Epidemiologic Study of TDP-43 Pathology in Aging and Dementia

描述（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，AD病理学通常与其他病理学混合，这些病理学进一步降低老年人的认知能力并增加老年人痴呆的几率。TDP-43病理学，一种称为额颞叶变性的罕见早老性痴呆综合征的标志物（FTLD-TDP），最近在大部分老年人的大脑中被发现，特别是那些患有AD病理学的人。TDP-43病理学在衰老和AD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病理学是否代表AD的第三种病理学或单独的共存疾病。我们的总体假设是，年龄相关的TDP-43病理学代表了与痴呆综合征相关的一个单独的病理过程，该痴呆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中的病理学进行流行病学研究来解决这些假设，通过利用来自2个流行病学临床病理学研究的现有临床、病理学和遗传学数据， 队列研究，并收集1400个大脑的新TDP-43病理学数据。首先，使用一系列分析模型，我们提出测试TDP-43病理学是否是一个单独的衰老病理学或介导AD病理学的影响。其次，我们建议调查TDP-43在衰老中的病理学是否与特定的认知特征相关，并分别增加认知能力下降的速度。我们还建议检查TDP-43病理学在无痴呆症的老年人中的作用，并单独检查TDP-43在无AD病理学的老年人中的作用。如果TDP-43病理学代表共存的FTLD-TDP，则在这些组中的每一个中，临床特征可能显示早期和突出的执行和语言障碍，而不是AD表型。第三，因为最年长的老年人是人口中增长最快的部分，并且因为AD病理学在这个年龄组中不相关，所以我们建议调查TDP-43病理学在这个重要的老年人亚组中的作用。最后，在最后两个目标中，我们建议调查遗传多态性（SNP）与TDP-43病理和认知的关联。我们认为，与FTLD相关的SNP与衰老中的TDP-43病理学相关;而与临床AD相关的SNP与衰老中的AD病理学相关。我们提出了令人信服的初步数据，以支持这些目标。这些拟议研究的结果将填补科学知识的一个重要空白，并可能影响未来 老年性认知障碍和痴呆的防治研究。

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.