Neurobiology of aging
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Neurobiology of aging · Mar 2014
Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia.
Homozygous mutations in exon 2 of TREM2, a gene involved in Nasu-Hakola disease, can cause frontotemporal dementia (FTD). Moreover, a rare TREM2 exon 2 variant (p. R47H) was reported to increase the risk of Alzheimer's disease (AD) with an odds ratio as strong as that for APOEε4. ⋯ Meta-analysis including 11 previously screened AD cohorts confirmed the association of p. R47H with AD (p = 2.93×10(-17)). Our data corroborate and extend previous findings to include an increased frequency of rare heterozygous TREM2 variations in AD and FTD, and show that TREM2 variants may play a role in neurodegenerative diseases in general.
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Neurobiology of aging · Mar 2014
Glial fibrillary acidic protein isoform expression in plaque related astrogliosis in Alzheimer's disease.
In Alzheimer's disease (AD), amyloid plaques are surrounded by reactive astrocytes with an increased expression of intermediate filaments including glial fibrillary acidic protein (GFAP). Different GFAP isoforms have been identified that are differentially expressed by specific subpopulations of astrocytes and that impose different properties to the intermediate filament network. We studied transcript levels and protein expression patterns of all known GFAP isoforms in human hippocampal AD tissue at different stages of the disease. ⋯ In conclusion, the various GFAP isoforms show differential transcript levels and are upregulated in a concerted manner in AD. The GFAP(+1) isoform defines a unique subset of astrocytes, with numbers increasing with AD progression. These data indicate the need for future exploration of underlying mechanisms concerning the functions of GFAPδ and GFAP(+1) isoforms in astrocytes and their possible role in AD pathology.
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Neurobiology of aging · Mar 2014
Choosing Alzheimer's disease prevention clinical trial populations.
To assist investigators in making design choices, we modeled Alzheimer's disease prevention clinical trials. We used longitudinal Clinical Dementia Rating Scale Sum of Boxes data, retention rates, and the proportions of trial-eligible cognitively normal participants age 65 and older in the National Alzheimer's Coordinating Center Uniform Data Set to model trial sample sizes, the numbers needed to enroll to account for drop out, and the numbers needed to screen to successfully complete enrollment. ⋯ Enriching for subjective memory complaints reduced sample sizes and numbers needed to enroll more than age enrichment, but increased the number needed to screen. We conclude that Alzheimer's disease prevention trials can enroll elderly participants with minimal effect on trial retention and that enriching for older individuals with memory complaints might afford efficient trial designs.
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Neurobiology of aging · Mar 2014
Cholinergic basal forebrain atrophy predicts amyloid burden in Alzheimer's disease.
We compared accuracy of hippocampus and basal forebrain cholinergic system (BFCS) atrophy to predict cortical amyloid burden in 179 cognitively normal subjects (CN), 269 subjects with early stages of mild cognitive impairment (MCI), 136 subjects with late stages of MCI, and 86 subjects with Alzheimer's disease (AD) dementia retrieved from the Alzheimer's Disease Neuroimaging Initiative database. Hippocampus and BFCS volumes were determined from structural magnetic resonance imaging scans at 3 Tesla, and cortical amyloid load from AV45 (florbetapir) positron emission tomography scans. ⋯ In logistic regression analysis, hippocampus and posterior BFCS volumes contributed significantly to discriminate MCI and AD from CN, but only BFCS volume predicted amyloid status. Our findings suggest that BFCS atrophy is more closely associated with cortical amyloid burden than hippocampus atrophy in predementia AD.
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Neurobiology of aging · Mar 2014
Effects of the neurotrophic agent T-817MA on oligomeric amyloid-β-induced deficits in long-term potentiation in the hippocampal CA1 subfield.
Formation of oligomeric amyloid-β (oAβ) is 1 of the most likely causes of Alzheimer's disease (AD). We hypothesized that in the early phase of AD, cognitive impairments observed before marked neuronal loss and brain atrophy might be associated with oAβ-induced synaptic dysfunction. T-817MA [1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate] has both neuroprotective and neurotrophic effects and is used to treat AD. ⋯ In addition, oAβ42 treatment significantly facilitated long-term depression (LTD). Treatment with T-817MA ameliorated the LTP reduction; however, T-817MA treatment did not inhibit the facilitation of LTD induction by oAβ42. These results suggest that T-817MA reverses oAβ-induced LTP reduction as it may occur in the early phase of AD.