Imaging Pathophysiology in Aging and Neurodegeneration

 描述(由申请人提供)：假设在过去的五年里，我们的团队一直在测试这种疾病(甚至在亚临床水平上)调节阿尔茨海默病(AD)认知综合征的发病。我们发现AD病理和血管疾病之间存在着重要但复杂的关系。我们已经报道，β沉积与脑结构有关，脑结构是胆固醇运输的标志 和炎症。综合考虑，在两年的随访中，海马区萎缩、白质损害和Aβ沉积的程度提供了强有力的痴呆预测。然而，尽管在85岁以上认知正常的受试者中，有一半被发现有Aβ沉积，但这些“Aβ阳性”受试者中有三分之二在两年内没有表现出临床进展。相反，在认知正常的受试者中，在两年后发展为AD综合征的受试者中，有三分之一的人是“Aβ阴性”。这些新的发现表明，血管疾病可能起到以下作用：1)作为调节因素改变AD病理的大脑补偿；2)作为AD病理的贡献者；或3)两者兼而有之。这些问题的含义是截然不同的，并影响我们对老年痴呆的病理生理学的理解，进而影响其预防性治疗。本PPG的目的是进一步了解老年两种最常见的病理--血管疾病和阿尔茨海默病--的症状前(或亚临床)动态过程与认知的关系。为了纵向检验这一动态过程，我们收集了两个队列：1)我们研究了15年的高龄个体(~90岁)的GEMS队列，他们的认知综合征的发生率非常高；2)心脏策略集中在风险评估(心脏评分)的队列较年轻(65-75岁)，认知综合征的预期发病率要低得多。将我们对宝石队列的观察扩展到临床变化频繁的后期阶段，并将其与尸检研究相结合的价值是显而易见的。心脏评分队列的重要性在于，它允许我们看到亚临床水平的重大变化(即，认知能力下降，但没有达到MCI/痴呆症状态)。如果我们在心脏评分队列中观察到血管疾病、AD病理和认知功能下降之间的关联，这将有力地支持GEMS队列产生的假说。这一设计使我们能够在5年内收集关于血管疾病、AD病理和认知之间关联的深入信息，否则需要10多年才能积累。GEMS队列(Project-1)和心脏评分队列(Project-2)中的这些研究通过将它们与Project-3中执行的详细神经病理评估和新应用的tau正电子发射断层扫描(PET)技术的药代动力学研究(Project-4)相结合而得到丰富，该技术旨在同时在tau-PET表征中添加缺失的成分，并提高在此PPG中获取的tau-PET数据的准确性和价值--以及整个领域。

 DESCRIPTION (provided by applicant): Hypothesis that systemic and cerebral vascular for the past five years, our group has been testing the disease (even at a subclinical level) modulates the onset of the cognitive syndrome of Alzheimer's disease (AD). We have found that there is an important, but complex, relationship between AD pathology and vascular disease. We have reported that Aβ deposition is linked to brain structure, markers of cholesterol transport and inflammation. Taken in combination, hippocampal atrophy, white matter lesions, and the extent of Aβ deposition provided powerful prediction of dementia after two years of follow-up. However, although half of cognitively normal subjects age 85+ were found to have Aβ deposition, two-thirds of these "Aβ-positive" subjects showed no clinical progression over two years. Conversely, one-third of the cognitively normal subjects who progressed to an AD syndrome over two years were "Aβ-negative". These new findings indicate that vascular disease may act as: 1) as a moderating factor that alters brain compensation for AD pathology; 2) as a contributor to AD pathology; or 3) both. The implications of these are critically different and impact our understanding of the pathophysiology of dementia in old age, and by extension, its preventive treatments. The goal of this PPG is to gain further insight into the pre- symptomatic (or subclinical) dynamic processes of the two most common pathologies in old age, vascular disease and AD, in relationship to cognition. In order to longitudinally examine this dynamic process, we have assembled two cohorts: 1) the GEMS cohort of very elderly individuals (~90 yrs) who have been studied by us for 15 years and where the incidence of cognitive syndromes is very high and 2) the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) cohort that is younger (65-75 yrs) and where the expected incidence of cognitive syndromes is much lower. The value of extending our observation of the GEMS cohort through this late stage of frequent clinical change and coupling this to a postmortem study is clear. The importance of the Heart SCORE cohort is that it allows us to see significant changes at the subclinical level (i.e., cognitive decline without reaching the MCI/dementia state). If we observe an association between vascular disease, AD pathology, and cognitive decline in the Heart SCORE cohort, this will strongly support the hypotheses generated from the GEMS cohort. This design allows us to gather in-depth information on the association between vascular disease, AD pathology and cognition within a 5-year period that would otherwise take more than a decade to accumulate. These studies in the GEMS cohort (Project-1) and the Heart SCORE cohort (Project-2) are enriched by coupling them to the detailed neuropathological evaluations performed in Project-3 and the pharmacokinetic study of the newly applied tau positron emission tomography (PET) technology (Project-4) that aims to simultaneously add missing components to the characterization of tau-PET and improve the accuracy and value of the tau-PET data acquired in this PPG - and by the field in general.