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)的病理(斑块和缠结)；然而AD的病理非常常见地与其他病理混合在一起，这些病理进一步降低了老年人的认知能力，增加了老年人患痴呆症的几率。TDP-43病理学是一种不常见的老年痴呆综合征的标志物，称为额颞叶变性(FTLD-TDP)，最近在很大一部分老年人的大脑中被发现，尤其是那些患有AD病理的人。TDP-43病理在衰老和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病理是否代表AD的第三种病理或一种单独的并存疾病。我们的主要假设是，与年龄相关的TDP-43病理代表了与痴呆综合征相关的单独的病理过程，具有与AD分开的独特的认知表型和特定的遗传危险因素。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，利用现有的来自2个流行病学临床-病理的临床、病理和遗传数据 队列研究，并收集1400个大脑的新的TDP-43病理数据。首先，使用一系列分析模型，我们建议检验TDP-43病理是一种单独的衰老病理，还是介导AD病理的作用。其次，我们建议调查TDP-43在衰老中的病理是否与特定的认知特征相关，并分别增加认知功能减退的速度。我们还建议研究TDP-43病理在没有痴呆的老年人中的作用，并单独检测没有AD病理的老年人的TDP-43。如果TDP-43病理表现为同时存在FTLD-TDP，则临床特征可能表现为早期和显著的执行和语言障碍，而不是这些组中的每一组的AD表型。第三，由于年龄最大的老年人是人口中增长最快的部分，而且AD病理在这个年龄组中的相关性不大，我们建议调查TDP-43病理在这一重要的老年人亚群中的作用。最后，在后两个目标中，我们建议研究遗传多态(SNPs)与TDP-43的病理和认知之间的关系。我们认为与FTLD相关的SNPs与TDP-43的衰老病理相关，而与临床AD相关的SNPs与衰老的AD病理相关。为了支持这些目标，我们提供了令人信服的初步数据。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 老年性认知功能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.