Epidemiologic Study of TDP-43 Pathology in Aging and Dementia

描述（由申请人提供）：痴呆症最常见的原因是阿尔茨海默病（AD）病理（斑块和缠结）；然而，阿尔茨海默病通常与其他病理混合，这进一步降低了老年人的认知能力，增加了痴呆症的几率。TDP-43病理是一种罕见的老年痴呆综合征，称为额颞叶变性（FTLD-TDP）的标志物，最近在很大比例的老年人大脑中被发现，特别是那些患有AD病理的人。TDP-43在衰老和AD病理中的作用尚不清楚，但越来越多的证据表明它是有害的。目前尚不清楚TDP-43病理是否代表AD的第三种病理或单独共存的疾病。我们的总体假设是，与年龄相关的TDP-43病理代表了与痴呆综合征相关的单独病理过程，该综合征具有独特的认知表型和与AD分离的特定遗传风险因素。我们建议通过对TDP-43在衰老和AD中的病理进行流行病学研究，利用来自2个流行病学临床病理研究所的现有临床、病理和遗传数据来解决这些假设

DESCRIPTION (provided by applicant): Dementia is most commonly caused by Alzheimer's disease (AD) pathology (plaques and tangles); however AD pathology is very commonly mixed with other pathologies which further lower cognition and increase the odds of dementia in older persons.TDP-43 pathology, a marker of an uncommon presenile dementia syndrome called Frontotemporal Lobar Degeneration (FTLD-TDP), has recently been identified in a large proportion of older brains especially those with AD pathology. The role of TDP-43 pathology in aging and AD is unknown but there is increasing evidence that it is detrimental. It is not known whether TDP-43 pathology represents a third pathology of AD or a separate coexisting disease. Our overarching hypothesis is that age-related TDP-43 pathology represents a separate pathologic process associated with a dementia syndrome with a distinct cognitive phenotype and specific genetic risk factors that are separate from AD. We propose to address these hypotheses by performing a epidemiologic study of TDP-43 pathology in aging and AD, by leveraging existing clinical, pathologic, and genetic data from 2 epidemiologic clinical-pathologic cohort studies, and collecting new TDP-43 pathology data on 1400 brains. First, using a series of analytic models, we propose to test whether TDP-43 pathology is a separate aging pathology or mediates the effects of AD pathology. Second, we propose to investigate whether TDP-43 pathology in aging is associated with a specific cognitive profile and separately increases the rate of cognitive decline. We also propose to examine the role of TDP-43 pathology in older persons without dementia, and separately examine TDP-43 in older persons without AD pathology. If TDP-43 pathology represents coexisting FTLD-TDP, the clinical profile may show early and prominent executive and language impairment rather than an AD phenotype in each of these groups. Third because the oldest-old are the fastest growing segment of the population and because AD pathology is not as relevant in this age-group, we propose to investigate the role of TDP-43 pathology in this important subgroup of older persons. Finally in the last two aims we propose to investigate the association of genetic polymorphisms (SNPs) with TDP-43 pathology and cognition. We propose that SNPs associated with FTLD are related to TDP-43 pathology in aging; whereas SNPs associated with clinical AD are related to AD pathology in aging. We present compelling preliminary data in the support of these aims. Results from these proposed studies will fill an important gap in scientific knowledge and are likely to impact future studies of prevention and treatment of cognitive impairment and dementia in aging.