and surgical history, exposure to various social, psychological and biological factors, family history of dementia. A structured questionnaire was based on AMDP-system. Some of the variables studied reached statistical significance: first of all unfavourable factors (especially poor livelihood) taking place during the person's childhood, the level of education and social activity. Family history of dementia among persons with Alzheimer type dementia also reached statistical significance. Head trauma was more frequent in patients with dementia, but the differences were not significant. The findings suggest a possible etiologic role for some environmental factors in dementia of the Alzheimer type. PMID:7652083

  13. Alzheimer's disease and type 2 diabetes via chronic inflammatory mechanisms.

    PubMed

    Mushtaq, Gohar; Khan, Jalaluddin A; Kumosani, Taha A; Kamal, Mohammad A

    2015-01-01

    Recent evidence has indicated that type 2 diabetes mellitus (T2DM) increases the risk of developing Alzheimer's disease (AD). Therefore, it is crucial to investigate the potential common processes that could explain this relation between AD and T2DM. In the recent decades, an abundance of evidence has emerged demonstrating that chronic inflammatory processes may be the major factors contributing to the development and progression of T2DM and AD. In this article, we have discussed the molecular underpinnings of inflammatory process that contribute to the pathogenesis of T2DM and AD and how they are linked to these two diseases. In depth understanding of the inflammatory mechanisms through which AD and T2DM are associated to each other may help the researchers to develop novel and more effective strategies to treat together AD and T2DM. Several treatment options have been identified which spurn the inflammatory processes and discourage the production of inflammatory mediators, thereby preventing or slowing down the onset of T2DM and AD.

  14. 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

  15. SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians.

    PubMed

    Miyashita, Akinori; Koike, Asako; Jun, Gyungah; Wang, Li-San; Takahashi, Satoshi; Matsubara, Etsuro; Kawarabayashi, Takeshi; Shoji, Mikio; Tomita, Naoki; Arai, Hiroyuki; Asada, Takashi; Harigaya, Yasuo; Ikeda, Masaki; Amari, Masakuni; Hanyu, Haruo; Higuchi, Susumu; Ikeuchi, Takeshi; Nishizawa, Masatoyo; Suga, Masaichi; Kawase, Yasuhiro; Akatsu, Hiroyasu; Kosaka, Kenji; Yamamoto, Takayuki; Imagawa, Masaki; Hamaguchi, Tsuyoshi; Yamada, Masahito; Morihara, Takashi; Moriaha, Takashi; Takeda, Masatoshi; Takao, Takeo; Nakata, Kenji; Fujisawa, Yoshikatsu; Sasaki, Ken; Watanabe, Ken; Nakashima, Kenji; Urakami, Katsuya; Ooya, Terumi; Takahashi, Mitsuo; Yuzuriha, Takefumi; Serikawa, Kayoko; Yoshimoto, Seishi; Nakagawa, Ryuji; Kim, Jong-Won; Ki, Chang-Seok; Won, Hong-Hee; Na, Duk L; Seo, Sang Won; Mook-Jung, Inhee; St George-Hyslop, Peter; Mayeux, Richard; Haines, Jonathan L; Pericak-Vance, Margaret A; Yoshida, Makiko; Nishida, Nao; Tokunaga, Katsushi; Yamamoto, Ken; Tsuji, Shoji; Kanazawa, Ichiro; Ihara, Yasuo; Schellenberg, Gerard D; Farrer, Lindsay A; Kuwano, Ryozo

    2013-01-01

    To discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10(-9)) and rs3781834 (P = 1.04×10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10(-5)) and rs744373 near BIN1 (P = 1.39×10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.

  16. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease.

    PubMed

    Nicolas, G; Charbonnier, C; Wallon, D; Quenez, O; Bellenguez, C; Grenier-Boley, B; Rousseau, S; Richard, A-C; Rovelet-Lecrux, A; Le Guennec, K; Bacq, D; Garnier, J-G; Olaso, R; Boland, A; Meyer, V; Deleuze, J-F; Amouyel, P; Munter, H M; Bourque, G; Lathrop, M; Frebourg, T; Redon, R; Letenneur, L; Dartigues, J-F; Génin, E; Lambert, J-C; Hannequin, D; Campion, D

    2016-06-01

    The SORL1 protein plays a protective role against the secretion of the amyloid β peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.

  17. The Usefulness of Biological and Neuroimaging Markers for the Diagnosis of Early-Onset Alzheimer's Disease

    PubMed Central

    Padovani, Alessandro; Gilberti, Nicola; Borroni, Barbara

    2011-01-01

    The recent proposed criteria for Alzheimer's Disease (AD) have strongly claimed the usefulness of biological and neuroimaging markers for early identification AD. Cerebrospinal fluid (CSF) Tau/Abeta ratio, hippocampal atrophy, posterior cingulate, and neocortical associative area hypometabolism, or amyloid burden evaluated by PiB compound, held the premises to increase diagnostic accuracy in the preclinical disease stages. Despite many efforts to identify subjects at risk of developing AD, less attention has been paid to presenile AD diagnosis. A few data are already available in early onset AD, mainly obtained in cases of monogenic disorder. In this paper, we discuss the current literature on the role of biological and neuroimaging markers in presenile AD. PMID:21559247

  18. The usefulness of biological and neuroimaging markers for the diagnosis of early-onset Alzheimer's disease.

    PubMed

    Padovani, Alessandro; Gilberti, Nicola; Borroni, Barbara

    2011-02-21

    The recent proposed criteria for Alzheimer's Disease (AD) have strongly claimed the usefulness of biological and neuroimaging markers for early identification AD. Cerebrospinal fluid (CSF) Tau/Abeta ratio, hippocampal atrophy, posterior cingulate, and neocortical associative area hypometabolism, or amyloid burden evaluated by PiB compound, held the premises to increase diagnostic accuracy in the preclinical disease stages. Despite many efforts to identify subjects at risk of developing AD, less attention has been paid to presenile AD diagnosis. A few data are already available in early onset AD, mainly obtained in cases of monogenic disorder. In this paper, we discuss the current literature on the role of biological and neuroimaging markers in presenile AD.

  19. 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

  20. 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

  1. 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.

  2. 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.

  3. 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

  4. [Risk factors for dementia of the Alzheimer's type].

    PubMed

    Bidzan, L; Ussorowska, D

    1994-01-01

    A case-control study was conducted on 16 cases of probable Alzheimer's disease and 32 controls matched for age. The first control group was younger while the second was at the same age as patients with dementia of the Alzheimer's type. The patients were diagnosed according to DSM IIIR criteria. Information was obtained on birth and childhood, medical and surgical history, exposure to various social, psychological and biological factors as well as a family history of dementia. A structured questionnaire based on the AMDP--system was completed. Some of the variables studied reached statistical significance. First of all the sum of unfavourable environmental factors taking place during the person's childhood and elderly was predictive. Also head trauma was more frequent in patients with dementia. The findings suggest a possible etiologic role for some environmental factors in dementia of the Alzheimer's type. PMID:7862761

  5. Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease.

    PubMed

    Lalli, M A; Bettcher, B M; Arcila, M L; Garcia, G; Guzman, C; Madrigal, L; Ramirez, L; Acosta-Uribe, J; Baena, A; Wojta, K J; Coppola, G; Fitch, R; de Both, M D; Huentelman, M J; Reiman, E M; Brunkow, M E; Glusman, G; Roach, J C; Kao, A W; Lopera, F; Kosik, K S

    2015-11-01

    We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0 ± 5.2 years compared with 41.1 ± 7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.

  6. Hippocampal Laminar Distribution of Tau Relates to Alzheimer's Disease and Age of Onset

    PubMed Central

    Seifan, Alon; Marder, Karen S.; Mez, Jesse; Noble, James M.; Cortes, Etty P.; Vonsattel, Jean Paul; Honig, Lawrence S.

    2015-01-01

    Background Cerebral deposition of phospho-tau in Alzheimer's disease (AD) occurs with varying patterns within hippocampus. Lamina-specific tau changes in AD may reflect trans-synaptic propagation of phospho-tau along neuroanatomical pathways. Objective To study patterns of tau deposition within inner (IML) and outer (OML) molecular layers of dentate gyrus and their clinical and neuropathological correlates. Methods 98 consecutive autopsied brains from the Columbia University Brain Bank were stained for phospho-tau using AT-8. Staining density was rated as High versus Low within IML and OML. Four patterns were observed among the 98 brains: High IML&OML, n = 44; High OML Only (n = 35); High IML Only (n = 5); and Low IML&OML (n = 14). Demographic, clinical, and neuropathological characteristics of these four groups were compared. Results High IML&OML subjects, versus High OML Only, were more likely to fulfill CERAD criteria for Definite AD (93% versus 66%, p < 0.01) and to have higher median Braak stage (6 versus 5, p < 0.01) and earlier mean age of onset (65.9 versus 73.7 y, p = 0.02), with similar symptom duration. Using logistic regression, the association between High IML&OML and AD remained significant after adjustment for demographics but not symptom duration. In the 70 subjects with Definite AD, High IML&OML was associated with younger age of onset (mean difference 3.7 years, 95%CI −6.7 to −0.7, p < 0.01), after adjustment for demographics and symptom duration. Conclusions Phospho-tau pathology, when prominent within both IML and OML, is associated with CERAD diagnosis of Definite AD and earlier age of onset in AD. Laminar patterns of tau deposition reflect regional involvements during disease course. PMID:25079799

  7. 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…

  8. 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…

  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.

  10. 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

  11. Association between polymorphisms of the insulin-degrading enzyme gene and late-onset Alzheimer disease.

    PubMed

    Wang, Shitao; He, Feiyan; Wang, Ying

    2015-06-01

    The insulin-degrading enzyme (IDE) gene is a strong positional and biological candidate for late-onset Alzheimer disease (LOAD) susceptibility, with recent studies independently demonstrating an association between IDE gene variants and LOAD. However, previous data have been controversial. To investigate the relationship between IDE gene polymorphisms and LOAD risk, a case-control association study of 406 Han Chinese participants in Xinjiang, China, was undertaken. The LOAD and control groups consisted of 202 and 204 participants, respectively. The single-nucleotide polymorphisms rs1887922 and rs1999764 of the IDE gene were linked to LOAD incidence. The presence of the CT+CC genotype of rs1999764 had a protective effect compared to the TT genotype (adjusted P=.0001; odds ratio [OR]=0.226; 95% confidence interval [CI]=0.116-0.441), while the CT+CC genotype of rs1887922 was associated with increased LOAD risk (adjusted P=.0001; OR=3.640; 95% CI=1.889-7.016). Moreover, the effects of rs1887922 and rs1999764 were associated with LOAD risk independent of the apolipoprotein E ∊4 polymorphism and were more significant in men and women, respectively. These results demonstrate that the polymorphisms rs1887922 and rs1999764 of the IDE gene are associated with LOAD susceptibility in the Xinjiang Han population.

  12. 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

  13. 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.

  14. 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

  15. 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. PMID:26998855

  16. 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.

  17. 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.

  18. ApoE genotype and familial Alzheimer's disease: a possible influence on age of onset in APP717 Val-->Ile mutated families.

    PubMed

    Nacmias, B; Latorraca, S; Piersanti, P; Forleo, P; Piacentini, S; Bracco, L; Amaducci, L; Sorbi, S

    1995-01-01

    Recent studies have shown a genetic association of the apolipoprotein E (ApoE) epsilon 4 allele with late onset familial and sporadic Alzheimer's disease (AD). In this study we analysed the possible association of the genetic polymorphism of the ApoE gene with age of onset in Italian familial Alzheimer's disease (FAD) families including two early onset familial Alzheimer's (EOFAD) families with the APP717 Val-->Ile mutation in the amyloid precursor protein (APP) gene on chromosome 21. In none of the FAD families analysed was there a significant effect of the ApoE genotype on the age of onset with the exception of one of the two mutated EOFAD families in which the epsilon 2 allele delayed the age of onset. PMID:7746463

  19. Type 3 diabetes is sporadic Alzheimer׳s disease: mini-review.

    PubMed

    de la Monte, Suzanne M

    2014-12-01

    Alzheimer׳s disease (AD) is the most common cause of dementia in North America. Growing evidence supports the concept that AD is a metabolic disease mediated by impairments in brain insulin responsiveness, glucose utilization, and energy metabolism, which lead to increased oxidative stress, inflammation, and worsening of insulin resistance. In addition, metabolic derangements directly contribute to the structural, functional, molecular, and biochemical abnormalities that characterize AD, including neuronal loss, synaptic disconnection, tau hyperphosphorylation, and amyloid-beta accumulation. Because the fundamental abnormalities in AD represent effects of brain insulin resistance and deficiency, and the molecular and biochemical consequences overlap with Type 1 and Type 2 diabetes, we suggest the term "Type 3 diabetes" to account for the underlying abnormalities associated with AD-type neurodegeneration. In light of the rapid increases in sporadic AD prevalence rates and vastly expanded use of nitrites and nitrates in foods and agricultural products over the past 30-40 years, the potential role of nitrosamine exposures as mediators of Type 3 diabetes is discussed.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. Phenotypic profile of early-onset familial Alzheimer's disease caused by presenilin-1 E280A mutation.

    PubMed

    Sepulveda-Falla, Diego; Glatzel, Markus; Lopera, Francisco

    2012-01-01

    Presenilin 1 (PS1) mutations are the most common cause of early-onset familial Alzheimer's disease (EOFAD). They show a common phenotypic profile characterized by early age of onset, severe dementia and distinct neurodegeneration. The largest population of EOFAD carries the E280A mutation in PS1 and resides in Antioquia, Colombia, currently comprising around 5,000 individuals. Carriers start showing memory impairment in the third decade of life, followed by progressive impairment of language and other cognitive processes. They reach mild cognitive impairment around 45 and dementia around 50 years of age. There is some phenotypic variability among the carriers of this single PS1 mutation. Some patients present with epilepsy, verbal impairment, and cerebellar ataxia. Neuropathologically, PS1 E280A cases show pronounced brain atrophy, severe amyloid-β pathology, distinct hyperphosphorylated tau-related pathology, and cerebellar damage. The earliest event identified by functional magnetic imaging resonance is hyperactivation within the right anterior hippocampus around 33 years of age. This well-studied population with a clear pre-clinical profile and wide phenotypic variability in age of onset and clinical presentation is ideally suited for clinical trials and to study molecular mechanisms of Alzheimer's disease. PMID:22766738

  5. "MODY2" (maturity onset diabetes of the young type 2).

    PubMed

    Heidenreich, Wayne F

    2014-01-01

    A 25-year-old male with "MODY2" (maturity onset diabetes of the young type 2) applied for life and disability insurance. MODY2 is also identified by the glucokinase gene that is mutated in this disorder. The etiology, clinical characteristics, and long-term risks of this disorder are reviewed. PMID:25622392

  6. A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death.

    PubMed

    Wetzel-Smith, Monica K; Hunkapiller, Julie; Bhangale, Tushar R; Srinivasan, Karpagam; Maloney, Janice A; Atwal, Jasvinder K; Sa, Susan M; Yaylaoglu, Murat B; Foreman, Oded; Ortmann, Ward; Rathore, Nisha; Hansen, David V; Tessier-Lavigne, Marc; Mayeux, Richard; Pericak-Vance, Margaret; Haines, Jonathan; Farrer, Lindsay A; Schellenberg, Gerard D; Goate, Alison; Behrens, Timothy W; Cruchaga, Carlos; Watts, Ryan J; Graham, Robert R

    2014-12-01

    We have identified a rare coding mutation, T835M (rs137875858), in the UNC5C netrin receptor gene that segregated with disease in an autosomal dominant pattern in two families enriched for late-onset Alzheimer's disease and that was associated with disease across four large case-control cohorts (odds ratio = 2.15, Pmeta = 0.0095). T835M alters a conserved residue in the hinge region of UNC5C, and in vitro studies demonstrate that this mutation leads to increased cell death in human HEK293T cells and in rodent neurons. Furthermore, neurons expressing T835M UNC5C are more susceptible to cell death from multiple neurotoxic stimuli, including β-amyloid (Aβ), glutamate and staurosporine. On the basis of these data and the enriched hippocampal expression of UNC5C in the adult nervous system, we propose that one possible mechanism in which T835M UNC5C contributes to the risk of Alzheimer's disease is by increasing susceptibility to neuronal cell death, particularly in vulnerable regions of the Alzheimer's disease brain. PMID:25419706

  7. Alzheimer disease

    MedlinePlus

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

  8. 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.

  9. Association between the TNFalpha-308 A/G polymorphism and the onset-age of Alzheimer disease.

    PubMed

    Alvarez, Victoria; Mata, Ignacio F; González, Pelayo; Lahoz, Carlos H; Martínez, Carmen; Peña, Joaquín; Guisasola, Luis M; Coto, Eliecer

    2002-07-01

    Local inflammatory processes associated with amyloid plaques would contribute to the progression of late-onset Alzheimer disease (LOAD). Tumor necrosis factors alpha (TNF(alpha)) and beta (LT(alpha)) are inflammatory cytokines involved in the local immune response occurring in the central nervous system of LOAD patients. Genetic variation at these genes could contribute to the risk of developing AD or influence the age at the onset of the disease. We genotyped 315 LOAD patients and 400 healthy controls for DNA-polymorphisms in the genes encoding TNF(alpha) (-308 G/A, -238G/A) and LT(alpha) (Asn26Thr). Carriers of -308A showed a mean age at onset 3 years younger than noncarriers of this allele (P = 0.019). Our data suggest an effect of the TNF(alpha)-308 polymorphism on the age at onset of late AD. This represents additional evidence of the importance of genetic variation at the proinflammatory components in the origin and progression of this common neurodegenerative disease.

  10. APOE and APOC1 gene polymorphisms are associated with cognitive impairment progression in Chinese patients with late-onset Alzheimer's disease

    PubMed Central

    Zhou, Qin; Peng, Dantao; Yuan, Xinrui; Lv, Zeping; Pang, Shenghang; Jiang, Wenyu; Yang, Chuyu; Shi, Xiaohong; Pang, Guofang; Yang, Yige; Xie, Haiqun; Zhang, Wandong; Hu, Caiyou; Yang, Ze

    2014-01-01

    Current evidence shows that apolipoprotein E (APOE), apolipoprotein CI (APOC1) and low density lipoprotein receptor-related protein (LRP) variations are related to late-onset Alzheimer's disease. However, it remains unclear if genetic polymorphisms in these genes are associated with cognitive decline in late-onset Alzheimer's disease patients. We performed a 30-month longitudinal cohort study to investigate the relationship between Alzheimer's disease and APOE, APOC1, and LRP. In this study, 78 Chinese Han patients with late-onset Alzheimer's disease were recruited form Guangxi Zhuang Autonomous Region in China. APOE, APOC1, and LRP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphisms. The Mini-Mental State Examination and Clinical Dementia Rating Scale were used to assess patients’ cognitive function. After a 30-month follow-up period, we found a significant reduction in Mini-Mental State Examination total score, a higher proportion of patients fulfilling cognitive impairment progression criteria, and a higher proportion of APOC1 H2 carriers in APOE ε4 carriers compared with non-carriers. In addition, the APOE ε4 allele frequency was significantly higher in the cognitive impairment progression group compared with the non-cognitive impairment progression group. In conclusion, APOE ε4 plays an important role in augmenting cognitive decline, and APOC1 H2 may act synergistically with APOE ε4 in increasing the risk of cognitive decline in Chinese patients with late-onset Alzheimer's disease. PMID:25206869

  11. Loss of functional connectivity is greater outside the default mode network in nonfamilial early-onset Alzheimer's disease variants.

    PubMed

    Lehmann, Manja; Madison, Cindee; Ghosh, Pia M; Miller, Zachary A; Greicius, Michael D; Kramer, Joel H; Coppola, Giovanni; Miller, Bruce L; Jagust, William J; Gorno-Tempini, Maria L; Seeley, William W; Rabinovici, Gil D

    2015-10-01

    The common and specific involvement of brain networks in clinical variants of Alzheimer's disease (AD) is not well understood. We performed task-free ("resting-state") functional imaging in 60 nonfamilial AD patients, including 20 early-onset AD (age at onset <65 years, amnestic/dysexecutive deficits), 24 logopenic aphasia (language deficits), and 16 posterior cortical atrophy patients (visual deficits), as well as 60 healthy controls. Seed-based connectivity analyses were conducted to assess differences between groups in 3 default mode network (DMN) components (anterior, posterior, and ventral) and 4 additional non-DMN networks: left and right executive-control, language, and higher visual networks. Significant decreases in connectivity were found across AD variants compared with controls in the non-DMN networks. Within the DMN components, patients showed higher connectivity in the anterior DMN, in particular in logopenic aphasia. No significant differences were found for the posterior and ventral DMN. Our findings suggest that loss of functional connectivity is greatest in networks outside the DMN in early-onset and nonamnestic AD variants and may thus be a better biomarker in these patients. PMID:26242705

  12. 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.

  13. Thyroid status in senile dementia of the Alzheimer type (SDAT).

    PubMed

    Thomas, D R; Hailwood, R; Harris, B; Williams, P A; Scanlon, M F; John, R

    1987-08-01

    Thyroid function was investigated in a group of 21 patients with severe senile dementia of the Alzheimer type (SDAT) and in a group of 17 age and sex matched normal controls. Free thyroid hormone levels (triiodothyronine (T3) and thyroxine (T4) were measured, as were also the thyrotrophin (TSH), prolactin (PRL) and growth hormone (GH) responses to thyrotrophin releasing hormone (TRH)). When compared to controls, patients demonstrated a significantly lower free T3 value (but not free T4), a blunted TSH response to TRH, slightly elevated basal PRL and GH values and a small GH response to TRH. However, all differences were small in biological terms and were within the laboratory's normal range. This emphasizes the relative normality of neuroendocrine function, particularly thyroid status, in SDAT.

  14. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis.

    PubMed

    Iturria-Medina, Y; Sotero, R C; Toussaint, P J; Mateos-Pérez, J M; Evans, A C

    2016-01-01

    Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD-abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions. PMID:27327500

  15. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis.

    PubMed

    Iturria-Medina, Y; Sotero, R C; Toussaint, P J; Mateos-Pérez, J M; Evans, A C

    2016-06-21

    Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD-abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

  16. 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

  17. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis

    PubMed Central

    Iturria-Medina, Y.; Sotero, R. C.; Toussaint, P. J.; Mateos-Pérez, J. M.; Evans, A. C.; Weiner, Michael W.; Aisen, Paul; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowki, John Q.; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Saykin, Andrew J.; Morris, John; Shaw, Leslie M.; Khachaturian, Zaven; Sorensen, Greg; Kuller, Lew; Raichle, Marc; Paul, Steven; Davies, Peter; Fillit, Howard; Hefti, Franz; Holtzman, Davie; Mesulam, M Marcel; Potter, William; Snyder, Peter; Schwartz, Adam; Montine, Tom; Thomas, Ronald G.; Donohue, Michael; Walter, Sarah; Gessert, Devon; Sather, Tamie; Jiminez, Gus; Harvey, Danielle; Bernstein, Matthew; Fox, Nick; Thompson, Paul; Schuff, Norbert; Borowski, Bret; Gunter, Jeff; Senjem, Matt; Vemuri, Prashanthi; Jones, David; Kantarci, Kejal; Ward, Chad; Koeppe, Robert A.; Foster, Norm; Reiman, Eric M.; Chen, Kewei; Mathis, Chet; Landau, Susan; Cairns, Nigel J.; Householder, Erin; Taylor-Reinwald, Lisa; Lee, Virginia; Korecka, Magdalena; Figurski, Michal; Crawford, Karen; Neu, Scott; Foroud, Tatiana M.; Potkin, Steven; Shen, Li; Faber, Kelley; Kim, Sungeun; Nho, Kwangsik; Thal, Leon; Buckholtz, Neil; Albert, Marylyn; Frank, Richard; Hsiao, John; Kaye, Jeffrey; Quinn, Joseph; Lind, Betty; Carter, Raina; Dolen, Sara; Schneider, Lon S.; Pawluczyk, Sonia; Beccera, Mauricio; Teodoro, Liberty; Spann, Bryan M.; Brewer, James; Vanderswag, Helen; Fleisher, Adam; Heidebrink, Judith L.; Lord, Joanne L.; Mason, Sara S.; Albers, Colleen S.; Knopman, David; Johnson, Kris; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Rountree, Susan; Dang, Mimi; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Ances, Beau; Carroll, Maria; Leon, Sue; Mintun, Mark A.; Schneider, Stacy; Oliver, Angela; Marson, Daniel; Griffith, Randall; Clark, David; Geldmacher, David; Brockington, John; Roberson, Erik; Grossman, Hillel; Mitsis, Effie; de Toledo-Morrell, Leyla; Shah, Raj C.; Duara, Ranjan; Varon, Daniel; Greig, Maria T.; Roberts, Peggy; Albert, Marilyn; Onyike, Chiadi; D'Agostino, Daniel; Kielb, Stephanie; Galvin, James E.; Cerbone, Brittany; Michel, Christina A.; Rusinek, Henry; de Leon, Mony J.; Glodzik, Lidia; De Santi, Susan; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Wong, Terence Z.; Arnold, Steven E.; Karlawish, Jason H.; Wolk, David; Smith, Charles D.; Jicha, Greg; Hardy, Peter; Sinha, Partha; Oates, Elizabeth; Conrad, Gary; Lopez, Oscar L.; Oakley, MaryAnn; Simpson, Donna M.; Porsteinsson, Anton P.; Goldstein, Bonnie S.; Martin, Kim; Makino, Kelly M.; Ismail, M. Saleem; Brand, Connie; Mulnard, Ruth A.; Thai, Gaby; Mc-Adams-Ortiz, Catherine; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Diaz-Arrastia, Ramon; King, Richard; Weiner, Myron; Martin-Cook, Kristen; DeVous, Michael; Levey, Allan I.; Lah, James J.; Cellar, Janet S.; Burns, Jeffrey M.; Anderson, Heather S.; Swerdlow, Russell H.; Apostolova, Liana; Tingus, Kathleen; Woo, Ellen; Silverman, Daniel H. S.; Lu, Po H.; Bartzokis, George; Graff-Radford, Neill R.; Parfitt, Francine; Kendall, Tracy; Johnson, Heather; Farlow, Martin R.; Hake, AnnMarie; Matthews, Brandy R.; Herring, Scott; Hunt, Cynthia; van Dyck, Christopher H.; Carson, Richard E.; MacAvoy, Martha G.; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Stefanovic, Bojana; Caldwell, Curtis; Hsiung, Ging-Yuek Robin; Feldman, Howard; Mudge, Benita; Assaly, Michele; Kertesz, Andrew; Rogers, John; Bernick, Charles; Munic, Donna; Kerwin, Diana; Mesulam, Marek-Marsel; Lipowski, Kristine; Wu, Chuang-Kuo; Johnson, Nancy; Sadowsky, Carl; Martinez, Walter; Villena, Teresa; Turner, Raymond Scott; Johnson, Kathleen; Reynolds, Brigid; Sperling, Reisa A.; Johnson, Keith A.; Marshall, Gad; Frey, Meghan; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Sabbagh, Marwan N.; Belden, Christine M.; Jacobson, Sandra A.; Sirrel, Sherye A.; Kowall, Neil; Killiany, Ronald; Budson, Andrew E.; Norbash, Alexander; Johnson, Patricia Lynn; Allard, Joanne; Lerner, Alan; Ogrocki, Paula; Hudson, Leon; Fletcher, Evan; Carmichael, Owen; Olichney, John; DeCarli, Charles; Kittur, Smita; Borrie, Michael; Lee, T-Y; Bartha, Rob; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M.; Potkin, Steven G.; Preda, Adrian; Nguyen, Dana; Tariot, Pierre; Reeder, Stephanie; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Scharre, Douglas W.; Kataki, Maria; Adeli, Anahita; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Pearlson, Godfrey D.; Blank, Karen; Anderson, Karen; Santulli, Robert B.; Kitzmiller, Tamar J.; Schwartz, Eben S.; Sink, Kaycee M.; Williamson, Jeff D.; Garg, Pradeep; Watkins, Franklin; Ott, Brian R.; Querfurth, Henry; Tremont, Geoffrey; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Rosen, Howard J.; Miller, Bruce L.; Mintzer, Jacobo; Spicer, Kenneth; Bachman, David; Finger, Elizabether; Pasternak, Stephen; Rachinsky, Irina; Drost, Dick; Pomara, Nunzio; Hernando, Raymundo; Sarrael, Antero; Schultz, Susan K.; Ponto, Laura L. Boles; Shim, Hyungsub; Smith, Karen Elizabeth; Relkin, Norman; Chaing, Gloria; Raudin, Lisa; Smith, Amanda; Fargher, Kristin; Raj, Balebail Ashok; Neylan, Thomas; Grafman, Jordan; Davis, Melissa; Morrison, Rosemary; Hayes, Jacqueline; Finley, Shannon; Friedl, Karl; Fleischman, Debra; Arfanakis, Konstantinos; James, Olga; Massoglia, Dino; Fruehling, J. Jay; Harding, Sandra; Peskind, Elaine R.; Petrie, Eric C.; Li, Gail; Yesavage, Jerome A.; Taylor, Joy L.; Furst, Ansgar J.

    2016-01-01

    Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions. PMID:27327500

  18. 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.

  19. 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.

  20. Early-onset Alzheimer's disease versus frontotemporal dementia: resolution with genetic diagnoses?

    PubMed

    Sha, Sharon J; Khazenzon, Anna M; Ghosh, Pia M; Rankin, Katherine P; Pribadi, Mochtar; Coppola, Giovanni; Geschwind, Daniel H; Rabinovici, Gil D; Miller, Bruce L; Lee, Suzee E

    2016-01-01

    We report a diagnostically challenging case of a 64-year-old man with a history of remote head trauma who developed mild behavioral changes and dyscalculia. He was diagnosed with clinical Alzheimer's disease (AD), with additional features consistent with behavioral variant frontotemporal dementia. Structural magnetic resonance imaging revealed atrophy in bilateral frontal and parietal cortices and hippocampi on visual inspection and left frontal pole and bilateral anterior temporal encephalomalacia, suspected to be due to head trauma. Consistent with the diagnosis of Alzheimer's pathology, positron emission tomography (PET) with Pittsburgh compound B suggested the presence of beta-amyloid. Fluorodeoxyglucose PET demonstrated hypometabolism in bilateral frontal and temporoparietal cortices. Voxel-based morphometry showed atrophy predominant in ventral frontal regions (bilateral orbitofrontal cortex, pregenual anterior cingulate/medial superior frontal gyrus), bilateral mid cingulate, bilateral lateral temporal cortex, and posterior insula. Bilateral caudate, thalamus, hippocampi, and cerebellum were prominently atrophied. Unexpectedly, a pathologic hexanucleotide repeat expansion in C9ORF72 was identified in this patient. This report underscores the clinical variability in C9ORF72 expansion carriers and the need to consider mixed pathologies, particularly when imaging studies are inconsistent with a single syndrome or pathology.

  1. 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, PFDR = 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, PFDR = 0.1832) and EXOC2 (rs17136239, P = 0.0325, PFDR = 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

  2. Identification of PSEN2 mutation p.N141I in Argentine pedigrees with early-onset familial Alzheimer's disease.

    PubMed

    Muchnik, Carolina; Olivar, Natividad; Dalmasso, María Carolina; Azurmendi, Pablo Javier; Liberczuk, Cynthia; Morelli, Laura; Brusco, Luis Ignacio

    2015-10-01

    Presenilin 2 gene (PSEN2) mutations account for <5% of all early-onset familial Alzheimer's disease (EOFAD) cases and only 13 have strong evidence for pathogenicity. We aimed to investigate the presence of PSEN2 mutation p.N141I and characterize the clinical phenotypes in 2 Argentine pedigrees (AR2 and AR3) with clinical symptoms of EOFAD. Detailed clinical assessments and genetic screening for PSEN2 and APOE genes were carried out in 19 individuals of AR2 and AR3 families. The p.N141I mutation was identified in all affected subjects and was associated with prominent early onset, rapidly progressive dementia, neurologic, and behavioral symptoms. AR2 and AR3 families share the same Volga German ancestry as all the families reported presenting this mutation. To our knowledge, this is the first report of PSEN2 mutation p.N141I in Argentina and even more, in South America. Our contribution increases the total number of described families carrying this mutation and help to improve the characterization of clinical phenotype in EOFAD associated to PSEN2 mutations.

  3. 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.

  4. Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease

    PubMed Central

    Kohli, Martin A.; Cukier, Holly N.; Hamilton-Nelson, Kara L.; Rolati, Sophie; Kunkle, Brian W.; Whitehead, Patrice L.; Züchner, Stephan L.; Farrer, Lindsay A.; Martin, Eden R.; Beecham, Gary W.; Haines, Jonathan L.; Vance, Jeffery M.; Cuccaro, Michael L.; Gilbert, John R.; Schellenberg, Gerard D.; Carney, Regina M.

    2016-01-01

    Objective: The genetic risk architecture of Alzheimer disease (AD) is complex with single pathogenic mutations leading to early-onset AD, while both rare and common genetic susceptibility variants contribute to the more widespread late-onset AD (LOAD); we sought to discover novel genes contributing to LOAD risk. Methods: Whole-exome sequencing and genome-wide genotyping were performed on 11 affected individuals in an extended family with an apparent autosomal dominant pattern of LOAD. Variants of interest were then evaluated in a large cohort of LOAD cases and aged controls. Results: We detected a single rare, nonsynonymous variant shared in all 11 LOAD individuals, a missense change in the tetratricopeptide repeat domain 3 (TTC3) gene. The missense variant, rs377155188 (p.S1038C), is predicted to be damaging. Affecteds-only multipoint linkage analysis demonstrated that this region of TTC3 has a LOD score of 2.66 in this family. Conclusion: The TTC3 p.S1038C substitution may represent a segregating, rare LOAD risk variant. Previous studies have shown that TTC3 expression is consistently reduced in LOAD patients and negatively correlated with AD neuropathology and that TTC3 is a regulator of Akt signaling, a key pathway disrupted in LOAD. This study demonstrates how utilizing whole-exome sequencing in a large, multigenerational family with a high incidence of LOAD could reveal a novel candidate gene. PMID:27066578

  5. 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.

  6. 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. PMID:26531229

  7. 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.

  8. [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. PMID:27395469

  9. Increased fibrillar amyloid-{beta} burden in normal individuals with a family history of late-onset Alzheimer's.

    PubMed

    Mosconi, Lisa; Rinne, Juha O; Tsui, Wai H; Berti, Valentina; Li, Yi; Wang, Huiyu; Murray, John; Scheinin, Noora; Någren, Kjell; Williams, Schantel; Glodzik, Lidia; De Santi, Susan; Vallabhajosula, Shankar; de Leon, Mony J

    2010-03-30

    Having a parent affected with late-onset Alzheimer's disease (LOAD) is a major risk factor among cognitively normal (NL) individuals. This (11)C-Pittsburgh Compound B (PiB)-PET study examines whether NL individuals with LOAD parents show increased fibrillar amyloid-beta (Abeta) deposition, a hallmark of Alzheimer's disease (AD) pathology and whether there are parent-of-origin effects. Forty-two 50- to 80-year-old NL persons were examined with PiB-PET. These individuals included 14 NL subjects with a maternal family history (FH) of LOAD (FHm), 14 NL subjects with a paternal FH (FHp), and 14 NL subjects with a negative family history of any dementia (FH-). Statistical parametric mapping and automated regions-of-interest were used to compare cerebral-to-cerebellar PiB standardized uptake value ratios, reflecting fibrillar Abeta burden, across groups. FH groups did not differ in age, gender, education, and apolipoprotein E (ApoE) status. NL FHm subjects showed higher PiB retention in AD-affected anterior and posterior cingulate cortex (PCC), precuneus, parietal, temporal, occipital, and frontal cortices, right basal ganglia, and thalamus, compared with FH- and FHp subjects. FHp subjects showed increased PiB retention in the PCC and frontal cortex, intermediate between FHm and FH- subjects. Results remained significant after controlling for age, gender, education, and ApoE status. Children of parents with LOAD, particularly those with affected mothers, have increased fibrillar Abeta load in AD-vulnerable regions compared with controls, perhaps accounting for the known increased risk for AD. Present findings may motivate further research on familial transmission and parent-of-origin effects in LOAD.

  10. "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

  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. 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.

  13. 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.

  14. 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. PMID:27036079

  15. 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.

  16. Onset of type 1 diabetes mellitus in two patients with maturity onset diabetes of the young.

    PubMed

    Maltoni, Giulio; Zucchini, Stefano; Scipione, Mirella; Mantovani, Vilma; Salardi, Silvana; Cicognani, Alessandro

    2012-03-01

    The association between maturity onset diabetes of the young (MODY) and type 1 diabetes mellitus (T1DM) has been rarely described. We report two patients affected by MODY who developed T1DM. Case 1: a 4-yr-old girl referred for glycosuria presented hemoglobin A1c (HbA1c) of 6.6%. Islet cell antibodies (ICA) and anti-glutamic acid decarboxylase (GADA) were initially negative. As her father, uncle and grandmother showed mild hyperglycemia, they were screened for MODY 2. A novel mutation in glucokinase gene was found in the family. Few months later, her glycemic control worsened consistently and she required insulin treatment. A high titer of GADA and ICA was then detected. Six years afterwards insulin requirement is 0.8 U/kg and HbA1c 6.7%. Case 2: a 15-yr-old boy treated for growth hormone deficiency was found with a blood glucose level of 106 mg/dL. HbA1c was 7.2%, ICA and GADA were negative. Family history was positive for autoimmune diseases and type 2 diabetes mellitus. The patient was investigated for MODY 2 and MODY 3, and a mutation of hepatocyte nuclear factor-1 alpha gene was found. The same mutation was found in the mother who had never been referred for hyperglycemia. After 1 yr, due to an unjustified worsening of the metabolic control, autoimmunity was again investigated and a mild positivity was found. He then required insulin therapy and after 5 yr current HbA1c was 8.2%. The diagnosis of MODY does not exclude the risk of developing T1DM. Therefore autoimmunity should be investigated when ordinary treatments fail and metabolic control unexpectedly worsens.

  17. 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.

  18. [Estimation of the risk of Alzheimer type dementia based on "Prognostic Questionnaire"].

    PubMed

    Bidzan, Leszek; Bidzan, Mariola

    2002-01-01

    The aim of undertaken studies was verification of usefulness of "Prognostic Questionnaire" for estimations of risk of Alzheimer type dementia. In support for own base were included 286 persons, which were investigated by scales creating of "Prognostic Questionnaire" in years 1991-1993. From among 286 persons originally classified to renewed study one surrendered 163 persons. Result in investigation MMSE equal or lower from 25 points was base to removal full psychiatric investigations which had in view recognition of Alzheimer type dementia or its exclusion. Possible Alzheimer disease were recognized at 23 persons. Sensitivity and specificity for "Prognostic Questionnaire" obtained for several critical values were marked. The study showed usefulness of joint interpretation of results of several clinical scales creating "Prognostic Questionnaire" for estimations of risk of Alzheimer type dementia. PMID:12647439

  19. 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

  20. A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease.

    PubMed

    Verheijen, Jan; Van den Bossche, Tobi; van der Zee, Julie; Engelborghs, Sebastiaan; Sanchez-Valle, Raquel; Lladó, Albert; Graff, Caroline; Thonberg, Håkan; Pastor, Pau; Ortega-Cubero, Sara; Pastor, Maria A; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Clarimon, Jordi; Lleó, Alberto; Fortea, Juan; de Mendonça, Alexandre; Martins, Madalena; Grau-Rivera, Oriol; Gelpi, Ellen; Bettens, Karolien; Mateiu, Ligia; Dillen, Lubina; Cras, Patrick; De Deyn, Peter P; Van Broeckhoven, Christine; Sleegers, Kristel

    2016-08-01

    The sortilin-related receptor 1 (SORL1) gene has been associated with increased risk for Alzheimer's disease (AD). Rare genetic variants in the SORL1 gene have also been implicated in autosomal dominant early-onset AD (EOAD). Here we report a large-scale investigation of the contribution of genetic variability in SORL1 to EOAD in a European EOAD cohort. We performed massive parallel amplicon-based re-sequencing of the full coding region of SORL1 in 1255 EOAD patients and 1938 age- and origin-matched control individuals in the context of the European Early-Onset Dementia (EOD) consortium, originating from Belgium, Spain, Portugal, Italy, Sweden, Germany, and Czech Republic. We identified six frameshift variants and two nonsense variants that were exclusively present in patients. These mutations are predicted to result in haploinsufficiency through nonsense-mediated mRNA decay, which could be confirmed experimentally for SORL1 p.Gly447Argfs*22 observed in a Belgian EOAD patient. We observed a 1.5-fold enrichment of rare non-synonymous variants in patients (carrier frequency 8.8 %; SkatOMeta p value 0.0001). Of the 84 non-synonymous rare variants detected in the full patient/control cohort, 36 were only detected in patients. Our findings underscore a role of rare SORL1 variants in EOAD, but also show a non-negligible frequency of these variants in healthy individuals, necessitating the need for pathogenicity assays. Premature stop codons due to frameshift and nonsense variants, have so far exclusively been found in patients, and their predicted mode of action corresponds with evidence from in vitro functional studies of SORL1 in AD. PMID:27026413

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

    PubMed

    Vélez, Jorge I; Rivera, Dora; Mastronardi, Claudio A; Patel, Hardip R; Tobón, Carlos; Villegas, Andrés; Cai, Yeping; Easteal, Simon; Lopera, Francisco; 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

  2. A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease.

    PubMed

    Verheijen, Jan; Van den Bossche, Tobi; van der Zee, Julie; Engelborghs, Sebastiaan; Sanchez-Valle, Raquel; Lladó, Albert; Graff, Caroline; Thonberg, Håkan; Pastor, Pau; Ortega-Cubero, Sara; Pastor, Maria A; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Clarimon, Jordi; Lleó, Alberto; Fortea, Juan; de Mendonça, Alexandre; Martins, Madalena; Grau-Rivera, Oriol; Gelpi, Ellen; Bettens, Karolien; Mateiu, Ligia; Dillen, Lubina; Cras, Patrick; De Deyn, Peter P; Van Broeckhoven, Christine; Sleegers, Kristel

    2016-08-01

    The sortilin-related receptor 1 (SORL1) gene has been associated with increased risk for Alzheimer's disease (AD). Rare genetic variants in the SORL1 gene have also been implicated in autosomal dominant early-onset AD (EOAD). Here we report a large-scale investigation of the contribution of genetic variability in SORL1 to EOAD in a European EOAD cohort. We performed massive parallel amplicon-based re-sequencing of the full coding region of SORL1 in 1255 EOAD patients and 1938 age- and origin-matched control individuals in the context of the European Early-Onset Dementia (EOD) consortium, originating from Belgium, Spain, Portugal, Italy, Sweden, Germany, and Czech Republic. We identified six frameshift variants and two nonsense variants that were exclusively present in patients. These mutations are predicted to result in haploinsufficiency through nonsense-mediated mRNA decay, which could be confirmed experimentally for SORL1 p.Gly447Argfs*22 observed in a Belgian EOAD patient. We observed a 1.5-fold enrichment of rare non-synonymous variants in patients (carrier frequency 8.8 %; SkatOMeta p value 0.0001). Of the 84 non-synonymous rare variants detected in the full patient/control cohort, 36 were only detected in patients. Our findings underscore a role of rare SORL1 variants in EOAD, but also show a non-negligible frequency of these variants in healthy individuals, necessitating the need for pathogenicity assays. Premature stop codons due to frameshift and nonsense variants, have so far exclusively been found in patients, and their predicted mode of action corresponds with evidence from in vitro functional studies of SORL1 in AD.

  3. 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

  4. 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

    2013-12-01

    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.

  5. An association study of the cholesteryl ester transfer protein TaqI B polymorphism with late onset Alzheimer's disease.

    PubMed

    Fidani, Liana; Goulas, Antonis; Crook, Richard; Petersen, Ronald C; Tangalos, Eric; Kotsis, Alexandros; Hardy, John

    2004-03-01

    Cholesteryl ester transfer protein (CETP) is reportedly able to affect the amount of cholesterol available for deposition and/or removal from peripheral tissues, in its capacity to mediate the transfer of cholesterol from high density lipoprotein (HDL) to very low density lipoprotein, in exchange for triacylglycerols from the latter. The TaqI B polymorphism of the human CETP gene has been associated with decreased CETP mass and an increase in HDL-cholesterol. While many studies have addressed the atherogenic or anti-atherogenic potential of this polymorphism, little is known about its effect on neurodegeneration, despite the fact that CETP is expressed in the brain and the disturbance of cholesterol homeostasis appears to be an important factor in the pathogenesis of Alzheimer's disease (AD). In this report, we have compared the distribution of the TaqI B polymorphism in an independent population of 102 clinically diagnosed late onset AD patients and a spousal control group of 97 individuals. We have also examined the possible interaction between this polymorphism and two other polymorphisms suspected of affecting cholesterol flux, namely apolipoprotein E APOE epsilon4, and lipoprotein lipase LPLS447X. No statistically significant differences have emerged with respect to either genotype or allele frequencies between the AD and control populations. CETP TaqI B did not interact significantly with either APOE epsilon4 or LPLS447X, in this study.

  6. Clinical Genetics of Alzheimer's Disease

    PubMed Central

    Zou, Zhangyu; Liu, Changyun; Che, Chunhui; Huang, Huapin

    2014-01-01

    Alzheimer's disease (AD) is the most common progressive neurodegenerative disease and the most common form of dementia in the elderly. It is a complex disorder with environmental and genetic components. There are two major types of AD, early onset and the more common late onset. The genetics of early-onset AD are largely understood with mutations in three different genes leading to the disease. In contrast, while susceptibility loci and alleles associated with late-onset AD have been identified using genetic 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 AD, the clinical features of EOAD according to genotypes, and the clinical implications of the genetics of AD. PMID:24955352

  7. 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.

  8. Environmental enrichment delays the onset of memory deficits and reduces neuropathological hallmarks in a mouse model of Alzheimer-like neurodegeneration.

    PubMed

    Berardi, Nicoletta; Braschi, Chiara; Capsoni, Simona; Cattaneo, Antonino; Maffei, Lamberto

    2007-06-01

    Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive memory deficits and cognitive decline. We explored the possibility that Environmental Enrichment (EE) may reduce the disease progression in a comprehensive mouse model for AD like neurodegeneration, the AD11 mice. AD11 mice, which express anti nerve growth factor (NGF) antibodies, develop an age dependent neurodegeneration which encompasses all hallmarks of human AD. We have tested the efficacy of EE starting from 2 months of age, that is before the onset of behavioural deficits in AD11 mice. At 7 months of age, visual recognition memory was tested with the Object Recognition Test (ORT), spatial memory with the Morris Water Maze (MWM) and the presence of AD pathological hallmarks (Abeta clusters, presence of hyperphosphorylated tau and cholinergic deficit) was assessed immunohistochemically. We found that in AD11 mice exposed to EE from 2 to 7 months of age performance in both memory tests was significantly better than in non EE AD11 mice and indistinguishable from that in wild-type mice of the same age. Exposure to EE from 2 to 7 months significantly reduce the appearance of AD neuropathological hallmarks. A group of AD11 mice was tested also at 12 months of age: we found that 12 months old AD11 mice exposed to EE from 2 to 7 months of age performed significantly better than non EE AD11 mice of the same age and did not differ from 12 months old wt mice. Thus, EE is able to prevent the onset of memory deficits up to at least 12 months of age and to restrain the progression of neurodegeneration in a mouse model of AD.

  9. Genetic variants influencing human aging from late-onset Alzheimer's disease (LOAD) genome-wide association studies (GWAS).

    PubMed

    Shi, Hui; Belbin, Olivia; Medway, Christopher; Brown, Kristelle; Kalsheker, Noor; Carrasquillo, Minerva; Proitsi, Petroula; Powell, John; Lovestone, Simon; Goate, Alison; Younkin, Steven; Passmore, Peter; Morgan, Kevin

    2012-08-01

    Genetics plays a crucial role in human aging with up to 30% of those living to the mid-80s being determined by genetic variation. Survival to older ages likely entails an even greater genetic contribution. There is increasing evidence that genes implicated in age-related diseases, such as cancer and neuronal disease, play a role in affecting human life span. We have selected the 10 most promising late-onset Alzheimer's disease (LOAD) susceptibility genes identified through several recent large genome-wide association studies (GWAS). These 10 LOAD genes (APOE, CLU, PICALM, CR1, BIN1, ABCA7, MS4A6A, CD33, CD2AP, and EPHA1) have been tested for association with human aging in our dataset (1385 samples with documented age at death [AAD], age range: 58-108 years; mean age at death: 80.2) using the most significant single nucleotide polymorphisms (SNPs) found in the previous studies. Apart from the APOE locus (rs2075650) which showed compelling evidence of association with risk on human life span (p = 5.27 × 10(-4)), none of the other LOAD gene loci demonstrated significant evidence of association. In addition to examining the known LOAD genes, we carried out analyses using age at death as a quantitative trait. No genome-wide significant SNPs were discovered. Increasing sample size and statistical power will be imperative to detect genuine aging-associated variants in the future. In this report, we also discuss issues relating to the analysis of genome-wide association studies data from different centers and the bioinformatic approach required to distinguish spurious genome-wide significant signals from real SNP associations.

  10. Brain Serotonergic and Noradrenergic Deficiencies in Behavioral Variant Frontotemporal Dementia Compared to Early-Onset Alzheimer's Disease.

    PubMed

    Vermeiren, Yannick; Janssens, Jana; Aerts, Tony; Martin, Jean-Jacques; Sieben, Anne; Van Dam, Debby; De Deyn, Peter P

    2016-06-15

    Routinely prescribed psychoactive drugs in behavioral variant frontotemporal dementia (FTD) for improvement of (non)cognitive symptoms are primarily based on monoamine replacement or augmentation strategies. These were, however, initially intended to symptomatically treat other degenerative, behavioral, or personality disorders, and thus lack disease specificity. Moreover, current knowledge on brain monoaminergic neurotransmitter deficiencies in this presenile disorder is scarce, particularly with reference to changes in Alzheimer's disease (AD). The latter hence favors neurochemical comparison studies in order to elucidate the monoaminergic underpinnings of FTD compared to early-onset AD, which may contribute to better pharmacotherapy. Therefore, frozen brain samples, i.e., Brodmann area (BA) 6/8/9/10/11/12/22/24/46, amygdala, and hippocampus, of 10 neuropathologically confirmed FTD, AD, and control subjects were analyzed by means of reversed-phase high-performance liquid chromatography. Levels of serotonergic, dopaminergic, and noradrenergic compounds were measured. In nine brain areas, serotonin (5-HT) concentrations were significantly increased in FTD compared to AD patients, while 5-hydroxyindoleacetic acid/5-HT ratios were decreased in eight regions, also compared to controls. Furthermore, in all regions, noradrenaline (NA) levels were significantly higher, and 3-methoxy-4-hydroxyphenylglycol/NA ratios were significantly lower in FTD than in AD and controls. Contrarily, significantly higher dopamine (DA) levels and reduced homovanillic acid/DA ratios were only found in BA12 and BA46. Results indicate that FTD is defined by distinct serotonergic and noradrenergic deficiencies. Additional research regarding the interactions between both monoaminergic networks is required. Similarly, clinical trials investigating the effects of 5-HT1A receptor antagonists or NA-modulating agents, such as α1/2/β1-blockers, seem to have a rationale and should be considered. PMID

  11. Alzheimer's disease and CADASIL are heritable, adult-onset dementias that both involve damaged small blood vessels.

    PubMed

    Marchesi, Vincent T

    2014-03-01

    This essay explores an alternative pathway to Alzheimer's dementia that focuses on damage to small blood vessels rather than late-stage toxic amyloid deposits as the primary pathogenic mechanism that leads to irreversible dementia. While the end-stage pathology of AD is well known, the pathogenic processes that lead to disease are often assumed to be due to toxic amyloid peptides that act on neurons, leading to neuronal dysfunction and eventually neuronal cell death. Speculations as to what initiates the pathogenic cascade have included toxic abeta peptide aggregates, oxidative damage, and inflammation, but none explain why neurons die. Recent high-resolution NMR studies of living patients show that lesions in white matter regions of the brain precede the appearance of amyloid deposits and are correlated with damaged small blood vessels. To appreciate the pathogenic potential of damaged small blood vessels in the brain, it is useful to consider the clinical course and the pathogenesis of CADASIL, a heritable arteriopathy that leads to damaged small blood vessels and irreversible dementia. CADASIL is strikingly similar to early onset AD in that it is caused by germ line mutations in NOTCH 3 that generate toxic protein aggregates similar to those attributed to mutant forms of the amyloid precursor protein and presenilin genes. Since NOTCH 3 mutants clearly damage small blood vessels of white matter regions of the brain that lead to dementia, we speculate that both forms of dementia may have a similar pathogenesis, which is to cause ischemic damage by blocking blood flow or by impeding the removal of toxic protein aggregates by retrograde vascular clearance mechanisms.

  12. Insulin-degrading enzyme: a link between Alzheimer's and type 2 diabetes mellitus.

    PubMed

    Haque, Rizwanul; Nazir, Aamir

    2014-03-01

    Enzymes play a very vital role in maintaining the homeostasis inside the body. Improper functioning of enzymes is associated with many diseases. Insulin-degrading enzyme (IDE), a ubiquitously expressed zinc metalloprotease, is believed to act as a junction point of Type 2 Diabetes and Alzheimer's disease. Recent studies provide inkling for the use of IDE as a potential target hence the design of its regulators would be a viable approach towards treatment of these diseases. This review provides an overview of the IDE structure and function; a relationship is drawn between IDE, Type 2 Diabetes mellitus and Alzheimer's disease and the approaches that make IDE a potential target, are discussed.

  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. 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

  15. 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

  16. 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.

  17. 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)

  18. Semantic Feature Knowledge and Picture Naming in Dementia of Alzheimer's Type: A New Approach

    ERIC Educational Resources Information Center

    Garrard, P.; Lambon Ralph, M.A.; Patterson, K.; Pratt, K.H.; Hodges, J.R.

    2005-01-01

    This study addresses continuing controversies concerning the nature of semantic impairment in early dementia of the Alzheimer type (DAT), and the relationship between conceptual knowledge and picture naming. A series of analyses of fine-grained feature knowledge data show that: (1) distinctive features of concepts were more vulnerable than shared;…

  19. Experimental Induction of Type 2 Diabetes in Aging-Accelerated Mice Triggered Alzheimer-Like Pathology and Memory Deficits

    PubMed Central

    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. PMID:24121970

  20. 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.

  1. Unrealistic Optimism, Sex, and Risk Perception of Type 2 Diabetes Onset: Implications for Education Programs

    PubMed Central

    Sealey-Potts, Claudia

    2015-01-01

    This study examined links among unrealistic optimism, sex, and risk perception of type 2 diabetes onset in college students. Participants included 660 college students who consented to complete a questionnaire. The results showed significant differences between students who perceived that they were at risk for type 2 diabetes onset and those who thought their peers were the ones at risk. A higher prevalence of participants thought their peers were the ones at risk for type 2 diabetes. Women were more likely than men to report a higher risk perception, indicating that their peers were at lower risk for diabetes onset. PMID:25717271

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

    PubMed

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

    2015-11-01

    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

  3. 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

  4. Early onset of hypersynchronous network activity and expression of a marker of chronic seizures in the Tg2576 mouse model of Alzheimer's disease.

    PubMed

    Bezzina, Charlotte; Verret, Laure; Juan, Cécile; Remaud, Jessica; Halley, Hélène; Rampon, Claire; Dahan, Lionel

    2015-01-01

    Cortical and hippocampal hypersynchrony of neuronal networks seems to be an early event in Alzheimer's disease pathogenesis. Many mouse models of the disease also present neuronal network hypersynchrony, as evidenced by higher susceptibility to pharmacologically-induced seizures, electroencephalographic seizures accompanied by spontaneous interictal spikes and expression of markers of chronic seizures such as neuropeptide Y ectopic expression in mossy fibers. This network hypersynchrony is thought to contribute to memory deficits, but whether it precedes the onset of memory deficits or not in mouse models remains unknown. The earliest memory impairments in the Tg2576 mouse model of Alzheimer's disease have been observed at 3 months of age. We thus assessed network hypersynchrony in Tg2576 and non-transgenic male mice at 1.5, 3 and 6 months of age. As soon as 1.5 months of age, Tg2576 mice presented higher seizure susceptibility to systemic injection of a GABAA receptor antagonist. They also displayed spontaneous interictal spikes on EEG recordings. Some Tg2576 mice presented hippocampal ectopic expression of neuropeptide Y which incidence seems to increase with age among the Tg2576 population. Our data reveal that network hypersynchrony appears very early in Tg2576 mice, before any demonstrated memory impairments. PMID:25768013

  5. Comprehensive analysis of APOE and selected proximate markers for late-onset Alzheimer's disease: patterns of linkage disequilibrium and disease/marker association.

    PubMed

    Yu, Chang-En; Seltman, Howard; Peskind, Elaine R; Galloway, Nichole; Zhou, Peter X; Rosenthal, Elisabeth; Wijsman, Ellen M; Tsuang, Debby W; Devlin, Bernie; Schellenberg, Gerard D

    2007-06-01

    The epsilon(4) allele of APOE confers a two- to fourfold increased risk for late-onset Alzheimer's disease (LOAD), but LOAD pathology does not all fit neatly around APOE. It is conceivable that genetic variation proximate to APOE contributes to LOAD risk. Therefore, we investigated the degree of linkage disequilibrium (LD) for a comprehensive set of 50 SNPs in and surrounding APOE using a substantial Caucasian sample of 1100 chromosomes. SNPs in APOE were further molecularly haplotyped to determine their phases. One set of SNPs in TOMM40, roughly 15 kb upstream of APOE, showed intriguing LD with the epsilon(4) allele and was strongly associated with the risk for developing LOAD. However, when all the SNPs were entered into a logit model, only the effect of APOE epsilon(4) remained significant. These observations diminish the possibility that loci in the TOMM40 gene may have a major effect on the risk for LOAD in Caucasians.

  6. 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

  7. 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.

  8. [The psychopathological pictures of the early stages of dementia syndromes (vasogenic and of Alzheimer's type)].

    PubMed

    Bidzan, L

    1998-01-01

    The goal of the research is to determine the early symptoms predicting dementia syndromes both Vasogenic and Alzheimer type. The investigations covered: 36 people without any psychopathological syndrome, 32 people with dementia of Alzheimer type and 36 people with vasogenic dementia. DSM IV criteria were accepted as a basis for recognition of dementia syndromes. The qualified patients underwent basic examination consisting of the following elements: AMDP scale (the estimation of psychic and somatic condition), Global Scale of Dementia, Hachinski scale, Blessed scale, Folsteins scale (MMS), Instrumental Activities of Daily Living, Physical self Maintenance Scale and two methods of the authors: Current Events Card and Prodromal Symptoms Card. On the basis of examinations the following conclusions can be stated:--persons in early stages of dementia differ from those without any symptoms of it by the occurrence of many psychopathological symptoms--not only connected with the cognitive sphere;--in the period preceding the development of dementia the frequency of occurrence of some symptoms is different according to etiology of the process (Alzheimer or vasogenic);--the applied clinical scales differ significantly in their value for the diagnosis and the estimation of intensification of dementia processes. PMID:9920996

  9. Discourse analysis of logical memory recall in normal aging and in dementia of the Alzheimer type.

    PubMed

    Johnson, David K; Storandt, Martha; Balota, David A

    2003-01-01

    This study examined the nature of errors in prose recall made in dementia compared with normal aging. Responses by 48 young adults, 47 nondemented older adults, and 70 people with very mild or mild Alzheimer's disease to the Logical Memory subtest of the Wechsler Memory Scale were examined in a propositional analysis. Compared with young adults, healthy older adults showed good immediate recall but deficits in retention over a delay. Demented individuals made errors of omission, not commission, at immediate recall. These errors probably reflect difficulty with attentional control rather than memory per se. In terms of clinical implications, veridical scoring of the Logical Memory subtest provides more sensitive detection of very mild dementia of the Alzheimer type than the current standard criteria for scoring. PMID:12597076

  10. [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?

  11. 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.

  12. Spotlight on rivastigmine transdermal patch: in dementia of the Alzheimer's type.

    PubMed

    Dhillon, Sohita

    2011-11-01

    Rivastigmine, a cholinesterase inhibitor, is available as a transdermal patch (Exelon® patch, Rivastach® patch, Prometax® patch) for the treatment of mild to moderate Alzheimer's disease. Rivastigmine transdermal patch was effective, in terms of improving cognitive and global function, and generally well tolerated in patients with mild to moderate dementia of the Alzheimer's type in a large, well designed trial. Most adverse events associated with rivastigmine patch were mild to moderate in severity, with the patch generally better tolerated than oral rivastigmine, especially in terms of cholinergic gastrointestinal adverse events. The patch also had good skin adhesion and a favourable skin tolerability profile in this study, with most application-site reactions being mild in severity. Additionally, in a safety and tolerability study, rivastigmine patch, regardless of concomitant memantine therapy, was generally well tolerated in patients switching from oral donepezil therapy. Thus, current evidence suggests that rivastigmine transdermal patch is an effective treatment option for patients with Alzheimer's disease, with the potential for improving compliance and providing sustained clinical benefit because of its ease of use and generally favourable tolerability profile.

  13. 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.

  14. Early onset type 2 diabetes: risk factors, clinical impact and management

    PubMed Central

    Idris, Iskandar

    2014-01-01

    Early onset type 2 diabetes mellitus (T2DM) is increasingly prevalent with a significant impact on the individual, healthcare service delivery and planning. The individuals are likely to be obese, lead a sedentary lifestyle, have a strong family history of T2DM, be of black and minority ethnic (BME) origin and come from a less affluent socioeconomic group. They have a heightened risk of developing microvascular and macrovascular complications, often at an earlier stage and with greater frequency than seen in type 1 diabetes. As such, early and aggressive risk factor management is warranted. Early onset T2DM is complex and impacts on service delivery with a need for multidisciplinary care of complications and comorbidities’, in addition to adequate educational and psychological support. This review on the impact of early onset T2DM provides the latest insights into this emerging epidemic. PMID:25364491

  15. Pilot whole-exome sequencing of a German early-onset Alzheimer's disease cohort reveals a substantial frequency of PSEN2 variants.

    PubMed

    Blauwendraat, Cornelis; Wilke, Carlo; Jansen, Iris E; Schulte, Claudia; Simón-Sánchez, Javier; Metzger, Florian G; Bender, Benjamin; Gasser, Thomas; Maetzler, Walter; Rizzu, Patrizia; Heutink, Peter; Synofzik, Matthis

    2016-01-01

    Early-onset Alzheimer's disease (EOAD) accounts for 1%-2% of all Alzheimer's disease (AD) subjects, with large variation in the reported genetic contribution of known dementia genes. In this pilot study, we genetically characterized a German EOAD cohort (23 subjects) by whole-exome sequencing, capturing variants in all recognized AD and frontotemporal dementia genes. After variant filtering, we identified 7 events of altogether 6 different rare variants in 6 subjects, including 4 novel variants. Four of the 6 variants, observed in 5 different index subjects (5/23 = 22%), were considered to be possibly pathogenic. These included 2 presenilin 2 (PSEN2) variants (p.N141I-previously denoted as a Volga German variant, observed in 2 index subjects; and p.L238P), 1 amyloid precursor protein (p.I716M), and 1 presenilin 1 (ΔE9). Using a control exome data set of 96 ethnically matched neurodegenerative disease controls (Parkinson's disease), we identified only 1 variant (PSEN2 p.T18M) (1%), demonstrating a significantly higher mutational burden in the EOAD group (p > 0.0001). Our findings demonstrate a substantial frequency of variants in dementia genes in EOAD, including several seemingly "sporadic" subjects. This indicates that heritability in EOAD might be higher than assumed. The finding of 3 subjects carrying potential pathogenic PSEN2 variants suggests that, in specific populations PSEN2 variants might be as frequent as (or more frequent than) presenilin 1, for example, in German populations which are influenced by Volga German heritage. Variants in AD genes were also associated with rare phenotypes such as frontal AD or primary progressive aphasia, demonstrating the need to screen AD genes in frontotemporal dementia-like phenotypes.

  16. Is impaired recall in dementia of the Alzheimer type a consequence of a contextual retrieval deficit?

    PubMed

    Pollmann, S; Haupt, M; Romero, B; Kurz, A

    1993-01-01

    Eighty-eight patients with mild to moderate dementia of the Alzheimer type were tested in a word list and a spatial pattern recall task. With increasing degree of dementia severity we found a decline in the initial recall scores while learning curves over five consecutive trials remained normal in the mildly demented patients. Furthermore, there was a loss of the primacy effect in the word list task in our moderately demented patients. These findings are consistent with the pattern that have been reported after medial temporal lobe dysfunction. The data are discussed in the framework of cognitive dual process theories of memory as indicators of a contextual retrieval deficit.

  17. 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

  18. 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

  19. 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

  20. Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4*

    PubMed Central

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

    2014-01-01

    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]. PMID:24644280

  1. 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

    2014-05-01

    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].

  2. Statistical study of solar type III bursts and auroral kilometric radiation onsets

    SciTech Connect

    Farrell, W.M.; Gurnett, D.A.

    1985-10-01

    Simultaneous occurrences of type III solar radio bursts and auroral kilometric radiation were observed by Calvert using ISEE 1 spectrograms. He presented evidence suggesting that the incoming type III burst stimulates the onset of auroral kilometric radiation (AKR). This paper presents a statistical study of the correlation between type III bursts and auroral kilometric radiation. A superposed epoch analysis was performed on as many as 186 type III events. The type III bursts were detected by the ISEE 3 spacecraft on the sunward side of the earth. At the same time the IMP 8 spacecraft was used to detect onsets of kilometric radiation on the nightside of the earth. For each event the intensities measured by ISEE 3(type III intensities) were subtracted from the intensities measured by IMP 8 (type III and possible AKR intensities). The resulting intensities for each event were then added to determine if kilometric radiation was preferentially observed following a type III burst. This analysis was performed at frequencies of 100, 178, and 500 kHz. The results of this study show that a statistically significant correlation exists between incoming type III bursts from the sun and kilometric radiation from the earth.

  3. Type II (adult onset) citrullinaemia: clinical pictures and the therapeutic effect of liver transplantation

    PubMed Central

    Ikeda, S; Yazaki, M; Takei, Y; Ikegami, T; Hashikura, Y; Kawasaki, S; Iwai, M; Kobayashi, K; Saheki, T

    2001-01-01

    OBJECTIVE—Adult onset type II citrullinemia is an inherited disorder of amino acid metabolism caused by a deficiency of liver specific argininosuccinate synthetase activity. Most of the patients with this disease were reported in Japan and therefore, this disease has not been well recognised outside this country. The detailed clinical pictures of the patients with type II citrullinaemia are reported and their outcomes after liver transplantation referred to.
METHODS—Ten patients with this disease were evaluated. Seven of them underwent liver transplants using a graft obtained from a healthy family member.
RESULTS—There were six men and four women; the age of onset of encephalopathy ranged from 17 to 51 years. The initial symptom in nine patients was sudden onset disturbance of consciousness, and one patient had long been regarded as having a chronic progressive psychotic illness. High concentrations of plasma citrulline and ammonia were commonly seen on admission. Although brain CT or MRI lacked any consistent findings, the EEG was abnormal in all patients, showing diffuse slow waves. Additionally, in five patients chronic pancreatitis preceded the onset of encephalopathy. After liver transplantation the metabolic abnormalities, including abnormal plasma concentrations of citrulline and ammonia, were immediately corrected and all neuropsychic symptoms soon disappeared, except for impaired cognitive function in one patient. Six out of these seven patients returned to their previous social lives, including work.
CONCLUSIONS—The clinical concept of adult onset type II citrullinaemia coincides well with the range of hepatic encephalopathy, and liver transplantation is a very promising therapeutic approach.

 PMID:11606680

  4. 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.

  5. KIR haplotypes are associated with late-onset type 1 diabetes in European–American families

    PubMed Central

    Traherne, J A; Jiang, W; Valdes, A M; Hollenbach, J A; Jayaraman, J; Lane, J A; Johnson, C; Trowsdale, J; Noble, J A

    2016-01-01

    Classical human leukocyte antigens (HLA) genes confer the strongest, but not the only, genetic susceptibility to type 1 diabetes. Killer cell immunoglobulin-like receptors (KIR), on natural killer (NK) cells, bind ligands including class I HLA. We examined presence or absence, with copy number, of KIR loci in 1698 individuals, from 339 multiplex type 1 diabetes families, from the Human Biological Data Interchange, previously genotyped for HLA. Combining family data with KIR copy number information allowed assignment of haplotypes using identity by descent. This is the first disease study to use KIR copy number typing and unambiguously define haplotypes by gene transmission. KIR A1 haplotypes were positively associated with T1D in the subset of patients without the high T1D risk HLA genotype, DR3/DR4 (odds ratio=1.29, P=0.0096). The data point to a role for KIR in type 1 diabetes risk in late-onset patients. In the top quartile (age of onset>14), KIR A2 haplotype was overtransmitted (63.4%, odds ratio=1.73, P=0.024) and KIR B haplotypes were undertransmitted (41.1%, odds ratio=0.70, P=0.0052) to patients. The data suggest that inhibitory ‘A' haplotypes are predisposing and stimulatory ‘B' haplotypes confer protection in both DR3/DR4-negative and late-onset patient groups. PMID:26492518

  6. Shared links between type 2 diabetes mellitus and Alzheimer's disease: A review.

    PubMed

    Mittal, Khyati; Katare, Deepshikha Pande

    2016-01-01

    Epidemiological studies have proved that, there are pathophysiological connections between Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD). Diabetic patients have higher incidences of cognitive impairment and hence they are more at the risk of developing AD. Some of the recent evidences have majorly stated the effects of insulin resistance in the disturbance of various biological processes and signaling pathways. Both hyperglycemia and hypoglycemic conditions contributes in dysfunctioning of cognitive abilities and functions. The present review summarizes the evidences which establish the possible links between the two pathologies on the account of molecular, biochemical and at histopathological level. The information regarding their interactions was collected from different databases and journals. The gathered information will clearly establish the link among the two pathologies and will be helpful in future for the development of drugs for Type 3 Diabetes.

  7. Semantic feature knowledge and picture naming in dementia of Alzheimer's type: a new approach.

    PubMed

    Garrard, Peter; Lambon Ralph, Matthew A; Patterson, Karalyn; Pratt, Katherine H; Hodges, John R

    2005-04-01

    This study addresses continuing controversies concerning the nature of semantic impairment in early dementia of the Alzheimer type (DAT), and the relationship between conceptual knowledge and picture naming. A series of analyses of fine-grained feature knowledge data show that: (1) distinctive features of concepts were more vulnerable than shared; (2) the amount of attribute knowledge about a concept was associated reliably, and in a graded fashion, with the ability to name a picture of that item; (3) sensory features were differentially important in naming; and (4) the degree of disruption to different types of attribute knowledge did not vary between items from living and nonliving domains. These findings are discussed in the context of contemporary cognitive and computational models of semantic memory organisation. PMID:15766770

  8. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease.

    PubMed

    Kapogiannis, Dimitrios; Boxer, Adam; Schwartz, Janice B; Abner, Erin L; Biragyn, Arya; Masharani, Umesh; Frassetto, Lynda; Petersen, Ronald C; Miller, Bruce L; Goetzl, Edward J

    2015-02-01

    Insulin resistance causes diminished glucose uptake in similar regions of the brain in Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2). Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)-serine-type 1 insulin receptor substrate (IRS-1) and less P-tyrosine-IRS-1. Plasma exosomes enriched for neural sources by immunoabsorption were obtained once from 26 patients with AD, 20 patients with DM2, 16 patients with frontotemporal dementia (FTD), and matched case control subjects. At 2 time points, they were obtained from 22 others when cognitively normal and 1 to 10 yr later when diagnosed with AD. Mean exosomal levels of extracted P-serine 312-IRS-1 and P-pan-tyrosine-IRS-1 by ELISA and the ratio of P-serine 312-IRS-1 to P-pan-tyrosine-IRS-1 (insulin resistance factor, R) for AD and DM2 and P-serine 312-IRS-1 and R for FTD were significantly different from those for case control subjects. The levels of R for AD were significantly higher than those for DM2 or FTD. Stepwise discriminant modeling showed correct classification of 100% of patients with AD, 97.5% of patients with DM2, and 84% of patients with FTD. In longitudinal studies of 22 patients with AD, exosomal levels of P-serine 312-IRS-1, P-pan-tyrosine-IRS-1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects. Insulin resistance reflected in R values from this blood test is higher for patients with AD, DM2, and FTD than case control subjects; higher for patients with AD than patients with DM2 or FTD; and accurately predicts development of AD up to 10 yr prior to clinical onset. PMID:25342129

  9. 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.

  10. 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

  11. Late-onset hereditary sensory neuropathy type I due to SPTLC1 mutation: autopsy findings.

    PubMed

    Lindahl, Andrea J; Lhatoo, Sam D; Campbell, Malcolm J; Nicholson, Garth; Love, Seth

    2006-12-01

    There is little published information on the autopsy findings in hereditary sensory neuropathy type I (HSN I), and none in genetically confirmed cases. We report the neuropathological findings in a 93-year-old woman with a disease of unusually late onset, who was part of a large HSN I kindred and in whom genetic analysis confirmed an SPTLC1 T399G mutation. PMID:16271825

  12. 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

  13. A Deeper Look into Type 1 Diabetes - Imaging Immune Responses during Onset of Disease.

    PubMed

    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

  14. 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.

  15. 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…

  16. 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 ...

  17. 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.

  18. Epigenomic approach in understanding Alzheimer's disease and type 2 diabetes mellitus.

    PubMed

    Shaik, Munvar M; Gan, Siew H; Kamal, Mohammad A

    2014-03-01

    Cognitive decline is a debilitating feature of Alzheimer's disease (AD). The causes leading to such impairment are still poorly understood and effective treatments for AD are still unavailable. Type 2 diabetes mellitus (T2DM) has been identified as a risk factor for AD due to desensitisation of insulin receptors in the brain. Recent studies have suggested that epigenetic mechanisms may also play a pivotal role in the pathogenesis of both AD and T2DM. This article describes the correlation between AD and T2DM and provides the insights to the epigenetics of AD. Currently, more research is needed to clarify the exact role of epigenetic regulation in the course and development of AD and also in relation to insulin. Research conducted especially in the earlier stages of the disease could provide more insight into its underlying pathophysiology to help in early diagnosis and the development of more effective treatment strategies.

  19. Relationship between falls and stride length variability in senile dementia of the Alzheimer type.

    PubMed

    Nakamura, T; Meguro, K; Sasaki, H

    1996-01-01

    In this study, 97 patients with senile dementia of the Alzheimer type (SDAT) in a nursing home were followed over a period of 2 years, and the relationship between falls and gait function was examined. The findings indicated that the number of fallers was significantly higher in moderate-stage SDAT patients than in the mild-stage patients. In the moderate-stage SDAT patients, walking speed and stride length, measured as indices to evaluate gait function, were significantly lower, and the stride length variability was significantly higher than in mild-stage patients. When comparing the gait indices of fallers and non-fallers by the severity of dementia, a significant difference was observed only in stride length variability. The gait abnormality associated with advanced severity in dementia is believed to be a factor affecting falling. In particular, stride length variability appeared to be an effective predictor of falling.

  20. 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

  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. PMID:26340637

  2. Auditory and Visual Cues for Topic Maintenance with Persons Who Exhibit Dementia of Alzheimer's Type.

    PubMed

    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. Shared Genetic Etiology between Type 2 Diabetes and Alzheimer's Disease Identified by Bioinformatics Analysis.

    PubMed

    Gao, Lei; Cui, Zhen; Shen, Liang; Ji, Hong-Fang

    2015-01-01

    Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two major health issues, and increasing evidence in recent years supports the close connection between these two diseases. The present study aimed to explore the shared genetic etiology underlying T2D and AD based on the available genome wide association studies (GWAS) data collected through August 2014. We performed bioinformatics analyses based on GWAS data of T2D and AD on single nucleotide polymorphisms (SNPs), gene, and pathway levels, respectively. Six SNPs (rs111789331, rs12721046, rs12721051, rs4420638, rs56131196, and rs66626994) were identified for the first time to be shared genetic factors between T2D and AD. Further functional enrichment analysis found lipid metabolism related pathways to be common between these two disorders. The findings may have important implications for future mechanistic and interventional studies for T2D and AD. PMID:26639962

  4. 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…

  5. 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).

  6. 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

  7. Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease.

    PubMed

    Proitsi, Petroula; Lupton, Michelle K; Velayudhan, Latha; Hunter, Gillian; Newhouse, Stephen; Lin, Kuang; Fogh, Isabella; Tsolaki, Magda; Daniilidou, Makrina; Pritchard, Megan; Craig, David; Todd, Stephen; Johnston, Janet A; McGuinness, Bernadette; Kloszewska, Iwona; Soininen, Hilkka; Mecocci, Patrizia; Vellas, Bruno; Passmore, Peter A; Sims, Rebecca; Williams, Julie; Brayne, Carol; Stewart, Robert; Sham, Pak; Lovestone, Simon; Powell, John F

    2014-12-01

    Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 individuals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (>10,000 individuals; 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988; 95% confidence interval, 0.972-1.004; p = 0.144 and odds ratio = 0.993; 95% confidence interval, 0.983-1.003; p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.

  8. Bacteriophage--a common divergent therapeutic approach for Alzheimer's disease and type II diabetes mellitus.

    PubMed

    Sohrab, Sayed S; Karim, Sajjad; Kamal, Mohammad A; Abuzenadah, Adel M; Chaudhary, Adeel G; Al-Qahtani, Mohammed H; Mirza, Zeenat

    2014-04-01

    Alzheimer's disease, the most important neurodegenerative disorder, is an irreversible, age-dependent disease of the brain characterized by problems in progressive impairments in memory, language, reasoning, behavior and visuospatial skills. It is characterized by the deposition of amyloid beta peptide, forming compact fibrillar plaques and neurofibrillary tau tangles. Another major and much more prevalent cause of morbidity and mortality in world is diabetes especially type 2 diabetes mellitus. It is caused by a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. Chronic wounds caused by antibiotic resistant bacterial infections that fail to heal are a common complication of diabetes mellitus and the most frequent reason for nontraumatic lower limb amputation. Holistically, these two diseases are linked at molecular level but the exact mechanism is a topic of debate. Bacteriophages are viruses infecting bacteria and lack ability to infect mammalian cells. They are neither causative agent for Alzheimer's disease or type 2 diabetes mellitus nor involved in their pathogenicity but promises for a novel divergent therapeutic approach. The great versatility of the phage system has led to the development of improved phage delivery vectors, as well as immunomodulation of anti-amyloid beta peptide response. Phages could also constitute valuable prophylaxis against bacterial infections, especially in immunocompromised patients like in the case of diabetes. Patients having diabetes have a high risk of developing foot ulcers which are difficult to be treated by antibiotics alone due to ever increasing antibiotic resistance strains. Combination therapy based on multiple phage and broad spectrum antibiotics holds great promise. The potential therapeutic phage therapy arises from its lack of natural tropism for mammalian cells, resulting in no adverse effects.

  9. 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.

  10. Diabetes mellitus Type II and cognitive capacity in healthy aging, mild cognitive impairment and Alzheimer's disease.

    PubMed

    Degen, Christina; Toro, Pablo; Schönknecht, Peter; Sattler, Christine; Schröder, Johannes

    2016-06-30

    While diabetes mellitus (DM) Type II has repeatedly been linked to Alzheimer´s disease (AD) and mild cognitive impairment (MCI), longitudinal research is scarce and disease duration has not always been taken into account. In a birth cohort born between 1930 and 1932 we investigated the influence of DM Type II and disease duration on neuropsychological functioning (memory/learning, attention, verbal fluency, visuospatial thinking and abstract thinking) across 14 years. Subjects who developed MCI or AD performed significantly poorer on all neuropsychological tests applied. While significant main effects DM Type II did not arise, its presence led to a significant deterioration of performance in the digit symbol test and visuospatial thinking over time. Additionally, in visuospatial thinking this change was more pronounced for individuals suffering from MCI/AD. We found that, as a concomitant disease DM Type II does not affect memory functioning, which is typically compromised in MCI and early AD. Rather, it may lead to deficits in cognitive flexibility and visuospatial thinking. DM Type II can be considered a frequent comorbid condition which can aggravate the course of MCI and AD. In this respect it may serve as a model for other comorbid conditions in AD. PMID:27082868

  11. Diabetes mellitus Type II and cognitive capacity in healthy aging, mild cognitive impairment and Alzheimer's disease.

    PubMed

    Degen, Christina; Toro, Pablo; Schönknecht, Peter; Sattler, Christine; Schröder, Johannes

    2016-06-30

    While diabetes mellitus (DM) Type II has repeatedly been linked to Alzheimer´s disease (AD) and mild cognitive impairment (MCI), longitudinal research is scarce and disease duration has not always been taken into account. In a birth cohort born between 1930 and 1932 we investigated the influence of DM Type II and disease duration on neuropsychological functioning (memory/learning, attention, verbal fluency, visuospatial thinking and abstract thinking) across 14 years. Subjects who developed MCI or AD performed significantly poorer on all neuropsychological tests applied. While significant main effects DM Type II did not arise, its presence led to a significant deterioration of performance in the digit symbol test and visuospatial thinking over time. Additionally, in visuospatial thinking this change was more pronounced for individuals suffering from MCI/AD. We found that, as a concomitant disease DM Type II does not affect memory functioning, which is typically compromised in MCI and early AD. Rather, it may lead to deficits in cognitive flexibility and visuospatial thinking. DM Type II can be considered a frequent comorbid condition which can aggravate the course of MCI and AD. In this respect it may serve as a model for other comorbid conditions in AD.

  12. [Phase-specific function of denial in type 1 diabetic patients after disease onset].

    PubMed

    Spiess, K; Sachs, G; Frischenschlager, O; Moser, G; Prager, R

    1994-01-01

    In a longitudinal study we examined 43 patients with type 1 diabetes one week after onset as well as 8 and 24 month later in order to analyze the psychological role of denial processes in correlation to metabolic functions. Only depression decreased over the studied period while coping and denial remained stable. However, the adaptive function of denial after onset with low anxiety, good coping and few complaints became maladaptive over the first two years and the correlation of denial with a centripetal kinship behavior loosened. The destructive effect of denial was indicated only by delayed requests for assistance while no correlation could be shown for phase-specific internal restructuring of the psychological function of denial to compliance and metabolic control. PMID:8147141

  13. 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.

    PubMed Central

    Tang, M. X.; Maestre, G.; Tsai, W. Y.; Liu, X. H.; Feng, L.; Chung, W. Y.; Chun, M.; Schofield, P.; Stern, Y.; Tycko, B.; Mayeux, R.

    1996-01-01

    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. PMID:8644717

  14. 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.

  15. Heterogeneity in Recent Onset Type 1 Diabetes – A Clinical Trial Perspective

    PubMed Central

    Bollyky, Jennifer B.; Xu, Ping; Butte, Atul J.; Wilson, Darrell M.; Beam, Craig A.; Greenbaum, Carla J.

    2015-01-01

    Background Type 1 Diabetes TrialNet is an NIH-sponsored clinical trial network aimed at altering the disease course of type 1 diabetes. The purpose of this study is to evaluate age-dependent heterogeneity in clinical, metabolic, and immunologic characteristics of individuals with recent-onset type 1 diabetes (T1D), to identify cohorts of interest and to aid in planning of future studies. Methods 883 individuals with recent onset T1D involved in five TrialNet studies were categorized by age as: ≥ 18, age 12-17, ages 8-12, and age <8. Data was compared with healthy age-matched subjects in the National Health and Nutrition Examination Survey. Results While only 2.0 % of individuals overall were excluded due to insufficient C-peptide values (<0.2 pmol/ml), 9.0% of those < age 8 did not meet this entry criteria. Leukopenia was present in 21.2% of individuals and lymphopenia in 11.6%; these frequencies were markedly different than age-matched healthy population. 24.5% of the cohort was overweight or obese. 31.1% of adults and 21.1% of children had neither HLA DR3 nor DR4. Conclusions The ability of recent onset T1D patients to meet key entry criteria for TrialNet studies, including C-peptide >0.2 pmol/ml, varies by age. Lower C-peptide level requirements for younger participants should be considered in the design of future trials. These data also highlight subgroups of type 1 diabetes patients, such as those with abnormal WBC or who are overweight, which allow for targeted studies of etiopathology and interventions. PMID:25689602

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

    NASA Astrophysics Data System (ADS)

    Khademi, April; Hosseinzadeh, Danoush

    2014-03-01

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

  17. 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.

  18. Generation of a novel mouse model that recapitulates early and adult onset glycogenosis type IV.

    PubMed

    Akman, H Orhan; Sheiko, Tatiana; Tay, Stacey K H; Finegold, Milton J; Dimauro, Salvatore; Craigen, William J

    2011-11-15

    Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by deficiency of the glycogen branching enzyme (GBE). The diagnostic feature 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 of disease onset. Absence of enzyme activity is lethal in utero or in infancy affecting primarily muscle and liver. However, residual enzyme activity (5-20%) leads to juvenile or adult onset of a disorder that primarily affects muscle as well as central and peripheral nervous system. Here, we describe two mouse models of GSD IV that reflect this spectrum of disease. Homologous recombination was used to insert flippase recognition target recombination sites around exon 7 of the Gbe1 gene and a phosphoglycerate kinase-Neomycin cassette within intron 7, leading to a reduced synthesis of GBE. Mice bearing this mutation (Gbe1(neo/neo)) exhibit a phenotype similar to juvenile onset GSD IV, with wide spread accumulation of PG. Meanwhile, FLPe-mediated homozygous deletion of exon 7 completely eliminated GBE activity (Gbe1(-/-)), leading to a phenotype of lethal early onset GSD IV, with significant in utero accumulation of PG. Adult mice with residual GBE exhibit progressive neuromuscular dysfunction and die prematurely. Differently from muscle, PG in liver is a degradable source of glucose and readily depleted by fasting, emphasizing that there are structural and regulatory differences in glycogen metabolism among tissues. Both mouse models recapitulate typical histological and physiological features of two human variants of branching enzyme deficiency. PMID:21856731

  19. Abundant type 10 17 beta-hydroxysteroid dehydrogenase in the hippocampus of mouse Alzheimer's disease model.

    PubMed

    He, Xue Ying; Wen, Guang Yeong; Merz, George; Lin, Dawei; Yang, Ying Zi; Mehta, Penkaj; Schulz, Horst; Yang, Song Yu

    2002-02-28

    A full-length cDNA of mouse type 10 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD10) was cloned from brain, representing the accurate nucleotide sequence information that rendered possible an accurate deduction of the amino acid sequence of the wild-type enzyme. A comparison of sequences and three-dimensional models of this enzyme revealed that structures previously reported by other groups carry either a truncated or mutated amino-terminal sequence. Fusion of the first 11 residues of the wild-type enzyme to the green fluorescent protein directed the reporter protein into mitochondria. Thus, the N-terminus was identified as a mitochondrial targeting signal that accounts for the intracellular localization of the mouse enzyme. This enzyme is normally associated with mitochondria, not with the endoplasmic reticulum as suggested by its trivial name 'endoplasmic reticulum-associated amyloid-beta biding protein (ERAB)'. After its C-terminal region was used to raise rabbit anti-17 betaHSD10 antibodies, immunogold electron microscopy showed that an abundance of this enzyme could be found in hippocampal synaptic mitochondria of betaAPP transgenic mice, but not in normal controls. High levels of this enzyme may disrupt steroid hormone homeostasis in synapses and contribute to synapse loss in the hippocampus of the mouse Alzheimer's disease model. PMID:11869808

  20. 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.

  1. An association of virus infection with type 2 diabetes and Alzheimer's disease.

    PubMed

    Karim, Sajjad; Mirza, Zeenat; Kamal, Mohammad A; Abuzenadah, Adel M; Azhar, Esam I; Al-Qahtani, Mohammed H; Sohrab, Sayed S

    2014-04-01

    Diabetes mellitus type 2 is a metabolic disorder characterized by high blood glucose due to insulin deficiency or resistance. Alzheimer's disease (AD) is a complex neurodegenerative disease leading to irreversible loss of neurons, intellectual abilities, memory and reasoning. The worldwide prevalence of diabetes and AD in elderly population is a major public health concern. Interestingly, both health issues are unraveling the puzzling links. The clinico-pathological relationship between diabetes and AD has been reported at genomic and proteomic levels. The association of virus infection in type 2 diabetes mellitus and AD has been reported in few recent studies, some have shown direct evidence of virus infection in diabetes and AD while other have shown that diabetes increases the risk of developing AD. This review aims to summarize the association of few common viruses like Hepatitis C Virus and Herpes Simplex Virus-1 which affects both these two age-related devastating diseases. We also discuss the pathological links of Influenza virus, Cytomegalovirus, West Nile virus, Enterovirus, Herpes Simplex Virus-2, Hepatitis viruses in diabetes and Influenza virus, Picornavirus and Borna disease virus in AD. Establishing such relationships and defining their common pathogenesis and patho-physiological mechanisms may lead to new concepts and paths for developing novel preventive strategies and pharmacological treatment options for diabetes and AD. This study may aid in future for the identification of a single or a panel of likely blood-based viral biomarkers for early diagnosis of diabetes and AD with high sensitivity and specificity.

  2. Type 2 Diabetes Mellitus and Alzheimer's Disease: Bridging the Pathophysiology and Management.

    PubMed

    Alam, Fahmida; Islam, Md Asiful; Sasongko, Teguh Haryo; Gan, Siew Hua

    2016-01-01

    Although type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are two independent diseases, evidences from epidemiological, pathophysiological and animal studies have indicated a close pathophysiological relationship between these diseases. Due to the pathophysiological similarity of T2DM and AD, which includes insulin resistance and deficiency, protein aggregation, oxidative stress, inflammation, autophagocytosis and advanced glycation end products; AD is often referred to as "type 3 diabetes". In addition to the targeted regimens usually used for treating T2DM and AD individually, currently, anti-diabetic drugs are successfully used to reduce the cognitive decline in AD patients. Therefore, if a common pathophysiology of T2DM and AD could be clearly determined, both diseases could be managed more efficiently, possibly by shared pharmacotherapy in addition to understanding the broader spectrum of preventive strategies. The aim of this review is to discuss the pathophysiological bridge between T2DM and AD to lay the foundation for the future treatment strategies in the management of both diseases. PMID:27229721

  3. 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.

  4. Effect of Calcitriol on Bone Turnover and Osteocalcin in Recent-Onset Type 1 Diabetes

    PubMed Central

    Napoli, Nicola; Strollo, Rocky; Pitocco, Dario; Bizzarri, Carla; Maddaloni, Ernesto; Maggi, Daria; Manfrini, Silvia; Schwartz, Ann; Pozzilli, Paolo

    2013-01-01

    Background Vitamin D supplementation in childhood improves the achievement of peak bone mass. We investigated the effect of supplementation with calcitriol on bone turnover in recent-onset type 1 diabetes (T1D). Moreover, the association between osteocalcin and parameters of β-cell function and metabolic control was examined. Methodology/Principal Findings We conducted a post-hoc analysis of a double-blind, placebo-controlled study of calcitriol supplementation to preserve β-cell function. 27 recent-onset T1D subjects, mean age 22 years, were randomized to 0.25 µg calcitriol per day or placebo (1∶1) and followed up for one year. Changes in bone formation (osteoclacin) and resorption (beta-CrossLaps) markers, and differences between placebo and calcitriol-treated group were evaluated. At baseline, osteocalcin levels were significantly lower in female than in male patients (P<0.01) while no other metabolic parameters as HbA1c and C-peptide differed between gender. No significant correlations were found in relation to HbA1c, insulin requirement and C-peptide. At 1 year follow-up, no significant differences were observed between calcitriol and placebo groups for osteocalcin and β-CrossLaps. In the placebo group osteocalcin levels were unrelated with parameters of metabolic control, such as C-peptide, insulin requirement or HbA1c. Changes of C-peptide, insulin requirement and HbA1c were not related to osteocalcin levels. Conclusions Supplementation with 0.25 µg calcitriol per day to patients with new-onset T1D does not affect circulating markers of bone turnover. OC levels were unrelated to β-cell function and other metabolic parameters suggesting that OC is ineffective to control pancreatic function in presence of aggressive autoimmune destruction. PMID:23437144

  5. 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.

  6. Alzheimer's Association

    MedlinePlus

    ... Get involved Last Updated: Our vision is a world without Alzheimer's Formed in 1980, the Alzheimer's Association ... Association ® . All rights reserved. Our vision is a world without Alzheimer's Formed in 1980, the Alzheimer's Association ...

  7. Estimation of the age at onset in spinocerebellar ataxia type 2 Cuban patients by survival analysis.

    PubMed

    Almaguer-Mederos, L E; Falcón, N S; Almira, Y R; Zaldivar, Y G; Almarales, D C; Góngora, E M; Herrera, M P; Batallán, K E; Armiñán, R R; Manresa, M V; Cruz, G S; Laffita-Mesa, J; Cyuz, T M; Chang, V; Auburger, G; Gispert, S; Pérez, L V

    2010-08-01

    Previous studies have investigated the close association that exists between CAG repeat number and the age at onset in SCA2 = spinocerebellar ataxia type 2. These studies have focused on affected individuals. To further characterize this association and estimate the risk of a carrier developing SCA2 at a particular age as a function of a specific CAG repeat size, we have analyzed a large group of 924 individuals, including 394 presymptomatic and 530 affected individuals with a CAG repeat length of 32-79 units. Using a Kaplan-Meier survival analysis, we obtained cumulative probability curves for disease manifestation at a particular age for each CAG repeat length in the 34-45 range. These curves were significantly different (p < 0.001) and showed small overlap. All these information may be very valuable in predictive-testing programs, in the planning of studies for the identification of other genetic and environmental factors as modifiers of age at onset, and in the design of clinical trials for people at enlarged risk for SCA2. PMID:20095980

  8. Autophagy dysfunction and its link to Alzheimer's disease and type II diabetes mellitus.

    PubMed

    Wilson, Cornelia M; Magnaudeix, Amandine; Yardin, Catherine; Terro, Faraj

    2014-03-01

    Epidemiological data testifies the increasing incidence of Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Some associations were made between occidental lifestyle and development of these pathologies, moreover AD and T2DM are linked since each pathology is a causative risk factor for the other. Interestingly, autophagy, a catabolic pathway whose efficiency declines with age is importantly impaired in the affected tissues. Autophagy regulation is dependent of cell metabolic status and consequently on the 5'AMP-activated protein kinase (AMPK) and mammalian target of rapamycin signaling pathways. These pathways are altered with aging and molecular, pharmacological and physiological interventions increase lifespan in various organismal models and favours healthy aging diminishing the occurrence of age-related diseases such as diabetes, cancer, cardiovascular and neurodegenerative pathologies. Decreasing calorie intake has been known for a long time to have a beneficial effect on longevity and health. Some drug agonists of AMPK are known to mimic these effects such as metformin or resveratrol, a polyphenol extracted from plants and present in red wine, a component of the French paradox related diet. In this review, we present the epidemiological and pathogenesis links existing between AD and T2DM with an insight into the perturbations of the autophagic process highlighting the crucial role of the AMPK in development of age and metabolic related diseases. Hence, in a last part we will discuss the possible interventions susceptible to combat both T2DM and AD.

  9. Status of acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease and type 2 diabetes mellitus.

    PubMed

    Mushtaq, Gohar; Greig, Nigel H; Khan, Jalaluddin A; Kamal, Mohammad A

    2014-01-01

    Both Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM) share the presence of systemic and neuro-inflammation, enhanced production and accumulation of β -amyloid peptide and abnormal levels of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Altered levels of AChE and BuChE both in AD as well as in T2DM imply that those two enzymes may be playing a pivotal role in the pathogenesis of the two disorders. AD and T2DM are both characterized by elevated levels of AChE and BuChE in the plasma. On the other hand, in AD the brain levels of AChE go down while those of BuChE go up, resulting in deregulation in balance between AChE and BuChE. This imbalance and change in the AChE/BuChE ratio causes cholinergic deficit in the brain, i.e. deficiency in the brain neurotransmitter acetylcholine. With better understanding of the inter-relationship of AChE and BuChE levels in normality as well as abnormality, AD and T2DM can be effectively treated. Thus, general cholinesterase inhibitors that inhibit both AChE and BuChE as well as highly selective BuChE inhibitors may have potential therapeutic benefits in the treatment of AD and other related dementias.

  10. 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.

  11. Changes in the volume of temporal lobe structures related to Alzheimer's type dementia.

    PubMed

    Moryś, Janusz; Bobek-Billewicz, Barbara; Dziewiatkowski, Jerzy; Bidzan, Leszek; Ussorowska, Dorota; Narklewicz, Olgierd

    2002-01-01

    We compared the volumes of the superior temporal gyrus, basolateral temporal area, parahippocampal gyrus, hippocampal head, amygdaloid body and the inferior horn of the lateral ventricle in 29 patients with dementia of Alzheimer's type (DAT) and in 14 cognitively normal controls. Measurements were performed on coronal MR images perpendicular to the long axis of the hippocampus then the raw data were normalised for intracranial volume. The volumes of all studied structures were significantly smaller in patients with DAT than in age-matched control group. The differences in the volume between DAT and age-matched control group were the largest for the amygdaloid body and the basolateral temporal area. The discriminant analysis including the volume of both the basolateral area and the left amygdaloid body allows for correct classification of 100% DAT patients and 93% controls. We conclude that the estimation of the volume of the amygdaloid body and basolateral temporal area seems to be the most important factor for DAT diagnosis. PMID:12230256

  12. Longitudinal evaluation of dementia of the Alzheimer type: a comparison of 3 standardized mental status examinations.

    PubMed

    Salmon, D P; Thal, L J; Butters, N; Heindel, W C

    1990-08-01

    We administered 3 commonly employed tests of mental status (the Information-Memory-Concentration test [IMC], the Mini-Mental State Examination [MMSE], and the Dementia Rating Scale [DRS]) to 92 patients with probable dementia of the Alzheimer type. The 3 tests were readministered to 55 of the patients (2-year subgroup) approximately 1 year later, and administered a 3rd time to 20 of the patients (3-year subgroup) approximately 2 years after their initial assessment. In all cases, scores on the 3 tests were highly correlated with each other. Examination of the annual rate of change (ARC) in score for the 2-year subgroup revealed an average decline of -3.24 error points on the IMC, 2.81 points on the MMSE, and 11.38 points on the DRS. Of the 3 tests, only the DRS evidenced greater sensitivity to change with increasing dementia severity. In the 3-year subgroup, the ARC between years 1 and 2 was not correlated with ARC between years 2 and 3 for any of the 3 tests. This finding suggests that a patient's rate of progression in 1 year may bear little relationship to future rate of decline. PMID:2381530

  13. Extraction Method of Brain Regions Using Balloon models for Diagnosis Support of Alzheimer-Type Dementia

    NASA Astrophysics Data System (ADS)

    Ito, Momoyo; Nishida, Makoto; Namura, Ikuro

    We intend to construct an image diagnosis support system for Alzheimer-type Dementia (ATD) that extracts temporal lobe regions and an intracranial region as interest regions from a T2-weighted MR frontal image and uses the cerebral atrophy rates at the regions of interest. In this paper, we specifically discuss extraction of regions of interest. The proposed method consists of three steps. First, we emphasis features of an obscure T2-weighted brain image. Second, we set a first contour that approximates a shape of the temporal lobe region to a triangle and apply Balloon models with the added presser force that push the initial contour outside in order to extract a temporal lobe region. Finally, we extract an intracranial region using extracted temporal lobe regions. Our proposed method can extract regions of interest along individual brain features by only a few interactions with three points. We demonstrate the potential of our method using actual diagnosis images. Moreover, we show a possibility to use of atrophy rate at the regions of interest for diagnosis support of ATD.

  14. 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.

  15. 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.

  16. Intrauterine onset of acute neuropathic type 2 Gaucher disease: identification of a novel insertion sequence.

    PubMed

    Felderhoff-Mueser, Ursula; Uhl, Johannes; Penzel, Roland; Van Landeghem, Frank; Vogel, Martin; Obladen, Michael; Kopitz, Jürgen

    2004-07-15

    A subset of patients with type 2 Gaucher disease is characterized by intrauterine onset of rapidly progressive neuropathic disease, arthrogryposis, hydrops fetalis and in some cases restrictive dermopathy. beta-Glucocerebrosidase (beta-glucosidase) activity is usually low or undetectable. In most cases death ensues either in-utero or within hours or days after birth. We report on an infant born to non-consanguineous parents of Caucasian origin presenting at birth with hydrops, arthrogryposis, severe respiratory distress, hepatosplenomegaly, and liver failure. Death occurred within several hours after delivery and autopsy revealed typical Gaucher cells in multiple organs in combination with severe apoptotic neurodegeneration throughout the brain. beta-Glucocerebrosidase activity was 1% of the norm in fibroblasts and a novel heterozygous insertion c.1515_1516insAGTGAGGGCAAT was identified by genomic sequencing and an insertion-specific seminested PCR. In addition, molecular studies revealed a previously described in type 1 Gaucher disease missense mutation c.476G --> A which results in a heterozygous substitution of R120Q. Our observations confirm considerable genotypic heterogeneity in patients with type 2 Gaucher disease. The transheterozygous combination of a mutation, previously described in type 1 Gaucher disease, together with a newly identified insertion may result in this severe phenotype. PMID:15214004

  17. Intrauterine onset of acute neuropathic type 2 Gaucher disease: identification of a novel insertion sequence.

    PubMed

    Felderhoff-Mueser, Ursula; Uhl, Johannes; Penzel, Roland; Van Landeghem, Frank; Vogel, Martin; Obladen, Michael; Kopitz, Jürgen

    2004-07-15

    A subset of patients with type 2 Gaucher disease is characterized by intrauterine onset of rapidly progressive neuropathic disease, arthrogryposis, hydrops fetalis and in some cases restrictive dermopathy. beta-Glucocerebrosidase (beta-glucosidase) activity is usually low or undetectable. In most cases death ensues either in-utero or within hours or days after birth. We report on an infant born to non-consanguineous parents of Caucasian origin presenting at birth with hydrops, arthrogryposis, severe respiratory distress, hepatosplenomegaly, and liver failure. Death occurred within several hours after delivery and autopsy revealed typical Gaucher cells in multiple organs in combination with severe apoptotic neurodegeneration throughout the brain. beta-Glucocerebrosidase activity was 1% of the norm in fibroblasts and a novel heterozygous insertion c.1515_1516insAGTGAGGGCAAT was identified by genomic sequencing and an insertion-specific seminested PCR. In addition, molecular studies revealed a previously described in type 1 Gaucher disease missense mutation c.476G --> A which results in a heterozygous substitution of R120Q. Our observations confirm considerable genotypic heterogeneity in patients with type 2 Gaucher disease. The transheterozygous combination of a mutation, previously described in type 1 Gaucher disease, together with a newly identified insertion may result in this severe phenotype.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα.

    PubMed

    Komatsu, Michiharu; Kimura, Takefumi; Yazaki, Masahide; Tanaka, Naoki; Yang, Yang; Nakajima, Takero; Horiuchi, Akira; Fang, Zhong-Ze; Joshita, Satoru; Matsumoto, Akihiro; Umemura, Takeji; Tanaka, Eiji; Gonzalez, Frank J; Ikeda, Shu-Ichi; Aoyama, Toshifumi

    2015-03-01

    SLC25A13 (citrin or aspartate-glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty acid (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (carnitine palmitoyl-CoA transferase 1α, medium- and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial β-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARα expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPARα. Collectively, down-regulation of PPARα is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPARα.

  3. White matter hyperintensities in middle-aged adults with childhood-onset type 1 diabetes

    PubMed Central

    Nunley, Karen A.; Ryan, Christopher M.; Orchard, Trevor J.; Aizenstein, Howard J.; Jennings, J. Richard; Ryan, John; Zgibor, Janice C.; Boudreau, Robert M.; Costacou, Tina; Maynard, John D.; Miller, Rachel G.

    2015-01-01

    Objective: Although microvascular complications are common in type 1 diabetes mellitus (T1DM), few studies have quantified the severity, risk factors, and implications of cerebral microvascular damage in these patients. As life expectancy in patients with T1DM increases, patients are exposed to age- and disease-related factors that may contribute to cerebral microvascular disease. Methods: Severity and volume of white matter hyperintensities (WMH) and infarcts were quantified in 97 middle-aged patients with childhood-onset T1DM (mean age and duration: 50 and 41 years, respectively) and 81 non-T1DM adults (mean age: 48 years), concurrent with cognitive and health-related measures. Results: Compared with non-T1DM participants, patients had more severe WMH (Fazekas scores 2 and 3 compared with Fazekas score 1, p < 0.0001) and slower information processing (digit symbol substitution, number correct: 65.7 ± 10.9 and 54.9 ± 13.6; pegboard, seconds: 66.0 ± 9.9 and 88.5 ± 34.2; both p < 0.0001) independent of age, education, or other factors. WMH were associated with slower information processing; adjusting for WMH attenuated the group differences in processing speed (13% for digit symbol, 11% for pegboard, both p ≤ 0.05). Among patients, prevalent neuropathies and smoking tripled the odds of high WMH burden, independent of age or disease duration. Associations between measures of blood pressure or hyperglycemia and WMH were not significant. Conclusions: Clinically relevant WMH are evident earlier among middle-aged patients with childhood-onset T1DM and are related to the slower information processing frequently observed in T1DM. Brain imaging in patients with T1DM who have cognitive difficulties, especially those with neuropathies, may help uncover cerebral microvascular damage. Longitudinal studies are warranted to fully characterize WMH development, risk factors, and long-term effects on cognition. PMID:25904692

  4. REACTIVATION OF LATENT VIRUSES IN INDIVIDUALS RECEIVING RITUXIMAB FOR NEW ONSET TYPE 1 DIABETES

    PubMed Central

    Kroll, Jing Lu; Beam, Craig; Li, Shaobing; Viscidi, Raphael; Dighero, Bonnie; Cho, Alice; Boulware, David; Pescovitz, Mark; Weinberg, Adriana

    2013-01-01

    Background 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. Objectives 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. Study Design 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. Results 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. Conclusions 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. PMID:23422292

  5. Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα.

    PubMed

    Komatsu, Michiharu; Kimura, Takefumi; Yazaki, Masahide; Tanaka, Naoki; Yang, Yang; Nakajima, Takero; Horiuchi, Akira; Fang, Zhong-Ze; Joshita, Satoru; Matsumoto, Akihiro; Umemura, Takeji; Tanaka, Eiji; Gonzalez, Frank J; Ikeda, Shu-Ichi; Aoyama, Toshifumi

    2015-03-01

    SLC25A13 (citrin or aspartate-glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty acid (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (carnitine palmitoyl-CoA transferase 1α, medium- and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial β-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARα expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPARα. Collectively, down-regulation of PPARα is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPARα. PMID:25533124

  6. Proteomics approaches to understand linkage between Alzheimer's disease and type 2 diabetes mellitus.

    PubMed

    Mirza, Zeenat; Ali, Ashraf; Ashraf, Ghulam Md; Kamal, Mohammad A; Abuzenadah, Adel M; Choudhary, Adeel G; Damanhouri, Ghazi A; Sheikh, Ishfaq A

    2014-03-01

    Alzheimer's disease (AD) is a progressive neurological disease of the brain leading to the irreversible loss of neurons and intellectual abilities. Diabetes mellitus type 2 (T2DM) is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. The prevalence of AD and T2DM is increasing at an alarming rate and has become a major public health concern worldwide. The clinico-pathological relationship between AD and T2DM has been debated for more than a decade. Recent epidemiological studies have provided direct evidence that T2DM is a strong risk factor for AD and numerous studies have demonstrated that patients with diabetes have an increased risk of developing AD as compared with healthy individuals. The underlying biological mechanisms that link the development of diabetes with AD are not fully understood and therefore are worth intensive research. The existence of proteomic links between AD and diabetes is an important topic currently under active debate. An understanding of the complex association between diabetes and AD is necessary for the development of novel drug therapies and lifestyle guidelines aimed at the treatment and/or prevention of these diseases. This review aims to summarize what is currently known about the biological and especially proteomic relationships and similarities between these two age-related devastating diseases of modern day life. This study may also aid in future for the identification of a single or a panel of potential blood-based protein biomarkers for early diagnosis of AD and T2DM with high sensitivity and specificity.

  7. Choroidal Thickness in Patients with Mild Cognitive Impairment and Alzheimer's Type Dementia

    PubMed Central

    Bulut, Mehmet; Yaman, Aylin; Erol, Muhammet Kazim; Kurtuluş, Fatma; Toslak, Devrim; Doğan, Berna; Turgut Çoban, Deniz; Kaya Başar, Ebru

    2016-01-01

    Aim. To asses both choroidal thickness differences among Alzheimer's type dementia (ATD) patients, mild cognitive impairment (MCI) patients, and healthy control (C) subjects and choroidal thickness relationships with cognitive performance. Methods. A total of 246 eyes of 123 people (41 ATD, 38 MCI, and 44 healthy C subjects) were included in this study. Complete ophthalmological and neurological examination was performed in all subjects. Choroidal thicknesses (CT) were measured at seven locations: the fovea, 500-1500-3000 μm temporal and 500-1500-3000 μm nasal to the fovea by enhanced depth imaging optical coherence tomography (EDI-OCT). Detailed neurological examination including mini mental state examination (MMSE) test which evaluates the cognitive function was applied to all participants. Results. The ages and genders of all participants were similar in all groups. Compared with healthy C subjects, the CT measurements at all regions were significantly thinner both in patients with ATD and in patients with MCI than in healthy C subjects (p < 0.05). The MMSE scores were significantly different among ATD patients, MCI patients, and healthy C subjects. They were 19.3 ± 1.8, 24.8 ± 0.9, and 27.6 ± 1.2 in ATD, MCI, and healthy controls, respectively (p < 0.001). There were also significant correlation between MMSE score and choroidal thickness at each location (p < 0.05). Conclusions. CT was reduced in ATD patients and MCI patients. Since vascular structures were affected in ATD patients and MCI patients, they had thin CT. Besides CT was correlated with degree of cognitive impairment. Therefore CT may be a new biomarker in diagnosis and follow-up of MCI and ATD patients. PMID:26925259

  8. 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.

  9. 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.

  10. 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. PMID:26577751

  11. 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.

  12. The relationship between naming and semantic knowledge for different categories in dementia of Alzheimer's type.

    PubMed

    Lambon Ralph, M A; Patterson, K; Hodges, J R

    1997-09-01

    We studied the relationship between naming and semantic memory in a group of 10 patients with dementia of Alzheimer's type. In an extension to a previous cross-sectional study (Hodges, J. R. et al., Brain and Language, 1996, 54, 302-325), this relationship was investigated at two longitudinal points within each patient's cognitive decline. Two types of naming performance were compared: items that each patient named correctly at the first stage but failed to name at the second stage, as contrasted with items named correctly at both stages (thereby providing a control for cognitive decline in general). Semantic knowledge of the concepts represented by the pictures in the naming test was investigated at each stage using definitions to the spoken object name, scored particularly for the number of sensory and associative/functional features provided by the patient. At stage 2, an analysis of the definitions for named-->unnamed items as contrasted with named-->named objects revealed a significant loss of both sensory and associative information. A comparison between natural kinds (animals and birds) and artefacts (household objects, vehicles, etc.), however, demonstrated a striking interaction between category and type of information contained in the definitions. Specifically, stage 2 definitions of artefacts in the named-->unnamed set showed a disproportionate loss of associative/functional information, while definitions of animal names that patients failed to produce in response to the pictures were notably lacking in sensory features. This pattern supports the notion that successful naming relies on a subset of critical semantic features which vary somewhat across different categories of semantic knowledge. We suggest that these findings are best encompassed by a conception of semantic organization, Weighted Overlappingly Organized Features (WOOF), in which (i) knowledge about all objects is represented by a central, distributed network of features activated by both

  13. Phenotype variability and early onset ataxia symptoms in spinocerebellar ataxia type 7: comparison and correlation with other spinocerebellar ataxias.

    PubMed

    Albuquerque, Marcus Vinicius Cristino de; Pedroso, José Luiz; Braga Neto, Pedro; Barsottini, Orlando Graziani Povoas

    2015-01-01

    The spinocerebellar ataxias (SCA) are a group of neurodegenerative disorders characterized by heterogeneous clinical presentation. Spinocerebellar ataxia type 7 (SCA7) is caused by an abnormal CAG repeat expansion and includes cerebellar signs associated with visual loss and ophthalmoplegia. Marked anticipation and dynamic mutation is observed in SCA7. Moreover, phenotype variability and very early onset of symptoms may occur. In this article, a large series of Brazilian patients with different SCA subtypes was evaluated, and we compared the age of onset of SCA7 with other SCA. From the 26 patients with SCA7, 4 manifested their symptoms before 10-year-old. Also, occasionally the parents may have the onset of symptoms after their children. In conclusion, our study highlights the genetic anticipation phenomenon that occurs in SCA7 families. Patients with very early onset ataxia in the context of a remarkable family history, must be considered and tested for SCA7.

  14. Rivastigmine transdermal patch: a review of its use in the management of dementia of the Alzheimer's type.

    PubMed

    Dhillon, Sohita

    2011-06-18

    Rivastigmine, a cholinesterase inhibitor, is available as a transdermal patch (Exelon(®) patch, Rivastach(®) patch, Prometax(®) patch) for the treatment of mild to moderate Alzheimer's disease. Rivastigmine transdermal patch was effective, in terms of improving cognitive and global function, and generally well tolerated in patients with mild to moderate dementia of the Alzheimer's type in a large, well designed trial. Most adverse events associated with rivastigmine patch were mild to moderate in severity, with the patch generally better tolerated than oral rivastigmine, especially in terms of cholinergic gastrointestinal adverse events. The patch also had good skin adhesion and a favourable skin tolerability profile in this study, with most application-site reactions being mild in severity. Additionally, in a safety and tolerability study, rivastigmine patch, regardless of concomitant memantine therapy, was generally well tolerated in patients switching from oral donepezil therapy. Thus, current evidence suggests that rivastigmine transdermal patch is an effective treatment option for patients with Alzheimer's disease, with the potential for improving compliance and providing sustained clinical benefit because of its ease of use and generally favourable tolerability profile.

  15. Dementia: Depression and Alzheimer's Disease

    MedlinePlus

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

  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. 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.

  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. 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. PMID:25592004

  20. 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.

  1. Loss of anergic B cells in prediabetic and new-onset type 1 diabetic patients.

    PubMed

    Smith, Mia J; Packard, Thomas A; O'Neill, Shannon K; Henry Dunand, Carole J; Huang, Min; Fitzgerald-Miller, Lisa; Stowell, Daniel; Hinman, Rochelle M; Wilson, Patrick C; Gottlieb, Peter A; Cambier, John C

    2015-05-01

    Although dogma predicts that under normal circumstances, potentially offensive autoreactive cells are silenced by mechanisms of immune tolerance, islet antigen-reactive B lymphocytes are known to play a crucial role in the development of autoimmunity in type 1 diabetes (T1D). Thus, participation of these cells in T1D may reflect escape from silencing mechanisms. Consistent with this concept, we found that in healthy subjects, high-affinity insulin-binding B cells occur exclusively in the anergic naive IgD(+), IgM(-) B-cell (BND) compartment. Antigen receptors expressed by these cells are polyreactive and have N-region additions, Vh usage, and charged complementarity-determining region 3 consistent with autoreactivity. Consistent with a potential early role in autoimmunity, these high-affinity insulin-binding B cells are absent from the anergic compartment of some first-degree relatives and all prediabetic and new-onset (<1 year) T1D patients tested, but return to normal levels in individuals diabetic for >1 year. Interestingly, these changes were correlated by transient loss of the entire BND compartment. These findings suggest that environmental events such as infection or injury may, by disrupting B-cell anergy, dispose individuals toward autoimmunity, the precise nature of which is specified by genetic risk factors, such as HLA alleles. PMID:25524915

  2. 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. PMID:27014774

  3. Geometric phase transition in the cellular network of the pancreatic islets may underlie the onset of type 1diabetes

    NASA Astrophysics Data System (ADS)

    Wang, Xujing

    Living systems are characterized by complexity in structure and emergent dynamic orders. In many aspects the onset of a chronic disease resembles phase transition in a dynamic system: quantitative changes accumulate largely unnoticed until a critical threshold is reached, which causes abrupt qualitative changes of the system. In this study we investigate this idea in a real example, the insulin-producing pancreatic islet β-cells and the onset of type 1 diabetes. Within each islet, the β-cells are electrically coupled to each other, and function as a network with synchronized actions. Using percolation theory we show how normal islet function is intrinsically linked to network connectivity, and the critical point where the islet cellular network loses site percolation, is consistent with laboratory and clinical observations of the threshold β-cell loss that causes islet functional failure. Numerical simulations confirm that the islet cellular network needs to be percolated for β-cells to synchronize. Furthermore, the interplay between site percolation and bond strength predicts the existence of a transient phase of islet functional recovery after disease onset and introduction of treatment, potentially explaining a long time mystery in the clinical study of type 1 diabetes: the honeymoon phenomenon. Based on these results, we hypothesized that the onset of T1D may be the result of a phase transition of the islet β-cell network. We further discuss the potential applications in identifying disease-driving factors, and the critical parameters that are predictive of disease onset.

  4. Age-of-Onset or Behavioral Sub-Types? A Prospective Comparison of Two Approaches to Characterizing the Heterogeneity within Antisocial Behavior

    ERIC Educational Resources Information Center

    Burt, S. Alexandra; Donnellan, M. Brent; Iacono, William G.; McGue, Matt

    2011-01-01

    There are two common approaches to sub-typing the well-documented heterogeneity within antisocial behavior: age-of-onset (i.e., childhood-onset versus adolescence-onset; see "Moffitt" 1993) and behavioral (i.e., physical aggression versus non-aggressive rule-breaking). These approaches appear to be associated, such that aggression is more…

  5. Reduction of Ca2+ stores and capacitative Ca2+ entry is associated with the familial Alzheimer's disease presenilin-2 T122R mutation and anticipates the onset of dementia.

    PubMed

    Giacomello, Marta; Barbiero, Laura; Zatti, Giancarlo; Squitti, Rosanna; Binetti, Giuliano; Pozzan, Tullio; Fasolato, Cristina; Ghidoni, Roberta; Pizzo, Paola

    2005-04-01

    Mutations in the presenilin genes PS1 and PS2, the major cause of familial Alzheimer's disease (FAD), are associated with alterations in Ca2+ signalling. In contrast to the majority of FAD-linked PS1 mutations, which cause an overload of intracellular Ca2+ pools, the FAD-linked PS2 mutation M239I reduces Ca2+ release from intracellular stores [Zatti, G., Ghidoni, R., Barbiero, L., Binetti, G., Pozzan, T., Fasolato, C., Pizzo, P., 2004. The presenilin 2 M239I mutation associated with Familial Alzheimer's Disease reduces Ca2+ release from intracellular stores. Neurobiol. Dis. 15/2, 269-278]. We here show that in human FAD fibroblasts another PS2 mutation (T122R) reduces both Ca2+ release and capacitative Ca2+ entry. The observation, done in two monozygotic twins, is of note since only one of the subjects showed overt signs of disease at the time of biopsy whereas the other one developed the disease 3 years later. This finding indicates that Ca2+ dysregulation anticipates the onset of dementia. A similar Ca2+ alteration occurred in HeLa and HEK293 cells transiently expressing PS2-T122R. Based on these data, the "Ca2+ overload" hypothesis in AD pathogenesis is here discussed and reformulated.

  6. Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

    PubMed Central

    Rigby, Mark R.; Harris, Kristina M.; Pinckney, Ashley; DiMeglio, Linda A.; Rendell, Marc S.; Felner, Eric I.; Dostou, Jean M.; Gitelman, Stephen E.; Griffin, Kurt J.; Tsalikian, Eva; Gottlieb, Peter A.; Greenbaum, Carla J.; Sherry, Nicole A.; Moore, Wayne V.; Monzavi, Roshanak; Willi, Steven M.; Raskin, Philip; Keyes-Elstein, Lynette; Long, S. Alice; Kanaparthi, Sai; Lim, Noha; Phippard, Deborah; Soppe, Carol L.; Fitzgibbon, Margret L.; McNamara, James; Nepom, Gerald T.; Ehlers, Mario R.

    2015-01-01

    BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D. METHODS. In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS. A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01). CONCLUSIONS. In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. TRIAL REGISTRATION.https://clinicaltrials.gov/ NCT00965458. FUNDING. NIH and Astellas. PMID:26193635

  7. Epigallocatechin gallate delays the onset of type 1 diabetes in spontaneous non-obese diabetic mice.

    PubMed

    Fu, Zhuo; Zhen, Wei; Yuskavage, Julia; Liu, Dongmin

    2011-04-01

    Type 1 diabetes (T1D) results from the autoimmune-mediated destruction of pancreatic β-cells, leading to deficiency of insulin production. Successful islet transplantation can normalise hyperglycaemia in T1D patients; however, the limited availability of the islets, loss of islet cell mass through apoptosis after islet isolation and potential autoimmune destruction of the transplanted islets prevent the widespread use of this procedure. Therefore, the search for novel and cost-effective agents that can prevent or treat T1D is extremely important to decrease the burden of morbidity from this disease. In the present study, we discovered that ( - )-epigallocatechin gallate (EGCG, 0·05 % in drinking-water), the primary polyphenolic component in green tea, effectively delayed the onset of T1D in non-obese diabetic (NOD) mice. At 32 weeks of age, eight (66·7 %) out of twelve mice in the control group developed diabetes, whereas only three (25 %) out of twelve mice in the EGCG-treated group became diabetic (P < 0·05). Consistently, mice supplemented with EGCG had significantly higher plasma insulin levels and survival rate but lower glycosylated Hb concentrations compared with the control animals. EGCG had no significant effects on food or water intake and body weight in mice, suggesting that the glucose-lowering effect was not due to an alteration in these parameters. While EGCG did not modulate insulitis, it elevated the circulating anti-inflammatory cytokine IL-10 level in NOD mice. These findings demonstrate that EGCG may be a novel, plant-derived compound capable of reducing the risk of T1D. PMID:21144096

  8. Potential Risk Factors for the Onset of Complex Regional Pain Syndrome Type 1: A Systematic Literature Review

    PubMed Central

    Shipton, Edward A.; Mulder, Roger T.

    2015-01-01

    Anaesthetists in the acute and chronic pain teams are often involved in treating Complex Regional Pain Syndromes. Current literature about the risk factors for the onset of Complex Regional Pain Syndrome Type 1 (CRPS 1) remains sparse. This syndrome has a low prevalence, a highly variable presentation, and no gold standard for diagnosis. In the research setting, the pathogenesis of the syndrome continues to be elusive. There is a growing body of literature that addresses efficacy of a wide range of interventions as well as the likely mechanisms that contribute to the onset of CRPS 1. The objective for this systematic search of the literature focuses on determining the potential risk factors for the onset of CRPS 1. Eligible articles were analysed, dated 1996 to April 2014, and potential risk factors for the onset of CRPS 1 were identified from 10 prospective and 6 retrospective studies. Potential risk factors for the onset of CRPS 1 were found to include being female, particularly postmenopausal female, ankle dislocation or intra-articular fracture, immobilisation, and a report of higher than usual levels of pain in the early phases of trauma. It is not possible to draw definite conclusions as this evidence is heterogeneous and of mixed quality, relevance, and weighting strength against bias and has not been confirmed across multiple trials or in homogenous studies. PMID:25688265

  9. Acute Versus Progressive Onset of Diabetes in NOD Mice: Potential Implications for Therapeutic Interventions in Type 1 Diabetes.

    PubMed

    Mathews, Clayton E; Xue, Song; Posgai, Amanda; Lightfoot, Yaima L; Li, Xia; Lin, Andrea; Wasserfall, Clive; Haller, Michael J; Schatz, Desmond; Atkinson, Mark A

    2015-11-01

    Most natural history models for type 1 diabetes (T1D) propose that overt hyperglycemia results after a progressive loss of insulin-secreting β-cell mass and/or function. To experimentally address this concept, we prospectively determined morning blood glucose measurements every other day in multiple cohorts (total n = 660) of female NOD/ShiLtJ mice starting at 8 weeks of age until diabetes onset or 26 weeks of age. Consistent with this notion, a majority of mice that developed diabetes (354 of 489 [72%]) displayed a progressive increase in blood glucose with transient excursions >200 mg/dL, followed by acute and persistent hyperglycemia at diabetes onset. However, 135 of the 489 (28%) diabetic animals demonstrated normal glucose values followed by acute (i.e., sudden) hyperglycemia. Interestingly, diabetes onset occurred earlier in mice with acute versus progressive disease onset (15.37 ± 0.3207 vs. 17.44 ± 0.2073 weeks of age, P < 0.0001). Moreover, the pattern of onset (i.e., progressive vs. acute) dramatically influenced the ability to achieve reversal of T1D by immunotherapeutic intervention, with increased effectiveness observed in situations of a progressive deterioration in euglycemia. These studies highlight a novel natural history aspect in this animal model, one that may provide important guidance for the selection of subjects participating in human trials seeking disease reversal. PMID:26216853

  10. In vivo seeding and cross-seeding of localized amyloidosis: a molecular link between type 2 diabetes and Alzheimer disease.

    PubMed

    Oskarsson, Marie E; Paulsson, Johan F; Schultz, Sebastian W; Ingelsson, Martin; Westermark, Per; Westermark, Gunilla T

    2015-03-01

    Several proteins have been identified as amyloid forming in humans, and independent of protein origin, the fibrils are morphologically similar. Therefore, there is a potential for structures with amyloid seeding ability to induce both homologous and heterologous fibril growth; thus, molecular interaction can constitute a link between different amyloid forms. Intravenous injection with preformed fibrils from islet amyloid polypeptide (IAPP), proIAPP, or amyloid-beta (Aβ) into human IAPP transgenic mice triggered IAPP amyloid formation in pancreas in 5 of 7 mice in each group, demonstrating that IAPP amyloid could be enhanced through homologous and heterologous seeding with higher efficiency for the former mechanism. Proximity ligation assay was used for colocalization studies of IAPP and Aβ in islet amyloid in type 2 diabetic patients and Aβ deposits in brains of patients with Alzheimer disease. Aβ reactivity was not detected in islet amyloid although islet β cells express AβPP and convertases necessary for Aβ production. By contrast, IAPP and proIAPP were detected in cerebral and vascular Aβ deposits, and presence of proximity ligation signal at both locations showed that the peptides were <40 nm apart. It is not clear whether IAPP present in brain originates from pancreas or is locally produced. Heterologous seeding between IAPP and Aβ shown here may represent a molecular link between type 2 diabetes and Alzheimer disease.

  11. Historical note on Darwin's consideration of early-onset dementia in older persons, thirty-six years before Alzheimer's initial case report.

    PubMed

    Snyder, Peter J; Pearn, Alison M

    2007-07-01

    In February 1871, the great naturalist Charles Darwin received a letter from Dr. James-Crichton Browne, who was serving as Director of the largest lunatic asylum in England. Darwin had been introduced to Crichton-Browne 2 years earlier by Henry Maudsley, who believed that the young psychiatrist could provide Darwin with clinical examples of extreme emotional expression, to aid him in preparing to write Expression of the Emotions in Man and Animals (1872). This particular letter from Crichton-Browne contained the first and only reference to "premature dotage" or "senile decay" found anywhere in Darwin's entire corpus of correspondence, which amounted to more than 80,000 pages of handwritten letters to nearly 2,000 individuals throughout his lifetime. Moreover, this letter from Crichton-Browne, received by Darwin 36 years before the first case report of senile dementia by Professor Alois Alzheimer, explicitly noted that such premature dotage is the result of "brain wasting." Crichton-Browne believed that senile dementia was the result of a central nervous system disease, with the emotional lability observed in his patients linked inextricably to the disease process. This early hypothesis, of interest to Darwin in 1871, anticipated the groundbreaking neurohistopathologic research and case description by Alzheimer 36 years later, and has been confirmed by all clinical research in this field since 1907. This concordance between psychological symptoms and Alzheimer's disease continues to be an important area of study, leading to recent advances in our understanding of the genetics, neurobiology, and neurochemistry of psychiatric illness in older adults.

  12. IL12RB2 Gene Is Associated with the Age of Type 1 Diabetes Onset in Croatian Family Trios

    PubMed Central

    Pehlić, Marina; Vrkić, Dina; Škrabić, Veselin; Jerončić, Ana; Stipančić, Gordana; Urojić, Anita Špehar; Marjanac, Igor; Jakšić, Jasminka; Kačić, Zrinka; Boraska, Vesna; Zemunik, Tatijana

    2012-01-01

    Background Common complex diseases are influenced by both genetic and environmental factors. Many genetic factors overlap between various autoimmune diseases. The aim of the present study is to determine whether four genetic variants known to be risk variants for several autoimmune diseases could be associated with an increased susceptibility to type 1 diabetes mellitus. Methods and Findings We genotyped four genetic variants (rs2358817, rs1049550, rs6679356, rs9865818) within VTCN1, ANXA11, IL12RB2 and LPP genes respectively, in 265 T1DM family trios in Croatian population. We did not detect association of these polymorphisms with T1DM. However, quantitative transmission disequilibrium test (QTDT, orthogonal model) revealed a significant association between the age of onset of T1DM and IL12RB2 rs6679356 variant. An earlier onset of T1DM was associated with the rs6679356 minor dominant allele C (p = 0.005). The association remained significant even after the Bonferroni correction for multiple testing and permutation. Conclusions Variants originally associated with juvenile idiopathic arthritis (VTCN1 gene), sarcoidosis (ANXA11 gene), primary biliary cirrhosis (IL12RB2 gene) and celiac disease (LPP gene) were not associated with type 1 diabetes in our dataset. Nevertheless, association of IL12RB2 rs6679356 polymorphism with the age of T1DM onset suggests that this gene plays a role in defining the time of disease onset. PMID:23152861

  13. The biological substrates of Alzheimer's disease

    SciTech Connect

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

    1986-01-01

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

  14. Identifying Niemann-Pick type C in early-onset ataxia: two quick clinical screening tools.

    PubMed

    Synofzik, Matthis; Fleszar, Zofia; Schöls, Ludger; Just, Jennifer; Bauer, Peter; Torres Martin, Juan V; Kolb, Stefan

    2016-10-01

    Niemann-Pick disease type C (NP-C) is a rare multisystemic lysosomal disorder which, albeit treatable, is still starkly underdiagnosed. As NP-C features early onset ataxia (EOA) in 85-90 % of cases, EOA presents a promising target group for undiagnosed NP-C patients. Here, we assessed the ability of the previously established NP-C suspicion index (SI) and a novel abbreviated '2/3 SI' tool for rapid appraisal of suspected NP-C in unexplained EOA. This was a retrospective observational study comparing 'NP-C EOA' cases (EOA patients with confirmed NP-C) with non-NP-C EOA controls (EOA patients negative for NP-C gene mutations). NP-C risk prediction scores (RPS) from both the original and 2/3 SIs were calculated and their discriminatory performance evaluated. Among 133 patients (47 NP-C EOA cases; 86 non-NP-C EOA controls), moderate (40-69 points) and high (≥70 points) RPS were common based on original SI assessments in non-NP-C EOA controls [16 (19 %) and 8 (9 %), respectively], but scores ≥70 points were far more frequent [46 (98 %)] among NP-C EOA cases. RPS cut-off values provided 98 % sensitivity and 91 % specificity for NP-C at 70-point cut-off, and ROC analysis revealed an AUC of 0.982. Using the 2/3 SI, 90 % of NP-C EOA cases had scores of 2 or 3, and RPS analysis showed an AUC of 0.961. In conclusion, the NP-C SI and the new, quick-to-apply 2/3 SI distinguished well between NP-C and non-NP-C patients, even in EOA populations with high background levels of broadly NPC-compatible multisystemic disease features. While the original SI showed the greatest sensitivity, both tools reliably aided identification of patients with unexplained EOA who warranted further investigation for NP-C.

  15. Obesity, Islet Cell Autoimmunity, and Cardiovascular Risk Factors in Youth at Onset of Type 1 Autoimmune Diabetes

    PubMed Central

    Cedillo, Maribel; Arena, Vincent C.; Zhou, Lei; Trucco, Massimo; Ize-Ludlow, Diego; Pietropaolo, Massimo; Becker, Dorothy J.

    2015-01-01

    Context: The current increase in childhood type 1 diabetes (T1D) and obesity has led to two conflicting hypotheses and conflicting reports regarding the effects of overweight on initiation and spreading of islet cell autoimmunity vs earlier clinical manifestation of preexisting autoimmune β-cell damage driven by excess weight. Objective: The objective of the study was to address the question of whether the degree of β-cell autoimmunity and age are related to overweight at diabetes onset in a large cohort of T1D youth. Design: This was a prospective cross-sectional study of youth with autoimmune T1D consecutively recruited at diabetes onset. Setting: The study was conducted at a regional academic pediatric diabetes center. Patients: Two hundred sixty-three consecutive children younger than 19 years at onset of T1D participated in the study. Main Outcome Measures: Relationships between body mass index and central obesity (waist circumference and waist to height ratio) and antigen spreading (islet cell autoantibody number), age, and cardiovascular (CVD) risk factors examined at onset and/or 3 months after the diagnosis were measured. Results: There were no significant associations between number of autoantibodies with measures of adiposity. Age relationships revealed that a greater proportion of those with central obesity (21%) were in the youngest age group (0–4 y) compared with those without central obesity (6%) (P = .001). Patients with central obesity had increased CVD risk factors and higher onset C-peptide levels (P < .05). Conclusions: No evidence was found to support the concept that obesity accelerates progression of autoantibody spreading once autoimmunity, marked by standard islet cell autoantibody assays, is present. Central obesity was present in almost one-third of the subjects and was associated with early CVD risk markers already at onset. PMID:25250632

  16. Ketosis onset type 2 diabetes had better islet β-cell function and more serious insulin resistance.

    PubMed

    Lu, Hongyun; Hu, Fang; Zeng, Yingjuan; Zou, Lingling; Luo, Shunkui; Sun, Ying; Liu, Hong; Sun, Liao

    2014-01-01

    Diabetic ketosis had been identified as a characteristic of type 1 diabetes mellitus (T1DM), but now emerging evidence has identified that they were diagnosed as T2DM after long time follow up. This case control study was aimed at comparing the clinical characteristic, β-cell function, and insulin resistance of ketosis and nonketotic onset T2DM and providing evidence for treatment selection. 140 cases of newly diagnosed T2DM patients were divided into ketosis (62 cases) and nonketotic onset group (78 cases). After correction of hyperglycemia and ketosis with insulin therapy, plasma C-peptide concentrations were measured at 0, 0.5, 1, 2, and 3 hours after 75 g glucose oral administration. Area under the curve (AUC) of C-peptide was calculated. Homoeostasis model assessment was used to estimate basal β-cell function (HOMA-β) and insulin resistance (HOMA-IR). Our results showed that ketosis onset group had higher prevalence of nonalcoholic fatty liver disease (NAFLD) than nonketotic group (P = 0.04). Ketosis onset group had increased plasma C-peptide levels at 0 h, 0.5 h, and 3 h and higher AUC(0-0.5), AUC₀₋₁, AUC₀₋₃ (P < 0.05). Moreover, this group also had higher HOMA-β and HOMA-IR than nonketotic group (P < 0.05). From these data, we concluded that ketosis onset T2DM had better islet β-cell function and more serious insulin resistance than nonketotic onset T2DM.

  17. Genetic Association between Presenilin 2 Polymorphisms and Alzheimer's Disease and Dementia of Lewy Body Type in a Japanese Population

    PubMed Central

    Suzuki, Ayako; Shibata, Nobuto; Kasanuki, Koji; Nagata, Tomoyuki; Shinagawa, Shunichiro; Kobayashi, Nobuyuki; Ohnuma, Tohru; Takeshita, Yoshihide; Kawai, Eri; Takayama, Toshiki; Nishioka, Kenya; Motoi, Yumiko; Hattori, Nobutaka; Nakayama, Kazuhiko; Yamada, Hisashi; Arai, Heii

    2016-01-01

    Background/Aims Mutations in the presenilin 2 (PSEN2) gene cause familial Alzheimer's disease (AD). Common polymorphisms affect gene activity and increase the risk of AD. Nonsynonymous polymorphisms in the PSEN2 gene showed Lewy body dementia (LBD) phenotypes clinically. Therefore, we aimed to investigate whether PSEN2 gene polymorphisms were associated with AD or LBD. Methods Seven single nucleotide polymorphisms (SNPs) of the gene were analyzed using a case-control study design comprising 288 AD patients, 76 LBD patients, and 105 age-matched controls. Results Linkage disequilibrium (LD) examination showed strong LD from rs1295645 to rs8383 on the gene in our cases from Japan. There were no associations between the SNPs studied here and AD onset, and haplotypic analyses did not detect genetic associations between AD and the PSEN2 gene. Although the number of the cases was small, the SNPs studied did not modify the risk of developing LBD in a Japanese population. Conclusion The common SNPs of the PSEN2 gene did not affect the risk of AD or LBD in a Japanese population. Because genetic variability of the PSEN2 gene is associated with behavioral and psychological symptoms of dementia (BPSD) in AD and LBD, further detailed analyses considering BPSD of both diseases would be required. PMID:27065294

  18. Ion Acoustic Wave Frequencies and Onset Times During Type 3 Solar Radio Bursts

    NASA Technical Reports Server (NTRS)

    Cairns, Iver H.; Robinson, P. A.

    1995-01-01

    Conflicting interpretations exist for the low-frequency ion acoustic (S) waves often observed by ISEE 3 in association with intense Langmuir (L) waves in the source regions of type III solar radio bursts near 1 AU. Two indirect lines of observational evidence, as well as plasma theory, suggest they are produced by the electrostatic (ES) decay L yields L(PRIME) + S. However, contrary to theoretical predictions, an existing analysis of the wave frequencies instead favors the electromagnetic (EM) decays L yields T + S, where T denotes an EM wave near the plasma frequency. This conflict is addressed here by comparing the observed wave frequencies and onset times with theoretical predictions for the ES and EM decays, calculated using the time-variable electron beam and magnetic field orientation data, rather than the nominal values used previously. Field orientation effects and beam speed variations are shown analytically to produce factor-of-three effects, greater than the difference in wave frequencies predicted for the ES and EM decays; effects of similar magnitude occur in the events analyzed here. The S-wave signals are extracted by hand from a sawtooth noise background, greatly improving the association between S waves and intense L waves. Very good agreement exists between the time-varying predictions for the ES decay and the frequencies of most (but not all) wave bursts. The waves occur only after the ES decay becomes kinematically allowed, which is consistent with the ES decay proceeding and producing most of the observed signals. Good agreement exists between the EM decay's predictions and a significant fraction of the S-wave observations while the EM decay is kinematically allowed. The wave data are not consistent, however, with the EM decay being the dominant nonlinear process. Often the observed waves are sufficiently broadband to overlap simultaneously the frequency ranges predicted for the ES and EM decays. Coupling the dominance of the ES decay with this

  19. Academic Skills in Children with Early-Onset Type 1 Diabetes: The Effects of Diabetes-Related Risk Factors

    ERIC Educational Resources Information Center

    Hannonen, Riitta; Komulainen, Jorma; Riikonen, Raili; Ahonen, Timo; Eklund, Kenneth; Tolvanen, Asko; Keskinen, Paivi; Nuuja, Anja

    2012-01-01

    Aim: The study aimed to assess the effects of diabetes-related risk factors, especially severe hypoglycaemia, on the academic skills of children with early-onset type 1 diabetes mellitus (T1DM). Method: The study comprised 63 children with T1DM (31 females, 32 males; mean age 9y 11mo, SD 4mo) and 92 comparison children without diabetes (40…

  20. Dominance of CTX-M-Type Extended-Spectrum β-Lactamase (ESBL)-Producing Escherichia coli Isolated from Patients with Community-Onset and Hospital-Onset Infection in China

    PubMed Central

    Xia, Shu; Fan, Xin; Huang, Zengguang; Xia, Liang; Xiao, Meng; Chen, Rongchang; Xu, Yingchun; Zhuo, Chao

    2014-01-01

    Objective To investigate CTX-M genotypes among extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) isolated from patients with community-onset and hospital-onset infections in China, their clonality and the distribution of CTX-M variants in different specimens of community-onset and hospital-onset infections. Methods ESBL-EC isolates were collected from general hospitals from 2011 to 2012 in China. Broth microdilution method antimicrobial susceptibility testing of 16 antibiotics was performed. Clinical data from community-onset and hospital-onset infections due to ESBL-EC were analyzed. ESBL-encoding genes were amplified by PCR and sequenced, and multilocus sequence typing (MLST) was performed for a random selection of predominant CTX-M type strains identified. Results A total of 1,168 ESBL-EC isolates were obtained from various clinical specimens, 41.7% of which were responsible for causing community-onset infections. The presence of urinary calculi was higher in community-onset infections, whereas malignancy, cardiovascular and cerebrovascular diseases, dementia, chronic renal disease, diabetes mellitus and surgical treatment were found to have higher proportions in hospital-onset infections. There was no significant difference in trauma between community-onset and hospital-onset infections. 96.2% of the isolates were detected to harbor blaCTX-M genes. blaCTX-M-1 group and blaCTX-M-9 group were detected at 40.7% and 48.7% respectively, and both positive group accounted for 10.6%. blaCTX-M-55 (24.8%) and blaCTX-M-15 (18.2%) were the major genotypes in blaCTX-M-1 group while blaCTX-M-14 (46.8%) was predominant in blaCTX-M-9 group. A comparison of blaCTX-M distribution in different specimens between ESBL-EC causing community-onset and hospital-onset infection showed no significant difference. A total of 229 isolates were tested for MLST. ST131 (14%) was the predominant type. ST648, ST405 and ST1193 were also detected. Conclusions Community-onset ESBL

  1. Rapid Onset of Motor Deficits in a Mouse Model of Spinocerebellar Ataxia Type 6 Precedes Late Cerebellar Degeneration123

    PubMed Central

    Ljungberg, Lovisa; Cormier, Alexander; Quilez, Sabrina

    2015-01-01

    Abstract Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant cerebellar ataxia that has been associated with loss of cerebellar Purkinje cells. Disease onset is typically at midlife, although it can vary widely from late teens to old age in SCA6 patients. Our study focused on an SCA6 knock-in mouse model with a hyper-expanded (84X) CAG repeat expansion that displays midlife-onset motor deficits at ∼7 months old, reminiscent of midlife-onset symptoms in SCA6 patients, although a detailed phenotypic analysis of these mice has not yet been reported. Here, we characterize the onset of motor deficits in SCA684Q mice using a battery of behavioral assays to test for impairments in motor coordination, balance, and gait. We found that these mice performed normally on these assays up to and including at 6 months, but motor impairment was detected at 7 months with all motor coordination assays used, suggesting that motor deficits emerge rapidly during a narrow age window in SCA684Q mice. In contrast to what is seen in SCA6 patients, the decrease in motor coordination was observed without alterations in gait. No loss of cerebellar Purkinje cells or striatal neurons were observed at 7 months, the age at which motor deficits were first detected, but significant Purkinje cell loss was observed in 2-year-old SCA684Q mice, arguing that Purkinje cell death does not significantly contribute to the early stages of SCA6. PMID:26730403

  2. Beta-Amyloid Deposition and Alzheimer's Type Changes Induced by Borrelia Spirochetes

    SciTech Connect

    Miklossy,J.; Kis, A.; Radenovic, A.; Miller, L.; Forro, L.; Martins, R.; Reiss, K.; Darbinian, N.; Darekar, P.; et al.

    2006-01-01

    The pathological hallmarks of Alzheimer's disease (AD) consist of {beta}-amyloid plaques and neurofibrillary tangles in affected brain areas. The processes, which drive this host reaction are unknown. To determine whether an analogous host reaction to that occurring in AD could be induced by infectious agents, we exposed mammalian glial and neuronal cells in vitro to Borrelia burgdorferi spirochetes and to the inflammatory bacterial lipopolysaccharide (LPS). Morphological changes analogous to the amyloid deposits of AD brain were observed following 2-8 weeks of exposure to the spirochetes. Increased levels of {beta}-amyloid presursor protein (A{beta}PP) and hyperphosphorylated tau were also detected by Western blots of extracts of cultured cells that had been treated with spirochetes or LPS. These observations indicate that, by exposure to bacteria or to their toxic products, host responses similar in nature to those observed in AD may be induced.

  3. Mutation of the Alzheimer's Disease Amyloid Gene in Hereditary Cerebral Hemorrhage, Dutch Type

    NASA Astrophysics Data System (ADS)

    Levy, Efrat; Carman, Mark D.; Fernandez-Madrid, Ivan J.; Power, Michael D.; Lieberburg, Ivan; van Duinen, Sjoerd G.; Bots, Gerard Th. A. M.; Luyendijk, Willem; Frangione, Blas

    1990-06-01

    An amyloid protein that precipitates in the cerebral vessel walls of Dutch patients with hereditary cerebral hemorrhage with amyloidosis is similar to the amyloid protein in vessel walls and senile plaques in brains of patients with Alzheimer's disease, Down syndrome, and sporadic cerebral amyloid angiopathy. Cloning and sequencing of the two exons that encode the amyloid protein from two patients with this amyloidosis revealed a cytosine-to-guanine transversion, a mutation that caused a single amino acid substitution (glutamine instead of glutamic acid) at position 22 of the amyloid protein. The mutation may account for the deposition of this amyloid protein in the cerebral vessel walls of these patients, leading to cerebral hemorrhages and premature death.

  4. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type.

    PubMed

    Levy, E; Carman, M D; Fernandez-Madrid, I J; Power, M D; Lieberburg, I; van Duinen, S G; Bots, G T; Luyendijk, W; Frangione, B

    1990-06-01

    An amyloid protein that precipitates in the cerebral vessel walls of Dutch patients with hereditary cerebral hemorrhage with amyloidosis is similar to the amyloid protein in vessel walls and senile plaques in brains of patients with Alzheimer's disease, Down syndrome, and sporadic cerebral amyloid angiopathy. Cloning and sequencing of the two exons that encode the amyloid protein from two patients with this amyloidosis revealed a cytosine-to-guanine transversion, a mutation that caused a single amino acid substitution (glutamine instead of glutamic acid) at position 22 of the amyloid protein. The mutation may account for the deposition of this amyloid protein in the cerebral vessel walls of these patients, leading to cerebral hemorrhages and premature death.

  5. [Dementia of the Alzheimer type: non-drug and drug therapy].

    PubMed

    Kressig, Reto W

    2015-04-01

    The optimal management of Alzheimer's disease (AD) involves a close alliance with AD caregivers and requires early diagnosis, multimodal management, including non-drug and drug interventions, and multispecialty care. Non-pharmacological approaches such as cognitive stimulation programs mostly benefit behavior and psychiatric symptoms in dementia patients. Pharmacologic management of AD consists of eliminating therapeutic redundancies and potentially deleterious medications (Beers Criteria). A pharmacologic foundation of Ginkgo Biloba and combination therapy with a cholinesterase inhibitor and memantine reduces decline in cognition and function, decreases and/or delays the emergence and impact of neuropsychiatric symptoms, postpones institutionalization, and works best when appropriately instituted early and maintained. Despite an existing reimbursement limitation by the health-insurance system in Switzerland, the combination of cholinesterase inhibitor and memantine is possible within the admitted MMSE ranges.

  6. Size matters: a study on naming and size knowledge in dementia of the Alzheimer type.

    PubMed

    Moreno-Martinez, F Javier

    2010-12-01

    Category-specificity was longitudinally studied over a period of 12 months in seven Alzheimer disease patients, with two semantic tasks differing with respect to verbal processing demands: picture naming and a size ordering task. Items from each task were matched on all cognitive and psycholinguistic variables known to differ across domains (living-nonliving). Naming performance of patients was poorer than that of normal controls. Regarding category-specific effects, while naming performance of patients was parallel to that of normal controls, patients' performance with the size ordering task revealed a different scaling of living things while that of nonliving things mirrored performance of normal controls. This suggests that caution is needed when the picture naming task is exclusively used to document category-specific effects. PMID:20544501

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

    PubMed Central

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

    2015-01-01

    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. PMID:25256347

  8. The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD). A mini-review.

    PubMed

    Hoyer, Siegfried

    2002-07-01

    Aging of the brain has been demonstrated to be the main risk factor for late-onset sporadic AD what is in contrast to early-onset familial AD in which mutations predominate the pathology. Aging of the brain was found to be associated with a multitude of aberrancies from normal in morphological, cellular and molecular terms. Recent findings provide clear evidence that the function of the neuronal insulin/insulin receptor signal transduction cascade is of pivotal significance to maintain normal cerebral blood flow and oxidative energy metabolism, work of the endoplasmatic reticulum/Golgi apparatus and the cell cycle in terminally differentiated neurons no longer in the cell cycle. It has become evident that normal metabolism of both amyloid precursor protein and tau-protein is part of interactive processes controlled by the neuronal I/IR signal transduction cascade. In normal brain aging, the function of this cascade starts to fail compared to normal resulting in adverse effects in CBF/oxidative energy metabolism, work of the endoplasmatic reticulum/Golgi apparatus and cell cycle. The aberrancies may not be drastic, but multifold and permanently existing, inclusive the metabolism of APP and tau-protein. The amount of intraneuronally formed betaA4 may increase, and tau-protein may become hyperphosphorylated. These processes as a whole may increase the vulnerability of the aging brain and may facilitate the generation of late-onset sporadic AD. PMID:12111436

  9. Social Network Data Validity: The Example of the Social Network of Caregivers of Older Persons with Alzheimer-Type Dementia*

    PubMed Central

    Carpentier, Normand; Ducharme, Francine

    2010-01-01

    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 factors that might influence the description of the support network by persons involved in caregiving. The issue warrants special attention, given that social relations – in their form and their content – constitute the raw material of network analysis. We propose that how persons describe their social network corresponds to a subjective process that rests, in part, on their representation of their cultural and social universe. PMID:20737030

  10. Genetic heterogeneity and Alzheimer`s disease

    SciTech Connect

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

    1994-09-01

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

  11. Alois Alzheimer on presenile dementia.

    PubMed

    Tonkonogy, J; Moak, G S

    1988-01-01

    The work of Alois Alzheimer on presenile dementia is a landmark in the history of psychiatry not fully appreciated by contemporary psychiatrists. In this paper, the history of his landmark work is reviewed in the context of the growing importance of psychiatric involvement in Alzheimer's disease. Annotated excerpts from Alzheimer's second paper (1911), never before translated into English, are presented. The historical significance of Alzheimer's findings vis-a-vis Kraepelinian psychiatry and the relationship of his investigations to modern psychiatric research in primary degenerative dementia of the Alzheimer type are discussed.

  12. Long-term central pathology and cognitive impairment are exacerbated in a mixed model of Alzheimer's disease and type 2 diabetes.

    PubMed

    Infante-Garcia, Carmen; Ramos-Rodriguez, Juan Jose; Galindo-Gonzalez, Lucia; Garcia-Alloza, Monica

    2016-03-01

    Type 2 diabetes (T2D) is a well-characterized risk factor for Alzheimer's disease (AD), the most common cause of dementia. Since both, T2D and dementia are closely related to aging and they chronically coexist in elderly patients, it is of particular relevance to know whether long-term evolution of T2D and dementia interfere with each other years after the onset of the diseases. In order to elucidate this interaction, we have characterized a mixed model of T2D and AD, the APP/PS1xdb/db mouse, at 36 weeks of age, when both diseases have long coexisted and evolved. In aged APP/PS1xdb/db mice we observed dysfunctional metabolic control, when compared with diabetic mice alone, suggesting that AD may also contribute to T2D pathology in the long-term. Learning and memory were severely impaired in APP/PS1xdb/db mice, accompanied by reduced cortical size, neuronal branching simplification and reduction of dendritic spine density. Increased tau phosphorylation was also observed in old APP/PS1xdb/db mice. A shift in amyloid-β (Aβ) pathology was detected, and while insoluble Aβ was reduced, more toxic soluble species were favoured. Microglia burden was significantly increased in the proximity of senile plaques and an overall increase of spontaneous haemorrhages was also observed in APP/PS1xdb/db mice, suggesting a possible disruption of the blood brain barrier in the mixed model. It is therefore feasible that strict metabolic control may slow or delay central complications when T2D and dementia coexist in the long term. PMID:26708068

  13. Potential contribution of the Alzheimer's disease risk locus BIN1 to episodic memory performance in cognitively normal Type 2 diabetes elderly.

    PubMed

    Greenbaum, Lior; Ravona-Springer, Ramit; Lubitz, Irit; Schmeidler, James; Cooper, Itzik; Sano, Mary; Silverman, Jeremy M; Heymann, Anthony; Beeri, Michal Schnaider

    2016-04-01

    In recent years, several promising susceptibility loci for late-onset Alzheimer's disease (AD) were discovered, by implementing genome-wide association studies (GWAS) approach. Recent GWAS meta-analysis has demonstrated the association of 19 loci (in addition to the APOE locus) with AD in the European ancestry population at genome-wide significance level. Since Type 2 Diabetes (T2D) is a substantial risk factor for cognitive decline and dementia, the 19 single nucleotide polymorphisms (SNPs) that represent the 19 AD loci were studied for association with performance in episodic memory, a primary cognitive domain affected by AD, in a sample of 848 cognitively normal elderly Israeli Jewish T2D patients. We found a suggestive association of SNP rs6733839, located near the bridging integrator 1 (BIN1) gene, with this phenotype. Controlling for demographic (age, sex, education, disease duration and ancestry) covariates, carriers of two copies of the AD risk allele T (TT genotype) performed significantly worse (p=0.00576; p=0.00127 among Ashkenazi origin sub-sample) in episodic memory compared to carriers of the C allele (CT+CC genotypes). When including additional potential covariates (clinical and APOE genotype), results remained significant (p=0.00769; p=0.00148 among Ashkenazi). Interestingly, as validated in multiple large studies, BIN1 is one of the most established AD risk loci, with a high odds ratio. Although preliminary and require further replications, our findings support a contribution of BIN1 to individual differences in episodic memory performance among T2D patients. PMID:26947052

  14. Common mechanisms involved in Alzheimer's disease and type 2 diabetes: a key role of chronic bacterial infection and inflammation

    PubMed Central

    Miklossy, Judith; McGeer, Patrick L.

    2016-01-01

    Strong epidemiologic evidence and common molecular mechanisms support an association between Alzheimer's disease (AD) and type 2-diabetes. Local inflammation and amyloidosis occur in both diseases and are associated with periodontitis and various infectious agents. This article reviews the evidence for the presence of local inflammation and bacteria in type 2 diabetes and discusses host pathogen interactions in chronic inflammatory disorders. Chlamydophyla pneumoniae, Helicobacter pylori and spirochetes are demonstrated in association with dementia and brain lesions in AD and islet lesions in type 2 diabetes. The presence of pathogens in host tissues activates immune responses through Toll-like receptor signaling pathways. Evasion of pathogens from complement-mediated attack results in persistent infection, inflammation and amyloidosis. Amyloid beta and the pancreatic amyloid called amylin bind to lipid bilayers and produce Ca(2+) influx and bacteriolysis. Similarly to AD, accumulation of amylin deposits in type 2 diabetes may result from an innate immune response to chronic bacterial infections, which are known to be associated with amyloidosis. Further research based on an infectious origin of both AD and type 2 diabetes may lead to novel treatment strategies. PMID:26961231

  15. Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations.

    PubMed

    Mancini, Cecilia; Nassani, Stefano; Guo, Yiran; Chen, Yulan; Giorgio, Elisa; Brussino, Alessandro; Di Gregorio, Eleonora; Cavalieri, Simona; Lo Buono, Nicola; Funaro, Ada; Pizio, Nicola Renato; Nmezi, Bruce; Kyttala, Aija; Santorelli, Filippo Maria; Padiath, Quasar Salem; Hakonarson, Hakon; Zhang, Hao; Brusco, Alfredo

    2015-01-01

    Autosomal recessive inherited ataxias are a growing group of genetic disorders. We report two Italian siblings presenting in their mid-50s with difficulty in walking, dysarthria and progressive cognitive decline. Visual loss, ascribed to glaucoma, manifested a few years before the other symptoms. Brain MRI showed severe cerebellar atrophy, prevalent in the vermis, with marked cortical atrophy of both hemispheres. Exome sequencing identified a novel homozygous mutation (c.935G > A;p.Ser312Asn) in the ceroid neuronal lipofuscinosis type 5 gene (CLN5). Bioinformatics predictions and in vitro studies showed that the mutation was deleterious and likely affects ER-lysosome protein trafficking. Our findings support CLN5 hypomorphic mutations cause autosomal recessive cerebellar ataxia, confirming other reports showing CLN mutations are associated with adult-onset neurodegenerative disorders. We suggest CLN genes should be considered in the molecular analyses of patients presenting with adult-onset autosomal recessive cerebellar ataxia.

  16. MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium.

    PubMed

    Pastor, Pau; Moreno, Fermín; Clarimón, Jordi; Ruiz, Agustín; Combarros, Onofre; Calero, Miguel; López de Munain, Adolfo; Bullido, Maria J; de Pancorbo, Marian M; Carro, Eva; Antonell, Anna; Coto, Eliecer; Ortega-Cubero, Sara; Hernandez, Isabel; Tárraga, Lluís; Boada, Mercè; Lleó, Alberto; Dols-Icardo, Oriol; Kulisevsky, Jaime; Vázquez-Higuera, José Luis; Infante, Jon; Rábano, Alberto; Fernández-Blázquez, Miguel Ángel; Valentí, Meritxell; Indakoetxea, Begoña; Barandiarán, Myriam; Gorostidi, Ana; Frank-García, Ana; Sastre, Isabel; Lorenzo, Elena; Pastor, María A; Elcoroaristizabal, Xabier; Lennarz, Martina; Maier, Wolfang; Rámirez, Alfredo; Serrano-Ríos, Manuel; Lee, Suzee E; Sánchez-Juan, Pascual

    2015-01-01

    The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD. PMID:26444794

  17. MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium.

    PubMed

    Pastor, Pau; Moreno, Fermín; Clarimón, Jordi; Ruiz, Agustín; Combarros, Onofre; Calero, Miguel; López de Munain, Adolfo; Bullido, Maria J; de Pancorbo, Marian M; Carro, Eva; Antonell, Anna; Coto, Eliecer; Ortega-Cubero, Sara; Hernandez, Isabel; Tárraga, Lluís; Boada, Mercè; Lleó, Alberto; Dols-Icardo, Oriol; Kulisevsky, Jaime; Vázquez-Higuera, José Luis; Infante, Jon; Rábano, Alberto; Fernández-Blázquez, Miguel Ángel; Valentí, Meritxell; Indakoetxea, Begoña; Barandiarán, Myriam; Gorostidi, Ana; Frank-García, Ana; Sastre, Isabel; Lorenzo, Elena; Pastor, María A; Elcoroaristizabal, Xabier; Lennarz, Martina; Maier, Wolfang; Rámirez, Alfredo; Serrano-Ríos, Manuel; Lee, Suzee E; Sánchez-Juan, Pascual

    2015-01-01

    The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.

  18. Recessive mutations in PCBD1 cause a new type of early-onset diabetes.

    PubMed

    Simaite, Deimante; Kofent, Julia; Gong, Maolian; Rüschendorf, Franz; Jia, Shiqi; Arn, Pamela; Bentler, Kristi; Ellaway, Carolyn; Kühnen, Peter; Hoffmann, Georg F; Blau, Nenad; Spagnoli, Francesca M; Hübner, Norbert; Raile, Klemens

    2014-10-01

    Mutations in several genes cause nonautoimmune diabetes, but numerous patients still have unclear genetic defects, hampering our understanding of the development of the disease and preventing pathogenesis-oriented treatment. We used whole-genome sequencing with linkage analysis to study a consanguineous family with early-onset antibody-negative diabetes and identified a novel deletion in PCBD1 (pterin-4 α-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 α), a gene that was recently proposed as a likely cause of diabetes. A subsequent reevaluation of patients with mild neonatal hyperphenylalaninemia due to mutations in PCBD1 from the BIODEF database identified three additional patients who had developed HNF1A-like diabetes in puberty, indicating early β-cell failure. We found that Pcbd1 is expressed in the developing pancreas of both mouse and Xenopus embryos from early specification onward showing colocalization with insulin. Importantly, a morpholino-mediated knockdown in Xenopus revealed that pcbd1 activity is required for the proper establishment of early pancreatic fate within the endoderm. We provide the first genetic evidence that PCBD1 mutations can cause early-onset nonautoimmune diabetes with features similar to dominantly inherited HNF1A-diabetes. This condition responds to and can be treated with oral drugs instead of insulin, which is important clinical information for these patients. Finally, patients at risk can be detected through a newborn screening for phenylketonuria.

  19. Molecular and clinical correlations in spinocerebellar ataxia type I: Evidence for familial effects on the age at onset

    SciTech Connect

    Ranum, L.P.W.; Chung, M.; Schut, L.J.; Duvick, L.A. ); Banfi, S.; McCall, A. ); Bryer, A.; Ramesar, R.; Subramony, S.H.; Goldfarb, L.

    1994-08-01

    The spinocerebellar ataxias are a group of debilitating neurodegenerative diseases for which a clinical classification system has proved unreliable. The authors have recently isolated the gene for spinocerebellar ataxia type 1 (SCA1) and have shown that the disease is caused by an expanded, unstable, CAG trinucleotide repeat within an expressed gene. Normal alleles have a size range of 19-36 repeats, while SCA1 alleles have 42-81 repeats. In this study, they examined the frequency and variability of the SCA1 repeat expansion in 87 kindreds with diverse ethnic backgrounds and dominantly inherited ataxia. All nine families for which linkage to the SCA1 region of 6p had previously been established showed repeat expansion, while 3 of the remaining 78 showed a similar abnormality. For 113 patients from the families with repeat expansion, inverse correlations between CAG repeat size and both age at onset and disease duration were observed. Repeat size accounted for 66% of the variation in age at onset in these patients. After correction for repeat size, interfamilial differences in age at onset remained significant, suggesting that additional genetic factors affect the expression of the SCA1 gene product. 48 refs., 4 figs.

  20. The amnestic syndrome of hippocampal type in Alzheimer's disease: an MRI study.

    PubMed

    Sarazin, Marie; Chauviré, Valérie; Gerardin, Emilie; Colliot, Olivier; Kinkingnéhun, Serge; de Souza, Leonardo Cruz; Hugonot-Diener, Laurence; Garnero, Line; Lehéricy, Stéphane; Chupin, Marie; Dubois, Bruno

    2010-01-01

    The Free and Cued Selective Reminding Test (FCSRT) is a verbal episodic memory test used to identify patients with mild Alzheimer's disease (AD). The present study investigates the relationships between performance on FCSRT and grey matter atrophy assessed with structural MRI in patients with AD. Three complementary MRI-based analyses (VBM analysis, ROI-based analysis, and three-dimensional hippocampal surface-based shape analysis) were performed in 35 patients with AD to analyze correlations between regional atrophy and their scores for episodic memory using the FCSRT. With VBM analysis, the total score on the FCSRT was correlated with left medial temporal lobe atrophy including the left hippocampus but also the thalami. In addition, using ROI-based analysis, the total recall score on the FCSRT was correlated with the left hippocampal volume. With three-dimensional hippocampal surface-based shape analysis, both free recall and total recall scores were correlated with regions corresponding approximately to the CA1 field. No correlation was found with short term memory scores using any of these methods of analysis. In AD, the FCSRT may be considered as a useful clinical marker of memory disorders due to medial temporal damage, specially the CA1 field of the hippocampus. PMID:20847406

  1. Effect of Gallic Acid on Dementia Type of Alzheimer Disease in Rats: Electrophysiological and Histological Studies

    PubMed Central

    Hajipour, Somayeh; Sarkaki, Alireza; Farbood, Yaghoob; Eidi, Akram; Mortazavi, Pejman; Valizadeh, Zohreh

    2016-01-01

    Introduction: To study the effect of gallic acid (GA) on hippocampal long-term potentiation (LTP) and histological changes in animal model of Alzheimer disease (AD) induced by beta-amyloid (Aβ). Methods: Sixty-four adult male Wistar rats (300±20 g) were divided into 8 groups: 1) Control (Cont); 2) AD; 3) Sham; 4–7) AD+GA (50, 100, and 200 mg/kg for 10 days, orally) or vehicle, 8) Cont+GA100, Aβ (1μg/μL in each site) was infused into hippocampus bilaterally. Changes of amplitude and slope of LTP induced in hippocampal dentate gyrus (DG) were evaluated by high frequency stimulation (HFS) of perforant path (PP). Results: Data showed that LTP amplitude and area under curve significantly impaired in AD rats (P<0.001), while significantly improved in AD rats treated with GA (P<0.05, P<0.01). Conclusion: Current findings suggest that GA reduces neural damage and brain amyloid neuropathology and improves cognitive function via free radicals scavenging and inhibiting oligomerization of Aβ but with no effect on healthy rats. PMID:27303604

  2. Similar pattern of peripheral neuropathy in mouse models of type 1 diabetes and Alzheimer's disease.

    PubMed

    Jolivalt, C G; Calcutt, N A; Masliah, E

    2012-01-27

    There is an increasing awareness that diabetes has an impact on the CNS and that diabetes is a risk factor for Alzheimer's disease (AD). Links between AD and diabetes point to impaired insulin signaling as a common mechanism leading to defects in the brain. However, diabetes is predominantly characterized by peripheral, rather than central, neuropathy, and despite the common central mechanisms linking AD and diabetes, little is known about the effect of AD on the peripheral nervous system (PNS). In this study, we compared indexes of peripheral neuropathy and investigated insulin signaling in the sciatic nerve of insulin-deficient mice and amyloid precursor protein (APP) overexpressing transgenic mice. Insulin-deficient and APP transgenic mice displayed similar patterns of peripheral neuropathy with decreased motor nerve conduction velocity, thermal hypoalgesia, and loss of tactile sensitivity. Phosphorylation of the insulin receptor and glycogen synthase kinase 3β (GSK3β) was similarly affected in insulin-deficient and APP transgenic mice despite significantly different blood glucose and plasma insulin levels, and nerve of both models showed accumulation of Aβ-immunoreactive protein. Although diabetes and AD have different primary etiologies, both diseases share many abnormalities in both the brain and the PNS. Our data point to common deficits in the insulin-signaling pathway in both neurodegenerative diseases and support the idea that AD may cause disorders outside the higher CNS.

  3. Association of tripartite motif family-like 2 (TRIML2) polymorphisms with late-onset Alzheimer's disease risk in a Korean population.

    PubMed

    Kang, Won Sub; Park, Jin Kyung; Kim, Young Jong; Cho, Ah Rang; Park, Hae Jeong; Kim, Su Kang; Paik, Jong-Woo; Lee, Kang Joon; Na, Hae Ri; Kim, Young Youl; Lim, Hyun Kook; Jeong, Hyun-Ghang; Kim, Jong Woo

    2016-09-01

    Apoptosis is a prominent feature in the progression of Alzheimer's disease (AD), regulated in part by the activity of p53. As tripartite motif family-like 2 (TRIML2), a member of the TRIM family of proteins, has been implicated in the regulation of p53-mediated apoptosis, we hypothesized that TRIML2 polymorphisms may result in an increased AD susceptibility. Here, we investigated the association between coding region single nucleotide polymorphisms (cSNPs) in TRIML2 and AD in a Korean population. Two cSNPs (rs79698746 and rs2279551) were genotyped using the Sequenom iPLEX(®) Gold assay and direct sequencing in 162 AD patients and 191 controls. Multiple logistic regression models were used to determine the odds ratios, 95% confidence intervals, and p-values. Significant associations were observed between AD and the allelic frequencies of two SNPs (rs79698746, p=0.007; rs2279551, p=0.01); genotype frequencies were also significantly different between the two groups [rs79698746: p=0.003 in the codominant 2 model (CC vs. TT), p=0.01 in the dominant model (TC/CC vs. TT), p=0.016 in the recessive model (CC vs. TT/TC), and p=0.0025 in the log-additive model (TC vs. CC vs. TT); rs2279551: p=0.003 in the codominant 2 model (CC vs. TT), p=0.011 in the dominant model (TC/CC vs. TT), p=0.019 in the recessive model (CC vs. TT/TC), and p=0.0028 in the log-additive model (TC vs. CC vs. TT)]. In the haplotype analyses, CC haplotypes containing two cSNPs were significantly associated with AD (p=0.013). Taken together, these findings indicate that the C allele of both SNPs was associated with an increased risk of AD. These results suggest that TRIML2 may contribute to AD susceptibility. PMID:27471163

  4. [Diabetic ketoacidosis with a fatal issue: is it a MODY3 (maturity-onset diabetes of the young type 3)?].

    PubMed

    Dehan, C; Tran Van, D; Delacour, H; Deroudilhe, G; Fritsch, N; Chiappini, J; Dardare, E; Gardet, V

    2008-01-01

    Ketoacidotic coma is one of the possible diabetes mellitus first symptoms. It results from complete or relative lack of insuline and is often associated with type 1 diabetes. The authors report a case of a 45-years old woman with inaugural diabetes of which atypical features have motivated the study of MODY gene (maturity-onset diabetes of the young). Gly574ser polymorphism in the HNF-1alpha gene was found, in homozygous state, and the question of the responsibility of this polymorphism in this diabete is asked. PMID:18390429

  5. Comprehensive Analysis of APOE and Selected Proximate Markers for Late-onset Alzheimer Disease: Pattern of Linkage Disequilibrium and Disease/Marker Association

    PubMed Central

    Yu, Chang-En; Seltman, Howard; Peskind, Elaine R.; Galloway, Nichole; Zhou, Peter X.; Rosenthal, Elisabeth; Wijsman, Ellen M.; Tsuang, Debby W.; Devlin, Bernie; Schellenberg, Gerard D.

    2007-01-01

    The ε4 allele of APOE confers a two- to four-fold increased risk for late-onset Alzheimer’s disease (LOAD), but LOAD pathology does not all fit neatly around APOE. It is conceivable that genetic variation proximate to APOE contributes to LOAD risk. Therefore, we investigated the degree of linkage disequilibrium (LD) for a comprehensive set of 50 SNPs in and surrounding the APOE using a substantial Caucasian sample of 1100 chromosomes. SNPs in APOE were further molecular haplotyped to determine their phases. One set of SNPs in TOMM40, roughly 15 Kb upstream of APOE, showed intriguing LD with the ε4 allele, and were strongly associated with the risk for developing AD. However, when all the SNPs were entered into a logit model, only the effect of APOE ε4 remained significant. These observations diminish the possibility that loci in the TOMM40 may have a major effect on the risk of LOAD in Caucasians. PMID:17434289

  6. Youth-Onset Type 2 Diabetes Consensus Report: Current Status, Challenges, and Priorities.

    PubMed

    Nadeau, Kristen J; Anderson, Barbara J; Berg, Erika G; Chiang, Jane L; Chou, Hubert; Copeland, Kenneth C; Hannon, Tamara S; Huang, Terry T-K; Lynch, Jane L; Powell, Jeff; Sellers, Elizabeth; Tamborlane, William V; Zeitler, Philip

    2016-09-01

    Type 2 diabetes is a significant and increasing burden in adolescents and young adults. Clear strategies for research, prevention, and treatment of the disease in these vulnerable patients are needed. Evidence suggests that type 2 diabetes in children is different not only from type 1 but also from type 2 diabetes in adults. Understanding the unique pathophysiology of type 2 diabetes in youth, as well as the risk of complications and the psychosocial impact, will enable industry, academia, funding agencies, advocacy groups, and regulators to collectively evaluate both current and future research, treatment, and prevention approaches. This Consensus Report characterizes type 2 diabetes in children, evaluates the fundamental differences between childhood and adult disease, describes the current therapeutic options, and discusses challenges to and approaches for developing new treatments. PMID:27486237

  7. The role of glycogen synthase kinase 3 in the early stages of Alzheimers' disease.

    PubMed

    Hernández, Félix; Avila, Jesús

    2008-11-26

    There are two different types of Alzheimers' disease, familiar Alzheimers' disease (FAD) and Sporadic Alzheimers' disease (SAD), and the origin of the disease could be different in both familial and sporadic cases. In terms of FAD, mutations in three different genes are likely to promote the onset of the disease whereas for SAD, different risk factors might be involved. Nevertheless, downstream of the initial causes of the disease some common factors may be involved. In this review, rather than the differences, we have focused on some of the common features shared by Alzheimers' patients, irrespective of the origin of their disorder. Among these common features, at the molecular level, the activation of the protein kinase GSK3 may be relevant.

  8. GSTO1*E155del polymorphism associated with increased risk for late-onset Alzheimer's disease: association hypothesis for an uncommon genetic variant.

    PubMed

    Piacentini, Sara; Polimanti, Renato; Squitti, Rosanna; Mariani, Stefania; Migliore, Simone; Vernieri, Fabrizio; Rossini, Paolo Maria; Manfellotto, Dario; Fuciarelli, Maria

    2012-01-11

    Glutathione S-transferases are multifunctional enzymes involved in cellular detoxification. A genetic linkage was found between Alzheimer's Disease (AD) and the chromosome 10q, where the GSTO1 and GSTO2 genes are located, leading to the hypothesis that GST Omega class (GSTO) genes may be an AD risk factor. Since it is still controversial, we decided to explore GSTO polymorphisms in Italian cohorts. We analyzed 119 AD patients and 114 healthy controls for the GSTO gene polymorphisms. In particular we investigated two common polymorphisms (GSTO1*A140D, GSTO2*N142D) and two uncommon variants (GSTO1*E155del, GSTO1*E208K) to find loci associated with AD risk. Detection of GSTO1*A140D and GSTO2*N142D was performed by PCR-RFLP, while GSTO1*E155del and GSTO1*E208K were detected using confronting two-pair primer and allele specific PCR, respectively. While GSTO1*A140D, GSTO1*E208K and GSTO2*N142D polymorphisms did not show significant outcomes, the GSTO1*E155del polymorphism is associated with AD [P=0.003; adjusted OR=3.70 (1.57-8.75)]. Our results suggest that GSTO1-1 plays a role in AD since the GSTO1*del155 variant is involved in changes in GSTO1-1 activities decreasing in enzyme stability. Specifically, three hypotheses may explain the role of GSTO1-1 in the pathophysiology of AD: the antioxidant activity of GSTO1-1 may protect brain tissue against oxidative stress; GSTO1-1 activity regulate interleukin-1β activation and its genetic variation may act to modulate inflammation in AD; GSTO1-1 is involved in the arsenic biotransformation pathway and gene polymorphisms may be implicated in the modulation of arsenic neurotoxicity. In conclusion, we hypothesized that GSTO1*E155del is an uncommon genetic variant associated with AD risk. PMID:22100662

  9. [Update on Alzheimer's disease].

    PubMed

    Dubois, B

    2009-03-01

    As the general population ages, the prevalence of Alzheimer's disease increases steadily. In France, 850,000 people are affected, with an annual incidence of 165,000 new cases. It is estimated that in 2020, 1.2 million people will be concerned in France. Nearly half of these patients, about 400,000, will have moderate to severe disease. These figures, issuing from the Eurodem group and the Paquid study, are estimates but clearly forecast an increase in upcoming years. While the disease generally affects elderly subjects, it is also known to occur early, before the age of 60. Nearly 20,000 patients will have an early onset form of the disease. Alzheimer's disease is first and foremost a brain disease, with lesions starting early in life. These early onset forms raise difficult diagnostic problems since these patients' problems are often mistakenly thought to arise from psychiatric disorders and treated as such in institutions inadapted to the patients' conditions.

  10. Sex Dimorphism Profile of Alzheimer's Disease-Type Pathologies in an APP/PS1 Mouse Model.

    PubMed

    Jiao, Shu-Sheng; Bu, Xian-Le; Liu, Yu-Hui; Zhu, Chi; Wang, Qing-Hua; Shen, Lin-Lin; Liu, Cheng-Hui; Wang, Ye-Ran; Yao, Xiu-Qing; Wang, Yan-Jiang

    2016-02-01

    Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by parenchymal and vascular beta-amyloid (Aβ) burden, tau pathology, neuroinflammation, and loss of neurons and synapses. There is a clear sex difference in the prevalence of AD. However, sex differences in AD-type pathologies have not been systematically documented. Applying 12-month-old female and male APP/PS1 mice as a model, we investigated the sex dimorphism in these major pathological indices. Compared with male APP/PS1 mice, the females exhibited higher parenchymal Aβ burdens, with the sex difference in hippocampus being the most significant. Female APP/PS1 mice had more severe cerebral amyloid angiopathy and subsequent microhemorrhage. In addition, female APP/PS1 mice also showed higher levels of phosphorylated tau and proinflammatory cytokines, more severe astrocytosis and microgliosis, and greater neuronal and synaptic degenerations. The present study systematically described a sex dimorphism in AD-type pathologic indices, suggesting that gender should be taken into account in designing studies involving these pathological indices and when interpreting the relevant findings in those studies.

  11. [Psychometric speech studies in Alzheimer's dementia with the Aachen aphasia test].

    PubMed

    Lang, C; Bozikake-Leisch, E; Spambalg, M; Bartelsen, P; Treig, T

    1991-10-01

    Dementias of the Alzheimer type seem to be frequently accompanied by language disturbances. These may represent a feature which can be of help in distinguishing them from other types of dementias. We used the Aachen aphasia test in 32 patients suffering from Alzheimer dementia according to research criteria, and a mixed sample of 35 patients suffering from other dementias. From these 2 groups 2 subsamples of 21 patients each were gathered which were comparable with regard to age, disease onset, level of education, verbal intelligence and severity of senility. Nevertheless it was possible to distinguish the groups to a certain degree on grounds of psychometric language criteria alone. Alzheimer patients were more severely handicapped communicatively, less dysarthric, produced more automatisms and discretely more phonemic paraphasias with fluent speech which was sometimes paragrammatic. A relatively better level of repetition compared to the Token test and written language was fairly specific. A computer-assisted classification yielded language disturbances similar to Wernicke's aphasia more often than with non-Alzheimer dementias. We found no Alzheimer patients with a Broca's type of language disorder, while amnestic and global types were bound to the level of overall impairment to a certain degree. The significance of these results with regard to the use of psychometric language test in the dementias, particularly Alzheimer's dementia, and to differential diagnostic considerations are reviewed briefly.

  12. Establishing genomic/transcriptomic links between Alzheimer's disease and type 2 diabetes mellitus by meta-analysis approach.

    PubMed

    Mirza, Zeenat; Kamal, Mohammad A; Buzenadah, Adel M; Al-Qahtani, Mohammed H; Karim, Sajjad

    2014-04-01

    Meta-analysis methods exist for combining multiple microarray datasets. However, there are a wide range of issues associated with microarray meta-analysis and a limited ability to compare the performance of different metaanalysis methods. Using cDNA microarray technology (Partek Genomics Suite 6.6) and global pathway analysis with Ingenuity Pathway Analysis tool (IPA, Inc), we examined the transcript level in type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) patients and controls. To understand the molecular link between T2DM and AD, we compared the gene expression pattern and pathway involved. Microarray analysis identified 235 differentially expressed genes between T2DM patients and controls; and 834 between AD and controls at two fold change and a false discovery rate of 0.05. Significantly changed expression of "myeloid leukemia cell differentiation protein 1; RAS guanyl releasing protein 1; S100 calcium-binding protein A8; prostaglandin- endoperoxide synthase 2; parvalbumin; endoplasmic reticulum aminopeptidase 1; phosphoglycerate kinase 1; Eukaryotic translation initiation factor 3 subunit F; Interleukin-1 beta; tubulin, beta 2A; glycine receptor alpha 1 and ribosomal protein S24" genes were highly associated with T2DM, whereas "neuronal differentiation 6; G-protein coupled receptor 83; phosphoserine phosphatase; bobby sox homolog or HMG box -containing protein 2; Glutathione S-transferase theta 1; alpha-2-glycoprotein 1 zinc-binding; Heat shock 70kDa protein 1B; transportin 1, Acidic leucine-rich nuclear phosphoprotein 32 family member B; Nuclear factor of activated T-cells 5; inositol 1,4,5-trisphosphate 3-kinase B; prenylcysteine oxidase 1 like" were found to be strongly related with AD. We also found a set of differentially expressed genes; "ARP2 actin-related protein 2; Cell division control protein 42; cytoplasmic polyadenylation element binding protein 4; Early growth response protein 1; ectonucleotide pyrophosphatase/phosphodiesterase 5

  13. Sporadic infantile-onset spinocerebellar ataxia caused by missense mutations of the inositol 1,4,5-triphosphate receptor type 1 gene.

    PubMed

    Sasaki, Masayuki; Ohba, Chihiro; Iai, Mizue; Hirabayashi, Shinichi; Osaka, Hitoshi; Hiraide, Takuya; Saitsu, Hirotomo; Matsumoto, Naomichi

    2015-05-01

    Mutations in the inositol 1,4,5-triphosphate receptor type 1 gene (ITPR1) have been identified in families with early-onset spinocerebellar ataxia type 29 (SCA29) and late-onset SCA15, but have not been found in sporadic infantile-onset cerebellar ataxia. We examined if mutations of ITPR1 are also involved in sporadic infantile-onset SCA. Sixty patients with childhood-onset cerebellar atrophy of unknown etiology and their families were examined by whole-exome sequencing. We found de novo heterozygous ITPR1 missense mutations in four unrelated patients with sporadic infantile-onset, nonprogressive cerebellar ataxia. Patients displayed nystagmus, tremor, and hypotonia from very early infancy. Nonprogressive ataxia, motor delay, and mild cognitive deficits were common clinical findings. Brain magnetic resonance imaging revealed slowly progressive cerebellar atrophy. ITPR1 missense mutations cause infantile-onset cerebellar ataxia. ITPR1-related SCA includes sporadic infantile-onset cerebellar ataxia as well as SCA15 and SCA29.

  14. The Effect of Resting Heart Rate on the New Onset of Microalbuminuria in Patients With Type 2 Diabetes

    PubMed Central

    Schmieder, Roland E.; Bramlage, Peter; Haller, Hermann; Ruilope, Luis M.; Böhm, Michael

    2016-01-01

    Abstract The association between resting heart rate and new-onset microalbuminuria in patients with type 2 diabetes is not clear. The objective of the current analysis was to assess the relationship between heart rate and incidence of microalbuminuria in patients with type 2 diabetes. Data from the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study were retrospectively analyzed. New-onset microalbuminuria was documented and related to heart rate as recorded at baseline and last assessment, and the mean of the measurements taken during the double-blind part of the ROADMAP trial. Patients (n = 4299) had a mean age of 57.8 ± 8.7 years and 46.3% were male. Characteristics were not different between the olmesartan and the placebo groups, except for a higher systolic blood pressure (136.7 vs 135.7 mm Hg; P = 0.04) and albumin creatinine ratio (5.9 vs 5.5; P = 0.03). Increased risk of microalbuminuria was found with increasing heart rate, independent of whether baseline [highest vs lowest quartile odds ratio (OR) 1.39; 95% confidence interval (95% CI) 1.03–1.87; P = 0.032], last assessment (OR 1.71; 95% CI 1.26–2.31; P = 0.001), or mean heart rate was considered (OR: 1.77; 95% CI: 1.30–2.41; P = 0.0003). The greater risk of new-onset microalbuminuria with a high baseline heart rate was also found when data were adjusted for mean systolic blood pressure (OR: 1.35; 95% CI: 1.00–1.82; P = 0.0496; interaction P < 0.0001). Although there was no risk increase with baseline heart rate in the placebo group (P = 0.8253 for trend), microalbuminuria was less frequent in patients receiving olmesartan in the low heart rate quartiles (P = 0.002 for trend). A low heart rate reduces the risk of patients with type 2 diabetes developing microalbuminuria, independent of blood pressure. The data demonstrate potential benefits of reducing the heart rate of type 2 diabetes patients, and indicate that olmesartan

  15. Weight trajectory of youth with new-onset type 1 diabetes comparing standard and enhanced dietary education.

    PubMed

    Majumdar, Indrajit; Bethin, Kathleen; Quattrin, Teresa

    2015-05-01

    Youth with type 1 diabetes (T1DM) gain weight after insulin therapy initiation. We aimed to study the effects of Enhanced Dietary Counseling (EDC) compared to Standard of Care Dietary Counseling (SDC) on BMI trajectory in youth with new-onset T1DM. Youth with new-onset T1DM (n = 47; 8.9 + 4.2 years) were randomized 6 weeks post-diagnosis to either SDC per American Diabetes Association guidelines (n = 25) or EDC (n = 22: SDC plus monthly nutritional education and 3-day food records (FRs) at 6 and 24 weeks). Weights and heights were measured at diagnosis, 6 weeks, 3, 6, and 12 months post-diagnosis; pre-diagnosis BMI was obtained from pediatricians' records. BMI Z score was used to track BMI change. Knowledge of recommended daily energy intake (DEI) and daily carbohydrate intake was assessed at follow-up visits. Changes in BMI Z scores were similar in SDC versus EDC subjects from pre-diagnosis to 12 months post-diagnosis. BMI Z score at 12 months exceeded pre-diagnosis level in 58.5 % subjects (54.5 % EDC vs. 63.1 % SDC, p = 0.75). From 6 weeks to 6 months, percentage of subjects correctly recalling recommended DEI increased in EDC along with percentage of subjects meeting recommended daily fruit servings intake from 25 % (6 weeks) to 64 % (6 months), p = 0.047). EDC did not prevent BMI Z score increases in youth with new-onset T1DM, and BMI Z score exceeded pre-diagnosis levels in >50 % 12 months post-diagnosis. A family-based approach and/or additional intervention may be needed to prevent excessive weight gain.

  16. RECENT INCIDENCE OF TYPE 1 DIABETES MELLITUS IN MONTENEGRO: A SHIFT TOWARD YOUNGER AGE AT DISEASE ONSET.

    PubMed

    Samardžić, Mira; Martinović, Milica; Nedović-Vuković, Mirjana; Popović-Samardžić, Milena

    2016-03-01

    In the last several decades, a great number of studies have pointed to a dramatic increase of type 1 diabetes mellitus (T1DM) incidence in the whole world, especially in younger age groups. Therefore, the aim of the study was to assess changes in the age distribution at onset of T1DM in Montenegro children aged < 15 years during a 15-year period (1997-2011) and analyze the seasonal pattern. Primary case ascertainment was from diabetes register, secondary and tertiary independent data sources were hospital case records and register of children receiving free test stripes in pharmacy. Standardized incidence rates were calculated using the Poisson regression. Case ascertainment was 100% complete using the capture-recapture method. The mean age-standardized incidence was 18.6/100,000 (95% CI: 13.0-24.1) from 2007 to 2011 compared with 13.4/100,000 95% CI, 11.5-15.5) from 1997 to 2006. The incidence of T1DM increased predominantly in younger age groups. Relative increase of incidence per 5-year period was largest in boys aged 0-4 and 5-9 years: 64.7% (95% CI: 20.6-10.7; p = 0.004) and 52.8% (95% CI: 16.9-88.8; p = 0.004), respectively. Seasonality in monthly case counts of T1DM was apparent. The greatest number of cases were diagnosed during autumn and winter months. In conclusion, the onset of T1DM was found to occur at an ever younger age in Montenegro children. Our results indicated a seasonal pattern of the disease onset.

  17. RECENT INCIDENCE OF TYPE 1 DIABETES MELLITUS IN MONTENEGRO: A SHIFT TOWARD YOUNGER AGE AT DISEASE ONSET.

    PubMed

    Samardžić, Mira; Martinović, Milica; Nedović-Vuković, Mirjana; Popović-Samardžić, Milena

    2016-03-01

    In the last several decades, a great number of studies have pointed to a dramatic increase of type 1 diabetes mellitus (T1DM) incidence in the whole world, especially in younger age groups. Therefore, the aim of the study was to assess changes in the age distribution at onset of T1DM in Montenegro children aged < 15 years during a 15-year period (1997-2011) and analyze the seasonal pattern. Primary case ascertainment was from diabetes register, secondary and tertiary independent data sources were hospital case records and register of children receiving free test stripes in pharmacy. Standardized incidence rates were calculated using the Poisson regression. Case ascertainment was 100% complete using the capture-recapture method. The mean age-standardized incidence was 18.6/100,000 (95% CI: 13.0-24.1) from 2007 to 2011 compared with 13.4/100,000 95% CI, 11.5-15.5) from 1997 to 2006. The incidence of T1DM increased predominantly in younger age groups. Relative increase of incidence per 5-year period was largest in boys aged 0-4 and 5-9 years: 64.7% (95% CI: 20.6-10.7; p = 0.004) and 52.8% (95% CI: 16.9-88.8; p = 0.004), respectively. Seasonality in monthly case counts of T1DM was apparent. The greatest number of cases were diagnosed during autumn and winter months. In conclusion, the onset of T1DM was found to occur at an ever younger age in Montenegro children. Our results indicated a seasonal pattern of the disease onset. PMID:27333720

  18. Examination of blood-brain barrier permeability in dementia of the Alzheimer type with (68Ga)EDTA and positron emission tomography

    SciTech Connect

    Schlageter, N.L.; Carson, R.E.; Rapoport, S.I.

    1987-02-01

    Positron emission tomography with (/sup 68/Ga)ethylenediaminetetraacetic acid ((/sup 68/Ga)EDTA) was used to examine the integrity of the blood-brain barrier (BBB) in five patients with dementia of the Alzheimer type and in five healthy age-matched controls. Within a scanning time of 90 min, there was no evidence that measurable intravascular tracer entered the brain in either the dementia or the control group. An upper limit for the cerebrovascular permeability-surface area product of (68Ga)EDTA was estimated as 2 X 10(-6) s-1 in both groups. The results provide no evidence for breakdown of the BBB in patients with dementia of the Alzheimer type.

  19. Word-stem priming and recognition in type 2 diabetes mellitus, Alzheimer's disease patients and healthy older adults.

    PubMed

    Redondo, María Teresa; Beltrán-Brotóns, José Luís; Reales, José Manuel; Ballesteros, Soledad

    2015-11-01

    The present study investigated (a) whether the pattern of performance on implicit and explicit memory of patients with type 2 diabetes mellitus (DM2) is more similar to those of patients with Alzheimer's disease (AD) or to cognitively normal older adults and (b) whether glycosylated hemoglobin levels (a measure of glucose regulation) are related to performance on the two memory tasks, implicit word-stem completion and "old-new" recognition. The procedures of both memory tasks included encoding and memory test phases separated by a short delay. Three groups of participants (healthy older adults, DM2 patients and AD patients) completed medical and psychological assessments and performed both memory tasks on a computer. The results of the word-stem completion task showed similar implicit memory in the three groups. By contrast, explicit recognition of the three groups differed. Implicit memory was not affected by either normal or pathological aging, but explicit memory deteriorated in the two groups of patients, especially in AD patients, showing a severe impairment compared to the cognitively healthy older adults. Importantly, glycosylated hemoglobin levels were not related to performance on either implicit or explicit memory tasks. These findings revealed a clear dissociation between explicit and implicit memory tasks in normal and pathological aging. Neuropsychologists and clinicians working with TM2 patients should be aware that the decline of voluntary, long-term explicit memory could have a negative impact on their treatment management. By contrast, the intact implicit memory of the two clinical groups could be used in rehabilitation.

  20. Targeting BuChE-inflammatory pathway by SK0506 to manage type 2 diabetes and Alzheimer disease.

    PubMed

    Kamal, M A; Tan, Y; Seale, J P; Qu, X

    2009-12-01

    Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) affect a large percent of the population worldwide. Experimental studies have revealed that T2DM and AD share several molecular processes that underlie their respective degenerative pathology. Based on this information, we quantified TNF-α, IL-6 levels, serum glucose, serum triglyceride, hepatic triglyceride, serum AST, serum ALT and butyrylcholinesterase (BuChE) in various rat tissues. HFD was fed to rats resulting in increased body weight, fasting blood glucose, IL-6, TNF-α levels, hepatic triglyceride, serum AST, serum ALT and BuChE. SK0506 treatment significantly prevented weight gain induced by HFD feeding. SK0506, but not Rosiglitazone, significantly reduced serum and hepatic triglycerides levels. Treatment with SK0506 also ameliorated elevated levels of both inflammatory markers (TNF-α and IL-6) and serum liver enzymes (ALT and AST) significantly in HFD fed rats. BuChE activity also reduced in skeletal muscle and adipose tissues of rats treated by SK0506. In conclusion, current study has opened new potential avenues towards research for management of T2DM and AD by Chinese herbal extracts, ‘‘SK0506’’.

  1. Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain.

    PubMed

    Butterfield, D Allan; Di Domenico, Fabio; Barone, Eugenio

    2014-09-01

    Alzheimer disease (AD) is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. Epidemiological data show that the incidence of AD increases with age and doubles every 5 years after 65 years of age. From a neuropathological point of view, amyloid-β-peptide (Aβ) leads to senile plaques, which, together with hyperphosphorylated tau-based neurofibrillary tangles and synapse loss, are the principal pathological hallmarks of AD. Aβ is associated with the formation of reactive oxygen (ROS) and nitrogen (RNS) species, and induces calcium-dependent excitotoxicity, impairment of cellular respiration, and alteration of synaptic functions associated with learning and memory. Oxidative stress was found to be associated with type 2 diabetes mellitus (T2DM), which (i) represents another prevalent disease associated with obesity and often aging, and (ii) is considered to be a risk factor for AD development. T2DM is characterized by high blood glucose levels resulting from increased hepatic glucose production, impaired insulin production and peripheral insulin resistance, which close resemble to the brain insulin resistance observed in AD patients. Furthermore, growing evidence suggests that oxidative stress plays a pivotal role in the development of insulin resistance and vice versa. This review article provides molecular aspects and the pharmacological approaches from both preclinical and clinical data interpreted from the point of view of oxidative stress with the aim of highlighting progresses in this field.

  2. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease.

    PubMed

    De Felice, Fernanda G; Ferreira, Sergio T

    2014-07-01

    A growing body of evidence supports an intriguing clinical/epidemiological connection between Alzheimer disease (AD) and type 2 diabetes (T2D). T2D patients have significantly increased risk of developing AD and vice versa. Recent studies have begun to reveal common pathogenic mechanisms shared by AD and metabolic disorders, notably obesity and T2D. In T2D and obesity, low-grade chronic inflammation is a key mechanism leading to peripheral insulin resistance, which progressively causes tissue deterioration and overall health decline. In the brain, proinflammatory signaling was recently found to mediate impaired neuronal insulin signaling, synapse deterioration, and memory loss. Here, we review evidence indicating that inflammation, insulin resistance, and mitochondrial dysfunction are common features in AD and T2D. We further propose the hypothesis that dementia and its underlying neuronal dysfunction are exacerbated or driven by peripheral inflammation. Identification of central and peripheral inflammation as potential mediators of brain dysfunction in AD may lead to the development of effective treatments for this devastating disease.

  3. GSK3: a key target for the development of novel treatments for type 2 diabetes mellitus and Alzheimer disease.

    PubMed

    Gao, Chong; Hölscher, Christian; Liu, Yueze; Li, Lin

    2011-12-21

    As a constitutively active kinase, glycogen synthase kinase 3 (GSK3) is a kinase which regulates body metabolism by phosphorylation of glycogen synthase (GS) and other substrates. Considerable evidence suggests that GSK3 is involved in the common pathology underlying Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). The overexpression or overactivation of GSK3 could induce a series of pathological changes, most of which are hallmarks of AD and T2DM. Therefore, GSK3 could be a novel target to treat these two age-dependent diseases. The inhibition of this kinase can prevent the aggregation of β-amyloid (Aβ) and hyperphosphorylation of tau protein. GSK3 inhibition can also be a promising strategy to ameliorate neurodegenerative developments. Its potential association with memory formation has been shown in electrophysiological and behavioral experiments. The neuroprotective effects of novel drugs developed to treat T2DM, glucagon-like peptide 1 (GLP-1) and its long-lasting analogs, have a possible link to GSK3 modification. Recent investigations of the interaction between the phosphatidylinositol 3 kinase (PI3K) signaling pathway and the protective effect of novel GPL-1 receptor agonist geniposide on PC12 cells support this theory.

  4. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease.

    PubMed

    De Felice, Fernanda G; Ferreira, Sergio T

    2014-07-01

    A growing body of evidence supports an intriguing clinical/epidemiological connection between Alzheimer disease (AD) and type 2 diabetes (T2D). T2D patients have significantly increased risk of developing AD and vice versa. Recent studies have begun to reveal common pathogenic mechanisms shared by AD and metabolic disorders, notably obesity and T2D. In T2D and obesity, low-grade chronic inflammation is a key mechanism leading to peripheral insulin resistance, which progressively causes tissue deterioration and overall health decline. In the brain, proinflammatory signaling was recently found to mediate impaired neuronal insulin signaling, synapse deterioration, and memory loss. Here, we review evidence indicating that inflammation, insulin resistance, and mitochondrial dysfunction are common features in AD and T2D. We further propose the hypothesis that dementia and its underlying neuronal dysfunction are exacerbated or driven by peripheral inflammation. Identification of central and peripheral inflammation as potential mediators of brain dysfunction in AD may lead to the development of effective treatments for this devastating disease. PMID:24931033

  5. Responders and non-responders to bifemelane hydrochloride in Alzheimer-type and multi-infarct dementia.

    PubMed

    Shigeta, M; Nishikawa, Y; Shimizu, M; Usui, M; Hyoki, K; Kawamuro, Y

    1993-01-01

    Although metabolically active compounds sometime attenuate cognitive deficits of dementia patients, this mechanism has not been discussed or investigated. We hypothesized that these compounds improve cognitive disorders not by directly acting on this cognitive function, but by increasing the arousal level. Based on this hypothesis, we investigated the change of arousal levels and the improvement of intellectual functions in 10 patients with Alzheimer-type dementia (ATD) and 10 patients with multi-infarct dementia (MID) before and 3 months after pharmacotherapy using bifemelane hydrochloride. For each patient, a psychological test battery was carried out and the arousal level was evaluated using the frequency of rapid eye movements in the electro-oculogram (EOG) and the frequency analysis of electroencephalogram (EEG) before and after the treatment. Evaluation of the cognitive improvement was made and eight out of the 20 patients were regarded as responders to the treatment. The frequency of small rapid eye movements (SREM) in the EOG increased significantly only in responders and the rate of change in SREM appearance in responders was significantly different from that in non-responders. This finding suggests that a part of the intellectual improvement in ATD and MID results from the increased level of arousal.

  6. Elevated Risk of Type 2 Diabetes for Development of Alzheimer Disease: a Key Role for Oxidative Stress in Brain

    PubMed Central

    Butterfield, D. Allan; Di Domenico, Fabio; Barone, Eugenio

    2014-01-01

    Alzheimer disease (AD) is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. Epidemiological data show that the incidence of AD increases with age and doubles every 5 years after 65 years of age. From a neuropathological point of view, amyloid-β-peptide (Aβ) leads to senile plaques, which, together with hyperphosphorylated tau-based neurofibrillary tangles and synapse loss, are the principal pathological hallmarks of AD. Aβ is associated with the formation of reactive oxygen (ROS) and nitrogen (RNS) species, and induces calcium-dependent excitotoxicity, impairment of cellular respiration, and alteration of synaptic functions associated with learning and memory. Oxidative stress was found to be associated with type 2 diabetes mellitus (T2DM), which (i) represents another prevalent disease associated with obesity and often aging, and (ii) is considered to be a risk factor for AD development. T2DM is characterized by high blood glucose levels resulting from increased hepatic glucose production, impaired insulin production and peripheral insulin resistance, which close resemble to the brain insulin resistance observed in AD patients. Furthermore, growing evidence suggest that oxidative stress play a pivotal role in the development of insulin resistance and vice versa. This review article provides molecular aspects and the pharmacological approaches from both preclinical and clinical data and interpreted from the point of view of oxidative stress with the aim to highlight progresses in this field. PMID:24949886

  7. A possible link of gut microbiota alteration in type 2 diabetes and Alzheimer's disease pathogenicity: an update.

    PubMed

    Alam, Mohammad Z; Alam, Qamre; Kamal, Mohammad A; Abuzenadah, Adel M; Haque, Absarul

    2014-04-01

    Imbalances in gut microbiota are associated with metabolic disorder, which are a group of obesity-related metabolic abnormalities that increase an individual's risk of developing type 2 diabetes (T2D) and Alzheimer's disease (AD). Although a number of risk factors have been postulated that may trigger the development of AD, the root cause of this disease is still a matter of debate. This review further investigates the etiology of AD by accumulating the current role played by gut microbiota in human, and trying to establish an inter-link between T2D and AD pathogenesis. There is a growing body of evidence which suggests that obesity is associated with alteration in the normal gut flora, reduced bacterial diversity, metabolic pathways and altered representation of bacterial genes. Obesity and T2D are considered to be induced as a result of changes within the composition of gut microbiota. The evidence gathered so far clearly advocates the involvement of gut microbes in causing obesity, a state of chronic and low-grade inflammation. Hence, understanding the microbiota of the gut is significant in relation to inflammation, as it is a key contributor for diabetes which has a direct relation to the AD pathogenesis. Comparative analysis of gut microbiota may enable further novel insight into the complex biology of AD, which is very important in order to take preventive measure such as early diagnosis, identification of new therapeutic targets and development of novel drugs.

  8. Early-onset severe hereditary sensory and autonomic neuropathy type 1 with S331F SPTLC1 mutation.

    PubMed

    Suh, Bum Chun; Hong, Young Bin; Nakhro, Khriezhanuo; Nam, Soo Hyun; Chung, Ki Wha; Choi, Byung-Ok

    2014-02-01

    Hereditary sensory and autonomic neuropathy type I (HSAN I) is an autosomal dominant disease characterized by prominent sensory impairment, resulting in foot ulcers or amputations and has a juvenile to adult onset. The major underlying causes of HSAN I are mutations in SPTLC1, which encodes the first subunit of serine palmitoyltransferase (SPT). To date, there have been no reports with regard to an HSAN patient of Korean origin. In this report we discussed an HSAN I patient with a missense mutation in SPTLC1 (c.992C>T: p.S331F). The patient had noticed frequent falls, lower leg weakness and hand tremors at age five. The patient also presented with foot ulcers, muscle hypotrophy, cataracts, hoarseness, vocal cord palsy and respiratory difficulties and succumbed to the condition at the age of 28 years. In accordance with previous reports, a mutation in Ser331 in the present patient was associated with early-onset and a severe phenotype. Therefore, Ser331 in SPTLC1 is a crucial amino acid, which characterizes the HSAN I phenotype. PMID:24247255

  9. Assessing onset and length of greening period in six vegetation types in Oaxaca, Mexico, using NDVI-precipitation relationships.

    PubMed

    Gómez-Mendoza, L; Galicia, L; Cuevas-Fernández, M L; Magaña, V; Gómez, G; Palacio-Prieto, J L

    2008-07-01

    Variations in the normalized vegetation index (NDVI) for the state of Oaxaca, in southern Mexico, were analyzed in terms of precipitation anomalies for the period 1997-2003. Using 10-day averages in NDVI data, obtained from AVHRR satellite information, the response of six types of vegetation to intra-annual and inter-annual fluctuations in precipitation were examined. The onset and temporal evolution of the greening period were studied in terms of precipitation variations through spectral analysis (coherence and phase). The results indicate that extremely dry periods, such as those observed in 1997 and 2001, resulted in low values of NDVI for much of Oaxaca, while good precipitation periods produced a rapid response (20-30 days of delay) from a stressed to a non-stressed condition in most vegetation types. One of these rapid changes occurred during the transition from dry to wet conditions during the summer of 1998. As in many parts of the tropics and subtropics, the NDVI reflects low frequency variations in precipitation on several spatial scales. Even after long dry periods (2001-2002), the various regional vegetation types are capable of recovering when a good rainy season takes place, indicating that vegetation types such as the evergreen forests in the high parts of Oaxaca respond better to rainfall characteristics (timing, amount) than to temperature changes, as is the case in most mid-latitudes. This finding may be relevant to prepare climate change scenarios for forests, where increases in surface temperature and precipitation anomalies are expected.

  10. Chicken Embryos as a Potential New Model for Early Onset Type I Diabetes

    PubMed Central

    Shi, Liheng; Ko, Michael L.; Huang, Cathy Chia-Yu; Park, So-Young; Hong, Min-Pyo; Ko, Gladys Y.-P.

    2014-01-01

    Diabetic retinopathy (DR) is the leading cause of blindness among the American working population. The purpose of this study is to establish a new diabetic animal model using a cone-dominant avian species to address the distorted color vision and altered cone pathway responses in prediabetic and early diabetic patients. Chicken embryos were injected with either streptozotocin (STZ), high concentration of glucose (high-glucose), or vehicle at embryonic day 11. Cataracts occurred in varying degrees in both STZ- and high glucose-induced diabetic chick embryos at E18. Streptozotocin-diabetic chicken embryos had decreased levels of blood insulin, glucose transporter 4 (Glut4), and phosphorylated protein kinase B (pAKT). In STZ-injected E20 embryos, the ERG amplitudes of both a- and b-waves were significantly decreased, the implicit time of the a-wave was delayed, while that of the b-wave was significantly increased. Photoreceptors cultured from STZ-injected E18 embryos had a significant decrease in L-type voltage-gated calcium channel (L-VGCC) currents, which was reflected in the decreased level of L-VGCCα1D subunit in the STZ-diabetic retinas. Through these independent lines of evidence, STZ-injection was able to induce pathological conditions in the chicken embryonic retina, and it is promising to use chickens as a potential new animal model for type I diabetes. PMID:25133191

  11. Young-Onset Dementia

    PubMed Central

    Kuruppu, Dulanji K; Matthews, Brandy R

    2014-01-01

    Young-onset dementia (YOD) is an neurological syndrome that affects behavior and cognition of patients younger than 65 years of age. Although frequently misdiagnosed, a systematic approach, reliant upon attainment of detailed medical history, collateral history from an informant, neuropsychological testing, laboratory studies, and neuroimaging, may facilitate earlier and more accurate diagnosis with subsequent intervention. The differential diagnosis of YOD is extensive and includes early-onset forms of adult neurodegenerative conditions including Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy body dementias, Huntington's disease, and prion disease. Late-onset forms of childhood neurodegenerative conditions may also present as YOD and include mitochondrial disorders, lysosomal storage disorders, and leukodystrophies. Potentially reversible etiologies including inflammatory disorders, infectious diseases, toxic/metabolic abnormalities, transient epileptic amnesia, obstructive sleep apnea, and normal pressure hydrocephalus also represent important differential diagnostic considerations in YOD. This review will present etiologies, diagnostic strategies, and options for management of YOD with comprehensive summary tables for clinical reference. PMID:24234358

  12. Adult-onset dysphagia lusoria secondary to a dissecting aberrant right subclavian artery associated with type B acute aortic dissection

    PubMed Central

    Singh, Sarabjeet; Grewal, Puneet Dhillon; Symons, John; Ahmed, Aziz; Khosla, Sandeep; Arora, Rohit

    2008-01-01

    The case of a 78-year-old African American woman who presented at the Mount Sinai Medical Center (Chicago, USA) with excruciating backache is presented. Computed tomography of the chest at the time of admission showed dissection of the aortic arch, descending aorta and dissection of an aberrant right subclavian artery. She was managed medically for Stanford type B acute aortic dissection. The patient was asymptomatic at presentation, but started complaining of new-onset dysphagia during her stay in the hospital. An esophagogram was performed and suggested posterior impingement of the esophagus, a classic sign of an aberrant right subclavian artery. Because the patient had multiple underlying comorbidities and the dysphagia was mild and intermittent, surgery was deferred. The patient was discharged home after complete stabilization and was scheduled for a follow-up appointment. PMID:18209773

  13. Three-year follow-up of a patient with early-onset Alzheimer's disease with presenilin-2 N141I mutation - case report and review of the literature.

    PubMed

    Nikisch, G; Hertel, A; Kiessling, B; Wagner, Th; Krasz, D; Hofmann, E; Wiedemann, G

    2008-12-01

    Autosomal dominant early-onset Alzheimer disease (EOAD) is a heterogeneous condition that has been associated with mutations in 3 different genes: the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. Most cases are due to mutations in the PSEN1 gene, whereas mutations in the APP and PSEN2 genes are rare. Mutation analysis of the APP, PSEN1 and PSEN2 genes was performed. We herein report the case of a German EOAD patient with a family history of dementia and a missense mutation at codon 141 (N141I) of the PSEN2 gene. To our knowledge, this is the first German EOAD patient without a Volga-German ancestry and a positive family history for dementia carries the mutation PSEN-2 N141I. The patient came to our clinic for the first time when she was 47 years old. During the following 3 years, her Mini-Mental State Examination (MMSE) score dropped from 28 to 0. Mild cognitive impairment (MCI) was an early symptom that was already present during the first consultation. The concentration in cerebrospinal fluid (CSF) of tau-protein (1151 pg/ml) was increased, whereas the concentration of beta-amyloid protein (Abeta1-42) was decreased (335 pg/ml). Magnetic resonance imaging (MRI) revealed only slight changes in the early stage of the disease and positron emission tomography with (18F) fluoro-2-deoxy-D-glucose (18F-FDG PET) demonstrated glucose reduction left parietal and in the precuneus region. Follow-up MRI and 18F-FDG PET studies showed progression of atrophy of the left entorhinal cortex with relative sparing of the hippocampus and progressive hypometabolism of both temporoparietal lobes and left frontal lobe. PMID:19073399

  14. Two Siblings with Adolescent/Adult Onset Niemann-Pick Disease Type C in Korea

    PubMed Central

    2016-01-01

    Niemann–Pick disease, type C (NP-C), is caused by NPC1 or NPC2 gene mutations. Progressive neurological, psychiatric, and visceral symptoms are characteristic. Here, we present cases of a brother (Case 1) and sister (Case 2) in their mid-20s with gait disturbance and psychosis. For the Case 1, neurological examination revealed dystonia, ataxia, vertical supranuclear-gaze palsy (VSGP), and global cognitive impairment. Case 2 showed milder, but similar symptoms, with cortical atrophy. Abdominal computed tomography showed hepatosplenomegaly in both cases. NPC1 gene sequencing revealed compound heterozygote for exon 9 (c.1552C>T [R518W]) and exon 18 (c.2780C>T [A927V]). Filipin-staining tests were also positive. When a young patient with ataxia or dystonia shows VSGP, NP-C should be considered. PMID:27366019

  15. Early Treatment With Olmesartan Prevents Juxtamedullary Glomerular Podocyte Injury and the Onset of Microalbuminuria in Type 2 Diabetic Rats

    PubMed Central

    Sofue, Tadashi; Kiyomoto, Hideyasu; Kobori, Hiroyuki; Urushihara, Maki; Nishijima, Yoko; Kaifu, Kumiko; Hara, Taiga; Matsumoto, Sachiko; Ichimura, Atsuhiko; Ohsaki, Hiroyuki; Hitomi, Hirofumi; Kawachi, Hiroshi; Hayden, Melvin R.; Whaley-Connell, Adam; Sowers, James R.; Ito, Sadayoshi; Kohno, Masakazu; Nishiyama, Akira

    2012-01-01

    Background Studies were performed to determine if early treatment with an angiotensin II (Ang II) receptor blocker (ARB), olmesartan, prevents the onset of microalbuminuria by attenuating glomerular podocyte injury in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with type 2 diabetes mellitus. Methods OLETF rats were treated with either a vehicle, olmesartan (10 mg/kg/day) or a combination of nonspecific vasodilators (hydralazine 15 mg/kg/day, hydrochlorothiazide 6 mg/kg/day, and reserpine 0.3 mg/kg/day; HHR) from the age of 7–25 weeks. Results OLETF rats were hypertensive and had microalbuminuria from 9 weeks of age. At 15 weeks, OLETF rats had higher Ang II levels in the kidney, larger glomerular desmin-staining areas (an index of podocyte injury), and lower gene expression of nephrin in juxtamedullary glomeruli, than nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. At 25 weeks, OLETF rats showed overt albuminuria, and higher levels of Ang II in the kidney and larger glomerular desmin-staining areas in superficial and juxtamedullary glomeruli compared to LETO rats. Reductions in mRNA levels of nephrin were also observed in superficial and juxtamedullary glomeruli. Although olmesartan did not affect glucose metabolism, it decreased blood pressure and prevented the renal changes in OLETF rats. HHR treatment also reduced blood pressure, but did not affect the renal parameters. Conclusions This study demonstrated that podocyte injury occurs in juxtamedullary glomeruli prior to superficial glomeruli in type 2 diabetic rats with microalbuminuria. Early treatment with an ARB may prevent the onset of albuminuria through its protective effects on juxtamedullary glomerular podocytes. PMID:22318512

  16. Alois Alzheimer (1864-1915) and the Alzheimer syndrome.

    PubMed

    Vishal, Sharma; Sourabh, Aggarwal; Harkirat, Singh

    2011-02-01

    Alois Alzheimer is known for his seminal work in recognizing a form of presenile dementia. His early interests were natural history and botany. He started his medical education in Berlin and attended the universities of Wurzburg and Tübingen. Nissl and Alzheimer worked together on extensive investigation of the pathology of the nervous system, especially the anatomy of the cerebral cortex. In 1902 Emil Kraepelin invited Alzheimer to work with him in the university psychiatric clinic in Heidelberg. In 1903 both moved to work in the university psychiatric clinic in Munich. It was during these years that Alzheimer described the Alzheimer's disease. He also described brain changes in arteriosclerosis, loss of nerve cells in Huntington's disease in the corpus striatum and brain changes in epilepsy. Alzheimer presented a preliminary report of his histological findings in 1906 at Tübingen about a 51-year-old lady who had developed presenile dementia and died within four years of onset of the disease. He published his findings in 1907, reporting the atrophic brain with neurofibrillary deposits and areas in the cerebrum resistant to staining. During the later years of his career Alzheimer concentrated on the study of changes in glial cells. His best-known works from this period were on Westphal-Strümpell pseudo-sclerosis of the brain, now assumed to be the same as Wilson's Disease. His death, at age 51, was the result of cardiac failure following endocarditis.

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

    SciTech Connect

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

    1994-09-01

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

  18. Simultaneous type 1 diabetes onset in mother and son coincident with an enteroviral infection.

    PubMed

    Hindersson, Maria; Maria, Hindersson; Elshebani, Asma; Orn, Anders; Anders, Orn; Tuvemo, Torsten; Torsten, Tuvemo; Frisk, Gun; Gun, Frisk

    2005-06-01

    Enterovirus (EV) infections have been implicated in the development of type 1 diabetes. (T1D). They may cause beta-cell destruction either by cytolytic infection of the cells or indirectly by triggering the autoimmune response. Virus was isolated from a woman at diagnosis of T1D (Tuvemo 1) and in addition, virus was isolated from her son at diagnosis of T1D at the same day (Tuvemo 2). None of the isolates could initially be serotyped by conventional methods. The Tuvemo 1 virus was genotyped and after sub-cultivation it was also serotyped as Coxsackievirus B5. The mother revealed antibodies against GAD65. The boy and the father both revealed a significant increase in neutralization antibody titre against two strains of CBV-4, clearly indicating a recent or ongoing EV infection. In addition, the brother showed such a titre rise against another CBV-4 strain (E2) and against a CBV-5 strain (4429). These results show that the whole family had a proven EV infection at the time of T1D diagnosis of the mother and the 10-years-old boy, indicating that the infection might cause or accelerate the T1D.

  19. Characterizing and modeling mechanical properties and onset of short circuit for three types of lithium-ion pouch cells

    NASA Astrophysics Data System (ADS)

    Sahraei, Elham; Meier, Joseph; Wierzbicki, Tomasz

    2014-02-01

    Three types of lithium ion pouch cells ranging from small consumer electric cells with LiCoO2 cathode to large (electric vehicle size) cells with nanophosphate chemistry were tested under several local and global compression scenarios, including compression between two flat plates and local indentation with a flat cylindrical punch, a conical punch, and three hemispherical punches. Load, displacement, temperature, and voltage were recorded in all tests. The punch displacements were stopped when a drop in force and voltage of the cell, as well as a rise in temperature indicated a short circuit in the cell. Finite element models were developed for each cell type. Two tests were used for calibration of the constitutive properties of each type of cell, and the remaining tests served for the validation of the computational model. The models successfully predicted the load displacement relation and contour of deformations in the cells. Additionally, the models closely predict the force and punch displacement corresponding to the onset of short circuit in the cell. The current results are building confidence in robustness and accuracy of the present calibration and modeling approach.

  20. Word-stem priming and recognition in type 2 diabetes mellitus, Alzheimer's disease patients and healthy older adults.

    PubMed

    Redondo, María Teresa; Beltrán-Brotóns, José Luís; Reales, José Manuel; Ballesteros, Soledad

    2015-11-01

    The present study investigated (a) whether the pattern of performance on implicit and explicit memory of patients with type 2 diabetes mellitus (DM2) is more similar to those of patients with Alzheimer's disease (AD) or to cognitively normal older adults and (b) whether glycosylated hemoglobin levels (a measure of glucose regulation) are related to performance on the two memory tasks, implicit word-stem completion and "old-new" recognition. The procedures of both memory tasks included encoding and memory test phases separated by a short delay. Three groups of participants (healthy older adults, DM2 patients and AD patients) completed medical and psychological assessments and performed both memory tasks on a computer. The results of the word-stem completion task showed similar implicit memory in the three groups. By contrast, explicit recognition of the three groups differed. Implicit memory was not affected by either normal or pathological aging, but explicit memory deteriorated in the two groups of patients, especially in AD patients, showing a severe impairment compared to the cognitively healthy older adults. Importantly, glycosylated hemoglobin levels were not related to performance on either implicit or explicit memory tasks. These findings revealed a clear dissociation between explicit and implicit memory tasks in normal and pathological aging. Neuropsychologists and clinicians working with TM2 patients should be aware that the decline of voluntary, long-term explicit memory could have a negative impact on their treatment management. By contrast, the intact implicit memory of the two clinical groups could be used in rehabilitation. PMID:26253308

  1. Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer's disease model.

    PubMed

    Ongali, Brice; Nicolakakis, Nektaria; Tong, Xin-Kang; Aboulkassim, Tahar; Papadopoulos, Panayiota; Rosa-Neto, Pedro; Lecrux, Clotilde; Imboden, Hans; Hamel, Edith

    2014-08-01

    Angiotensin II (AngII) receptor blockers that bind selectively AngII type 1 (AT1) receptors may protect from Alzheimer's disease (AD). We studied the ability of the AT1 receptor antagonist losartan to cure or prevent AD hallmarks in aged (~18months at endpoint, 3months treatment) or adult (~12months at endpoint, 10months treatment) human amyloid precursor protein (APP) transgenic mice. We tested learning and memory with the Morris water maze, and evaluated neurometabolic and neurovascular coupling using [(18)F]fluoro-2-deoxy-D-glucose-PET and laser Doppler flowmetry responses to whisker stimulation. Cerebrovascular reactivity was assessed with on-line videomicroscopy. We measured protein levels of oxidative stress enzymes (superoxide dismutases SOD1, SOD2 and NADPH oxidase subunit p67phox), and quantified soluble and deposited amyloid-β (Aβ) peptide, glial fibrillary acidic protein (GFAP), AngII receptors AT1 and AT2, angiotensin IV receptor AT4, and cortical cholinergic innervation. In aged APP mice, losartan did not improve learning but it consolidated memory acquisition and recall, and rescued neurovascular and neurometabolic coupling and cerebrovascular dilatory capacity. Losartan normalized cerebrovascular p67phox and SOD2 protein levels and up-regulated those of SOD1. Losartan attenuated astrogliosis, normalized AT1 and AT4 receptor levels, but failed to rescue the cholinergic deficit and the Aβ pathology. Given preventively, losartan protected cognitive function, cerebrovascular reactivity, and AT4 receptor levels. Like in aged APP mice, these benefits occurred without a decrease in soluble Aβ species or plaque load. We conclude that losartan exerts potent preventive and restorative effects on AD hallmarks, possibly by mitigating AT1-initiated oxidative stress and normalizing memory-related AT4 receptors.

  2. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials

    PubMed Central

    Moran, Antoinette; Bundy, Brian; Becker, Dorothy J; DiMeglio, Linda A; Gitelman, Stephen E; Goland, Robin; Greenbaum, Carla J; Herold, Kevan C; Marks, Jennifer B; Raskin, Philip; Sanda, Srinath; Schatz, Desmond; Wherrett, Diane K; Wilson, Darrell M; Krischer, Jeffrey P; Skyler, Jay S; Pickersgill, Linda; de Koning, Eelco; Ziegler, Anette-G; Böehm, Bernhard; Badenhoop, Klaus; Schloot, Nanette; Bak, Jens Friis; Pozzilli, Paolo; Mauricio, Didac; Donath, Marc Y; Castaño, Luis; Wägner, Ana; Lervang, Hans Henrik; Perrild, Hans; Poulsen, Thomas Mandrup

    2013-01-01

    Summary Background Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes. Methods We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6–45 years and those in the anakinra trial were aged 18–35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. Findings Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial

  3. Lipid rafts participate in aberrant degradative autophagic-lysosomal pathway of amyloid-beta peptide in Alzheimer's disease

    PubMed Central

    Zhou, Xin; Yang, Chun; Liu, Yufeng; Li, Peng; Yang, Huiying; Dai, Jingxing; Qu, Rongmei; Yuan, Lin

    2014-01-01

    Amyloid-beta peptide is the main component of amyloid plaques, which are found in Alzheimer's disease. The generation and deposition of amyloid-beta is one of the crucial factors for the onset and progression of Alzheimer's disease. Lipid rafts are glycolipid-rich liquid domains of the plasma membrane, where certain types of protein tend to aggregate and intercalate. Lipid rafts are involved in the generation of amyloid-beta oligomers and the formation of amyloid-beta peptides. In this paper, we review the mechanism by which lipid rafts disturb the aberrant degradative autophagic-lysosomal pathway of amyloid-beta, which plays an important role in the pathological process of Alzheimer's disease. Moreover, we describe this mechanism from the view of the Two-system Theory of fasciology and thus, suggest that lipid rafts may be a new target of Alzheimer's disease treatment. PMID:25206748

  4. Downregulation of Type II Diabetes Mellitus and Maturity Onset Diabetes of Young Pathways in Human Pancreatic Islets from Hyperglycemic Donors

    PubMed Central

    Groop, Leif

    2014-01-01

    Although several molecular pathways have been linked to type 2 diabetes (T2D) pathogenesis, it is uncertain which pathway has the most implication on the disease. Changes in the expression of an entire pathway might be more important for disease pathogenesis than changes in the expression of individual genes. To identify the molecular alterations in T2D, DNA microarrays of human pancreatic islets from donors with hyperglycemia (n = 20) and normoglycemia (n = 58) were subjected to Gene Set Enrichment Analysis (GSEA). About 178 KEGG pathways were investigated for gene expression changes between hyperglycemic donors compared to normoglycemic. Pathway enrichment analysis showed that type II diabetes mellitus (T2DM) and maturity onset diabetes of the young (MODY) pathways are downregulated in hyperglycemic donors, while proteasome and spliceosome pathways are upregulated. The mean centroid of gene expression of T2DM and MODY pathways was shown to be associated positively with insulin secretion and negatively with HbA1c level. To conclude, downregulation of T2DM and MODY pathways is involved in islet function and might be involved in T2D. Also, the study demonstrates that gene expression profiles from pancreatic islets can reveal some of the biological processes related to regulation of glucose hemostats and diabetes pathogenesis. PMID:25379510

  5. Cognitive and Disease-Modifying Effects of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition in Male Tg2576 Mice, a Model of Alzheimer's Disease

    PubMed Central

    Sooy, Karen; Noble, June; McBride, Andrew; Binnie, Margaret; Yau, Joyce L. W.; Seckl, Jonathan R.; Walker, Brian R.

    2015-01-01

    Chronic exposure to elevated levels of glucocorticoids has been linked to age-related cognitive decline and may play a role in Alzheimer's disease. In the brain, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies intracellular glucocorticoid levels. We show that short-term treatment of aged, cognitively impaired C57BL/6 mice with the potent and selective 11β-HSD1 inhibitor UE2316 improves memory, including after intracerebroventricular drug administration to the central nervous system alone. In the Tg2576 mouse model of Alzheimer's disease, UE2316 treatment of mice aged 14 months for 4 weeks also decreased the number of β-amyloid (Aβ) plaques in the cerebral cortex, associated with a selective increase in local insulin-degrading enzyme (involved in Aβ breakdown and known to be glucocorticoid regulated). Chronic treatment of young Tg2576 mice with UE2316 for up to 13 months prevented cognitive decline but did not prevent Aβ plaque formation. We conclude that reducing glucocorticoid regeneration in the brain improves cognition independently of reduced Aβ plaque pathology and that 11β-HSD1 inhibitors have potential as cognitive enhancers in age-associated memory impairment and Alzheimer's dementia. PMID:26305888

  6. Screening for the APP codon 670/671 mutations in Alzheimer's disease.

    PubMed

    Houlden, H; Crawford, F; Rossor, M; Mullan, M

    1993-05-14

    A mutation at codons 670 and 671 of exon 16 of the amyloid precursor protein has recently been identified as a cause of early onset familial Alzheimer's disease. Using restriction enzyme digestion, screening failed to reveal the occurrence of this mutation in 43 families with early onset, 31 families with late onset, 30 cases of sporadic Alzheimer's disease or 30 clinically normal individuals.

  7. Botulinum toxin type A combined with cervical spine manual therapy for masseteric hypertrophy in a patient with Alzheimer-type dementia: a case report

    PubMed Central

    Villafañe, Jorge H.; Fernandez-de-las-Peñas, Cesar; Pillastrini, Paolo

    2012-01-01

    Objective The purpose of this case study is to present the findings of combining botulinum toxin type A (BoNT-A) and cervical spine manual therapy to address masseter muscle spasticity in a patient with Alzheimer-type dementia. Case Report A 78-year-old woman with bilateral spasticity of the masseteric regions for 2 years was referred for physiotherapy. She had trismus and bruxism, and could neither close nor open her mouth normally; thus, she was unable to be fed orally in a normal manner. Intervention and Outcome The patient underwent combined treatment with BoNT-A and cervical spine manual therapy. A medical physician (neurologist) performed the BoNT-A injections into 2 points at the center of the lower third of the masseter muscle. A physical therapist performed manual therapy interventions targeted at the cervical spine. Manual therapy started the day after the BoNT-A injection and continued for 5 sessions per week for a total period of 2 weeks. Clinical outcomes were measured including spasticity (Modified Ashworth Scale), functionality (Barthel Index), and jaw opening. Outcomes were conducted at baseline, 2 weeks after treatment, and at 2-month follow-up session after finishing the treatment. The patient improved in all of the outcomes at the end of treatment, and these results were maintained during the follow-up. After treatment, the patient was able to feed with minimal caregiver dependency because oral feeding was possible. Conclusion The patient in this study responded positively to a combination of BoNT-A and manual therapy, resulting in decreased masseter muscles spasticity and improved trismus and bruxism. PMID:23843761

  8. A rare diabetes ketoacidosis in combined severe hypernatremic hyperosmolarity in a new-onset Asian adolescent with type I diabetes.

    PubMed

    Kim, Hyung Jin; Kim, Dong Hyun; Jun, Yong Hoon; Lee, Ji Eun

    2014-01-01

    A 13-year-old Asian boy presented with an 8 h history of lethargy and vomiting. He had a 3-week history of polyuria, polydipsia and a 6 kg weight loss over a period of 1 month. Fluid intake prior to admission was over 6 L of sports drinks and cola per day. Initial biochemical findings were as follows: plasma glucose 1351 mg/dL, serum sodium 154 mEq/L, serum osmolarity 425 mOsm/L, arterial blood pH 6.96 and urine ketone of 3+. He was treated with intensive fluid resuscitation and an insulin infusion. He completely recovered without any neurological deficits. Severe hypernatremia is rare in diabetic ketoacidosis (DKA) but was exhibited in this case. Excess intake of carbonated carbohydrate-rich beverages may exacerbate the initial severe presentation of type I diabetes mellitus (T1DM). To the best of our knowledge, this is the first case of an Asian child with DKA combined with severe hypernatremic hyperosmolarity at onset of T1DM. PMID:25519868

  9. Early-Onset Type 2 Diabetes Impairs Skeletal Acquisition in the Male TALLYHO/JngJ Mouse

    PubMed Central

    Van Vliet, M.; Motyl, K.; Karim, L.; Brooks, D. J.; Louis, L.; Conlon, C.; Rosen, C. J.; Bouxsein, M. L.

    2014-01-01

    Type 2 diabetes (T2D) incidence in adolescents is rising and may interfere with peak bone mass acquisition. We tested the effects of early-onset T2D on bone mass, microarchitecture, and strength in the TALLYHO/JngJ mouse, which develops T2D by 8 weeks of age. We assessed metabolism and skeletal acquisition in male TALLYHO/JngJ and SWR/J controls (n = 8–10/group) from 4 weeks to 8 and 17 weeks of age. Tallyho mice were obese; had an approximately 2-fold higher leptin and percentage body fat; and had lower bone mineral density vs SWR at all time points (P < .03 for all). Tallyho had severe deficits in distal femur trabecular bone volume fraction (−54%), trabecular number (−27%), and connectivity density (−82%) (P < .01 for all). Bone formation was higher in Tallyho mice at 8 weeks but lower by 17 weeks of age vs SWR despite similar numbers of osteoblasts. Bone marrow adiposity was 7- to 50-fold higher in Tallyho vs SWR. In vitro, primary bone marrow stromal cell differentiation into osteoblast and adipocyte lineages was similar in SWR and Tallyho, suggesting skeletal deficits were not due to intrinsic defects in Tallyho bone-forming cells. These data suggest the Tallyho mouse might be a useful model to study the skeletal effects of adolescent T2D. PMID:25051433

  10. A rare diabetes ketoacidosis in combined severe hypernatremic hyperosmolarity in a new-onset Asian adolescent with type I diabetes.

    PubMed

    Kim, Hyung Jin; Kim, Dong Hyun; Jun, Yong Hoon; Lee, Ji Eun

    2014-12-17

    A 13-year-old Asian boy presented with an 8 h history of lethargy and vomiting. He had a 3-week history of polyuria, polydipsia and a 6 kg weight loss over a period of 1 month. Fluid intake prior to admission was over 6 L of sports drinks and cola per day. Initial biochemical findings were as follows: plasma glucose 1351 mg/dL, serum sodium 154 mEq/L, serum osmolarity 425 mOsm/L, arterial blood pH 6.96 and urine ketone of 3+. He was treated with intensive fluid resuscitation and an insulin infusion. He completely recovered without any neurological deficits. Severe hypernatremia is rare in diabetic ketoacidosis (DKA) but was exhibited in this case. Excess intake of carbonated carbohydrate-rich beverages may exacerbate the initial severe presentation of type I diabetes mellitus (T1DM). To the best of our knowledge, this is the first case of an Asian child with DKA combined with severe hypernatremic hyperosmolarity at onset of T1DM.

  11. Psychological moderator variables and metabolic control in recent onset type 1 diabetic patients--a two year longitudinal study.

    PubMed

    Spiess, K; Sachs, G; Moser, G; Pietschmann, P; Schernthaner, G; Prager, R

    1994-04-01

    The relationships between psychosocial adjustment and subsequent glycaemic control were prospectively examined in forty-three adult patients during the first 2 yr after onset of type 1 diabetes mellitus. Decreasing depression was the single psychosocial parameter that changed over time. No correlations were found between the decrease in HbA1c levels and psychological variables at 8- and 16-month follow-ups. Global and specific coping features such as high control attitude, low coping anxiety and low emotional attribution correlated significantly with the decrease in HbA1c levels at the 2-yr follow-up, whereas stressful life events, depression, state-trait anxiety did not correlate. In a regression analysis coping explained 22% variance of the 2 yr decrease in HbA1c levels. We conclude that coping is a better predictor for metabolic control than emotional adaptation and life events. Metabolic control might deteriorate with prolonged stage of the disease being a first sign for psychophysiological coping exhaustion. PMID:8027964

  12. Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset.

    PubMed

    Cabrera, Susanne M; Wang, Xujing; Chen, Yi-Guang; Jia, Shuang; Kaldunski, Mary L; Greenbaum, Carla J; Mandrup-Poulsen, Thomas; Hessner, Martin J

    2016-04-01

    It was hypothesized that IL-1 antagonism would preserve β-cell function in new onset Type 1 diabetes (T1D). However, the Anti-Interleukin-1 in Diabetes Action (AIDA) and TrialNet Canakinumab (TN-14) trials failed to show efficacy of IL-1 receptor antagonist (IL-1Ra) or canakinumab, as measured by stimulated C-peptide response. Additional measures are needed to define immune state changes associated with therapeutic responses. Here, we studied these trial participants with plasma-induced transcriptional analysis. In blinded analyses, 70.2% of AIDA and 68.9% of TN-14 participants were correctly called to their treatment arm. While the transcriptional signatures from the two trials were distinct, both therapies achieved varying immunomodulation consistent with IL-1 inhibition. On average, IL-1 antagonism resulted in modest normalization relative to healthy controls. At endpoint, signatures were quantified using a gene ontology-based inflammatory index, and an inverse relationship was observed between measured inflammation and stimulated C-peptide response in IL-1Ra- and canakinumab-treated patients. Cytokine neutralization studies showed that IL-1α and IL-1β additively contribute to the T1D inflammatory state. Finally, analyses of baseline signatures were indicative of later therapeutic response. Despite the absence of clinical efficacy by IL-1 antagonist therapy, transcriptional analysis detected immunomodulation and may yield new insight when applied to other clinical trials. PMID:26692253

  13. Relationship between neuropsychological impairment and grey and white matter changes in adult-onset myotonic dystrophy type 1.

    PubMed

    Baldanzi, Sigrid; Cecchi, Paolo; Fabbri, Serena; Pesaresi, Ilaria; Simoncini, Costanza; Angelini, Corrado; Bonuccelli, Ubaldo; Cosottini, Mirco; Siciliano, Gabriele

    2016-01-01

    Myotonic dystrophy type 1 (DM1) has a wide phenotypic spectrum and potentially may affect central nervous system with mild to severe involvement. Our aim was to investigate grey matter (GM) and white matter (WM) structural alterations in a sample of adult-onset DM1 patients and to evaluate relationship with clinical and cognitive variables. Thirty DM1 patients underwent neuropsychological investigation and 3T-MRI protocol. GM and WM changes were evaluated calculating brain parenchymal fraction (BPF), voxel-based morphometry (VBM), white matter lesion load (LL% and Fazekas scale) and tract based spatial statistical (TBSS). Patients showed main impairment in tests exploring executive and mnesic domains with visuo-spatial involvement, significantly related to BPF. VBM revealed clusters of widespread GM reduction and TBSS revealed areas of decreased fractional anisotropy (FA) and increased radial diffusivity (RD), mean diffusivity (MD) and axial diffusivity (AD) in patients compared to a group of matched healthy controls. Multiple regression analyses showed areas of significant negative relationship between left temporal atrophy and verbal memory, between RD and mnesic and visuo-spatial cognitive domains, and between AD and verbal memory. TBSS results indicate that the involvement of normal appearance WM, beyond the signal changes detected with conventional MR imaging (Fazekas scale and LL%), was associated with neuropsychological deficit. These data suggest that disrupted complex neuronal networks can underlie cognitive-behavioural dysfunctions in DM1. PMID:27437180

  14. Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset.

    PubMed

    Cabrera, Susanne M; Wang, Xujing; Chen, Yi-Guang; Jia, Shuang; Kaldunski, Mary L; Greenbaum, Carla J; Mandrup-Poulsen, Thomas; Hessner, Martin J

    2016-04-01

    It was hypothesized that IL-1 antagonism would preserve β-cell function in new onset Type 1 diabetes (T1D). However, the Anti-Interleukin-1 in Diabetes Action (AIDA) and TrialNet Canakinumab (TN-14) trials failed to show efficacy of IL-1 receptor antagonist (IL-1Ra) or canakinumab, as measured by stimulated C-peptide response. Additional measures are needed to define immune state changes associated with therapeutic responses. Here, we studied these trial participants with plasma-induced transcriptional analysis. In blinded analyses, 70.2% of AIDA and 68.9% of TN-14 participants were correctly called to their treatment arm. While the transcriptional signatures from the two trials were distinct, both therapies achieved varying immunomodulation consistent with IL-1 inhibition. On average, IL-1 antagonism resulted in modest normalization relative to healthy controls. At endpoint, signatures were quantified using a gene ontology-based inflammatory index, and an inverse relationship was observed between measured inflammation and stimulated C-peptide response in IL-1Ra- and canakinumab-treated patients. Cytokine neutralization studies showed that IL-1α and IL-1β additively contribute to the T1D inflammatory state. Finally, analyses of baseline signatures were indicative of later therapeutic response. Despite the absence of clinical efficacy by IL-1 antagonist therapy, transcriptional analysis detected immunomodulation and may yield new insight when applied to other clinical trials.

  15. An autopsy case of adult-onset hereditary spastic paraplegia type 2 with a novel mutation in exon 7 of the proteolipid protein 1 gene.

    PubMed

    Suzuki, Satoshi O; Iwaki, Toru; Arakawa, Kenji; Furuya, Hirokazu; Fujii, Naoki; Iwaki, Akiko

    2011-12-01

    We report an autopsy case of rare adult-onset spastic paraplegia type 2 (SPG2) with a novel missense mutation in exon 7 of the proteolipid protein 1 gene (PLP1). The patient was a 67-year-old man whose elder brother had died of a similar disease with onset in his 40s. Thirty-three years before death at the age of 35, he noticed difficulty in walking. He gradually became abasic over a period of 6 years. He also developed progressive dementia and eventually became bed-ridden by 28 years after onset. At autopsy, gross inspection revealed diffuse, moderate atrophy of the cerebrum with a dilated ventricular system and softening of the white matter throughout the central nervous system (CNS). Histopathologically, the CNS showed widespread myelin pallor in the white matter. By contrast, the gray matter and peripheral nerves were well preserved. Some white matter tracts, including the corticospinal tracts, were preferentially affected, and severe axonal degeneration was observed in these tracts. Genetic analysis revealed a novel mutation, p.Tyr263Cys, in exon 7 of PLP1. This case represents an adult-onset SPG2 patient with one of the oldest ages of onset reported to date. The late onset and long clinical course suggest that this novel mutation does not affect the maturation of oligodendrocytes, but is related to insufficient maintenance of myelin.

  16. Treatments for Alzheimer's Disease

    MedlinePlus

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

  17. Alzheimer--certitudes and hypotheses.

    PubMed

    Amihăesei, Ioana Cristina; Cojocarut, Elena; Mungiu, O C

    2013-01-01

    Alzheimer's disease is a degenerative, progressive and irreversible condition, which affects cognitive functions. It was first described in 1907, by the German physician Alois Alzheimer. Although at the time, it was considered a rare disease, in 2010 in the world were estimated 35.6 million cases of dementia, most of these with the diagnosis of Alzheimer's disease. Typical neuropathologic lesions are represented by the amyloid plaques, neurofibrilar tangles and synapses and neurons losses. It was hypothesized that the amyloid protein has prion-like properties. Even from the first descriptions of the disease, atypical features were observed - the second case described by the physician Alois Alzheimer, had only plaques, the tangles were missing. About 19 % of the healthy old subjects present in the brain the same lesions as Alzheimer's cases, while in 10 % of the cases of disease, in necropsy are present only the plaques or only the tangles. These aspects are even more paradoxical, as the certain diagnosis is established only at necropsy, on anatomopathological lesions. Even so, the international diagnosis criteria, based on clinical aspects, can establish a certain, probable or a possible diagnosis. It exist an early-onset form, as well as a late-onset form of disease (which appears after 80-85 years of life); genes are involved in the genesis of the disease. A lot of money are spent to find an efficient medication in the treatment of the disease (tramiprosate--an amyloid-antagonist, Dimebon, gamma-secretase inhibitors or a vaccine--a synthetic form of the amyloid protein); for the moment the used medication may at its best only to temporary improve the symptoms. Some scientists believe that approx. 30 % of the cases are wrongly diagnosed with Alzheimer, being in fact other forms of dementia, or that we deal with several biologic processes, generating rather an Alzheimer's syndrome, meanwhile others are unsatisfied by a poor diagnosed disease and its popular receipt

  18. Understanding Alzheimer's

    MedlinePlus

    ... inhibitors. Scientists believe they prevent the breakdown of acetylcholine, a brain chemical that may be important for ... Alzheimer's progresses, the brain produces less and less acetylcholine; therefore, cholinesterase inhibitors may eventually lose their effect. ...

  19. Alzheimer's Project

    MedlinePlus

    ... about the films on our message board . Watch films free online now "The Memory Loss Tapes" (85 ... ALZHEIMER'S PROJECT" is a presentation of HBO Documentary Films and the National Institute on Aging at the ...

  20. Alzheimer's Myths

    MedlinePlus

    ... dementia . Myth 2: Alzheimer’s disease is not fatal. Reality: Alzheimer's disease has no survivors. It destroys brain ... any threat. Myth 5: Aspartame causes memory loss. Reality: This artificial sweetener, marketed under such brand names ...

  1. Alzheimer's Caregivers

    MedlinePlus

    Caring for someone who has Alzheimer's disease (AD) can be stressful and overwhelming. It's important to take care of yourself. Ask for and accept help. Talk to the doctor. Find out what treatments might help control symptoms or address ...

  2. Disease Expression and HLA Types in Early and Late Onset Disease of Malaysian Patients with Systemic Lupus Erythematosus.

    PubMed

    Radzi, A M; Huan, K S; Yahaya, N; Shahera, A; Kong, N; Mohd Noah, R

    2001-07-01

    Age has been suggested to modify systemic lupus erythematosus expression. In this study we have attempted to study 13 patients with late onset (40 years and above) and 90 with early onset disease (below 40 years) to determine whether age-related differences in disease expression exist and whether the genetic make-up influences the age of disease onset. We found that patients with late onset disease initially presented with pericarditis (31% vs 3%, P<0.005) and a lower incidence of malar rash (31% vs 57%, p<0.05). During the disease course, there was a lower incidence of mucocutaneous symptoms especially malar rash (p<0.005) and psychosis (p<0.05) in the late onset group. Serological parameters were similar in both groups. There was a prevalence of HLA-DQA1*0103 in Chinese patients with late onset disease (pcorr=0.004). These findings suggest that a subgroup of late onset patients may experience milder disease and that the risk conferred by the HLA-DQA1*0103 may be significant among these patients. PMID:22893758

  3. Disease Expression and HLA Types in Early and Late Onset Disease of Malaysian Patients with Systemic Lupus Erythematosus

    PubMed Central

    Radzi, Azizah Mohd; Huan, Kuak Soo; Yahaya, Normaznah; Shahera, Ainol; Kong, Norella; Mohd Noah, Rahim

    2001-01-01

    Age has been suggested to modify systemic lupus erythematosus expression. In this study we have attempted to study 13 patients with late onset (40 years and above) and 90 with early onset disease (below 40 years) to determine whether age-related differences in disease expression exist and whether the genetic make-up influences the age of disease onset. We found that patients with late onset disease initially presented with pericarditis (31% vs 3%, P<0.005) and a lower incidence of malar rash (31% vs 57%, p<0.05). During the disease course, there was a lower incidence of mucocutaneous symptoms especially malar rash (p<0.005) and psychosis (p<0.05) in the late onset group. Serological parameters were similar in both groups. There was a prevalence of HLA-DQA1*0103 in Chinese patients with late onset disease (pcorr=0.004). These findings suggest that a subgroup of late onset patients may experience milder disease and that the risk conferred by the HLA-DQA1*0103 may be significant among these patients. PMID:22893758

  4. The contribution of list length to the absence of the primacy effect in word recall in dementia of the Alzheimer type.

    PubMed

    Bemelmans, K J; Goekoop, J G

    1991-11-01

    It has repeatedly been demonstrated that patients with dementia of the Alzheimer type (DAT) show an absence of the primacy effect when asked to recall a list of items. The results of the present study show that the absence of the primacy effect in DAT patients is related to list length but probably in a way that is qualitatively not specific since it follows the same pattern as in normal ageing. It is also demonstrated that DAT patients differ in learning style. It is suggested that this indicates a reduced capacity to maintain controlled processing.

  5. Alzheimer's disease.

    PubMed

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

    2016-07-30

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

  6. Alzheimer's disease.

    PubMed

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

    2016-07-30

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

  7. [Diabetes mellitus and Alzheimer's disease].

    PubMed

    Salacz, Pál; Csibri, Eva

    2011-03-27

    The incidence of Alzheimer's disease and diabetes is increasing with age. Thus, in light of demographic change and aging societies, they are becoming a growing issue for public health. Further, there are linkages between the two diseases. In particular, risk assessment studies suggest that type 2 diabetes mellitus is a risk factor of Alzheimer's disease. Hence, even though Alzheimer's disease can only be influenced to a limited extent, optimal treatment of diabetes mellitus may have also a positive effect on Alzheimer's disease. While the relationship between the two diseases is not yet completely clear, in addition to the known vascular effects of diabetes mellitus recent results shed light on central nervous system effects directly influencing the neurodegenerative process. Treatment of central insulin resistance, a phenomenon explored in recent years, may be a promising avenue, not only in addressing metabolic disorder, but also Alzheimer's disease.

  8. Correlation between glycemic trends assessed by 24 h continuous monitoring and autonomic activity in patients with recent onset type 2 diabetes.

    PubMed

    Borgognoni, Laura; Picciarella, Alice; Di Stefano, Angelo; Fontana, Vincenzo; Russo, Alessandro; Pascucci, Matteo; Paris, Alberto; Tubani, Luigi; Fiorentini, Alessandra

    2013-04-01

    We observe, in patients with type 2 diabetes of recent onset, the activity of the autonomic nervous system and glucose metabolic impairment. The data indicate the hyperactivity of the sympathetic and minimal changes in glucose values. The role played by glycemia appeared to be less important than that represented by insulin resistance. PMID:23497980

  9. Pediatric diabetes consortium type 1 diabetes new onset (NeOn) study: Factors associated with HbA1c levels one year after diagnosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To identify determinants of hemoglobin A1c (HbA1c) levels 1 yr after the diagnosis of type 1 diabetes (T1D) in participants in the Pediatric Diabetes Consortium (PDC) T1D New Onset (NeOn) Study. Diabetes-specific as well as socioeconomic factors during the first year following diagnosis were analyze...

  10. Estimating the Height of CMEs Associated with a Major SEP Event at the Onset of the Metric Type II Radio Burst during Solar Cycles 23 and 24

    NASA Astrophysics Data System (ADS)

    Mäkelä, P.; Gopalswamy, N.; Akiyama, S.; Xie, H.; Yashiro, S.

    2015-06-01

    We studied the coronal mass ejection (CME) height at the onset of 59 metric type II radio bursts associated with major solar energetic particle (SEP) events, excluding ground level enhancements (GLEs), during solar cycles 23 and 24. We calculated CME heights using a simple flare-onset method used by Gopalswamy et al. to estimate CME heights at the metric type II onset for cycle 23 GLEs. We found the mean CME height for non-GLE events (1.72 R⊙) to be ˜12% greater than that (1.53 R⊙) for cycle 23 GLEs. The difference could be caused by more impulsive acceleration of the GLE-associated CMEs. For cycle 24 non-GLE events, we compared the CME heights obtained using the flare-onset method and the three-dimensional spherical-shock fitting method and found the correlation to be good (CC = 0.68). We found the mean CME height for cycle 23 non-GLE events (1.79 R⊙) to be greater than that for cycle 24 non-GLE events (1.58 R⊙), but statistical tests do not definitely reject the possibility of coincidence. We suggest that the lower formation height of the shocks during cycle 24 indicates a change in the Alfvén speed profile because solar magnetic fields are weaker and plasma density levels are closer to the surface than usual during cycle 24. We also found that complex type III bursts showing diminution of type III emission in the 7-14 MHz frequency range are more likely associated with events with a CME height at the type II onset above 2 R⊙, supporting suggestions that the CME/shock structure causes the feature.

  11. ESTIMATING THE HEIGHT OF CMEs ASSOCIATED WITH A MAJOR SEP EVENT AT THE ONSET OF THE METRIC TYPE II RADIO BURST DURING SOLAR CYCLES 23 AND 24

    SciTech Connect

    Mäkelä, P.; Akiyama, S.; Xie, H.; Yashiro, S.; Gopalswamy, N.

    2015-06-10

    We studied the coronal mass ejection (CME) height at the onset of 59 metric type II radio bursts associated with major solar energetic particle (SEP) events, excluding ground level enhancements (GLEs), during solar cycles 23 and 24. We calculated CME heights using a simple flare-onset method used by Gopalswamy et al. to estimate CME heights at the metric type II onset for cycle 23 GLEs. We found the mean CME height for non-GLE events (1.72 R{sub ☉}) to be ∼12% greater than that (1.53 R{sub ☉}) for cycle 23 GLEs. The difference could be caused by more impulsive acceleration of the GLE-associated CMEs. For cycle 24 non-GLE events, we compared the CME heights obtained using the flare-onset method and the three-dimensional spherical-shock fitting method and found the correlation to be good (CC = 0.68). We found the mean CME height for cycle 23 non-GLE events (1.79 R{sub ☉}) to be greater than that for cycle 24 non-GLE events (1.58 R{sub ☉}), but statistical tests do not definitely reject the possibility of coincidence. We suggest that the lower formation height of the shocks during cycle 24 indicates a change in the Alfvén speed profile because solar magnetic fields are weaker and plasma density levels are closer to the surface than usual during cycle 24. We also found that complex type III bursts showing diminution of type III emission in the 7–14 MHz frequency range are more likely associated with events with a CME height at the type II onset above 2 R{sub ☉}, supporting suggestions that the CME/shock structure causes the feature.

  12. Sporadic Early-Onset Colorectal Cancer Is a Specific Sub-Type of Cancer: A Morphological, Molecular and Genetics Study

    PubMed Central

    Kirzin, Sylvain; Marisa, Laetitia; Guimbaud, Rosine; De Reynies, Aurélien; Legrain, Michèle; Laurent-Puig, Pierre; Cordelier, Pierre; Pradère, Bernard; Bonnet, Delphine; Meggetto, Fabienne; Portier, Guillaume; Brousset, Pierre; Selves, Janick

    2014-01-01

    Sporadic early onset colorectal carcinoma (EOCRC) which has by definition no identified hereditary predisposition is a growing problem that remains poorly understood. Molecular analysis could improve identification of distinct sub-types of colorectal cancers (CRC) with therapeutic implications and thus can help establish that sporadic EOCRC is a distinct entity. From 954 patients resected for CRC at our institution, 98 patients were selected. Patients aged 45–60 years were excluded to help define “young” and “old” groups. Thirty-nine cases of sporadic EOCRC (patients≤45 years with microsatellite stable tumors) were compared to both microsatellite stable tumors from older patients (36 cases, patients>60 years) and to groups of patients with microsatellite instability. Each group was tested for TP53, KRAS, BRAF, PIK3CA mutations and the presence of a methylator phenotype. Gene expression profiles were also used for pathway analysis. Compared to microsatellite stable CRC from old patients, sporadic EOCRC were characterized by distal location, frequent synchronous metastases and infrequent synchronous adenomas but did not have specific morphological characteristics. A familial history of CRC was more common in sporadic EOCRC patients despite a lack of identified hereditary conditions (p = 0.013). Genetic studies also showed the absence of BRAF mutations (p = 0.022) and the methylator phenotype (p = 0.005) in sporadic EOCRC compared to older patients. Gene expression analysis implicated key pathways such as Wnt/beta catenin, MAP Kinase, growth factor signaling (EGFR, HGF, PDGF) and the TNFR1 pathway in sporadic EOCRC. Wnt/beta catenin signaling activation was confirmed by aberrant nuclear beta catenin immunostaining (p = 0.01). This study strongly suggests that sporadic EOCRC is a distinct clinico-molecular entity presenting as a distal and aggressive disease associated with chromosome instability. Furthermore, several signaling pathways

  13. Liver transplantation versus conservative treatment for adult-onset type II citrullinemia: our experience and a review of the literature.

    PubMed

    Kimura, N; Kubo, N; Narumi, S; Toyoki, Y; Ishido, K; Kudo, D; Umehara, M; Yakoshi, Y; Hakamada, K

    2013-11-01

    Adult-onset type II citrullinemia (CTLN2), an autosomal recessive disorder caused by a mutation in the SLC25A13 gene, is characterized by increased serum citrulline and ammonia levels. Patients with CTLN2 also display various neuropsychiatric symptoms. Many individuals with CTLN2 are fond of protein-rich and/or lipid-rich foods with an aversion to carbohydrate-rich foods. We herein report two cases of CTLN2 treated with living donor liver transplantation (LDLT) and provide a review of the pertinent literature. Case 1 was a 43-year-old man admitted to our hospital for repetitive episodes of consciousness disturbance. Case 2 was a 37-year-old man admitted to our hospital because of abnormal behavior associated with hyperammonemia. A definitive diagnosis of CTLN2 was accomplished by DNA analysis in both patients, who successfully underwent LDLT using liver segments from donor siblings with confirmed heterozygous gene expression. Case 2 also underwent conservative therapy with arginine and a high-fat, carbohydrate-restricted diet prior to LDLT. Postoperative recovery was uneventful and food was unrestricted in both patients. We also identified 77 cases of CTLN2 in the literature and reviewed them in terms of outcome of both liver transplantation and conservative therapy. The survival rate in patients treated by liver transplantation was 100%, whereas that in patients treated by conservative treatment showed improvement from 39.5% to 76.5% over the years. Liver transplantation is a practical treatment that fundamentally improves patient quality of life after transplantation. However, recent studies have suggested that arginine and sodium pyruvate administration combined with intensive nutritional support is also an effective therapy for CTLN2. Further development of conservative therapy may provide a safer, more affordable alternative to liver transplantation in the near future.

  14. Genomic differences in the background of different severity in juvenile-onset respiratory papillomatoses associated with human papillomavirus type 11.

    PubMed

    Gáll, Tamás; Kis, Andrea; Tatár, Tímea Zsófia; Kardos, Gábor; Gergely, Lajos; Szarka, Krisztina

    2013-10-01

    This study aimed to compare complete genome sequences of human papillomavirus (HPV) type 11 from two solitary papillomas (considered minimally aggressive), two moderately (six and nine episodes) and two highly aggressive (30 and 33 episodes) juvenile-onset respiratory papillomatoses. Genomic regions were sequenced using the Sanger method; sequences were compared to available GenBank genomes. Activity of the long control region (LCR) was assessed in HEp-2 cell line using luciferase assays and compared to that of the reference (GenBank Accession Number M14119). Site-directed mutagenesis was performed to confirm the association of polymorphisms with differences in LCR activity. Eleven alterations resulted in amino acid changes in different open reading frames. A72E in E1 and Q86K in E2 proteins were exclusively present in a moderately aggressive disease, L1 alterations A476V and S486F were unique to a severe papillomatosis. HPV11s in both solitary papillomas had identical LCRs containing a T7546C polymorphism, which strongly attenuated LCR activity, as confirmed by site-directed mutagenesis. This strong attenuator polymorphism was also present in the other four genomes showing significantly higher activities, but in these other alterations with demonstrable but statistically not significant attenuating (A7413C, 7509 T deletion) or enhancing (C7479T, T7904A) effect on transactivating potential (as demonstrated by site-directed mutagenesis) were also detected. LCR activities corresponded well to severity, excepting the highly aggressive papillomatosis with the L1 alterations. Presence of intratypic variants cannot explain differences in severity of respiratory papillomatoses associated with HPV11; virulence seems to be determined by the interaction of multiple genetic differences. PMID:23649705

  15. Genotypes of p53 codon 72 correlate with age at onset of type 1 diabetes in a sex-specific manner.

    PubMed

    Bitti, Maria Luisa Manca; Saccucci, Patrizia; Capasso, Francesca; Piccinini, Simona; Angelini, Federica; Rapini, Novella; Porcari, Marta; Arcano, Susanna; Petrelli, Arianna; Del Duca, Elisabetta; Bottini, Egidio; Gloria-Bottini, Fulvia

    2011-01-01

    In type 1 diabetes mellitus (T1D) p53 pathways are up-regulated and there is an increased susceptibility to apoptosis. The hypothesis is that p53 codon 72 polymorphism could be associated with T1D. A total of 286 children with T1D and a control sample of 730 subjects were studied. p53 codon 72 polymorphism was analysed by polymerase chain reaction. A large increase of p53 *Arg/*Arg was observed in T1D patients with age at onset < 6 years. A strong linear correlation between *Arg/*Arg genotype and age at onset was observed in females. The involvement of the *Arg/*Arg genotype in apoptosis suggests that during the autoimmune process leading to T1D, genetic factors that favor apoptosis may contribute to the onset of overt disease. PMID:21932578

  16. Protection against Myocardial Ischemia-Reperfusion Injury at Onset of Type 2 Diabetes in Zucker Diabetic Fatty Rats Is Associated with Altered Glucose Oxidation

    PubMed Central

    Povlsen, Jonas Agerlund; Løfgren, Bo; Dalgas, Christian; Birkler, Rune Isak Dupont; Johannsen, Mogens; Støttrup, Nicolaj Brejnholt; Bøtker, Hans Erik

    2013-01-01

    Background Inhibition of glucose oxidation during initial reperfusion confers protection against ischemia-reperfusion (IR) injury in the heart. Mitochondrial metabolism is altered with progression of type 2 diabetes (T2DM). We hypothesized that the metabolic alterations present at onset of T2DM induce cardioprotection by metabolic shutdown during IR, and that chronic alterations seen in late T2DM cause increased IR injury. Methods Isolated perfused hearts from 6 (prediabetic), 12 (onset of T2DM) and 24 (late T2DM) weeks old male Zucker diabetic fatty rats (ZDF) and their age-matched heterozygote controls were subjected to 40 min ischemia/120 min reperfusion. IR injury was assessed by TTC-staining. Myocardial glucose metabolism was evaluated by glucose tracer kinetics (glucose uptake-, glycolysis- and glucose oxidation rates), myocardial microdialysis (metabolomics) and tissue glycogen measurements. Results T2DM altered the development in sensitivity towards IR injury compared to controls. At late diabetes ZDF hearts suffered increased damage, while injury was decreased at onset of T2DM. Coincident with cardioprotection, oxidation of exogenous glucose was decreased during the initial and normalized after 5 minutes of reperfusion. Metabolomic analysis of citric acid cycle intermediates demonstrated that cardioprotection was associated with a reversible shutdown of mitochondrial glucose metabolism during ischemia and early reperfusion at onset of but not at late type 2 diabetes. Conclusions The metabolic alterations of type 2 diabetes are associated with protection against IR injury at onset but detrimental effects in late diabetes mellitus consistent with progressive dysfunction of glucose oxidation. These findings may explain the variable efficacy of cardioprotective interventions in individuals with type 2 diabetes. PMID:23704975

  17. [Alzheimer's disease and depression].

    PubMed

    Gallarda, T

    1999-11-01

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

  18. TyG Index Change Is More Determinant for Forecasting Type 2 Diabetes Onset Than Weight Gain.

    PubMed

    Navarro-González, David; Sánchez-Íñigo, Laura; Fernández-Montero, Alejandro; Pastrana-Delgado, Juan; Martinez, Jose Alfredo

    2016-05-01

    The risk of type 2 diabetes associated with obesity appears to be influenced by other metabolic abnormalities, and there is controversy about the harmless condition of the metabolically healthy obese (MHO) state. The aim of this study is to assess the risk of diabetes and the impact of changes in weight and in triglyceride-glucose index (TyG index), according to the metabolic health and obesity states.We analyzed prospective data of the Vascular Metabolic CUN cohort, a population-based study among a White European population (mean follow-up, 8.9 years). Incident diabetes was assessed in 1923 women and 3016 men with a mean age at baseline of 55.33 ± 13.68 and 53.78 ± 12.98 years old.A Cox proportional-hazard analysis was conducted to estimate the hazard ratio (HR) of diabetes on metabolically healthy nonobese (MHNO), metabolically healthy obese, metabolically unhealthy nonobese (MUNO), and metabolically unhealthy obese (MUO). A continuous standardized variable (z-score) was derived to compute the HR for diabetes per 1-SD increment in the body mass index (BMI) and the TyG index.MHO, MUNO, and MUO status were associated with the development of diabetes, HR of 2.26 (95% CI: 1.25-4.07), 3.04 (95% CI: 1.69-5.47), and 4.04 (95% CI: 2.14-7.63), respectively. MUNO individuals had 1.82 greater risk of diabetes compared to MHO subjects (95% CI: 1.04-3.22). The HRs for incident diabetes per 1-SD increment in BMI and TyG indexes were 1.23 (95% CI: 1.04-1.44) and 1.54 (95% CI: 1.40-1.68). The increase in BMI did not raise the risk of developing diabetes among metabolically unhealthy subjects, whereas increasing the TyG index significantly affect the risk in all metabolic health categories.Metabolic health is more important determinant for diabetes onset than weight gain. The increase in weight does not raise the risk of developing diabetes among metabolically unhealthy subjects. PMID:27175686

  19. Neuronutrition and Alzheimer's Disease

    PubMed Central

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

    2010-01-01

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

  20. Pittsburgh compound B-negative dementia: a possibility of misdiagnosis of patients with non-alzheimer disease-type dementia as having AD.

    PubMed

    Shimada, Hiroyuki; Ataka, Suzuka; Takeuchi, Jun; Mori, Hiroshi; Wada, Yasuhiro; Watanabe, Yasuyoshi; Miki, Takami

    2011-09-01

    Amyloid imaging has been used to detect amyloid deposition in the brain. We performed Pittsburgh compound B (PiB)-positron emission tomography on 63 patients with dementia having cognitive decline or memory disturbance. In addition, we measured the patients' apolipoprotein E4 (apo E4) status and cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)1-42, tau, and P-tau. Finally, the patients were diagnosed as having probable Alzheimer disease (AD) on the basis of their neuropsychological findings and because they met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria. Among the patients diagnosed with probable AD, 10 patients were PiB negative. The CSF levels of P-tau and tau in PiB-negative patients were significantly lower than those in the PiB-positive patients. In addition, the CSF levels of Aβ1-42 in the PiB-negative patients were significantly higher than those in the PiB-positive patients. None of the PiB-negative patients were apo E4 carriers. These results suggest that the PiB-negative patient group included not only AD patients but also non-AD-type dementia patients. However, our finding is based on a relatively small number of patients and therefore should be replicated in a larger cohort. In addition, it will be necessary to categorize these participants by longitudinal follow-up and postmortem pathological examinations.

  1. Successful non-operative management of spontaneous type II gallbladder perforation in a patient with Alzheimer's disease.

    PubMed

    Alessiani, Mario; Peloso, Andrea; Tramelli, Paola; Magnani, Enzo

    2014-01-01

    A 77-year-old man with Alzheimer's disease was admitted to a rural hospital in June 2012 and an acute cholecistytis was first diagnosed. Surgery was not considered as a possible option due to the critical condition of the patient and his severe comorbidities. After 2 days of broad-spectrum antibiotics, the patient worsened and developed severe sepsis. A gallbladder perforation with intrahepatic abscess formation was diagnosed on ultrasonography (US) and abdominal CT scan. The patient underwent percutaneous US-guided gallbladder drainage with resolution of the sepsis and rapid clinical improvement. After 1 month, the drainage was removed and the patient was discharged. He survived in good condition for 18 months and he passed away from pneumonitis in December 2013. This case shows that in a case of acute cholecystitis with gallbladder perforation, percutaneous gallbladder drainage can be a lifesaving procedure in elderly patients with severe comorbidities (including Alzheimer's disease) who are not candidates for elective surgery.

  2. Expression of Alzheimer-Type Neurofibrillary Epitopes in Primary Rat Cortical Neurons Following Infection with Enterococcus faecalis

    PubMed Central

    Underly, Robert; Song, Mee-Sook; Dunbar, Gary L.; Weaver, Charles L.

    2016-01-01

    The neurofibrillary tau pathology and amyloid deposits seen in Alzheimer’s disease (AD) also have been seen in bacteria-infected brains. However, few studies have examined the role of these bacteria in the generation of tau pathology. One suggested link between infection and AD is edentulism, the complete loss of teeth. Edentulism can result from chronic periodontal disease due to infection by Enterococcus faecalis. The current study assessed the ability to generate early Alzheimer-like neurofibrillary epitopes in primary rat cortical neurons through bacterial infection by E. faecalis. Seven-day old cultured neurons were infected with E. faecalis for 24 and 48 h. An upward molecular weight shift in tau by Western blotting (WB) and increased appearance of tau reactivity in cell bodies and degenerating neurites was found in the 48 h infection group for the antibody CP13 (phospho-Serine 202). A substantial increase in reactivity of Alz-50 was seen at 24 and 48 h after infection. Furthermore, extensive microtubule-associated protein 2 (MAP2) reactivity also was seen at 24 and 48 h post-infection. Our preliminary findings suggest a potential link between E. faecalis infection and intracellular changes that may help facilitate early AD-like neurofibrillary pathology. HighlightsEnterococcus faecalis used in the generation of AD neurofibrillary epitopes in rat.Infection increases Alz-50, phospho-Serine 202 tau, and MAP2 expression.Infection by Enterococcus may play a role in early Alzheimer neurofibrillary changes. PMID:26834627

  3. Seven-year Observational Study on the Association between Glycemic Control and the New Onset of Macroangiopathy in Japanese Subjects with Type 2 Diabetes.

    PubMed

    Kimura, Tomohiko; Kaneto, Hideaki; Kanda-Kimura, Yukiko; Shimoda, Masashi; Kamei, Shinji; Anno, Takatoshi; Kawasaki, Fumiko; Hashiramoto, Mitsuru; Matsuki, Michihiro; Mune, Tomoatsu; Kaku, Kohei

    2016-01-01

    Objective To examine the association between glycemic control and the new onset of macroangiopathy in Japanese subjects with type 2 diabetes. Methods We examined seven-year follow-up data for 572 patients. We divided the subjects by the average of seven-year glycemic control based on the guidelines. First, we excluded the subjects with a past history of macroangiopathy and then examined the incidence of the new onset of macroangiopathy. Results The incidence of ischemic heart disease (IHD) was 1.0% per year, and that of cerebral vascular disease (CVD) was 1.0% per year. However, IHD events were not observed at all for five years in the most intensive glycemic control group (HbA1c<6%). Similarly, CVD events were not observed at all for seven years in the most intensive glycemic control group (HbA1c<6%). In addition, the cumulative incidence rate of IHD tended to increase as the glycemic control became poorer (HbA1c<6%, 4.5%; 6%≤HbA1c<7%, 6.0%; 7%≤HbA1c<8%, 7.2%; HbA1c≥8%, 10.7%). Furthermore, a logistic regression analysis showed that the duration of diabetes and HbA1c level were independent risk factors contributing to the onset of IHD, but not to the onset of CVD. Conclusion This seven-year observational study showed the possible association between glycemic control and the onset of macroangiopathy in a total of 572 Japanese subjects with type 2 diabetes.

  4. Life Course Socioeconomic Transition and its Association with Early Onset Type 2 Diabetes: Protocol for a Sequential Exploratory Mixed Method Study

    PubMed Central

    Raman, V Kutty; Nochikattil, Santhosh Kumar

    2016-01-01

    Introduction The prevalence of early onset type 2 diabetes (Diabetes below the age of 45 years) is increasing worldwide. Transition in socio-economic position–i.e. Life Course Socio-Economic Transition (LSET) - may contribute to the development of early onset T2D through complex processes involving economic and occupational opportunities as well as individual life style choices. Aim To develop and validate the life course socioeconomic transition questionnaire and to know the association between life courses socioeconomic transition and early onset type 2 diabetes. Materials and Methods This study follows sequential exploratory mixed method study design. It consists of one qualitative strand followed by two quantitative strands. Qualitative strand consist of in- depth interview among the community dwellers to develop a tool for measuring LSET. Two quantitative strands consist of the validation of the questionnaire by conducting cross-sectional survey among 200 randomly selected community dwellers and a hospital based case control study using the same questionnaire. Results Those who have a history of lower SEP during his childhood period and enjoying higher SEP during his adulthood period have an increased risk for developing type 2 diabetes at their younger age (18-45 years). Conclusion This study will help to develop a validated life course socioeconomic transition questionnaire and application of that tool in an epidemiological study. PMID:27504317

  5. Insulin Resistance in Alzheimer's Disease

    PubMed Central

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

    2014-01-01

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

  6. Characterization of hippocampal Cajal-Retzius cells during development in a mouse model of Alzheimer's disease (Tg2576)

    PubMed Central

    Yu, Dongming; Fan, Wenjuan; Wu, Ping; Deng, Jiexin; Liu, Jing; Niu, Yanli; Li, Mingshan; Deng, Jinbo

    2014-01-01

    Cajal-Retzius cells are reelin-secreting neurons in the marginal zone of the neocortex and hippocampus. The aim of this study was to investigate Cajal-Retzius cells in Alzheimer's disease pathology. Results revealed that the number of Cajal-Retzius cells markedly reduced with age in both wild type and in mice over-expressing the Swedish double mutant form of amyloid precursor protein 695 (transgenic (Tg) 2576 mice). Numerous reelin-positive neurons were positive for activated caspase 3 in Tg2576 mice, suggesting that Cajal-Retzius neuronal loss occurred via apoptosis in this Alzheimer's disease model. Compared with wild type, the number of Cajal-Retzius cells was significantly lower in Tg2576 mice. Western blot analysis confirmed that reelin levels were markedly lower in Tg2576 mice than in wild-type mice. The decline in Cajal-Retzius cells in Tg2576 mice was found to occur concomitantly with the onset of Alzheimer's disease amyloid pathology and related behavioral deficits. Overall, these data indicated that Cajal-Retzius cell loss occurred with the onset and development of Alzheimer's disease. PMID:25206826

  7. Updating and inhibition processes in working memory: a comparison between Alzheimer's type dementia and frontal lobe focal damage.

    PubMed

    Borgo, Francesca; Giovannini, Lorena; Moro, Raffaella; Semenza, Carlo; Arcicasa, Mauro; Zaramella, Marco

    2003-11-01

    A large debate has recently focused on the componential nature of the working-memory system (), as evidenced by functional-imaging studies and by using more sophisticated experimental paradigms. The present work aims at further disentangling the role and effects of central executive (CE) and of phonological loop (PL). It is suggested that maintaining active verbal information mostly relates to an intact PL, while the inhibition of interfering information preponderantly involves the CE. To distinguish these effects, two groups of brain damaged patients were administered with an updating task. Frontal lobe patients showed major difficulties in inhibiting interfering information, an ability requiring an involvement of the CE component. In contrast, Alzheimer's dementia patients evidenced a relative impairment in maintaining relevant information, requiring the intervention of the PL.

  8. Increasing burden, younger age at onset and worst metabolic control in migrant than in Italian children with type 1 diabetes: an emerging problem in pediatric clinics.

    PubMed

    Cadario, Francesco; Cerutti, Franco; Savastio, Silvia; Rabbone, Ivana; Tumini, Stefano; Bruno, Graziella

    2014-04-01

    To assess burden and clinical features of type 1 diabetes in migrant with respect to Italian children. Prevalent children with type 1 diabetes were identified through a multicenter study, including 46 pediatric outpatients diabetic clinics. A nested case-control study was also performed, comparing features at diabetes onset and after 1 year of insulin treatment in 84 migrants and 75 Italian children with onset in 2011, matched for age and sex. Out of 7,812 children cared for by pediatric diabetologists, 761 (10%) were migrant and 548 of them were born in Italy. Age at diagnosis was lower in migrants born in Italy (5.1 years, interquartile range (IQR) 2.2-7.7) than in those born in their original countries (7.8 years, IQR 5.3-10.3) and in Italians (9.8 years, IQR 5.9-13.0, p < 0.001). At diabetes onset, migrants had lower frequencies of positivities of markers of β-cell autoimmunity (96 vs. 99.5%, p < 0.01), higher values of weight loss (11 vs. 7%, p < 0.01), HbA1c (70 vs. 58 mmol/mol, p < 0.001), and insulin requirement (0.70 ± 0.03 vs. 0.63 ± 0.10 UI/kg/die, p = 0.05) and lower levels of 25-OH vitamin D3 (15.0 ± 2.8 vs. 20.8 ± 1.3, p = 0.03). Moreover, they experienced higher frequencies of hospitalizations during the first year of disease (19.2 vs. 2.7%, p < 0.001). Burden of type 1 diabetes in migrant children is increasing in Italy, with younger age at onset and different clinical features than in Italian children. Higher hospitalization rates and poorer glycemic control over the first year underline that approach to diabetes care in migrants needs to be improved. PMID:24065151

  9. Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimer's disease as well as in wild-type mice.

    PubMed

    Kemppainen, Susanna; Lindholm, Päivi; Galli, Emilia; Lahtinen, Hanna-Maija; Koivisto, Henna; Hämäläinen, Elina; Saarma, Mart; Tanila, Heikki

    2015-09-15

    Cerebral dopamine neurotrophic factor (CDNF) protects and repairs dopamine neurons in animal models of Parkinson's disease, which motivated us to investigate its therapeutic effect in an animal model of Alzheimer's disease (AD). We employed an established APP/PS1 mouse model of AD and gave intrahippocampal injections of CDNF protein or CDNF transgene in an AAV2 viral vector to 1-year-old animals. We performed a behavioral test battery 2 weeks after the injections and collected tissue samples after the 3-week test period. Intrahippocampal CDNF-therapy improved long-term memory in both APP/PS1 mice and wild-type controls, but did not affect spontaneous exploration, object neophobia or early stages of spatial learning. The memory improvement was not associated with decreased brain amyloid load or enhanced hippocampal neurogenesis. Intracranial CDNF treatment has beneficial effects on long-term memory and is well tolerated. The CDNF molecular mechanisms of action on memory await further studies.

  10. Xenon contrast CT-CBF scanning of the brain differentiates normal age-related changes from multi-infarct dementia and senile dementia of Alzheimer type

    SciTech Connect

    Tachibana, H.; Meyer, J.S.; Okayasu, H.; Shaw, T.G.; Kandula, P.; Rogers, R.L.

    1984-07-01

    Local cerebral blood flow (LCBF) and partition coefficients (L lambda) were measured during inhalation of stable xenon gas with serial CT scanning among normal volunteers (N . 15), individuals with multi-infarct dementia (MID, N . 10), and persons with senile dementia of Alzheimer type (SDAT, N . 8). Mean gray matter flow values were reduced in both MID and SDAT. Age-related declines in LCBF values in normals were marked in frontal cortex and basal ganglia. LCBF values were decreased beyond normals in frontal and temporal cortices and thalamus in MID and SDAT, in basal ganglia only in MID. Unlike SDAT and age-matched normals, L lambda values were reduced in fronto-temporal cortex and thalamus in MID. Multifocal nature of lesions in MID was apparent. Coefficients of variation for LCBFs were greater in MID compared with SDAT and/or age-matched normals.

  11. A Case of Successful Coil Embolization for a Late-Onset Type Ia Endoleak after Endovascular Aneurysm Repair with the Chimney Technique

    PubMed Central

    Toyofuku, Takahiro; Inoue, Yoshinori

    2016-01-01

    Juxtarenal aortic aneurysms (JRAAs) are challenging to treat by endovascular aneurysm repair (EVAR) procedures. The chimney technique with EVAR (Ch-EVAR) is one of the feasible and less invasive treatments for JRAAs. However, the main concern of Ch-EVAR is the potential risk of “gutters,” which can lead to type Ia endoleak (EL). Most type Ia ELs after Ch-EVAR procedures occurred intraoperatively, and these ELs could be treated using an endovascular technique. However, late-onset type Ia ELs could be extremely rare, which might have a fear of conservative treatment. Type Ia ELs are associated with an increased risk of aneurysm rupture; therefore reintervention is recommended as soon as possible, and we should be aware of the occurrence of type Ia ELs after the Ch-EVAR procedure. PMID:27699077

  12. A Case of Successful Coil Embolization for a Late-Onset Type Ia Endoleak after Endovascular Aneurysm Repair with the Chimney Technique

    PubMed Central

    Toyofuku, Takahiro; Inoue, Yoshinori

    2016-01-01

    Juxtarenal aortic aneurysms (JRAAs) are challenging to treat by endovascular aneurysm repair (EVAR) procedures. The chimney technique with EVAR (Ch-EVAR) is one of the feasible and less invasive treatments for JRAAs. However, the main concern of Ch-EVAR is the potential risk of “gutters,” which can lead to type Ia endoleak (EL). Most type Ia ELs after Ch-EVAR procedures occurred intraoperatively, and these ELs could be treated using an endovascular technique. However, late-onset type Ia ELs could be extremely rare, which might have a fear of conservative treatment. Type Ia ELs are associated with an increased risk of aneurysm rupture; therefore reintervention is recommended as soon as possible, and we should be aware of the occurrence of type Ia ELs after the Ch-EVAR procedure.

  13. L-type calcium channel blockers and substance P induce angiogenesis of cortical vessels associated with beta-amyloid plaques in an Alzheimer mouse model.

    PubMed

    Daschil, Nina; Kniewallner, Kathrin M; Obermair, Gerald J; Hutter-Paier, Birgit; Windisch, Manfred; Marksteiner, Josef; Humpel, Christian

    2015-03-01

    It is well established that L-type calcium channels (LTCCs) are expressed in astroglia. However, their functional role is still speculative, especially under pathologic conditions. We recently showed that the α1 subunit-like immunoreactivity of the CaV1.2 channel is strongly expressed in reactive astrocytes around beta-amyloid plaques in 11-month-old Alzheimer transgenic (tg) mice with the amyloid precursor protein London and Swedish mutations. The aim of the present study was to examine the cellular expression of all LTCC subunits around beta-amyloid plaques by in situ hybridization using (35)S-labeled oligonucleotides. Our data show that messenger RNAs (mRNAs) of the LTCC CaV1.2 α1 subunit as well as all auxiliary β and α2δ subunits, except α2δ-4, were expressed in the hippocampus of age-matched wild-type mice. It was unexpected to see, that cells directly located in the plaque core in the cortex expressed mRNAs for CaV1.2 α1, β2, β4, and α2δ-1, whereas no expression was detected in the halo. Furthermore, cells in the plaque core also expressed preprotachykinin-A mRNA, the precursor for substance P. By means of confocal microscopy, we demonstrated that collagen-IV-stained brain vessels in the cortex were associated with the plaque core and were immunoreactive for substance P. In cortical organotypic brain slices of adult Alzheimer mice, we could demonstrate that LTCC blockers increased angiogenesis, which was further potentiated by substance P. In conclusion, our data show that brain vessels associated with beta-amyloid plaques express substance P and an LTCC and may play a role in angiogenesis. PMID:25619662

  14. Changes in ideal cardiovascular health status and risk of new-onset type 2 diabetes: The Kailuan prospective study.

    PubMed

    Liu, Xiaoxue; Shi, Jihong; Wang, Anxin; Song, Qiaofeng; Huang, Zhe; Zhu, Chenrui; Du, Xin; Zhang, Ying; Chen, Shuohua; Wang, Xizhu; Wu, Shouling

    2016-08-01

    The aim of the present study was to investigate the association between the altered ideal cardiovascular health status (ΔCHS) and the risk of developing diabetes mellitus in the Kailuan population of China.We included 50,656 Chinese adults aged 18 years or older (11,704 men and 38,952 women) without baseline diabetes mellitus in this study. Information about 7 individual components of the cardiovascular health metrics during 2006 to 2008 was collected. A ΔCHS score was defined as the changes of ideal cardiovascular health status (CHS) from the year 2006 to 2008. New-onset diabetes was identified based on the history of diabetes, currently treated with insulin or oral hypoglycemic agents, or having a fasting blood glucose concentration ≥7.0 mmol/L during the 2010 to 2011 and 2012 to 2013 surveys. After a mean follow-up period of 3.80 years, a total of 3071 (6.06%) participants developed diabetes mellitus. Cox proportional hazards regression was used to calculate the hazard ratios and 95% confidence intervals for the CHS change and new-onset diabetes.A strong inverse association between the positive CHS changes and lower risks of developing diabetes mellitus was observed. After adjusting for age, sex, alcohol consumption, and other potential confounders, the hazard ratios for new-onset diabetes were 0.73, 0.59, 0.49, and 0.42 (95% confidence interval: 0.37-0.82; P trend <0.001) for those who met ΔCHS = -1, 0, 1, and ≥2, respectively, compared with the participants with ΔCHS ≤-2.The study concluded that the improved CHS was associated with the reduced risk of developing diabetes mellitus in this investigated Chinese population. PMID:27559955

  15. Cognitive training and cognitive rehabilitation for persons with mild to moderate dementia of the Alzheimer's or vascular type: a review

    PubMed Central

    2013-01-01

    Cognitive impairments, and particularly memory deficits, are a defining feature of the early stages of Alzheimer's disease and vascular dementia. Interventions that target these cognitive deficits and the associated difficulties with activities of daily living are the subject of ever-growing interest. Cognitive training and cognitive rehabilitation are specific forms of non-pharmacological intervention to address cognitive and non-cognitive outcomes. The present review is an abridged version of a Cochrane Review and aims to systematically evaluate the evidence for these forms of intervention in people with mild Alzheimer's disease or vascular dementia. Randomized controlled trials (RCTs), published in English, comparing cognitive rehabilitation or cognitive training interventions with control conditions and reporting relevant outcomes for the person with dementia or the family caregiver (or both), were considered for inclusion. Eleven RCTs reporting cognitive training interventions were included in the review. A large number of measures were used in the different studies, and meta-analysis could be conducted for several primary and secondary outcomes of interest. Several outcomes were not measured in any of the studies. Overall estimates of the treatment effect were calculated by using a fixed-effects model, and statistical heterogeneity was measured by using a standard chi-squared statistic. One RCT of cognitive rehabilitation was identified, allowing the examination of effect sizes, but no meta-analysis could be conducted. Cognitive training was not associated with positive or negative effects in relation to any of the reported outcomes. The overall quality of the trials was low to moderate. The single RCT of cognitive rehabilitation found promising results in relation to some patient and caregiver outcomes and was generally of high quality. The available evidence regarding cognitive training remains limited, and the quality of the evidence needs to improve

  16. Population-based cohort study of anti-infective medication use before and after the onset of type 1 diabetes in children and adolescents.

    PubMed

    Fazeli Farsani, Soulmaz; Souverein, Patrick C; van der Vorst, Marja M J; Knibbe, Catherijne A J; de Boer, Anthonius; Mantel-Teeuwisse, Aukje K

    2014-08-01

    A population-based cohort study was conducted in the Dutch PHARMO database to investigate prevalence and patterns of anti-infective medication use in children and adolescents with type 1 diabetes (T1D) before and after the onset of this disease. All patients <19 years with at least 2 insulin prescriptions (1999 to 2009) were identified (T1D cohort) and compared with an age- and sex-matched (ratio: 1 up to 4) diabetes-free reference group. The prevalence and average number of anti-infective use was studied from (up to) 8 years before until a maximum of 4 years after the onset of T1D. A total of 925 patients with T1D and 3,591 children and adolescents in the reference cohort (51% boys, mean age of 10.1 [standard deviation, 4.5] years) were included. The overall prevalence of anti-infective use (62.6 compared to 52.6%, P < 0.001) and average number of prescriptions (2.71 compared to 1.42 per child, P < 0.001) in the T1D cohort were significantly higher than those in the reference cohort after the onset of diabetes. This pattern was consistent across sex and age categories and already observed in the year before the onset of type 1 diabetes. Patients in the T1D cohort received more antibacterials (49.8 compared to 40%, P < 0.001), antimycotics (4.0 compared to 1.3%, P < 0.001), antivirals (2.5 compared to 0.4%, P < 0.001), and second-line antibiotics, such as aminoglycosides, quinolones, and third-generation cephalosporins and carbapenems. Our findings that elevated anti-infective use in the T1D cohort exists in the period before the onset of type 1 diabetes and the consumption of more second-line anti-infective compounds in this time period warrant further research.

  17. Alzheimer's disease in one monozygotic twin

    PubMed Central

    Hunter, Richard; Dayan, A. D.; Wilson, John

    1972-01-01

    A woman of 64 died after an illness lasting 15 years and characterized by a progressive amnesic syndrome followed by global dementia. The brain showed changes typical of Alzheimer's disease. Her monozygotic twin sister was clinically not affected and died two years later of carcinoma. This is the second report of monozygotic twin sisters apparently discordant for presenile dementia of Alzheimer type. PMID:5084139

  18. Seizures in Alzheimer's disease.

    PubMed

    Born, H A

    2015-02-12

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

  19. Habitual physical activity (HPA) as a factor in sustained executive function in Alzheimer-type dementia: a cohort study.

    PubMed

    Farina, Nicolas; Tabet, Naji; Rusted, Jennifer

    2014-01-01

    Evidence from studies on healthy older adults and mild cognitive impairment (MCI) populations suggests that physical activity interventions have a positive effect on executive function. In this study, we consider whether HPA is positively associated with executive function in Alzheimer's disease (AD). Eighty-two participants with a diagnosis of mild to moderate AD completed six measures of executive function. Objective measures of physical status were taken. In addition, informants completed questionnaires on the participants' HPA and other lifestyle factors. A composite measure of executive function was the primary outcome. A multistage multiple regression was used to determine how much variance HPA accounted for. The final model comprised disease severity, cognitive reserve, cognitive activities, neuropsychiatric status and HPA status. The final model accounted for a total of 57% of the variance of executive performance, of which HPA itself accounted for 8% of the variance. HPA status is associated executive performance in an AD population even after controlling for key covariates. The findings encourage clinicians to recommend HPA and its cognitive benefits to AD patients and their carers.

  20. The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer's disease, mild cognitive impairment or Parkinson's disease.

    PubMed

    Dursun, Erdinç; Gezen-Ak, Duygu; Hanağası, Haşmet; Bilgiç, Başar; Lohmann, Ebba; Ertan, Sibel; Atasoy, İrem L; Alaylıoğlu, Merve; Araz, Ömür Selin; Önal, Burak; Gündüz, Ayşegül; Apaydın, Hülya; Kızıltan, Güneş; Ulutin, Turgut; Gürvit, Hakan; Yılmazer, Selma

    2015-06-15

    Alzheimer's disease (EOAD, LOAD), mild cognitive impairment (MCI), Parkinson's disease (PD) and healthy controls were included to determine the serum interleukin-1s (IL-1α, IL-1β), IL-6 and alpha-2-macroglobulin (α2M) levels using ELISA. IL-6 might be a significant contributor to the inflammatory response in LOAD. The MCI data indicate that IL-1s, α2M and BDNF are somehow related, and this relationship might allow MCI patients to be more similar to the healthy controls. A correlation analysis of multiple biomarkers in different neurodegenerative disorders might be more useful than determining the levels of a single cytokine in a single disorder.

  1. Frequent loss of genome gap region in 4p16.3 subtelomere in early-onset type 2 diabetes mellitus.

    PubMed

    Kudo, Hirohito; Emi, Mitsuru; Ishigaki, Yasushi; Tsunoda, Uiko; Hinokio, Yoshinori; Ishii, Miho; Sato, Hidenori; Yamada, Tetsuya; Katagiri, Hideki; Oka, Yoshitomo

    2011-01-01

    A small portion of Type 2 diabetes mellitus (T2DM) is familial, but the majority occurs as sporadic disease. Although causative genes are found in some rare forms, the genetic basis for sporadic T2DM is largely unknown. We searched for a copy number abnormality in 100 early-onset Japanese T2DM patients (onset age <35 years) by whole-genome screening with a copy number variation BeadChip. Within the 1.3-Mb subtelomeric region on chromosome 4p16.3, we found copy number losses in early-onset T2DM (13 of 100 T2DM versus one of 100 controls). This region surrounds a genome gap, which is rich in multiple low copy repeats. Subsequent region-targeted high-density custom-made oligonucleotide microarray experiments verified the copy number losses and delineated structural changes in the 1.3-Mb region. The results suggested that copy number losses of the genes in the deleted region around the genome gap in 4p16.3 may play significant roles in the etiology of T2DM.

  2. Joint effect of the SMN2 and SERF1A genes on childhood-onset types of spinal muscular atrophy in Serbian patients.

    PubMed

    Brkušanin, Miloš; Kosać, Ana; Jovanović, Vladimir; Pešović, Jovan; Brajušković, Goran; Dimitrijević, Nikola; Todorović, Slobodanka; Romac, Stanka; Milić Rašić, Vedrana; Savić-Pavićević, Dušanka

    2015-11-01

    Spinal muscular atrophy (SMA) is caused by functional loss of the survival of motor neuron 1 (SMN1) gene. Despite genetic homogeneity, phenotypic variability indicates the involvement of disease modifiers. SMN1 is located in 5q13.2 segmental duplication, enriched in genes and prone to unequal rearrangements, which results in copy number polymorphism (CNP). We examined the influence of CNP of 5q13.2 genes and their joint effect on childhood-onset SMA phenotype. Multiplex ligation-dependent probe amplification (MLPA) was used to construct 5q13.2 alleles and assess copy number of the SMN2, small EDRK-rich factor 1A (SERF1A) and NLR family apoptosis inhibitory protein (NAIP) genes in 99 Serbian patients with SMN1 homozygous absence (23-type I, 37-type II and 39-mild type III) and 122 patients' parents. Spearman rank test was performed to test correlation of individual genes and SMA type. Generalized linear models and backward selection were performed to obtain a model explaining phenotypic variation with the smallest set of variables. 5q13.2 alleles most commonly associated with type I harbored large-scale deletions, while those detected in types II and III originated from conversion of SMN1 to SMN2. Inverse correlation was observed between SMN2, SERF1A and NAIP CNP and SMA type (P=2.2e-16, P=4.264e-10, P=2.722e-8, respectively). The best minimal model describing phenotypic variability included SMN2 (P<2e-16), SERF1A (P<2e-16) and their interaction (P=0.02628). SMN2 and SERF1A have a joint modifying effect on childhood-onset SMA phenotype. PMID:26311540

  3. Lost opportunities to prevent early onset type 2 diabetes mellitus after a pregnancy complicated by gestational diabetes

    PubMed Central

    Bernstein, Judith A; McCloskey, Lois; Gebel, Christina M; Iverson, Ronald E; Lee-Parritz, Aviva

    2016-01-01

    Objectives Gestational diabetes mellitus (GDM) greatly increases the risk of developing diabetes in the decade after delivery, but few women receive appropriately timed postpartum glucose testing (PPGT) or a referral to primary care (PC) for continued monitoring. This qualitative study was designed to identify barriers and facilitators to testing and referral from patient and providers' perspectives. Methods We interviewed patients and clinicians in depth about knowledge, values, priorities, challenges, and recommendations for increasing PPGT rates and PC linkage. Interviews were coded with NVIVO data analysis software, and analyzed using an implementation science framework. Results Women reported motivation to address GDM for the health of the fetus. Most women did not anticipate future diabetes for themselves, and focused on delivery outcomes rather than future health risks. Patients sought and received reassurance from clinicians, and were unlikely to discuss early onset following GDM or preventive measures. PPGT barriers described by patients included provider not mentioning the test or setting it up, transportation difficulties, work responsibilities, fatigue, concerns about fasting while breastfeeding, and timing of the test after discharge from obstetrics, and no referral to PC for follow-up. Practitioners described limited communication among multiple care providers during pregnancy and delivery, systems issues, and separation of obstetrics from PC. Conclusions Patients' barriers to PPGT included low motivation for self-care, structural obstacles, and competing priorities. Providers reported the need to balance risk with reassurance, and identified systems failures related to test timing, limitations of electronic medical record systems (EMR), lack of referrals to PC, and inadequate communication between specialties. Prevention of early onset has great potential for medical cost savings and improvements in quality of life. PMID:27347422

  4. Emergence of OXA-162 Carbapenemase- and DHA-1 AmpC Cephalosporinase-Producing Sequence Type 11 Klebsiella pneumoniae Causing Community-Onset Infection in Greece

    PubMed Central

    Voulgari, Evangelia; Poulou, Aggeliki; Dimitroulia, Evangelia; Politi, Lida; Ranellou, Kyriaki; Gennimata, Vassiliki; Markou, Fani; Pournaras, Spyros

    2015-01-01

    OXA-48-like carbapenemases have only recently emerged in Europe. OXA-162 is a rare OXA-48 variant usually coexpressed with extended-spectrum β-lactamases. Here, we report the identification of the first OXA-162 carbapenemase-producing Klebsiella pneumoniae isolates, which coexpressed an AmpC cephalosporinase (DHA-1), retrieved from a patient in Greece. They belonged to a single sequence type (ST11) and caused the first documented community-onset urinary tract infections attributable to an OXA-48-like-producing Enterobacteriaceae strain. PMID:26666930

  5. Emergence of OXA-162 Carbapenemase- and DHA-1 AmpC Cephalosporinase-Producing Sequence Type 11 Klebsiella pneumoniae Causing Community-Onset Infection in Greece.

    PubMed

    Voulgari, Evangelia; Poulou, Aggeliki; Dimitroulia, Evangelia; Politi, Lida; Ranellou, Kyriaki; Gennimata, Vassiliki; Markou, Fani; Pournaras, Spyros; Tsakris, Athanassios

    2016-03-01

    OXA-48-like carbapenemases have only recently emerged in Europe. OXA-162 is a rare OXA-48 variant usually coexpressed with extended-spectrum β-lactamases. Here, we report the identification of the first OXA-162 carbapenemase-producing Klebsiella pneumoniae isolates, which coexpressed an AmpC cephalosporinase (DHA-1), retrieved from a patient in Greece. They belonged to a single sequence type (ST11) and caused the first documented community-onset urinary tract infections attributable to an OXA-48-like-producing Enterobacteriaceae strain. PMID:26666930

  6. Nonketotic hyperosmolar syndrome as an acute complication of type 1 diabetes onset in a 20-month-old boy with congenital central nervous system defect.

    PubMed

    Chumiecki, Miron; Minkina-Pedras, Mariola; Chobot, Agata; Jarosz-Chobot, Przemysława

    2012-01-01

    Hyperglycemic hyperosmolar syndrome (HHS) is one of the most severe acute complications of type 2 diabetes, but may also be developed in type 1 diabetes. Similar to ketoacidosis,HHS still remains one of the major causes of morbidity and mortality in patients with diabetes,despite a significant progress in understanding its pathogenesis and greater consensus on HHS diagnosis and treatment. It is mainly observed in elderly patients with type 2 diabetes. However,it may also occur in children,especially in infants and those with concomitant central nervous system (CNS) defects or suffering from severe infections associated with dehydration. The authors report a case of HHS in a 20-month-old child with central nervous system abnormality. Symptoms observed in our patient are characteristic for HHS. It must be emphasized that HHS may accompany diabetes onset also in children.

  7. Amyloid beta peptide immunotherapy in Alzheimer disease.

    PubMed

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

    2014-12-01

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

  8. Diagnosis of Alzheimer's disease with [18F]PET in mild and asymptomatic stages.

    PubMed

    Drzezga, Alexander

    2009-01-01

    With longer life expectancy, dementia based on the age-related Alzheimers' disease (AD) has turned into one of the most prevalent disorders of older age, representing a serious medical and socio-economic issue. There has been growing interest in early diagnosis of this disease, particularly regarding the initiation of new treatment strategies ahead of the onset of irreversible neuronal damage. It is accepted that the pathologic changes underlying AD appear in the brain years to decades before the symptomatic stages. Consequently, clinical measures of cognitive impairment, as used for definition of dementia, will not allow early diagnosis of AD-pathology in the mild or asymptomatic stages. Thus, a need for complementary sensitive biomarkers is apparent. Brain imaging markers are among the most promising candidates for this diagnostic challenge. Particularly, [18F]FDG PET as a marker of regional neuronal function has been demonstrated to represent a most sensitive and specific method for early identification of AD-pathology and thus for prediction of dementia of the Alzheimer type (DAT), even in the mild and asymptomatic stages. Currently, systematic data of comparable quality are hardly available for any other imaging procedure. The purpose of this article is to describe the typical findings of [18F]FDG PET in different stages of AD and to demonstrate its value for early and reliable diagnosis of Alzheimer's disease, particularly ahead of the stage of dementia of the Alzheimer's type.

  9. Role of lipoprotein(a) in predicting the severity of new on-set coronary artery disease in type 2 diabetics: A Gensini score evaluation.

    PubMed

    Chen, Juan; Zhang, Yan; Liu, Jun; Chen, Man-Hua; Guo, Yuan-Lin; Zhu, Cheng-Gang; Xu, Rui-Xia; Dong, Qian; Li, Jian-Jun

    2015-07-01

    The objective of the study was to investigate the usefulness of serum lipoprotein(a) level in predicting the severity of new on-set coronary artery disease in type 2 diabetics. A total of 1254 new on-set, consecutive coronary artery disease patients were classified into two groups: diabetes group (n = 380) and non-diabetes group (n = 874). The relationship between serum lipoprotein(a) levels and the severity of coronary artery disease assessed by Gensini score was analysed. Data showed that the diabetes group had higher serum triglyceride and high sensitivity C-reactive protein levels but lower high-density lipoprotein cholesterol levels (all p < 0.05). The multivariate logistic regression analysis suggested that lipoprotein(a) was an independent predictor for high Gensini score (odds ratio = 1.82, 95% confidence interval: 1.10-3.12, p = 0.029) after adjusting for traditional cardiovascular risk factors. Additionally, lipoprotein(a) levels were positively correlated with Gensini score (rho = 0.15, p = 0.014) and significantly elevated according to the tertiles of Gensini score (p = 0.008) in diabetics. However, no such results were observed in non-diabetics. Our data indicate that lipoprotein(a) is an independent predictor for the severity of new on-set coronary artery disease patients accompanied by type 2 diabetes, suggesting that these patients may benefit from lipoprotein(a) management in clinical assessment.

  10. Long term effects of the implantation of Wharton's jelly-derived mesenchymal stem cells from the umbilical cord for newly-onset type 1 diabetes mellitus.

    PubMed

    Hu, Jianxia; Yu, Xiaolong; Wang, Zhongchao; Wang, Fang; Wang, Li; Gao, Hong; Chen, Ying; Zhao, Wenjuan; Jia, Zhaotong; Yan, Shengli; Wang, Yangang

    2013-01-01

    Type 1 diabetes mellitus (T1DM) is an autoimmune disorder resulted from T cell-mediated destruction of pancreatic β-cells, how to regenerate β-cells and prevent the autoimmune destruction of remnant and neogenetic β-cells is a tough problem. Immunomodulatory propertity of mesenchymal stem cell make it illuminated to overcome it. We assessed the long-term effects of the implantation of Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) from the umbilical cord for Newly-onset T1DM. Twenty-nine patients with newly onset T1DM were randomly divided into two groups, patients in group I were treated with WJ-MSCs and patients in group II were treated with normal saline based on insulin intensive therapy. Patients were followed-up after the operation at monthly intervals for the first 3 months and thereafter every 3 months for the next 21 months, the occurrence of any side effects and results of laboratory examinations were evaluated. There were no reported acute or chronic side effects in group I compared with group II, both the HbA1c and C peptide in group I patients were significantly better than either pretherapy values or group II patients during the follow-up period. These data suggested that the implantation of WJ-MSCs for the treatment of newly-onset T1DM is safe and effective. This therapy can restore the function of islet β cells in a longer time, although precise mechanisms are unknown, the implantation of WJ-MSCs is expected to be an effective strategy for treatment of type1 diabetes.

  11. Islet autoantibodies in Latvian subjects with non-insulin-dependent diabetes mellitus: slow-onset type 1 diabetes or polyendocrine autoimmunity?

    PubMed

    Shtauvere-Brameus, A; Falorni, A; Rumba, I; Sanjeevi, C B

    2002-04-01

    In Latvia diabetes mellitus is diagnosed using the WHO's clinical criteria; assays for the detection of autoantibodies are not available, and hence slowly progressive autoimmune diabetes is likely to be missed. Autoantibodies against glutamic acid decarboxylase (GAD65) and protein tyrosine phosphatase (IA-2) among patients with clinically diagnosed NIDDM identify group of patients with slow-onset type 1 diabetes or LADA. The aim of this study was to estimate the risk of polyendocrine autoimmunity among clinically diagnosed NIDDM patients from Latvia. One hundred NIDDM patients and 100 healthy controls were tested for GAD65 and IA-2 autoantibodies as well as 21-hydroxylase (21-OH) and tissue transglutaminase (TTG) antibodies by RIA assay. Age at onset was >or= 30 years, and duration of disease less than 5 years. Of 100 patients, 85 were on oral hypoglycemic agents and 15 were on insulin. Body mass index (BMI) under 19 was recorded in 1% (1 of 100 cases), while overweight (BMI > 25.5 in females and 27 in males) was documented in 45% (45 of 100 cases). GAD65 antibodies were found in 30 of 100 (30%) and IA-2 antibodies in 40 of 100 (40%) patients. Either GAD65 or IA-2 antibodies were found in 55 of 100 (55%). None of the patients carried antibodies against 21-OH and only 1 of 100 (1%) carried antibodies against TTG. From the results obtained in our study we conclude that in Latvian adult NIDDM subjects, islet autoantibodies identify groups of slow-onset type 1 diabetes but not polyendocrine autoimmunity.

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

    PubMed

    Zhagn, Lili; Li, Zhiping

    2014-09-01

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

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

    PubMed

    Zhagn, Lili; Li, Zhiping

    2014-09-01

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

  14. Insulin as a Bridge between Type 2 Diabetes and Alzheimer Disease – How Anti-Diabetics Could be a Solution for Dementia

    PubMed Central

    Sebastião, Inês; Candeias, Emanuel; Santos, Maria S.; de Oliveira, Catarina R.; Moreira, Paula I.; Duarte, Ana I.

    2014-01-01

    Type 2 diabetes (T2D) and Alzheimer disease (AD) are two major health issues nowadays. T2D is an ever increasing epidemic, affecting millions of elderly people worldwide, with major repercussions in the patients’ daily life. This is mostly due to its chronic complications that may affect brain and constitutes a risk factor for AD. T2D principal hallmark is insulin resistance which also occurs in AD, rendering both pathologies more than mere unrelated diseases. This hypothesis has been reinforced in the recent years, with a high number of studies highlighting the existence of several common molecular links. As such, it is not surprising that AD has been considered as the “type 3 diabetes” or a “brain-specific T2D,” supporting the idea that a beneficial therapeutic strategy against T2D might be also beneficial against AD. Herewith, we aim to review some of the recent developments on the common features between T2D and AD, namely on insulin signaling and its participation in the regulation of amyloid β (Aβ) plaque and neurofibrillary tangle formation (the two major neuropathological hallmarks of AD). We also critically analyze the promising field that some anti-T2D drugs may protect against dementia and AD, with a special emphasis on the novel incretin/glucagon-like peptide-1 receptor agonists. PMID:25071725

  15. High-Molecular-Weight Paired Helical Filaments from Alzheimer Brain Induces Seeding of Wild-Type Mouse Tau into an Argyrophilic 4R Tau Pathology in Vivo.

    PubMed

    Audouard, Emilie; Houben, Sarah; Masaracchia, Caterina; Yilmaz, Zehra; Suain, Valérie; Authelet, Michèle; De Decker, Robert; Buée, Luc; Boom, Alain; Leroy, Karelle; Ando, Kunie; Brion, Jean-Pierre

    2016-10-01

    In Alzheimer disease, the development of tau pathology follows neuroanatomically connected pathways, suggesting that abnormal tau species might recruit normal tau by passage from cell to cell. Herein, we analyzed the effect of stereotaxic brain injection of human Alzheimer high-molecular-weight paired helical filaments (PHFs) in the dentate gyrus of wild-type and mutant tau THY-Tau22 mice. After 3 months of incubation, wild-type and THY-Tau22 mice developed an atrophy of the dentate gyrus and a tau pathology characterized by Gallyas and tau-positive grain-like inclusions into granule cells that extended in the hippocampal hilus and eventually away into the alveus, and the fimbria. Gallyas-positive neuropil threads and oligodendroglial coiled bodies were also observed. These tau inclusions were composed only of mouse tau, and were immunoreactive with antibodies to 4R tau, phosphotau, misfolded tau, ubiquitin, and p62. Although local hyperphosphorylation of tau was increased in the dentate gyrus in THY-Tau22 mice, the development of neurofibrillary tangles made of mutant human tau was not accelerated in the hippocampus, indicating that wild-type human PHFs were inefficient in seeding tau aggregates made of G272V/P301S mutant human tau. Our results indicate thus that injection of human wild-type Alzheimer PHF seeded aggregation of wild-type murine tau into an argyrophilic 4R tau pathology, and constitutes an interesting model independent of expression of a mutant tau protein.

  16. High-Molecular-Weight Paired Helical Filaments from Alzheimer Brain Induces Seeding of Wild-Type Mouse Tau into an Argyrophilic 4R Tau Pathology in Vivo.

    PubMed

    Audouard, Emilie; Houben, Sarah; Masaracchia, Caterina; Yilmaz, Zehra; Suain, Valérie; Authelet, Michèle; De Decker, Robert; Buée, Luc; Boom, Alain; Leroy, Karelle; Ando, Kunie; Brion, Jean-Pierre

    2016-10-01

    In Alzheimer disease, the development of tau pathology follows neuroanatomically connected pathways, suggesting that abnormal tau species might recruit normal tau by passage from cell to cell. Herein, we analyzed the effect of stereotaxic brain injection of human Alzheimer high-molecular-weight paired helical filaments (PHFs) in the dentate gyrus of wild-type and mutant tau THY-Tau22 mice. After 3 months of incubation, wild-type and THY-Tau22 mice developed an atrophy of the dentate gyrus and a tau pathology characterized by Gallyas and tau-positive grain-like inclusions into granule cells that extended in the hippocampal hilus and eventually away into the alveus, and the fimbria. Gallyas-positive neuropil threads and oligodendroglial coiled bodies were also observed. These tau inclusions were composed only of mouse tau, and were immunoreactive with antibodies to 4R tau, phosphotau, misfolded tau, ubiquitin, and p62. Although local hyperphosphorylation of tau was increased in the dentate gyrus in THY-Tau22 mice, the development of neurofibrillary tangles made of mutant human tau was not accelerated in the hippocampus, indicating that wild-type human PHFs were inefficient in seeding tau aggregates made of G272V/P301S mutant human tau. Our results indicate thus that injection of human wild-type Alzheimer PHF seeded aggregation of wild-type murine tau into an argyrophilic 4R tau pathology, and constitutes an interesting model independent of expression of a mutant tau protein. PMID:27497324

  17. An elderly-onset limb girdle muscular dystrophy type 1B (LGMD1B) with pseudo-hypertrophy of paraspinal muscles.

    PubMed

    Furuta, Mitsuru; Sumi-Akamaru, Hisae; Takahashi, Masanori P; Hayashi, Yukiko K; Nishino, Ichizo; Mochizuki, Hideki

    2016-09-01

    Mutations in LMNA, encoding A-type lamins, lead to diverse disorders, collectively called "laminopathies," which affect the striated muscle, cardiac muscle, adipose tissue, skin, peripheral nerve, and premature aging. We describe a patient with limb-girdle muscular dystrophy type 1B (LGMD1B) carrying a heterozygous p.Arg377His mutation in LMNA, in whom skeletal muscle symptom onset was at the age of 65 years. Her weakness started at the erector spinae muscles, which showed marked pseudo-hypertrophy even at the age of 72 years. Her first episode of syncope was at 44 years; however, aberrant cardiac conduction was not revealed until 60 years. The p.Arg377His mutation has been previously reported in several familial LMNA-associated myopathies, most of which showed muscle weakness before the 6th decade. This is the first report of pseudo-hypertrophy of paravertebral muscles in LMNA-associated myopathies. The pseudo-hypertrophy of paravertebral muscles and the elderly-onset of muscle weakness make this case unique and reportable.

  18. Presenile onset of spinocerebellar ataxia type 1 presenting with conspicuous psychiatric symptoms and widespread anti-expanded polyglutamine antibody- and fused in sarcoma antibody-immunopositive pathology.

    PubMed

    Iwasaki, Yasushi; Mori, Keiko; Ito, Masumi; Mimuro, Maya; Yoshida, Mari

    2015-09-01

    A 50-year-old Japanese man showed slowly progressive gait disturbance and dysarthria. Neurological examination 5 years after onset revealed slow eye movement with nystagmus as well as limb and truncal ataxia. Magnetic resonance imaging showed atrophy of the cerebellum and brainstem. Because genetic examination revealed CAG repeat expansion of the ataxin-1 gene, the patient was diagnosed with spinocerebellar ataxia type 1. Ten years after onset, he showed psychiatric symptoms with cognitive impairment, and antipsychotic drugs were administered. As psychiatric symptoms gradually worsened, particularly with regard to resisting nursing care and shouting, the doses of the drugs were increased. Although the clinicopathologic findings were generally identical to previously reported spinocerebellar ataxia type 1 cases with the exception of the conspicuous psychiatric symptoms, there are two notable immunohistochemical findings. Firstly, numerous anti-expanded polyglutamine antibody-immunopositive neuronal inclusions were extensively observed, including in the cerebral cortex and limbic system, but not in the Purkinje cells. Secondly, anti-fused in sarcoma antibody-immunopositive intranuclear inclusions were extensively observed. We posit that the anti-expanded polyglutamine antibody-immunopositive neuronal inclusions and possibly the anti-fused in sarcoma antibody-immunopositive inclusions, particularly those in the neocortex and limbic system, may correspond to the psychiatric symptoms and cognitive impairment that were observed in the patient.

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

    PubMed Central

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

    2010-01-01

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

  20. Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage.

    PubMed

    Vos, Stephanie J B; Verhey, Frans; Frölich, Lutz; Kornhuber, Johannes; Wiltfang, Jens; Maier, Wolfgang; Peters, Oliver; Rüther, Eckart; Nobili, Flavio; Morbelli, Silvia; Frisoni, Giovanni B; Drzezga, Alexander; Didic, Mira; van Berckel, Bart N M; Simmons, Andrew; Soininen, Hilkka; Kłoszewska, Iwona; Mecocci, Patrizia; Tsolaki, Magda; Vellas, Bruno; Lovestone, Simon; Muscio, Cristina; Herukka, Sanna-Kaisa; Salmon, Eric; Bastin, Christine; Wallin, Anders; Nordlund, Arto; de Mendonça, Alexandre; Silva, Dina; Santana, Isabel; Lemos, Raquel; Engelborghs, Sebastiaan; Van der Mussele, Stefan; Freund-Levi, Yvonne; Wallin, Åsa K; Hampel, Harald; van der Flier, Wiesje; Scheltens, Philip; Visser, Pieter Jelle

    2015-05-01

    Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer

  1. Type of uromodulin mutation and allelic status influence onset and severity of uromodulin-associated kidney disease in mice.

    PubMed

    Kemter, Elisabeth; Prueckl, Petra; Sklenak, Stefanie; Rathkolb, Birgit; Habermann, Felix A; Hans, Wolfgang; Gailus-Durner, Valérie; Fuchs, Helmut; Hrabě de Angelis, Martin; Wolf, Eckhard; Aigner, Bernhard; Wanke, Ruediger

    2013-10-15

    Uromodulin-associated kidney disease (UAKD) is a dominant heritable renal disease in humans which is caused by mutations in the uromodulin (UMOD) gene and characterized by heterogeneous clinical appearance. To get insights into possible causes of this heterogeneity of UAKD, we describe the new mutant mouse line Umod(C93F), leading to disruption of a putative disulfide bond which is also absent in a known human UMOD mutation, and compare the phenotype of this new mouse line with the recently published mouse line Umod(A227T). In both mutant mouse lines, which were both bred on the C3H background, the Umod mutations cause a gain-of-toxic function due to a maturation defect of the mutant uromodulin leading to a dysfunction of thick ascending limb of Henle's loop (TALH) cells of the kidney. Umod mutant mice exhibit increased plasma urea and Cystatin levels, impaired urinary concentration ability, reduced fractional excretion of uric acid and nephropathological alterations including uromodulin retention in TALH cells, interstitial fibrosis and inflammatory cell infiltrations, tubular atrophy and occasional glomerulo- und tubulocystic changes, a phenotype highly similar to UAKD in humans. The maturation defect of mutant uromodulin leads to the accumulation of immature uromodulin in the endoplasmic reticulum (ER) and to ER hyperplasia. Further, this study was able to demonstrate for the first time in vivo that the severity of the uromodulin maturation defect as well as onset and speed of progression of renal dysfunction and morphological alterations are strongly dependent on the particular Umod mutation itself and the zygosity status.

  2. Leptin in Alzheimer's disease.

    PubMed

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

    2015-10-23

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

  3. A 3-year follow-up study of β-cell function in patients with early-onset type 2 diabetes

    PubMed Central

    Zhou, Shaoling; Meng, Xiaomei; Wang, Shuyan; Ren, Ruizhen; Hou, Weikai; Huang, Kuixiang; Shi, Hongli

    2016-01-01

    Insulin resistance and reduced β-cell glucose sensitivity are present in patients with type 2 diabetes. In the present study, we investigated the changes in β-cell function in patients with type 2 diabetes during a 3-year follow-up study. A total of 48 patients with early-onset type 2 diabetes (EOD) and 55 patients with late-onset type 2 diabetes (LOD) were enrolled. Weight, height, waist circumference, hip circumference, blood pressure and plasma levels of lipids, glucose, fasting serum C-peptide (CPR0) and serum C-peptide 6 min after glucagon stimulation (CPR6) were measured. In addition, islet β-cell secretory activity was detected. Subjects with EOD had lower Systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), fasting CPR0, CPR6 and greater glycated hemoglobin A1c (HbA1c), triglyceride (TG) compared with subjects with LOD. CPR0, CPR6 and TG were decreased in both EOD and LOD groups 3 years later. The ratio of β-cell function failure was 29.17 and 10.91% in the EOD and LOD groups, respectively, and there was significant difference between the two groups. A positive correlation was identified between the CPR0 and waist-hip ratio, HbA1c in the EOD group. A similar positive correlation was observed between CPR0 and BMI in the LOD group. Collectively, islet β-cell function has declined in patients with EOD, and this change may be more evident when compared with those with LOD. PMID:27446326

  4. [Alzheimer's disease. Present and future role of genetics].

    PubMed

    Roks, Gerwin

    2003-02-01

    Research in the field of Alzheimer's disease has shown that genetic factors play an important role in the aetiology of the disease. Until now, four genes have been found to be implicated in Alzheimer's disease. Mutations in the amyloid precursor protein gene (APP) and the presenilin genes (PSEN1 en PSEN2) cause early onset Alzheimer's disease. These mutations segregate in an autosomal dominant pattern. The fourth gene involved in Alzheimer's disease is the apolipoprotein E gene (APOE). Carriers of the E4 variant of APOE have an increased risk of Alzheimer's disease. Being a carrier of this E4 variant increases the risk of both early- and late-onset Alzheimer's disease. Of the four Alzheimer-genes, APOE plays the most important role in the general population. Mutations in APP and the presenilin genes account for less than 1% of the prevalence of the disease in the general population compared to 10-17% for the APOE variation. Up till now the impact of genetics in daily clinical practice is very limited. However, genetics has caused major progress in molecular-biological knowledge, especially of the amyloid metabolism, creating optimism about novel biological markers and eventually therapeutic strategies. In Alzheimer's genetics break-throughs are to be expected using classical methods such as the candidate-gene or linkage approach. Novel strategies such as genetic research in isolated populations are promising. PMID:12629906

  5. The Effect of Resting Heart Rate on the New Onset of Microalbuminuria in Patients With Type 2 Diabetes: A Subanalysis of the ROADMAP Study.

    PubMed

    Schmieder, Roland E; Bramlage, Peter; Haller, Hermann; Ruilope, Luis M; Böhm, Michael

    2016-04-01

    The association between resting heart rate and new-onset microalbuminuria in patients with type 2 diabetes is not clear. The objective of the current analysis was to assess the relationship between heart rate and incidence of microalbuminuria in patients with type 2 diabetes. Data from the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study were retrospectively analyzed. New-onset microalbuminuria was documented and related to heart rate as recorded at baseline and last assessment, and the mean of the measurements taken during the double-blind part of the ROADMAP trial. Patients (n = 4299) had a mean age of 57.8 ± 8.7 years and 46.3% were male. Characteristics were not different between the olmesartan and the placebo groups, except for a higher systolic blood pressure (136.7 vs 135.7 mm Hg; P = 0.04) and albumin creatinine ratio (5.9 vs 5.5; P = 0.03). Increased risk of microalbuminuria was found with increasing heart rate, independent of whether baseline [highest vs lowest quartile odds ratio (OR) 1.39; 95% confidence interval (95% CI) 1.03-1.87; P = 0.032], last assessment (OR 1.71; 95% CI 1.26-2.31; P = 0.001), or mean heart rate was considered (OR: 1.77; 95% CI: 1.30-2.41; P = 0.0003). The greater risk of new-onset microalbuminuria with a high baseline heart rate was also found when data were adjusted for mean systolic blood pressure (OR: 1.35; 95% CI: 1.00-1.82; P = 0.0496; interaction P < 0.0001). Although there was no risk increase with baseline heart rate in the placebo group (P = 0.8253 for trend), microalbuminuria was less frequent in patients receiving olmesartan in the low heart rate quartiles (P = 0.002 for trend). A low heart rate reduces the risk of patients with type 2 diabetes developing microalbuminuria, independent of blood pressure. The data demonstrate potential benefits of reducing the heart rate of type 2 diabetes patients, and indicate that olmesartan could, in

  6. Genetics Home Reference: Alzheimer disease

    MedlinePlus

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

  7. Circulating miR-126 is a potential biomarker to predict the onset of type 2 diabetes mellitus in susceptible individuals.

    PubMed

    Zhang, Tao; Li, Liling; Shang, Qingkun; Lv, ChunFang; Wang, ChangYi; Su, Bing

    Type 2 diabetes mellitus (T2DM) is a major public health problem in China. Diagnostic markers are urgently needed to identify individuals at risk of developing T2DM and thus encouraging healthier life styles. Circulating miRNAs are valuable sources for non-invasive biomarkers of various diseases. The aim of this study was to examine whether reduced miR-126 expression could predict the onset of T2DM in susceptible individuals. Two groups of study subjects were involved, one group was diagnosed T2DM in 2013 and the other group was healthy control. To this end, our results showed that miR-126 expression were already decreased before the manifestation of T2DM. Univariable logistic regression confirmed that the plasma miR-126 level was inversely associated with the onset of DM (P = 0.0158 ˂ 0.05), suggesting reduced miR-126 is a predictor for the onset of T2DM. According to the logistic regression model and ROC curve, a cut-off points of miR-126 plasma level as 35 is recommended for clinical study to predict whether an individual is more likely to develop T2DM. If miR-126 expression is lower than 35, the individual is more likely to T2DM in the next 2 years. In conclusion, our results support the notion that the circulating miR-126 can be developed into a non-invasive and rapid diagnostic tool for the prediction of susceptible individuals to developing T2DM. PMID:25986735

  8. Invokana (Canagliflozin) as a dual inhibitor of acetylcholinesterase and sodium glucose co-transporter 2: advancement in Alzheimer's disease- diabetes type 2 linkage via an enzoinformatics study.

    PubMed

    Rizvi, Syed M D; Shakil, Shahnawaz; Biswas, Deboshree; Shakil, Shazi; Shaikh, Sibhghatulla; Bagga, Paramdeep; Kamal, Mohammad A

    2014-04-01

    Acetylcholinesterase (AChE) is a primary target for Alzheimer's therapy while recently sodium glucose cotransporter 2 (SGLT2) has gained importance as a potential target for Type 2 Diabetes Mellitus (T2DM) therapy. The present study emphasizes the molecular interactions between a new Food and Drug Administration (FDA) approved antidiabetic drug 'Invokana' (chemically known as Canagliflozin) with AChE and SGLT2 to establish a link between the treatment of T2DM and Alzheimer's Disease (AD). Docking study was performed using 'Autodock4.2'. Both hydrophobic and π-π interactions play an important role in the correct positioning of Canagliflozin within SGLT2 and catalytic site (CAS) of AChE to permit docking. Free energy of binding (ΔG) for 'Canagliflozin-SGLT2' interaction and 'Canagliflozin - CAS domain of AChE' interaction were found to be -10.03 kcal/mol and -9.40 kcal/mol, respectively. During 'Canagliflozin-SGLT2' interaction, Canagliflozin was found to interact with the most important amino acid residue Q457 of SGLT2. This residue is known for its interaction with glucose during reabsorption in kidney. However, 'Canagliflozin-CAS domain of AChE' interaction revealed that out of the three amino acids constituting the catalytic triad (S203, H447 and E334), two amino acid residues (S203 and H447) interact with Canagliflozin. Hence, Invokana (Canagliflozin) might act as a potent dual inhibitor of AChE and SGLT2. However, scope still remains in the determination of the three-dimensional structure of SGLT2-Canagliflozin and AChE-Canagliflozin complexes by X-ray crystallography to validate the described data. Since the development of diabetes is associated with AD, the design of new AChE inhibitors based on antidiabetic drug scaffolds would be particularly beneficial. Moreover, the present computational study reveals that Invokana (Canagliflozin) is expected to form the basis of a future dual therapy against diabetes associated neurological disorders.

  9. Correlation Between Cerebral Atrophy and Texture Features in Alzheimer-type Dementia Brains: A 3-Year Follow-up MRI Study

    NASA Astrophysics Data System (ADS)

    Kodama, Naoki; Takeuchi, Hiroshi

    We assessed relationships between six texture features and changes in atrophy of the cerebral parenchyma, the hippocampus, and the parahippocampal gyrus in the Alzheimer-type dementia (ATD) brain to determine whether or not the features reflect cerebral atrophy in ATD patients. The subjects of this study were 10 ATD patients, and underwent an magnetic resonanse imaging test of the head annually for at least 3 consecutive years. They consisted of three men and seven women, with a mean age of 71.4 ± 6.7 years. The results of study, the mean run length nonuniformity (RLN), angular second moment (ASM), and contrast (CON) increased with time, whereas the mean gray level nonuniformity (GLN), run percentage (RPC), and entropy (ENT) decreased with time. There was a statistically significant correlation between brain-intracranial area ratio (BIR) and GLN (p = 0.039), between BIR and ASM (p = 0.011), and between BIR and ENT (p = 0.023) as well as between parahippocampal-intracranial area ratio and GLN (p = 0.049). These results indicate that the six texture features were shown to reflect gray matter atrophy associated with ATD and to change with the progress of the disease. Although the course of ATD can be followed up by measuring a hippocampal area or volume and determining a decrease in the area or volume, texture features should be a more effective instrument for identifying the progress of ATD.

  10. Adenosine Type A2A Receptor in Peripheral Cell from Patients with Alzheimer's Disease, Vascular Dementia, and Idiopathic Normal Pressure Hydrocephalus: A New/Old Potential Target.

    PubMed

    Arosio, Beatrice; Casati, Martina; Gussago, Cristina; Ferri, Evelyn; Abbate, Carlo; Scortichini, Valeria; Colombo, Elena; Rossi, Paolo Dionigi; Mari, Daniela

    2016-09-01

    As the European population gets older, the incidence of neurological disorders increases with significant impact on social costs. Despite differences in disease etiology, several brain disorders in the elderly (e.g., Alzheimer's disease, vascular dementia, normal pressure hydrocephalus) share dementia as a common clinical feature. The current treatment for the majority of these diseases is merely symptomatic and does not modify the course of the illness. Symptoms of normal pressure hydrocephalus are the only ones that can be modified if they are recognized in time and treated appropriately. Therefore, an important clinical strategy may be disclosed by pathogenic pathways that can be modified and to find drugs that can slow down or even arrest disease progression. Possibly a way to answer this question could be by re-examining all the molecules which have so far succeeded in improving many aspects of cognitive deterioration in some neurodegenerative conditions, that were not considered because of controversial opinions. The main purpose of this summary is to further substantiate the hypothesis that the pathway of adenosine type A2A receptor could be used as a potential target to develop new/old therapeutic strategies.

  11. [Cerebral white matter bundle alterations in patients with dementia of Alzheimer type and patients with multi-infarct dementia--magnetic resonance imaging study].

    PubMed

    Yoshii, F; Shinohara, Y; Duara, R

    1990-01-01

    The widths of the anterior white matter bundle (AWM) and the interhemispheric (AWM-TER) and intrahemispheric (AWM-TRA) bundles at the level of the foramen of Monro on horizontal inversion recovery MRI scans were measured in 17 patients with dementia of Alzheimer type (DAT), 16 patients with multi-infarct dementia (MID) and 47 age-matched normal subjects (NOR). The area of the corpus callosum (CC) on midsagittal spin-echo MRI scans was also measured in 12 DAT, 11 MID and 36 NOR. The Mini-mental score in patients with DAT was 20.8 +/- 5.9, which was not significantly different from that of 22.9 +/- 5.4 in patients with MID. The width of AWM was not significantly decreased in either DAT or MID compared with NOR. However, the width of AWM-TER in DAT and MID showed a significant decrease from that in NOR. The width of AWM-TRA was decreased significantly only in DAT. Compared with NOR, the area of the CC in DAT and MID was decreased by 7.0% (p less than 0.05) and 6.5%, respectively. The white matter bundle has an important role in the connectivity of the brain. Although loss of white matter occurs in both DAT and MID, the change appears more diffuse in DAT than MID. PMID:2331816

  12. The economic costs of Alzheimer's disease.

    PubMed

    Hay, J W; Ernst, R L

    1987-09-01

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

  13. Molecular imaging of Alzheimer disease pathology.

    PubMed

    Kantarci, K

    2014-06-01

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

  14. Self-reported dietary intake of youth with recent onset of type 2 diabetes: results from the TODAY study.

    PubMed

    Delahanty, Linda; Kriska, Andrea; Edelstein, Sharon; Amodei, Nancy; Chadwick, Jennifer; Copeland, Kenneth; Galvin, Bryan; El Ghormli, Laure; Haymond, Morey; Kelsey, Megan M; Lassiter, Chad; Milaszewski, Kerry; Syme, Amy; Mayer-Davis, Elizabeth

    2013-03-01

    Despite the widely recognized importance of diet in managing diabetes, few studies have documented usual dietary intake in young people with type 2 diabetes. The objectives of our study were to assess dietary intake among a large, ethnically diverse cohort of young people with type 2 diabetes and compare intake to current recommendations. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study is a multicenter randomized clinical trial of 699 youth aged 10 to 17 years. At baseline, following a run-in period that included standard diabetes education, diet was assessed using a food frequency questionnaire between 2004 and 2009. Analysis of variance and nonparametric tests were used to compare mean and median nutrient intakes; logistic regression was used to compare the odds of meeting predefined dietary intake recommendation cutpoints between subgroups of age, sex, and race-ethnicity. Percent of energy from saturated fat was consistently 13% to 14% across all subgroups-substantially exceeding national recommendations. Overall, only 12% of youth met Healthy People 2010 guidelines for intake of <10% of energy from saturated fat and only 1% of youth met American Diabetes Association recommendations for intake of <7% of energy from saturated fat. Dietary intake fell substantially below other Healthy People 2010 targets; only 3% met calcium intake goals, 11% met fruit consumption goals, 5% met vegetable consumption goals, and 67% met grain intake goals. Overall, dietary intake in this large cohort of young people with type 2 diabetes fell substantially short of recommendations, in ways that were consistent by sex, age, and race-ethnicity. The data suggest a critical need for better approaches to improve dietary intake of these young people.

  15. Self-reported dietary intake of youth with recent onset of type 2 diabetes: results from the TODAY study.

    PubMed

    Delahanty, Linda; Kriska, Andrea; Edelstein, Sharon; Amodei, Nancy; Chadwick, Jennifer; Copeland, Kenneth; Galvin, Bryan; El Ghormli, Laure; Haymond, Morey; Kelsey, Megan M; Lassiter, Chad; Milaszewski, Kerry; Syme, Amy; Mayer-Davis, Elizabeth

    2013-03-01

    Despite the widely recognized importance of diet in managing diabetes, few studies have documented usual dietary intake in young people with type 2 diabetes. The objectives of our study were to assess dietary intake among a large, ethnically diverse cohort of young people with type 2 diabetes and compare intake to current recommendations. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study is a multicenter randomized clinical trial of 699 youth aged 10 to 17 years. At baseline, following a run-in period that included standard diabetes education, diet was assessed using a food frequency questionnaire between 2004 and 2009. Analysis of variance and nonparametric tests were used to compare mean and median nutrient intakes; logistic regression was used to compare the odds of meeting predefined dietary intake recommendation cutpoints between subgroups of age, sex, and race-ethnicity. Percent of energy from saturated fat was consistently 13% to 14% across all subgroups-substantially exceeding national recommendations. Overall, only 12% of youth met Healthy People 2010 guidelines for intake of <10% of energy from saturated fat and only 1% of youth met American Diabetes Association recommendations for intake of <7% of energy from saturated fat. Dietary intake fell substantially below other Healthy People 2010 targets; only 3% met calcium intake goals, 11% met fruit consumption goals, 5% met vegetable consumption goals, and 67% met grain intake goals. Overall, dietary intake in this large cohort of young people with type 2 diabetes fell substantially short of recommendations, in ways that were consistent by sex, age, and race-ethnicity. The data suggest a critical need for better approaches to improve dietary intake of these young people. PMID:23438494

  16. 15-year incidence of diabetic ketoacidosis at onset of type 1 diabetes in children from a regional setting (Auckland, New Zealand)

    PubMed Central

    Jefferies, Craig; Cutfield, Samuel W.; Derraik, José G. B.; Bhagvandas, Jignal; Albert, Benjamin B.; Hofman, Paul L.; Gunn, Alistair J.; Cutfield, Wayne S.

    2015-01-01

    We assessed the incidence of diabetic ketoacidosis (DKA) in children aged <15 years with newly diagnosed type 1 diabetes mellitus (T1DM) in the Auckland Region (New Zealand) in 1999–2013, in a retrospective review of a complete regional cohort. DKA and its severity were classified according to ISPAD 2014 guidelines. Of 730 children presenting with new-onset T1DM over the 15-year time period, 195 cases had DKA of any severity (27%). There was no change in the incidence of DKA or the proportion of children with severe DKA at presentation. The incidence of DKA among children aged <2.0 years (n = 40) was 53% compared to 25% for those aged 2–14 years (n = 690; p = 0.005). In children aged 2–14 years, increasing age at diagnosis was associated with greater likelihood of DKA at presentation (p = 0.025), with the odds of DKA increasing 1.06 times with each year increase in age. Non-Europeans were more likely to present in DKA than New Zealand Europeans (OR 1.52; p = 0.048). Despite a consistent secular trend of increasing incidence of T1DM, there was no reduction in the incidence of DKA in new-onset T1DM in the Auckland Region over time. Thus, it is important to explore ways to reduce DKA risk. PMID:25989414

  17. 15-year incidence of diabetic ketoacidosis at onset of type 1 diabetes in children from a regional setting (Auckland, New Zealand).

    PubMed

    Jefferies, Craig; Cutfield, Samuel W; Derraik, José G B; Bhagvandas, Jignal; Albert, Benjamin B; Hofman, Paul L; Gunn, Alistair J; Cutfield, Wayne S

    2015-05-19

    We assessed the incidence of diabetic ketoacidosis (DKA) in children aged <15 years with newly diagnosed type 1 diabetes mellitus (T1DM) in the Auckland Region (New Zealand) in 1999-2013, in a retrospective review of a complete regional cohort. DKA and its severity were classified according to ISPAD 2014 guidelines. Of 730 children presenting with new-onset T1DM over the 15-year time period, 195 cases had DKA of any severity (27%). There was no change in the incidence of DKA or the proportion of children with severe DKA at presentation. The incidence of DKA among children aged <2.0 years (n = 40) was 53% compared to 25% for those aged 2-14 years (n = 690; p = 0.005). In children aged 2-14 years, increasing age at diagnosis was associated with greater likelihood of DKA at presentation (p = 0.025), with the odds of DKA increasing 1.06 times with each year increase in age. Non-Europeans were more likely to present in DKA than New Zealand Europeans (OR 1.52; p = 0.048). Despite a consistent secular trend of increasing incidence of T1DM, there was no reduction in the incidence of DKA in new-onset T1DM in the Auckland Region over time. Thus, it is important to explore ways to reduce DKA risk.

  18. Longitudinal changes in cerebellar and subcortical volumes in adult-onset Niemann-Pick disease type C patients treated with miglustat.

    PubMed

    Bowman, Elizabeth A; Walterfang, Mark; Abel, Larry; Desmond, Patricia; Fahey, Michael; Velakoulis, Dennis

    2015-09-01

    Niemann-Pick disease type C (NPC) is a rare neurovisceral disorder resulting in impaired intracellular lipid trafficking. The only disease-modifying treatment available to date is miglustat, an iminosugar inhibiting the accumulation of lipid by-products in neurons. This study explored how changes in cerebellar grey and white matter volumes, and in subcortical volumes, related to patient treatment status and disability and ataxia ratings. Nine adult-onset NPC patients and 17 matched controls underwent T1-weighted MRI. One patient was not receiving miglustat, and pre-treatment data were available for a further patient. Semi-automated cerebellar and subcortical segmentation was undertaken, and the rates of change in putamen, hippocampal, thalamic and caudal volumes, and grey and white matter cerebellar volumes, were compared to rates of change in Iturriaga disability score, Brief Ataxia Rating Scale (BARS), and horizontal saccadic gain. Untreated NPC patients appeared to lose cerebellar grey and white matter, bilateral thalamic volume, and right caudate volume faster than treated patients. Cerebellar grey matter volume loss and volume loss in the left thalamus were significantly correlated with Iturriaga disability scale changes. Change in both cerebellar grey and white matter was correlated with decrease in horizontal saccadic gain, but not with change in BARS. This is the first study to examine longitudinal treatment effects of miglustat on cerebellar and subcortical volumes in patients with adult-onset NPC, and is evidence that miglustat may have a protective effect on cerebellar and subcortical structure and function. PMID:26092521

  19. Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet.

    PubMed

    Rocchi, Anna; Milioto, Carmelo; Parodi, Sara; Armirotti, Andrea; Borgia, Doriana; Pellegrini, Matteo; Urciuolo, Anna; Molon, Sibilla; Morbidoni, Valeria; Marabita, Manuela; Romanello, Vanina; Gatto, Pamela; Blaauw, Bert; Bonaldo, Paolo; Sambataro, Fabio; Robins, Diane M; Lieberman, Andrew P; Sorarù, Gianni; Vergani, Lodovica; Sandri, Marco; Pennuto, Maria

    2016-07-01

    Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The mechanism by which expansion of polyglutamine in AR causes muscle atrophy is unknown. Here, we investigated pathological pathways underlying muscle atrophy in SBMA knock-in mice and patients. We show that glycolytic muscles were more severely affected than oxidative muscles in SBMA knock-in mice. Muscle atrophy was associated with early-onset, progressive glycolytic-to-oxidative fiber-type switch. Whole genome microarray and untargeted lipidomic analyses revealed enhanced lipid metabolism and impaired glycolysis selectively in muscle. These metabolic changes occurred before denervation and were associated with a concurrent enhancement of mechanistic target of rapamycin (mTOR) signaling, which induced peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC1α) expression. At later stages of disease, we detected mitochondrial membrane depolarization, enhanced transcription factor EB (TFEB) expression and autophagy, and mTOR-induced protein synthesis. Several of these abnormalities were detected in the muscle of SBMA patients. Feeding knock-in mice a high-fat diet (HFD) restored mTOR activation, decreased the expression of PGC1α, TFEB, and genes involved in oxidative metabolism, reduced mitochondrial abnormalities, ameliorated muscle pathology, and extended survival. These findings show early-onset and intrinsic metabolic alterations in SBMA muscle and link lipid/glucose metabolism to pathogenesis. Moreover, our results highlight an HFD regime as a promising approach to support SBMA patients. PMID:26971100

  20. Spinocerebellar ataxia type 1 and Machado-Joseph disease: Incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia

    SciTech Connect

    Ranum, L.P.W.; Gomez, C.; Orr, H.T.

    1995-09-01

    The ataxias are a complex group of diseases with both environmental and genetic causes. Among the autosomal dominant forms of ataxia the genes for two, spinocerebellar ataxia type 1 (SCA1) and Machado-Joseph disease (MJD), have been isolated. In both of these disorders the molecular basis of disease is the expansion of an unstable CAG trinucleotide repeat. To assess the frequency of the SCA1 and MJD trinucleotide repeat expansions among individuals diagnosed with ataxia, we have collected DNA from individuals representing 311 families with adult-onset ataxia of unknown etiology and screened these samples for trinucleotide repeat expansions within the SCA1 and MJD genes. Within this group there are 149 families with dominantly inherited ataxia. Of these, 3% have SCA1 trinucleotide repeat expansions, whereas 21% were positive for the MJD trinucleotide expansion. Thus, together SCA1 and MJD represent 24% of the autosomal dominant ataxias in our group, and the frequency of MJD is substantially greater than that of SCA1. For the 57 patients with MJD trinucleotide repeat expansions, a strong inverse correlation between CAG repeat size and age at onset was observed (r = -.838). Among the MJD patients, the normal and affected ranges of CAG repeat size are 14-40 and 68-82 repeats, respectively. For SCA1 the normal and affected ranges are much closer, containing 19-38 and 40-81 CAG repeats, respectively. 30 refs., 1 fig., 3 tabs.

  1. Weather conditions and their effect on the increase of the risk of type A acute aortic dissection onset in Berlin

    NASA Astrophysics Data System (ADS)

    Taheri Shahraiyni, Hamid; Sodoudi, Sahar; Cubasch, Ulrich

    2016-08-01

    In this study, a minimum distance classification and forward feature selection technique are joined to determine the relationship between weather conditions and the increase of the risk of type A acute aortic dissection (AAD) events in Berlin. The results demonstrate that changes in the amount of cloudiness and air temperature are the most representative weather predictors among the studied parameters. A discrimination surface was developed for the prediction of AAD events 6 h ahead, and it is found that, under a specific amount of cloudiness and air temperature, the risk of AAD events in Berlin increases about 20 %.

  2. Early onset Charcot-Marie-Tooth neuropathy type 2A and severe developmental delay: expanding the clinical phenotype of MFN2-related neuropathy.

    PubMed

    Tufano, Maria; Cappuccio, Gerarda; Terrone, Gaetano; Manganelli, Fiore; Pisciotta, Chiara; Geroldi, Alessandro; Capponi, Simona; Del Giudice, Ennio

    2015-12-01

    Charcot-Marie-Tooth (CMT) syndromes are a group of clinically heterogeneous disorders of the peripheral nervous system. Mutations of mitofusin 2 (MFN2) have been recognized to be associated with CMT type 2A (CMT2A). CMT2A is primarily an axonal disorder resulting in motor and sensory neuropathy. We report a male child with psychomotor delay, dysmorphic features, and weakness of lower limbs associated with electrophysiological features of severe, sensory-motor, axonal neuropathy. The patient was diagnosed with early onset CMT2A and severe psychomotor retardation associated with c.310C>T mutation (p.R104W) in MFN2 gene. CMT2A should be considered in patients with both axonal sensory-motor neuropathy and developmental delay.

  3. MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot–Marie–Tooth disease type 1B

    PubMed Central

    Saporta, Mario A. C.; Shy, Brian R.; Patzko, Agnes; Bai, Yunhong; Pennuto, Maria; Ferri, Cinzia; Tinelli, Elisa; Saveri, Paola; Kirschner, Dan; Crowther, Michelle; Southwood, Cherie; Wu, Xingyao; Gow, Alexander; Feltri, M. Laura; Wrabetz, Lawrence

    2012-01-01

    Mutations in myelin protein zero (MPZ) cause Charcot–Marie–Tooth disease type 1B. Many dominant MPZ mutations, including R98C, present as infantile onset dysmyelinating neuropathies. We have generated an R98C ‘knock-in’ mouse model of Charcot–Marie–Tooth type 1B, where a mutation encoding R98C was targeted to the mouse Mpz gene. Both heterozygous (R98C/+) and homozygous (R98C/R98C) mice develop weakness, abnormal nerve conduction velocities and morphologically abnormal myelin; R98C/R98C mice are more severely affected. MpzR98C is retained in the endoplasmic reticulum of Schwann cells and provokes a transitory, canonical unfolded protein response. Ablation of Chop, a mediator of the protein kinase RNA-like endoplasmic reticulum kinase unfolded protein response pathway restores compound muscle action potential amplitudes of R98C/+ mice but does not alter the reduced conduction velocities, reduced axonal diameters or clinical behaviour of these animals. R98C/R98C Schwann cells are developmentally arrested in the promyelinating stage, whereas development is delayed in R98C/+ mice. The proportion of cells expressing c-Jun, an inhibitor of myelination, is elevated in mutant nerves, whereas the proportion of cells expressing the promyelinating transcription factor Krox-20 is decreased, particularly in R98C/R98C mice. Our results provide a potential link between the accumulation of MpzR98C in the endoplasmic reticulum and a developmental delay in myelination. These mice provide a model by which we can begin to understand the early onset dysmyelination seen in patients with R98C and similar mutations. PMID:22689911

  4. The Alzheimer's Project

    MedlinePlus

    ... Navigation Bar Home Current Issue Past Issues The Alzheimer's Project Past Issues / Spring 2009 Table of Contents ... of this page please turn Javascript on. The Alzheimer's Project A 4-Part Documentary Series Starting May ...

  5. The Genetics of Alzheimer Disease

    PubMed Central

    Tanzi, Rudolph E.

    2012-01-01

    Family history is the second strongest risk factor for Alzheimer disease (AD) following advanced age. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations in APP, PSEN1, and PSEN2 virtually guarantee early-onset (<60 years) familial AD, which represents ∼5% of AD. On the other hand, common gene polymorphisms, such as the ε4 and ε2 variants of the APOE gene, can influence susceptibility for ∼50% of the common late-onset AD. These four genes account for 30%–50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of 11 additional AD candidate genes. This paper reviews the past, present, and future attempts to elucidate the complex and heterogeneous genetic underpinnings of AD. PMID:23028126

  6. Physical activity for the prevention and management of youth-onset type 2 diabetes mellitus: focus on cardiovascular complications.

    PubMed

    McGavock, Jonathan; Sellers, Elizabeth; Dean, Heather

    2007-12-01

    With the growing prevalence of childhood obesity and type 2 diabetes mellitus (T2DM) in youth, the challenge of cardiovascular disease risk management has entered the paediatric realm, affecting specialists, family physicians and allied healthcare professionals alike. Currently, there is little evidence to support optimal strategies for management of T2DM in youth and the associated cardiovascular complications. Physical activity plays a powerful role in the prevention and management of T2DM and cardiovascular disease in adults. This review will focus on the role of physical activity for the prevention of T2DM in youth and its associated cardiovascular complications. The first part describes the prevalence of cardiovascular risk factors in this cohort. The second part focuses on the role of physical activity in the prevention and management of T2DM in youth. Collectively, the limited intervention and observation studies published to date suggest that daily targets of 60-90 minutes of physical activity and less than 60 minutes of screen time (i.e. time spent in front of a television, computer or video games) are required for the prevention and management of T2DM in youth. Large-scale intervention studies are needed to determine the most effective physical activity strategies for the prevention and management of T2DM in youth.

  7. Characteristics of children and adolescents at onset of type 2 diabetes in a Tertiary Hospital in Bangladesh

    PubMed Central

    Zabeen, Bedowra; Nahar, Jebun; Tayyeb, Samin; Mohsin, Fauzia; Nahar, Nazmun; Azad, Kishwar

    2016-01-01

    Introduction: Recent data show that the prevalence of diabetes among children and adolescents is increasing in some ethnic groups. The worldwide epidemic of childhood obesity has been accompanied by an increase in the incidence of type 2 diabetes (T2D) in youth. Methods: The aim of this study was to describe the baseline characteristics of children and adolescents diagnosed ≤18 years who had features of T2D and presented at Changing Diabetes in Children, Paediatric Diabetes Clinic at Bangladesh Institute of Research and Rehabilitation of Diabetes, Endocrine, and Metabolic Disorders. All patients who were newly diagnosed and came to the clinic from March 2011 to March 2015 were included. Results: Among 939 newly registered patients, 77 (8%) had a diagnosis of T2D. The age at diagnosis was 9–10 years in 11 patients (14%), 11–14 years in 46 (60%) and 15–17 years in other 20 patients (26%). Majority of the children had a positive family history of T2D (94%) and 58% were obese. Median fasting insulin (27.9 [17.3–99.3]) was high in 76% patients. Insulin was started initially along with metformin in 40 patients and could be stopped in six patients in 3 months. Conclusion: Our study reflects that T2D is emerging as a problem in children and adolescents in Bangladesh. PMID:27730073

  8. The onset of flood basalt volcanism, Northern Paraná Basin, Brazil: A precise U-Pb baddeleyite/zircon age for a Chapecó-type dacite

    NASA Astrophysics Data System (ADS)

    Janasi, Valdecir de Assis; de Freitas, Vivian Azor; Heaman, Larry H.

    2011-02-01

    We report the first U-Pb baddeleyite/zircon date for a felsic volcanic rock from the Paraná Large Igneous Province in south Brazil. The new date of 134.3 ± 0.8 Ma for a hypocrystalline Chapecó-type dacite from Ourinhos (northern Paraná basin) is an important regional time marker for the onset of flood basalt volcanism in the northern and western portion of the province. The dated dacite was erupted onto basement rocks and is overlain by a high-Ti basalt sequence, interpreted to be correlative with Pitanga basalts elsewhere. This new U-Pb date for the Ourinhos dacite is consistent with the local stratigraphy being slightly older than the few reliable step-heating 40Ar/39Ar dates currently available for overlying high-Ti basalts (133.6-131.5 Ma). This indicates an ~ 3 Ma time span for the building of the voluminous high-Ti lava sequence of the Paraná basin. On the other hand, it overlaps the 40Ar/39Ar dates (134.8-134.1 Ma) available for the stratigraphically older low-Ti basalt (Gramado + Esmeralda types) and dacite-rhyolite (Palmas type) sequences from South Brazil, which is consistent with the short-lived character of this volcanism and its rapid succession by the high-Ti sequence.

  9. Social participation and the onset of functional disability by socioeconomic status and activity type: The JAGES cohort study.

    PubMed

    Ashida, Toyo; Kondo, Naoki; Kondo, Katsunori

    2016-08-01

    The impact of social participation on older adults' health may differ by individual socioeconomic status (SES). Consequently, we examined SES effect modification on the associations between types of social activity participation and incident functional disability. Cohort data from the 2003 Japan Gerontological Evaluation Study (JAGES) was utilized. This included individuals who were aged 65 or older and functionally independent at baseline. Analysis was carried out on 12,991 respondents after acquisition of information about their long-term care (LTC) status in Japan. Incident functional disability was defined based on medical certification and LTC information was obtained from municipal insurance databases. Cox proportional hazard regression was conducted for analysis. Results indicated that participants in a sport (hazard ratio [HR]: 0.66; 95% confidence interval [CI]: 0.51, 0.85) or hobby group (HR: 0.69; 95% CI: 0.55, 0.87), or who had a group facilitator role (HR: 0.82; 95% CI: 0.66, 1.02) were less likely to be disabled. While men with 13 or more years of education were less likely to become disabled if they held facilitator roles, this association was weak among men with 0-5years of education (HR of interaction term between 0 and 5years of education and facilitator role dummy variable=3.95; 95% CI: 1.30, 12.05). In conclusion, the association between group participation and smaller risk of the functional disability was stronger among highly educated older adults. Intervention programs promoting social participation should consider participants' socioeconomic backgrounds. PMID:27235600

  10. Social participation and the onset of functional disability by socioeconomic status and activity type: The JAGES cohort study.

    PubMed

    Ashida, Toyo; Kondo, Naoki; Kondo, Katsunori

    2016-08-01

    The impact of social participation on older adults' health may differ by individual socioeconomic status (SES). Consequently, we examined SES effect modification on the associations between types of social activity participation and incident functional disability. Cohort data from the 2003 Japan Gerontological Evaluation Study (JAGES) was utilized. This included individuals who were aged 65 or older and functionally independent at baseline. Analysis was carried out on 12,991 respondents after acquisition of information about their long-term care (LTC) status in Japan. Incident functional disability was defined based on medical certification and LTC information was obtained from municipal insurance databases. Cox proportional hazard regression was conducted for analysis. Results indicated that participants in a sport (hazard ratio [HR]: 0.66; 95% confidence interval [CI]: 0.51, 0.85) or hobby group (HR: 0.69; 95% CI: 0.55, 0.87), or who had a group facilitator role (HR: 0.82; 95% CI: 0.66, 1.02) were less likely to be disabled. While men with 13 or more years of education were less likely to become disabled if they held facilitator roles, this association was weak among men with 0-5years of education (HR of interaction term between 0 and 5years of education and facilitator role dummy variable=3.95; 95% CI: 1.30, 12.05). In conclusion, the association between group participation and smaller risk of the functional disability was stronger among highly educated older adults. Intervention programs promoting social participation should consider participants' socioeconomic backgrounds.

  11. Viscoelastic and ultrastructural characteristics of whole blood and plasma in Alzheimer-type dementia, and the possible role of bacterial lipopolysaccharides (LPS).

    PubMed

    Bester, Janette; Soma, Prashilla; Kell, Douglas B; Pretorius, Etheresia

    2015-11-01

    Alzheimer-type dementia (AD) is a neurodegenerative disorder and the most common form of dementia. Patients typically present with neuro- and systemic inflammation and iron dysregulation, associated with oxidative damage that reflects in hypercoagulability. Hypercoagulability is closely associated with increased fibrinogen and in AD patients fibrinogen has been implicated in the development of neuroinflammation and memory deficits. There is still no clear reason precisely why (a) this hypercoagulable state, (b) iron dysregulation and (c) increased fibrinogen could together lead to the loss of neuronal structure and cognitive function. Here we suggest an alternative hypothesis based on previous ultrastructural evidence of the presence of a (dormant) blood microbiome in AD. Furthermore, we argue that bacterial cell wall components, such as the endotoxin lipopolysaccharide (LPS) of Gram-negative strains, might be the cause of the continuing and low-grade inflammation, characteristic of AD. Here, we follow an integrated approach, by studying the viscoelastic and ultrastructural properties of AD plasma and whole blood by using scanning electron microscopy, Thromboelastography (TEG®) and the Global Thrombosis Test (GTT®). Ultrastructural analysis confirmed the presence and close proximity of microbes to erythrocytes. TEG® analysis showed a hypercoagulable state in AD. TEG® results where LPS was added to naive blood showed the same trends as were found with the AD patients, while the GTT® results (where only platelet activity is measured), were not affected by the added LPS, suggesting that LPS does not directly impact platelet function. Our findings reinforce the importance of further investigating the role of LPS in AD. PMID:26462180

  12. Decline of microtubule-associated protein tau after experimental stroke in differently aged wild-type and 3xTg mice with Alzheimer-like alterations.

    PubMed

    Michalski, Dominik; Preißler, Hartmut; Hofmann, Sarah; Kacza, Johannes; Härtig, Wolfgang

    2016-08-25

    Stroke therapies are still limited to a minority of patients. Considering time-dependent aspects of stroke, the penumbra concept describes the transition from functional to permanent tissue damage. Thereby, the role of cytoskeletal elements, as for instance microtubules with associated tau remains poorly understood and is therefore not yet considered for therapeutic approaches. This study explored the expression of microtubule-associated protein tau related to neuronal damage in stroke-affected brain regions. Wild-type and triple-transgenic mice of 3, 7 and 12months of age and with an Alzheimer-like background underwent experimental stroke. After 24h, brain sections were used for immunofluorescence labeling of tau and Neuronal Nuclei (NeuN). Potential functional consequences of cellular alterations were explored by statistical relationships to the general health condition, i.e. neurobehavioral deficits and loss of body weight. Immunoreactivity for whole tau decreased significantly in ischemic areas, while the decline at the border zone was more drastic for tau-immunoreactivity compared with the diminished NeuN labeling. Quantitative analyses confirmed pronounced sensitivity for tau-immunoreactivity in the ischemic border zone. Decline of tau- as well as NeuN-immunoreactivity correlated with body weight loss during the 24-h observation period. In conclusion, microtubule-associated protein tau was robustly identified as a highly sensitive cytoskeletal constitute under ischemic conditions, suggesting a pivotal role during the transition process toward long-lasting tissue damage. Consequently, cytoskeletal elements appear as promising targets for novel therapeutic approaches with the objective to impede ischemia-induced irreversible cellular degradation.

  13. Lysosomal β-galactosidase and β-hexosaminidase activities correlate with clinical stages of dementia associated with Alzheimer's disease and type 2 diabetes mellitus.

    PubMed

    Tiribuzi, Roberto; Orlacchio, Antonio; Crispoltoni, Lucia; Maiotti, Mariangela; Zampolini, Mauro; De Angeliz, Massimiliano; Mecocci, Patrizia; Cecchetti, Roberta; Bernardi, Giorgio; Datti, Alessandro; Martino, Sabata; Orlacchio, Aldo

    2011-01-01

    Multiple epidemiological studies have shown that individuals affected by type-2 diabetes mellitus (T2DM) carry a 2-to-5-fold higher risk of developing Alzheimer's disease (AD) when compared to non-diabetic subjects. Thus, biochemical parameters that can be easily and routinely assessed for high-confidence evaluation of diabetic conditions leading to AD (AD-T2DM) are regarded as efficient tools aimed at early diagnosis and, in turn, timely AD treatment. In this regard, the activity of lysosomal glycohydrolases may of use, in light of the implication of these enzymes in early events that underlie AD pathology and an overt correlation, in diabetes, between altered metabolic homeostasis, abnormal glycohydrolase secretion in body fluids, and occurrence of diabetic complications. Based on marked up-regulation previously shown in a peripheral, cell-based model of AD, we selected β-Galactosidase, β-Hexosaminidase, and α-Mannosidase to discriminate T2DM from AD-T2DM subjects. A screen of 109, 114, and 116 patients with T2DM, AD and AD-T2DM, respectively, was performed by testing enzyme activities in both blood plasma and peripheral blood mononuclear cells. Compared to age-matched, healthy controls (n = 122), β-Galactosidase and β-Hexosaminidase activities markedly diverged across the three groups, whereas virtually unchanged values were observed for α-Mannosidase. In particular, plasma β-Galactosidase and β-Hexosaminidase levels were higher in patients with AD-T2DM compared to those with T2DM, suggesting different mechanisms leading to enzyme secretion. Statistical analyses based on ROC curves showed that both β-Galactosidase and β-Hexosaminidase activities, either intracellular or plasma-secreted, may be used to discriminate AD patients from controls and AD-T2DM from T2DM patients.

  14. Viscoelastic and ultrastructural characteristics of whole blood and plasma in Alzheimer-type dementia, and the possible role of bacterial lipopolysaccharides (LPS)

    PubMed Central

    Bester, Janette; Soma, Prashilla; Kell, Douglas B.; Pretorius, Etheresia

    2015-01-01

    Alzheimer-type dementia (AD) is a neurodegenerative disorder and the most common form of dementia. Patients typically present with neuro- and systemic inflammation and iron dysregulation, associated with oxidative damage that reflects in hypercoagulability. Hypercoagulability is closely associated with increased fibrin(ogen) and in AD patients fibrin(ogen) has been implicated in the development of neuroinflammation and memory deficits. There is still no clear reason precisely why (a) this hypercoagulable state, (b) iron dysregulation and (c) increased fibrin(ogen) could together lead to the loss of neuronal structure and cognitive function. Here we suggest an alternative hypothesis based on previous ultrastructural evidence of the presence of a (dormant) blood microbiome in AD. Furthermore, we argue that bacterial cell wall components, such as the endotoxin lipopolysaccharide (LPS) of Gram-negative strains, might be the cause of the continuing and low-grade inflammation, characteristic of AD. Here, we follow an integrated approach, by studying the viscoelastic and ultrastructural properties of AD plasma and whole blood by using scanning electron microscopy, Thromboelastography (TEG®) and the Global Thrombosis Test (GTT®). Ultrastructural analysis confirmed the presence and close proximity of microbes to erythrocytes. TEG® analysis showed a hypercoagulable state in AD. TEG® results where LPS was added to naive blood showed the same trends as were found with the AD patients, while the GTT® results (where only platelet activity is measured), were not affected by the added LPS, suggesting that LPS does not directly impact platelet function. Our findings reinforce the importance of further investigating the role of LPS in AD. PMID:26462180

  15. CBF tomograms with (/sup 99m/Tc-HM-PAO in patients with dementia (Alzheimer type and HIV) and Parkinson's disease--initial results

    SciTech Connect

    Costa, D.C.; Ell, P.J.; Burns, A.; Philpot, M.; Levy, R.

    1988-12-01

    We present preliminary data on the utility of functional brain imaging with (99mTc)-d,l-HM-PAO and single photon emission computed tomography (SPECT) in the study of patients with dementia of the Alzheimer type (DAT), HIV-related dementia syndrome, and the on-off syndrome of Parkinson's disease. In comparison with a group of age-matched controls, the DAT patients revealed distinctive bilateral temporal and posterior parietal deficits, which correlate with detailed psychometric evaluation. Patients with amnesia as the main symptom (group A) showed bilateral mesial temporal lobe perfusion deficits (p less than 0.02). More severely affected patients (group B) with significant apraxia, aphasia, or agnosia exhibited patterns compatible with bilateral reduced perfusion in the posterior parietal cortex, as well as reduced perfusion to both temporal lobes, different from the patients of the control group (p less than 0.05). SPECT studies of HIV patients with no evidence of intracraneal space occupying pathology showed marked perfusion deficits. Patients with Parkinson's disease and the on-off syndrome studied during an on phase (under levodopa therapy) and on another occasion after withdrawal of levodopa (off) demonstrated a significant change in the uptake of (99mTc)-d,l-HM-PAO in the caudate nucleus (lower on off) and thalamus (higher on off). These findings justify the present interest in the functional evaluation of the brain of patients with dementia. (99mTc)-d,l-HM-PAO and regional cerebral blood flow (rCBF)/SPECT appear useful and highlight individual disorders of flow in a variety of neuropsychiatric conditions.

  16. Relationship of lipid and lipoprotein ratios with coronary severity in patients with new on-set coronary artery disease complicated with type 2 diabetics

    PubMed Central

    Du, Ying; Chen, Juan; Chen, Man-Hua; Yang, Sheng-Hua; Li, Sha; Guo, Yuan-Lin; Zhu, Cheng-Gang; Xu, Rui-Xia; Dong, Qian; Li, Jian-Jun

    2016-01-01

    Background Diabetes mellitus (DM) is associated with coronary artery disease (CAD) progression. Although previous studies have demonstrated the association of lipid and lipoprotein ratios with CAD, no data are currently available concerning the relationship between lipid and lipoprotein ratios and the severity of new on-set CAD in diabetics. Therefore, the aim of the present study was to investigate the usefulness of lipid and lipoprotein ratios in predicting the severity of CAD in patients with type 2 DM (T2DM). Methods A total of 380 consecutive T2DM patients with new on-set CAD were enrolled in the present study. Then, they were classified into the three groups according to Gensini score (GS) tertiles. The relationship between lipid and lipoprotein ratios currently used and the GS was investigated. Results Positive correlations of natural log-transformed GS (lnGS) with apolipoprotein B to apoA-I ratio (apoB/apoA-I), non-high-density lipoprotein cholesterol to apoA-I ratio (non-HDL-C/apoA-I), and low-density lipoprotein cholesterol to apoA-I ratio (LDL-C/apoA-I) were found (r = 0.18, 0.13, 0.12, respectively, all P < 0.05). Multivariate logistic analysis indicated apoB/apoA-I as the strongest predictor for high GS (OR = 5.67, 95% CI: 1.45–23.92, P = 0.003). Area under receivers operating characteristic curve of apoB/apoA-I was 0.63 (95% CI: 0.60–0.66, P = 0.001) for predicting high GS. The optimal cutoff value of apoB/apoA-I to predict high GS was 0.72 with the sensitivity of 61.2% and the specificity of 62.1%. Conclusions Lipid and lipoprotein ratios might be useful for predicting the severity of new on-set CAD in T2DM patients, and the apoB/apoA-I appeared as the most significant predictor in this population. PMID:27781059

  17. Streptozotocin-induced type-1-diabetes disease onset in Sprague-Dawley rats is associated with an altered intestinal microbiota composition and decreased diversity.

    PubMed

    Patterson, Elaine; Marques, Tatiana M; O'Sullivan, Orla; Fitzgerald, Patrick; Fitzgerald, Gerald F; Cotter, Paul D; Dinan, Timothy G; Cryan, John F; Stanton, Catherine; Ross, R Paul

    2015-01-01

    There is a growing appreciation that microbiota composition can significantly affect host health and play a role in disease onset and progression. This study assessed the impact of streptozotocin (STZ)-induced type-1-diabetes (T1D) on intestinal microbiota composition and diversity in Sprague-Dawley rats, compared with healthy controls over time. T1D was induced by injection of a single dose (60 mg STZ kg(-1)) of STZ, administered via the intraperitoneal cavity. Total DNA was isolated from faecal pellets at weeks 0 (pre-STZ injection), 1, 2 and 4 and from caecal content at week 5 from both healthy and T1D groups. High-throughput 16S rRNA sequencing was employed to investigate intestinal microbiota composition. The data revealed that although intestinal microbiota composition between the groups was similar at week 0, a dramatic impact of T1D development on the microbiota was apparent post-STZ injection and for up to 5 weeks. Most notably, T1D onset was associated with a shift in the Bacteroidetes : Firmicutes ratio (P<0.05), while at the genus level, increased proportions of lactic acid producing bacteria such as Lactobacillus and Bifidobacterium were associated with the later stages of T1D progression (P<0.05). Coincidently, T1D increased caecal lactate levels (P<0.05). Microbial diversity was also reduced following T1D (P<0.05). Principle co-ordinate analyses demonstrated temporal clustering in T1D and control groups with distinct separation between groups. The results provide a comprehensive account of how T1D is associated with an altered intestinal microbiota composition and reduced microbial diversity over time.

  18. Earlier Age of Onset of Chronic Hypertension and Type 2 Diabetes Mellitus After a Hypertensive Disorder of Pregnancy or Gestational Diabetes Mellitus.

    PubMed

    Heida, Karst Y; Franx, Arie; van Rijn, Bas B; Eijkemans, Marinus J C; Boer, Jolanda M A; Verschuren, Monique W M; Oudijk, Martijn A; Bots, Michiel L; van der Schouw, Yvonne T

    2015-12-01

    A prospective cohort study was conducted to assess the impact of a history of hypertensive disorder of pregnancy (HDP) or gestational diabetes mellitus (GDM) on the risk and age of onset of hypertension, type 2 diabetes mellitus (T2D), and cardiovascular disease (CVD) later in life, independent of hypertension and T2D. Between 1993 and 1997, 22 265 ever-pregnant women were included from the European Prospective Investigation into Cancer and Nutrition-NL study, aged 20 to 70 years at baseline. Details on complications of pregnancy and known hypertension were obtained by questionnaire. Blood pressure was measured at enrollment. Participants were followed for the occurrence of CVD events. Data were analyzed using ANCOVA, multivariable logistic regression, and Cox proportional hazard (with HDP and GDM as time-dependent variables for T2D and CVD) models. At enrollment, women with a HDP reported diagnosis of hypertension 7.7 years earlier (95% confidence interval [CI] 6.9-8.5) and women with GDM reported diagnosis of T2D 7.7 years earlier (95% CI 5.8-9.6) than women without pregnancy complications. After adjustment for potential confounders, HDP was associated with presence of hypertension at enrollment (odds ratio 2.12, 95% CI 1.98-2.28) and onset of CVD later in life (hazard ratio 1.21, 95% CI 1.10-1.32). After including the intermediates hypertension and T2D in the model, the risk of CVD later in life decreased (hazard ratio 1.09, 95% CI 1.00-1.20). GDM was associated with an increased risk of developing T2D later in life (hazard ratio 3.68, 95% CI 2.77-4.90), but not with risk of CVD. HDP and GDM have a substantial impact on the risk of CVD and are potentially important indicators for preventive cardiovascular risk management.

  19. Alzheimer's disease.

    PubMed

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

    2012-01-01

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

  20. Can oral infection be a risk factor for Alzheimer's disease?

    PubMed Central

    Olsen, Ingar; Singhrao, Sim K.

    2015-01-01

    Alzheimer's disease (AD) is a scourge of longevity that will drain enormous resources from public health budgets in the future. Currently, there is no diagnostic biomarker and/or treatment for this most common form of dementia in humans. AD can be of early familial-onset or sporadic with a late-onset. Apart from the two main hallmarks, amyloid-beta and neurofibrillary tangles, inflammation is a characteristic feature of AD neuropathology. Inflammation may be caused by a local central nervous system insult and/or by peripheral infections. Numerous microorganisms are suspected in AD brains ranging from bacteria (mainly oral and non-oral Treponema species), viruses (herpes simplex type I), and yeasts (Candida species). A causal relationship between periodontal pathogens and non-oral Treponema species of bacteria has been proposed via the amyloid-beta and inflammatory links. Periodontitis constitutes a peripheral oral infection that can provide the brain with intact bacteria and virulence factors and inflammatory mediators due to daily, transient bacteremias. If and when genetic risk factors meet environmental risk factors in the brain, disease is expressed, in which neurocognition may be impacted, leading to the development of dementia. To achieve the goal of finding a diagnostic biomarker and possible prophylactic treatment for AD, there is an initial need to solve the etiological puzzle contributing to its pathogenesis. This review therefore addresses oral infection as the plausible etiology of late-onset AD (LOAD). PMID:26385886

  1. Brain inflammation in Alzheimer disease and the therapeutic implications.

    PubMed

    McGeer, E G; McGeer, P L

    1999-10-01

    Immunohistochemical studies suggested the existence of a chronic inflammatory condition in affected regions of the brain in Alzheimer disease (AD). Since inflammation can be damaging to host tissue, it was hypothesized that antiinflammatory drugs might inhibit both the onset and the progression of AD. This hypothesis is supported by a number of epidemiological studies suggesting that the prevalence of AD in persons is reduced by 40 - 50% in persons using antiinflammatory drugs. In one small pilot trial in early AD, the nonsteroidal antiinflammatory drug indomethacin appeared to halt the progressive memory loss. Immunohistochemical and molecular biological studies on immune system components in AD brain are revealing the complexities of the innate immune reaction. This very complexity may offer points of therapeutic intervention for new types of antiinflammatory agents. The complement system, microglia and cytokines are key components. This review summarizes the present state of knowledge on the immune system elements found in AD brain.

  2. Challenges Associated with Metal Chelation Therapy in Alzheimer's Disease

    PubMed Central

    Hegde, Muralidhar L.; Bharathi, P.; Suram, Anitha; Venugopal, Chitra; Jagannathan, Ramya; Poddar, Pankaj; Srinivas, Pullabhatla; Sambamurti, Kumar; Rao, Kosagisharaf Jagannatha; Scancar, Janez; Messori, Luigi; Zecca, Luigi; Zatta, Paolo

    2010-01-01

    A close association between brain metal dishomeostasis and the onset and/or progression of Alzheimer's disease (AD) has been clearly established in a number of studies, although the underlying biochemical mechanisms remain obscure. This observation renders chelation therapy an attractive pharmacological option for the treatment of this disease. However, a number of requirements must be fulfilled in order to adapt chelation therapy to AD so that the term “metal targeted strategies” seems now more appropriate. Indeed, brain metal redistribution rather than brain metal scavenging and removal is the major goal of this type of intervention. The most recent developments in metal targeted strategies for AD will be discussed using, as useful examples, clioquinol, curcumin, and epigallocatechin, and the future perspectives will also be outlined. PMID:19363258

  3. The tangled story of Alois Alzheimer.

    PubMed

    Zilka, N; Novak, M

    2006-01-01

    In 1907, Bavarian psychiatrist Alois Alzheimer, who is considered to be a founding father of neuropathology, was first to describe the main neuropathologic characteristics of the peculiar disease in the brain of a woman showing progressive dementia when she was in her early 50s. Using a newly developed Bielschowsky's silver staining method, Alzheimer observed degenerating neurons with bundles of fibrils (neurofibrillary tangles) and miliary foci of silver-staining deposits scattered over the cortex (senile plaques). In 1910 Emil Kraepelin (Alois Alzheimer's superior) coined the term "Alzheimer's disease" to distinguish the presenile form of dementia from the more common senile variant. Alzheimer's findings were followed up, and soon a number of reports of similar cases appeared in the literature. During the time, both pathological hallmarks of Alzheimer's disease became the gold standard for post-mortem diagnosis of the disease. One hundred years later, dementia of Alzheimer's type is considered to be one of the most devastating illnesses of old age. Despite intensive research the cause of the disease still remains elusive (Fig. 2, Ref. 17).

  4. Cause-Specific Mortality Trends in a Large Population-Based Cohort With Long-Standing Childhood-Onset Type 1 Diabetes

    PubMed Central

    Secrest, Aaron M.; Becker, Dorothy J.; Kelsey, Sheryl F.; LaPorte, Ronald E.; Orchard, Trevor J.

    2010-01-01

    OBJECTIVE Little is known concerning the primary cause(s) of mortality in type 1 diabetes responsible for the excess mortality seen in this population. RESEARCH DESIGN AND METHODS The Allegheny County (Pennsylvania) childhood-onset (age <18 years) type 1 diabetes registry (n = 1,075) with diagnosis from 1965 to 1979 was used to explore patterns in cause-specific mortality. Cause of death was determined by a mortality classification committee of at least three physician epidemiologists, based on the death certificate and additional records surrounding the death. RESULTS Vital status for 1,043 (97%) participants was ascertained as of 1 January 2008, revealing 279 (26.0%) deaths overall (141 females and 138 males). Within the first 10 years after diagnosis, the leading cause of death was acute diabetes complications (73.6%), while during the next 10 years, deaths were nearly evenly attributed to acute (15%), cardiovascular (22%), renal (20%), or infectious (18%) causes. After 20 years' duration, chronic diabetes complications (cardiovascular, renal, or infectious) accounted for >70% of all deaths, with cardiovascular disease as the leading cause of death (40%). Women (P < 0.05) and African Americans (P < 0.001) have significantly higher diabetes-related mortality rates than men and Caucasians, respectively. Standardized mortality ratios (SMRs) for non–diabetes-related causes do not significantly differ from the general population (violent deaths: SMR 1.2, 95% CI 0.6–1.8; cancer: SMR 1.2, 0.5–2.0). CONCLUSIONS The excess mortality seen in type 1 diabetes is almost entirely related to diabetes and its comorbidities but varies by duration of diabetes and particularly affects women and African Americans. PMID:20739685

  5. Thrombocytopenia-associated multiorgan failure occurring in an infant at the onset of type 1 diabetes successfully treated with fresh frozen plasma.

    PubMed

    Kumar, Revati; McSharry, Brent; Bradbeer, Peter; Wiltshire, Esko; Jefferies, Craig

    2016-07-01

    TAMOF is a devastating microangiopathy that can occur in association with the new onset of T1DM, and should be considered with the onset of thrombocytopenia, renal failure, and raised LDH. Treatment with fresh frozen plasma should be considered as a first-line option in such cases prior to plasma exchange. PMID:27386126

  6. Thrombocytopenia-associated multiorgan failure occurring in an infant at the onset of type 1 diabetes successfully treated with fresh frozen plasma.

    PubMed

    Kumar, Revati; McSharry, Brent; Bradbeer, Peter; Wiltshire, Esko; Jefferies, Craig

    2016-07-01

    TAMOF is a devastating microangiopathy that can occur in association with the new onset of T1DM, and should be considered with the onset of thrombocytopenia, renal failure, and raised LDH. Treatment with fresh frozen plasma should be considered as a first-line option in such cases prior to plasma exchange.

  7. Novel role of red wine-derived polyphenols in the prevention of Alzheimer's disease dementia and brain pathology: experimental approaches and clinical implications.

    PubMed

    Pasinetti, Giulio Maria

    2012-10-01

    Recent studies suggest that by the middle of this century, as many as 14 million Americans will have Alzheimer's disease, creating an enormous strain on families, the health care system and the federal budget. There are still widespread misconceptions about issues related to the prevention and/or treatment of disease pathogenesis, leaving us unprepared to deal with the disease. To address these challenges, several therapeutic approaches are currently under investigation, mainly in an attempt to delay disease onset and eventually slow down its progression. Recent epidemiological evidence has implicated the protective role of dietary polyphenols from grape products against Alzheimer's disease. Furthermore, experimental evidence supports the hypothesis that certain bioactive grape-derived polyphenols may protect against Alzheimer's disease-type cognitive deterioration, in part by interfering with the generation and assembly of β-amyloid peptides into neurotoxic oligomeric aggregated species. Brain-targeting polyphenols have been shown to significantly reduce the generation of β-amyloid peptides in primary cortico-hippocampal neuron cultures, and preliminary results indicate that they may influence neuronal synaptic plasticity. Recent evidence has also implicated the role of certain grape-derived preparations in beneficially modulating tau neuropathology, including reducing tau aggregation. Studies suggest that dietary polyphenolics may benefit Alzheimer's disease by modulating multiple disease-modifying modalities, both β-amyloid-dependent and independent mechanisms, and provide impetus for the development of polyphenolic compounds for Alzheimer's disease prevention and/or therapy.

  8. Autoimmune polyglandular syndrome type 2 manifested as Hashimoto's thyroiditis and adrenocortical insufficiency, in Turner syndrome woman, with onset following introduction of treatment with recombinant human growth hormone.

    PubMed

    Cyniak-Magierska, Anna; Lasoń, Agnieszka; Smyczyńska, Joanna; Lewiński, Andrzej

    2015-01-01

    Autoimmune polyglandular syndrome is a constellation of signs and symptoms of simultaneous insufficiencies of several endocrine glands. Autoimmune polyglandular syndrome type 2 (APS 2) may be diagnosed when the adrenocortical insufficiency is associated with an autoimmune thyroid disease (Hashimoto's thyroiditis or Graves' disease), and/or insulin-dependent diabetes mellitus. Turner syndrome is the most common chromosomal disorder in females, caused by complete or partial X chromosome monosomy. We present the case of a 20-year-old woman with Turner syndrome, in whom APS 2 (Hashimoto's thyroiditis and adrenocortical insufficiency) has been diagnosed after introduction of recombinant human growth hormone (rhGH) therapy. In Turner syndrome, examination of the patient must regularly be conducted in order to diagnose a possible onset of autoimmune diseases; respective treatment must be applied as soon as the diagnosis is established. In particular, therapy of rhGH, used for short stature treatment, may be a trigger factor of adrenal insufficiency. The cortisol level in blood should be assessed before rhGH administration and carefully monitored during the therapy, especially in case of autoimmune thyroid disease coexistence.

  9. Three years of liraglutide treatment offers continuously optimal glycemic control in a pediatric patient with maturity-onset diabetes of the young type 3.

    PubMed

    Urakami, Tatsuhiko; Habu, Masako; Okuno, Misako; Suzuki, Junichi; Takahashi, Shori; Yorifuji, Tohru

    2015-03-01

    Sulfonylureas (SUs) are recommended as the first-line pharmacological treatment in patients with uncontrolled maturity-onset diabetes of the young type 3 (MODY3). In contrast, glucagon-like peptide-1 (GLP-1) receptor agonists have the advantages of a low risk of hypoglycemia and maintained β-cell function. We report a pediatric patient with MODY3 treated with a GLP-1 receptor agonist, liraglutide. A 12-year-old Japanese girl with MODY3 had been treated with insulin for 6 months since the time of diagnosis. After genetic analysis, we switched her treatment from insulin to liraglutide. After switching to liraglutide, the patient maintained optimal glycemic control with hemoglobin A₁c levels of 6.8%-7.5% and had postprandial C-peptide levels >3.0 ng/mL during a 3-year treatment period. No adverse events associated with liraglutide were observed. GLP-1 receptor agonists are the potential medications for patients with MODY3 who maintain residual insulin secretion. PMID:25332292

  10. Autoimmune polyglandular syndrome type 2 manifested as Hashimoto's thyroiditis and adrenocortical insufficiency, in Turner syndrome woman, with onset following introduction of treatment with recombinant human growth hormone.

    PubMed

    Cyniak-Magierska, Anna; Lasoń, Agnieszka; Smyczyńska, Joanna; Lewiński, Andrzej

    2015-01-01

    Autoimmune polyglandular syndrome is a constellation of signs and symptoms of simultaneous insufficiencies of several endocrine glands. Autoimmune polyglandular syndrome type 2 (APS 2) may be diagnosed when the adrenocortical insufficiency is associated with an autoimmune thyroid disease (Hashimoto's thyroiditis or Graves' disease), and/or insulin-dependent diabetes mellitus. Turner syndrome is the most common chromosomal disorder in females, caused by complete or partial X chromosome monosomy. We present the case of a 20-year-old woman with Turner syndrome, in whom APS 2 (Hashimoto's thyroiditis and adrenocortical insufficiency) has been diagnosed after introduction of recombinant human growth hormone (rhGH) therapy. In Turner syndrome, examination of the patient must regularly be conducted in order to diagnose a possible onset of autoimmune diseases; respective treatment must be applied as soon as the diagnosis is established. In particular, therapy of rhGH, used for short stature treatment, may be a trigger factor of adrenal insufficiency. The cortisol level in blood should be assessed before rhGH administration and carefully monitored during the therapy, especially in case of autoimmune thyroid disease coexistence. PMID:26071578

  11. Optical light curve of GRB 121011A: a textbook for the onset of GRB afterglow in a mixture of ISM and wind-type medium

    NASA Astrophysics Data System (ADS)

    Xin, Li-Ping; Wei, Jian-Yan; Qiu, Yu-Lei; Deng, Jin-Song; Wang, Jing; Han, Xu-Hui

    2016-01-01

    We report the optical observations of GRB 121011A by the 0.8m TNT facility at Xinglong observatory, China. The light curve of the optical afterglow shows a smooth and featureless bump during the epoch of ∼130 s and ∼5000 s with a rising index of 1.57 ± 0.28 before the break time of 539 ± 44 s, and a decaying index of about 1.29 ± 0.07 up to the end of our observations. Moreover, the X-ray light curve decays in a single power-law with a slope of about 1.51 ± 0.03 observed by XRT onboard Swift from 100 s to about 10 000 s after the burst trigger. The featureless optical light curve could be understood as an onset process under the external-shock model. The typical frequency has been below or near the optical one before the deceleration time, and the cooling frequency is located between the optical and X-ray wavelengths. The external medium density has a transition from a mixed stage of ISM and wind-type medium before the peak time to the ISM at the later phase. The joint-analysis of X-ray and optical light curves shows that the emissions from both frequencies are consistent with the prediction of the standard afterglow model without any energy injections, indicating that the central engine has stopped its activity and does not restart anymore after the prompt phase.

  12. Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes.

    PubMed

    Winckler, Wendy; Weedon, Michael N; Graham, Robert R; McCarroll, Steven A; Purcell, Shaun; Almgren, Peter; Tuomi, Tiinamaija; Gaudet, Daniel; Boström, Kristina Bengtsson; Walker, Mark; Hitman, Graham; Hattersley, Andrew T; McCarthy, Mark I; Ardlie, Kristin G; Hirschhorn, Joel N; Daly, Mark J; Frayling, Timothy M; Groop, Leif; Altshuler, David

    2007-03-01

    An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation in the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, Ipf1, Tcf2, and NeuroD1 (MODY2 and MODY4-MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden, Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value <0.1 for association to type 2 diabetes in this initial screen were then genotyped in an additional 4,470 subjects from North America and Poland. Of 30 nominally significant SNPs from the initial sample, 8 achieved consistent results in the replication sample. We found the strongest effect at rs757210 in intron 2 of TCF2, with corrected P values <0.01 for an odds ratio (OR) of 1.13. This association was observed again in an independent sample of 5,891 unrelated case and control subjects and 500 families from the U.K., for an overall OR of 1.12 and a P value <10(-6) in >15,000 samples. We combined these results with our previous studies on HNF4alpha and TCF1 and explicitly tested for gene-gene interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions between these six genes. We conclude that although rare variants in these six genes explain most cases of MODY, common variants in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes. PMID:17327436

  13. Studies on the correlation with olfactory dysfunction in a transgenic mice model of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Rasheed, Ameer; Lee, Ji Hye; Suh, Yoo-Hun; Moon, Cheil

    2013-05-01

    Alzheimer's disease (AD) is a progressively debilitating neurodegenerative disorder characterized by the presence of proteinaceous deposits in the brain. AD often results in olfactory dysfunction and impaired olfactory perceptual acuity may be a potential biomarker for early diagnosis of AD. Until recently, there is no Alzheimer's nanoscope or any other high-end microscope developed to be capable of seeing buried feature of AD clearly. Modern neuroimaging techniques are more effective only after the occurrence of cognitive impairment. Therefore, early detection of Alzheimer's disease is critical in developing effective treatment of AD. H and E (Haematoxyline and Eosin) staining is performed for examining gross morphological changes, while TUNEL (transferase (TdT)-mediated dUTP nick end labeling) staining for monitoring neuronal death in the olfactory epithelium (OE). Furthermore, immunohistochemistry and western blot are performed to examine β-amyloid protein expression. AD model animals were Tg2576 (transgenic mice that overexpress a mutated form of the Aβ precursor protein), and 6 month (before onset of AD symptoms) and 14 month (after onset of AD symptoms) old WT (wild type) and transgenic mice were compared in their olfactory system. We found that in OE of Tg2576 mice, thickness and total number of cells were decreased, while the numbers of TUNEL-positive neurons, caspase-3 activation were significantly increased compared with age-matched WT. Our results demonstrate that the olfactory system may get deteriorated before onset of AD symptoms. Our findings imply that an olfactory biopsy could be served as an early and relatively simple diagnostic tool for potential AD patients.

  14. Protective role of adenovirus vector-mediated interleukin-10 gene therapy on endogenous islet β-cells in recent-onset type 1 diabetes in NOD mice

    PubMed Central

    LI, CHENG; ZHANG, LIJUAN; CHEN, YANYAN; LIN, XIAOJIE; LI, TANG

    2016-01-01

    The aim of the present study was to provide an animal experimental basis for the protective effect of the adenoviral vector-mediated interleukin-10 (Ad-mIL-10) gene on islet β-cells during the early stages of type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. A total of 24 female NOD mice at the onset of diabetes were allocated at random into three groups (n=8 per group): Group 1, intraperitoneally injected with 0.1 ml Ad-mIL-10; group 2, intraperitoneally injected with 0.1 ml adenovirus vector; and group 3, was a diabetic control. In addition to groups 1, 2 and 3, 8 age- and gender-matched NOD mice were intraperitoneally injected with 0.1 ml PBS and assigned to group 4 as a normal control. All mice were examined weekly for body weight, urine glucose and blood glucose values prior to onset of diabetes, and at 1, 2 and 3 weeks after that, and all mice were sacrificed 3 weeks after injection. Serum levels of interleukin (IL)-10, interferon (IFN)-γ, IL-4, insulin and C-peptide were evaluated, and in addition the degree of insulitis and the local expression of IL-10 gene in the pancreas were detected. The apoptosis rate of pancreatic β-cells was determined using a TUNEL assay. Compared with groups 2 and 3, IL-10 levels in the serum and pancreas were elevated in group 1. Serum IFN-γ levels were decreased while serum IL-4 levels and IFN-γ/IL-4 ratio were significantly increased in group 1 (P<0.01). C-peptide and insulin levels were higher in group 1 compared with groups 2 and 3, (P<0.01). Furthermore, compared with groups 2 and 3, the degree of insulitis, islet β-cell apoptosis rate and blood glucose values did not change significantly (P>0.05). The administration of the Ad-mIL-10 gene induced limited immune regulatory and protective effects on islet β-cell function in NOD mice with early T1D, while no significant reduction in insulitis, islet β-cell apoptosis rate and blood glucose was observed. PMID:27168782

  15. Evolution- and structure-based computational strategy reveals the impact of deleterious missense mutations on MODY 2 (maturity-onset diabetes of the young, type 2).

    PubMed

    George, Doss C Priya; Chakraborty, Chiranjib; Haneef, S A Syed; Nagasundaram, Nagarajan; Chen, Luonan; Zhu, Hailong

    2014-01-01

    Heterozygous mutations in the central glycolytic enzyme glucokinase (GCK) can result in an autosomal dominant inherited disease, namely maturity-onset diabetes of the young, type 2 (MODY 2). MODY 2 is characterised by early onset: it usually appears before 25 years of age and presents as a mild form of hyperglycaemia. In recent years, the number of known GCK mutations has markedly increased. As a result, interpreting which mutations cause a disease or confer susceptibility to a disease and characterising these deleterious mutations can be a difficult task in large-scale analyses and may be impossible when using a structural perspective. The laborious and time-consuming nature of the experimental analysis led us to attempt to develop a cost-effective computational pipeline for diabetic research that is based on the fundamentals of protein biophysics and that facilitates our understanding of the relationship between phenotypic effects and evolutionary processes. In this study, we investigate missense mutations in the GCK gene by using a wide array of evolution- and structure-based computational methods, such as SIFT, PolyPhen2, PhD-SNP, SNAP, SNPs&GO, fathmm, and Align GVGD. Based on the computational prediction scores obtained using these methods, three mutations, namely E70K, A188T, and W257R, were identified as highly deleterious on the basis of their effects on protein structure and function. Using the evolutionary conservation predictors Consurf and Scorecons, we further demonstrated that most of the predicted deleterious mutations, including E70K, A188T, and W257R, occur in highly conserved regions of GCK. The effects of the mutations on protein stability were computed using PoPMusic 2.1, I-mutant 3.0, and Dmutant. We also conducted molecular dynamics (MD) simulation analysis through in silico modelling to investigate the conformational differences between the native and the mutant proteins and found that the identified deleterious mutations alter the stability

  16. Nicergoline in senile dementia of Alzheimer type and multi-infarct dementia: a double-blind, placebo-controlled, clinical and EEG/ERP mapping study.

    PubMed

    Saletu, B; Paulus, E; Linzmayer, L; Anderer, P; Semlitsch, H V; Grünberger, J; Wicke, L; Neuhold, A; Podreka, I

    1995-02-01

    In a double-blind, placebo-controlled study on the therapeutic efficacy and central effects of nicergoline, an ergot alkaloid with metabolic, antithrombotic and vasoactive action, 112 patients with mild to moderate dementia, diagnosed according to DSM III-R criteria (MMS 13-25), living in pensioners' homes, were included. Fifty-six were subdiagnosed as senile dementia of the Alzheimer type (SDAT), 56 as multiinfarct dementia (MID), based on computed tomography and Hachinski scores (< or = 49 SDAT, > or = 7 MID). They received, after 2 weeks' run-in period (placebo), randomized for 8 weeks either 2 x 30 mg nicergoline (NIC) or 2 x 1 placebo (PLAC) orally. The four subgroups (SDAT/NIC. SDAT/PLAC, MID/NIC, MID/PLAC; 4 x 28 patients) were comparable in regard to age and sex. Only four, four, four and two patients of the respective groups did not finish the study for minor reasons. Confirmatory statistical analysis demonstrated in the target variable-the Clinical Global Impression (CGI)-a significant superiority of Global Impression (CGI)-a significant superiority of NIC over PLAC in both the SDAT and MID groups. Global improvement (CGI item 2) was seen in both nicergoline subgroups (3 and 3), while no changes occurred under placebo (4 and 4, respectively). The responder versus non-responder ratio was in the SDAT/NIC group 16/8, versus 8/16 in the SDAT/PLAC group (chi 2 = 4.1, P = 0.04); in the MID/NIC group 17/7, versus 7/19 in the MID/PLAC group (chi 2 = 7.96, P < 0.005). Furthermore, there was a significant improvement of the Mini-Mental State and the SCAG score in both the MID and SDAT group after 8 weeks of nicergoline, which was significantly superior to the minimal improvement or no change in placebo-treated SDAT and MID patients. EEG mapping demonstrated in NIC-treated SDAT and MID patients a significant decrease in delta and theta, increase in alpha 2 and beta activity and an acceleration of the centroid of the total power spectrum as compared with pretreatment

  17. Periodontal disease's contribution to Alzheimer's disease progression in Down syndrome.

    PubMed

    Kamer, Angela R; Fortea, Juan O; Videla, Sebastià; Mayoral, Angela; Janal, Malvin; Carmona-Iragui, Maria; Benejam, Bessy; Craig, Ronald G; Saxena, Deepak; Corby, Patricia; Glodzik, Lidia; Annam, Kumar Raghava Chowdary; Robbins, Miriam; de Leon, Mony J

    2016-01-01

    People with Down syndrome (DS) are at an increased risk for Alzheimer's disease (AD). After 60 years of age, >50% of DS subjects acquire dementia. Nevertheless, the age of onset is highly variable possibly because of both genetic and environmental factors. Genetics cannot be modified, but environmental risk factors present a potentially relevant intervention for DS persons at risk for AD. Among them, inflammation, important in AD of DS type, is potential target. Consistent with this hypothesis, chronic peripheral inflammation and infections may contribute to AD pathogenesis in DS. People with DS have an aggressive form of periodontitis characterized by rapid progression, significant bacterial and inflammatory burden, and an onset as early as 6 years of age. This review offers a hypothetical mechanistic link between periodontitis and AD in the DS population. Because periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.

  18. Periodontal disease's contribution to Alzheimer's disease progression in Down syndrome.

    PubMed

    Kamer, Angela R; Fortea, Juan O; Videla, Sebastià; Mayoral, Angela; Janal, Malvin; Carmona-Iragui, Maria; Benejam, Bessy; Craig, Ronald G; Saxena, Deepak; Corby, Patricia; Glodzik, Lidia; Annam, Kumar Raghava Chowdary; Robbins, Miriam; de Leon, Mony J

    2016-01-01

    People with Down syndrome (DS) are at an increased risk for Alzheimer's disease (AD). After 60 years of age, >50% of DS subjects acquire dementia. Nevertheless, the age of onset is highly variable possibly because of both genetic and environmental factors. Genetics cannot be modified, but environmental risk factors present a potentially relevant intervention for DS persons at risk for AD. Among them, inflammation, important in AD of DS type, is potential target. Consistent with this hypothesis, chronic peripheral inflammation and infections may contribute to AD pathogenesis in DS. People with DS have an aggressive form of periodontitis characterized by rapid progression, significant bacterial and inflammatory burden, and an onset as early as 6 years of age. This review offers a hypothetical mechanistic link between periodontitis and AD in the DS population. Because periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD. PMID:27239536

  19. Effects of Diabetic Ketoacidosis on Visual and Verbal Neurocognitive Function in Young Patients Presenting with New-Onset Type 1 Diabetes

    PubMed Central

    Jessup, Ashley B.; Grimley, Mary Beth; Meyer, Echo; Passmore, Gregory P.; Belger, Ayşenil; Hoffman, William H.; Çalıkoğlu, Ali S.

    2015-01-01

    Objective: To evaluate the effects of diabetic ketoacidosis (DKA) on neurocognitive functions in children and adolescents presenting with new-onset type 1 diabetes. Methods: Newly diagnosed patients were divided into two groups: those with DKA and those without DKA (non-DKA). Following metabolic stabilization, the patients took a mini-mental status exam prior to undergoing a baseline battery of cognitive tests that evaluated visual and verbal cognitive tasks. Follow-up testing was performed 8-12 weeks after diagnosis. Patients completed an IQ test at follow-up. Results: There was no statistical difference between the DKA and non-DKA groups neither in alertness at baseline testing nor in an IQ test at follow-up. The DKA group had significantly lower baseline scores than the non-DKA group for the visual cognitive tasks of design recognition, design memory and the composite visual memory index (VMI). At follow-up, Design Recognition remained statistically lower in the DKA group, but the design memory and the VMI tasks returned to statistical parity between the two groups. No significant differences were found in verbal cognitive tasks at baseline or follow-up between the two groups. Direct correlations were present for the admission CO2 and the visual cognitive tasks of VMI, design memory and design recognition. Direct correlations were also present for admission pH and VMI, design memory and picture memory. Conclusion: Pediatric patients presenting with newly diagnosed type 1 diabetes and severe but uncomplicated DKA showed a definite trend for lower cognitive functioning when compared to the age-matched patients without DKA. PMID:26831554

  20. Alzheimer's Disease Facts and Figures

    MedlinePlus

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

  1. [Alzheimer's disease and olfaction].

    PubMed

    Naudin, Marine; Mondon, Karl; Atanasova, Boriana

    2013-09-01

    Although olfactory disorders are not at the forefront of the clinical description of Alzheimer's disease (AD), they are common and often overlooked by clinicians and by patients who are largely unaware of their deficits. The past 30 years, the literature has shown early olfactory deficits in AD that is spreading across the olfactory spectrum with disease worsening. Partial overlap between brain areas implies both in olfaction and AD - especially limbic system - motivating these researches. This study describes olfactory parameters and tests using to investigate peripheral (odor threshold) and central (hedonicity, familiarity, intensity, discrimination, identification, olfactory memory) levels. Besides, this article takes an inventory of olfactory disorders in AD including odor threshold, discrimination, identification and olfactory memory capacities with controversial results observed in literature. At last, we discuss which type of olfactory dysfunction could have a clinical interest.

  2. Heterogeneity of neocortical cerebral blood flow deficits in dementia of the Alzheimer type: a [99mTc]-d,l-HMPAO SPECT study.

    PubMed Central

    Waldemar, G; Bruhn, P; Kristensen, M; Johnsen, A; Paulson, O B; Lassen, N A

    1994-01-01

    Regional cerebral blood flow (rCBF) was measured with high resolution brain dedicated single photon emission computer tomography (SPECT) and [99mTc]-d,l-hexamethyl-propylene-amine-oxime (HMPAO) in 25 patients with probable Alzheimer's disease and in 25 control subjects, selected according to rigorous inclusion and exclusion criteria. The aim was to analyse the topography of rCBF deficits in individual patients. In the group of patients with Alzheimer's disease as a whole, global CBF was reduced, but a factorial analysis of variance did not show disproportionate reduction of rCBF in any brain region. A parametric analysis of the rCBF data in individual patients was carried out with reference to normal values for internal rCBF ratios and to 13 different abnormal rCBF patterns. These theoretical patterns were predefined by showing significant hypoperfusion in at least one, or in any relevant combination of two, three, or four, of four major brain regions (a left and right frontal and a left and right posterior region). All patients with Alzheimer's disease and none of the control subjects had an abnormal rCBF pattern. Eleven of the 13 different patterns were seen in the patients. Frontal changes were seen in 19 (76%) of the patients, more often than previously reported. No single Alzheimer's disease pattern could be derived from our data. The number of regions with hypoperfusion, but not the presence of frontal changes, correlated significantly with the duration of disease. It is concluded that a clinical diagnosis of probable Alzheimer's disease is associated with heterogeneous patterns of rCBF deficits as measured with SPECT and [99mTc]-d,l-HMPAO. This heterogeneity may reflect different stages of the disease or cognitive subtypes and help explain published discrepancies concerning the topography of hypoperfusion in Alzheimer's disease. An analysis of individual rCBF data may add important information in the investigation of diseases with heterogeneous effects on

  3. Diagnosing young onset dementia can be challenging.

    PubMed

    Ahmed, Samrah; Baker, Ian; Butler, Christopher R

    2016-05-01

    Although the risk of developing dementia increases with age, onset can be as early as the third or fourth decade of life. Genetic influences play a more important role in younger than in older people with dementia, so young onset dementia may cluster in families. Diagnosing young onset dementia is challenging. The range of possible presenting features is broad, encompassing behavioural, cognitive, psychiatric and neurological domains, and symptoms are often subtle initially. Frequently the complaints are misattributed to stress or depression, and the patient is falsely reassured that they are too young to have dementia. The most common causes of young onset dementia are early onset forms of adult neurodegenerative conditions and alcohol. Vascular dementia is the second most common cause of young onset dementia after Alzheimer's disease. Conventional vascular risk factors may be absent and diagnosis relies on imaging evidence of cerebrovascular disease. Obtaining a detailed history remains the most important part of the workup and usually requires corroboration by a third party. Undertaking a basic neurological examination is also important. Those with suspected young onset dementia should be referred to a neurology-led cognitive disorders clinic where available as the differenti diagnosis is considerably broader tha in older adults and requires specialist investigation.

  4. Diagnosing young onset dementia can be challenging.

    PubMed

    Ahmed, Samrah; Baker, Ian; Butler, Christopher R

    2016-05-01

    Although the risk of developing dementia increases with age, onset can be as early as the third or fourth decade of life. Genetic influences play a more important role in younger than in older people with dementia, so young onset dementia may cluster in families. Diagnosing young onset dementia is challenging. The range of possible presenting features is broad, encompassing behavioural, cognitive, psychiatric and neurological domains, and symptoms are often subtle initially. Frequently the complaints are misattributed to stress or depression, and the patient is falsely reassured that they are too young to have dementia. The most common causes of young onset dementia are early onset forms of adult neurodegenerative conditions and alcohol. Vascular dementia is the second most common cause of young onset dementia after Alzheimer's disease. Conventional vascular risk factors may be absent and diagnosis relies on imaging evidence of cerebrovascular disease. Obtaining a detailed history remains the most important part of the workup and usually requires corroboration by a third party. Undertaking a basic neurological examination is also important. Those with suspected young onset dementia should be referred to a neurology-led cognitive disorders clinic where available as the differenti diagnosis is considerably broader tha in older adults and requires specialist investigation. PMID:27382914

  5. SPECT in Alzheimer`s disease and the dementias

    SciTech Connect

    Bonte, F.J.

    1991-12-31

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

  6. Usefulness of postmortem biochemistry in identification of ketosis: Diagnosis of ketoacidosis at the onset of autoimmune type 1 diabetes in an autopsy case with cold exposure and malnutrition.

    PubMed

    Tani, Naoto; Michiue, Tomomi; Chen, Jian-Hua; Oritani, Shigeki; Ishikawa, Takaki

    2016-09-01

    A severely malnourished, Japanese female in her twenties was found dead in her apartment. On autopsy, most of the findings from the internal examination were suggestive of hypothermia. Postmortem biochemistry, however, showed severely increased levels of glycated hemoglobin (HbA1c) and blood and urine glucose levels. Levels of acetone, 3-hydroxybutyric acid, and acetoacetate in various body fluids were also highly increased, indicating ketosis. The serum insulin and c-peptide levels were severely low, and subsequent testing was positive for anti-GAD antibodies. Immunohistochemical examination of the pancreatic islet cells revealed few insulin-positive cells but many glucagon-positive cells on staining. Furthermore, slight invasion of CD8-positive lymphocytes in the pancreatic islets of Langerhans was observed. Results of immunostaining of the pancreatic and bronchial epithelial tissues were partly positive for the Influenza A virus. We concluded that severe ketoacidosis associated with rapid-onset hyperglycemia due to autoimmune type 1 diabetes (AT1D) had occurred shortly before death. However, the ketosis was accompanied by hypothermia and malnutrition as well as diabetic ketoacidosis (DKA). Therefore, we retrospectively collected biochemical data on cases of hypothermia and malnutrition and compared them with the present case. Serum glucose, acetone, 3-hydroxybutyric acid, and acetoacetic acid can be used for screening and diagnosis to distinguish DKA from ketosis due to hypothermia and malnutrition. Therefore, in the present case, we diagnosed that the natural cause of death was due to AT1D. In conclusion, screening investigations for relevant biochemical markers can provide essential information for the diagnosis of metabolic disturbances, which fail to demonstrate characteristic autopsy findings. PMID:27591535

  7. Association between fetuin-A levels with insulin resistance and carotid intima-media thickness in patients with new-onset type 2 diabetes mellitus.

    PubMed

    Yin, Liang; Cai, Wei-Juan; Chang, Xiang-Yun; Li, Jun; Su, Xiang-Hui; Zhu, Ling-Yun; Wang, Xiao-Li; Sun, Kan

    2014-11-01

    Fetuin-A, which is known to inhibit insulin signaling and pathological calcification, has emerged as a diabetes risk biomarker. In the present study, the association between the fetuin-A levels with insulin resistance (IR) and carotid intima-media thickness (CIMT) was investigated in patients with new-onset type 2 diabetes mellitus (nT2DM). A total of 100 patients with nT2DM (nT2DM group) and 100 normal glucose tolerance (NGT group) controls were evaluated. The serum fetuin-A level was measured by a commercial solid-phase ELISA kit. The estimate of IR was calculated by homeostasis model assessment (HOMA-IR). CIMT was measured by B-mode ultrasound. The association between the serum fetuin-A levels and the metabolic parameters was also analyzed. The serum fetuin-A levels were increased significantly in the nT2DM group compared to the NGT group (368.5±15.6 mg/ml vs. 152.7±7.1 mg/ml, P<0.01). Fetuin-A was positively correlated with HOMA-IR, CIMT, glycated hemoglobin, triglyceride, low-density lipoprotein cholesterol, body mass index, systolic blood pressure, fasting blood glucose and 2 h post-glucose load blood glucose (P<0.05 and P<0.01), but negatively correlated with fasting plasma insulin, 2 h plasma insulin after glucose overload, high-density lipoprotein cholesterol and HOMA-β-cell insulin secretion index (P<0.05 and P<0.01). To the best of our knowledge, the study demonstrated for the first time that there is a significant association between the serum fetuin-A levels with IR and CIMT in nT2DM. These results indicate that serum fetuin-A levels can be used as independent markers in the diagnosis of macroangiopathies in nT2DM.

  8. Cardiovascular risk factors, micro and macrovascular complications at diagnosis in patients with young onset type 2 diabetes in India: CINDI 2

    PubMed Central

    Sosale, Bhavana; Sosale, Aravind R.; Mohan, Anjana R.; Kumar, Prassanna M.; Saboo, Banshi; Kandula, Sai

    2016-01-01

    Context: Type 2 diabetes mellitus (T2DM) in young adults is increasing in India. Data on the prevalence of cardiovascular (CV) risk factors and complications associated with young-onset T2DM (YOD) at the time of diagnosis of diabetes are limited. This data can aid in aggressive diabetes management, CV risk reduction, and prevention of complications. Aim: To determine the prevalence of CV risk factors, micro and macrovascular complications in patients with newly diagnosed YOD. To assess the percentage of patients who require statin therapy based on current American Diabetes Association (ADA) guidelines. Settings and Design: This was a retrospective cross-sectional study of 1500 patients with newly detected YOD across seven centers from 2013 to 2015. Designs and Methods: Patients were evaluated for complications of diabetes and CV risk factors such as body mass index (BMI), hypertension, dyslipidemia, and smoking. Statistical Analysis: Measurements have been presented as mean ± standard deviation; results on categorical measurements have been presented in percentages. Results: The mean age, glycated hemoglobin and BMI were 34.7 ± 4.2 years, 9.9 ± 2.4%, and 26.8 ± 4.7 kg/m2. Hypertension, dyslipidemia, BMI >23 kg/m2, and smoking were presented in 27.6%, 62.4%, 84.2%, and 24%. Diabetic retinopathy, neuropathy, and nephropathy were seen in 5.1%, 13.2%, and 0.9%. Ischemic heart disease, peripheral vascular disease, and stroke were presented in 0.7%, 2%, and 0.1%. As per current guidelines, 95.33% needed statin therapy. Conclusion: This study demonstrates that patients with YOD have micro and macrovascular complications at diagnosis. Nearly, every patient required a statin to reduce CV risk. This highlights the importance of screening patients with YOD for CV risk factors and complications of diabetes at the time of diagnosis. PMID:26904479

  9. Usefulness of postmortem biochemistry in identification of ketosis: Diagnosis of ketoacidosis at the onset of autoimmune type 1 diabetes in an autopsy case with cold exposure and malnutrition.

    PubMed

    Tani, Naoto; Michiue, Tomomi; Chen, Jian-Hua; Oritani, Shigeki; Ishikawa, Takaki

    2016-09-01

    A severely malnourished, Japanese female in her twenties was found dead in her apartment. On autopsy, most of the findings from the internal examination were suggestive of hypothermia. Postmortem biochemistry, however, showed severely increased levels of glycated hemoglobin (HbA1c) and blood and urine glucose levels. Levels of acetone, 3-hydroxybutyric acid, and acetoacetate in various body fluids were also highly increased, indicating ketosis. The serum insulin and c-peptide levels were severely low, and subsequent testing was positive for anti-GAD antibodies. Immunohistochemical examination of the pancreatic islet cells revealed few insulin-positive cells but many glucagon-positive cells on staining. Furthermore, slight invasion of CD8-positive lymphocytes in the pancreatic islets of Langerhans was observed. Results of immunostaining of the pancreatic and bronchial epithelial tissues were partly positive for the Influenza A virus. We concluded that severe ketoacidosis associated with rapid-onset hyperglycemia due to autoimmune type 1 diabetes (AT1D) had occurred shortly before death. However, the ketosis was accompanied by hypothermia and malnutrition as well as diabetic ketoacidosis (DKA). Therefore, we retrospectively collected biochemical data on cases of hypothermia and malnutrition and compared them with the present case. Serum glucose, acetone, 3-hydroxybutyric acid, and acetoacetic acid can be used for screening and diagnosis to distinguish DKA from ketosis due to hypothermia and malnutrition. Therefore, in the present case, we diagnosed that the natural cause of death was due to AT1D. In conclusion, screening investigations for relevant biochemical markers can provide essential information for the diagnosis of metabolic disturbances, which fail to demonstrate characteristic autopsy findings.

  10. Young onset dementia.

    PubMed

    Draper, B; Withall, A

    2016-07-01

    Young onset dementia (YOD), where symptoms of dementia have an onset before the age of 65, has become more prominent due to the population increase from the Baby Boomer generation. This clinical perspective examines key issues in the assessment, diagnosis and management of YOD. Challenges in the assessment and diagnosis of YOD are partly due to the diverse range of types of YOD, where degenerative dementias are less common and secondary dementias more common than in late onset dementia. Early symptoms are broad and include depression, behavioural change, neurological disorders, systemic disorders and mild cognitive impairment (MCI). Perceived diagnostic delay may result in frustration and distress in people with YOD and their families. Chronic depression and MCI are associated with longer time to diagnosis, and in these situations, clinicians need to establish appropriate review processes and communicate clearly. A diagnosis of YOD may have marked consequences for a younger person, including early retirement, financial impacts and the psychological challenge of coming to grips with cognitive decline. Partners, children and other supporters often have unmet needs, feel burdened by care and are at high risk of physical and emotional consequences. Concerns about the heritability of dementia may add to family distress. Recent community service developments in Australia for YOD are outlined and the challenges of residential care described. PMID:27405890

  11. Exploring Biomarkers for Alzheimer's Disease.

    PubMed

    Sharma, Neeti; Singh, Anshika Nikita

    2016-07-01

    Alzheimer's Disease (AD) is one of the most common form of dementia occurring in elderly population worldwide. Currently Aβ42, tau and p-tau in the cerebrospinal fluid is estimated for confirmation of AD. CSF which is being used as the potent source for biomarker screening is obtained by invasive lumbar punctures. Thus, there is an urgent need of minimal invasive methods for identification of diagnostic markers for early detection of AD. Blood serum and plasma serves as an appropriate source, due to minimal discomfort to the patients, promoting frequent testing, better follow-up and better consent to clinical trials. Hence, the need of the hour demands discovery of diagnostic and prognostic patient specific signature biomarkers by using emerging technologies of mass spectrometry, microarrays and peptidomics. In this review we summarize the present scenario of AD biomarkers such as circulatory biomarkers, blood based amyloid markers, inflammatory markers and oxidative stress markers being investigated and also some of the potent biomarkers which might be able to predict early onset of Alzheimer's and delay cognitive impairment. PMID:27630867

  12. Biomarker Modeling of Alzheimer's Disease

    PubMed Central

    Jack, Clifford R; Holtzman, David M

    2014-01-01

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

  13. 2016 Alzheimer's disease facts and figures.

    PubMed

    2016-04-01

    beneficiaries without these conditions, and Medicaid payments are 19 times as great. Total payments in 2016 for health care, long-term care and hospice services for people age ≥ 65 years with dementia are estimated to be $236 billion. The costs of Alzheimer's care may place a substantial financial burden on families, who often have to take money out of their retirement savings, cut back on buying food, and reduce their own trips to the doctor. In addition, many family members incorrectly believe that Medicare pays for nursing home care and other types of long-term care. Such findings highlight the need for solutions to prevent dementia-related costs from jeopardizing the health and financial security of the families of people with Alzheimer's and other dementias. PMID:27570871

  14. 2016 Alzheimer's disease facts and figures.

    PubMed

    2016-04-01

    beneficiaries without these conditions, and Medicaid payments are 19 times as great. Total payments in 2016 for health care, long-term care and hospice services for people age ≥ 65 years with dementia are estimated to be $236 billion. The costs of Alzheimer's care may place a substantial financial burden on families, who often have to take money out of their retirement savings, cut back on buying food, and reduce their own trips to the doctor. In addition, many family members incorrectly believe that Medicare pays for nursing home care and other types of long-term care. Such findings highlight the need for solutions to prevent dementia-related costs from jeopardizing the health and financial security of the families of people with Alzheimer's and other dementias.

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

    PubMed

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

    2013-01-01

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

  16. Immunotherapeutic Approaches to Alzheimer's Disease

    NASA Astrophysics Data System (ADS)

    Monsonego, Alon; Weiner, Howard L.

    2003-10-01

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

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

    SciTech Connect

    Higuchi, Susumu; Matsushita, Sachio; Hasegawa, Yoshio; Muramatsu, Taro

    1996-07-26

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

  18. Effects of Father Absence on Sex-Typed Behaviors in Male Children: Reason for the Absence and Age of Onset of the Absence

    ERIC Educational Resources Information Center

    Santrock, John W.

    1977-01-01

    The relation of (1) reason for father's absence (whether by death or by divorce) and (2) age of onset of father absence to teacher ratings and doll play interview scores of masculinity-feminity, aggression and dependency-independence were examined. (MS)

  19. [Genetic aspects of Alzheimer's disease (Review)].

    PubMed

    El Kadmiri, N; Hamzi, K; El Moutawakil, B; Slassi, I; Nadifi, S

    2013-12-01

    Alzheimer's disease is a degenerative brain disorder, which concerns memory, cognition and behavior pattern. Its etiology is unknown, it is characterized by typical histological lesions: senile plaques and neuro-fibrillary tangles. Alzheimer's disease is a multifactorial pathology, characterized by interactions between genetic and environmental factors. Genetic factors concern first of all the exceptional monogenic forms, characterized by early onset (<60 years), autosomal dominant forms. Mutations of the genes coding for amyloid-ß precursor protein or preselinins 1 and 2 are involved. The much more frequent sporadic forms also have genetic factors, the best studied being the apolipoprotein E4 coding allele and some more recent genotypes which will be mentioned. No causal, only symptomatic treatments are available.

  20. Association between Periodontitis and Alzheimer's Disease

    PubMed Central

    Abbayya, Keshava; Puthanakar, Nagraj Y; Naduwinmani, Sanjay; Chidambar, Y S

    2015-01-01

    Alzheimer's disease (AD) is a neurodegenerative disease which significantly increases with age. Its onset can be either early or late. AD is characterized by the salient inflammatory features, microglial activation, and increased levels of proinflammatory cytokines which contribute to the inflammatory status of the central nervous system (CNS). Whereas, periodontitis is a common oral infection associated with the gram negative anaerobic bacteria. Periodontitis can be marked as a “low-grade systemic disease” by release of proinflammatory cytokines into systemic circulation and elevation of C-reactive protein (CRP). Inflammation is known to play a pivotal role in both the disease process serving as a connecting link between periodontitis and AD. The present review throws a light on possible enigmatic link between AD and periodontitis. This review is designed by collecting data from PubMed database using key words like “Alzheimer's disease”, “inflammation”, “periodontitis”, and “proinflammatory cytokines”. PMID:26199919

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

    ERIC Educational Resources Information Center

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

    2011-01-01

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

  2. Alzheimer's Disease: Mechanism and Approach to Cell Therapy.

    PubMed

    Amemori, Takashi; Jendelova, Pavla; Ruzicka, Jiri; Urdzikova, Lucia Machova; Sykova, Eva

    2015-11-04

    Alzheimer's disease (AD) is the most common form of dementia. The risk of AD increases with age. Although two of the main pathological features of AD, amyloid plaques and neurofibrillary tangles, were already recognized by Alois Alzheimer at the beginning of the 20th century, the pathogenesis of the disease remains unsettled. Therapeutic approaches targeting plaques or tangles have not yet resulted in satisfactory improvements in AD treatment. This may, in part, be due to early-onset and late-onset AD pathogenesis being underpinned by different mechanisms. Most animal models of AD are generated from gene mutations involved in early onset familial AD, accounting for only 1% of all cases, which may consequently complicate our understanding of AD mechanisms. In this article, the authors discuss the pathogenesis of AD according to the two main neuropathologies, including senescence-related mechanisms and possible treatments using stem cells, namely mesenchymal and neural stem cells.

  3. Can Infections Cause Alzheimer's Disease?

    PubMed Central

    Mawanda, Francis; Wallace, Robert

    2013-01-01

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

  4. The effects of two polymorphisms on p21cip1 function and their association with Alzheimer's disease in a population of European descent.

    PubMed

    Yates, Sharon C; Zafar, Amen; Rabai, Erzsebet M; Foxall, James B; Nagy, Sheila; Morrison, Karen E; Clarke, Carl; Esiri, Margaret M; Christie, Sharon; Smith, A David; Nagy, Zsuzsanna

    2015-01-01

    With the exception of ApoE4, genome-wide association studies have failed to identify strong genetic risk factors for late-onset Alzheimer's disease, despite strong evidence of heritability, suggesting that many low penetrance genes may be involved. Additionally, the nature of the identified genetic risk factors and their relation to disease pathology is also largely obscure. Previous studies have found that a cancer-associated variant of the cell cycle inhibitor gene p21cip1 is associated with increased risk of Alzheimer's disease. The aim of this study was to confirm this association and to elucidate the effects of the variant on protein function and Alzheimer-type pathology. We examined the association of the p21cip1 variant with Alzheimer's disease and Parkinson's disease with dementia. The genotyping studies were performed on 719 participants of the Oxford Project to Investigate Memory and Ageing, 225 participants of a Parkinson's disease DNA bank, and 477 participants of the Human Random Control collection available from the European Collection of Cell Cultures. The post mortem studies were carried out on 190 participants. In the in-vitro study, human embryonic kidney cells were transfected with either the common or rare p21cip1 variant; and cytometry was used to assess cell cycle kinetics, p21cip1 protein expression and sub-cellular localisation. The variant was associated with an increased risk of Alzheimer's disease, and Parkinson's disease with dementia, relative to age matched controls. Furthermore, the variant was associated with an earlier age of onset of Alzheimer's disease, and a more severe phenotype, with a primary influence on the accumulation of tangle pathology. In the in-vitro study, we found that the SNPs reduced the cell cycle inhibitory and anti-apoptotic activity of p21cip1. The results suggest that the cancer-associated variant of p21cip1 may contribute to the loss of cell cycle control in neurons that may lead to Alzheimer-type

  5. The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy

    PubMed Central

    Siman, Robert; Cocca, Ryan; Dong, Yina

    2015-01-01

    The perforant pathway projection from layer II of the entorhinal cortex to the hippocampal dentate gyrus is especially important for long-term memory formation, and is preferentially vulnerable to developing a degenerative tauopathy early in Alzheimer’s disease (AD) that may spread over time trans-synaptically. Despite the importance of the perforant pathway to the clinical