Imaging Pathophysiology in Aging and Neurodegeneration

 描述（由申请人提供）：假设在过去的五年中，我们的小组一直在测试这种疾病（即使在亚临床水平）调节阿尔茨海默病（AD）认知综合征的发作。我们已经发现，有一个重要的，但复杂的，AD病理和血管疾病之间的关系。我们已经报道了Aβ沉积与脑结构，胆固醇运输的标志物， 和炎症。两年后随访，海马萎缩、白色病变和Aβ沉积程度联合起来，对痴呆提供了强有力的预测。然而，尽管有一半的85岁以上认知正常的受试者被发现有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，三分之一的认知正常的受试者在两年内进展为AD综合征，是“Aβ阴性”。这些新的发现表明，血管疾病可能作为：1）作为一个调节因素，改变大脑补偿AD病理; 2）作为一个贡献者AD病理;或3）两者兼而有之。这些影响是截然不同的，影响我们对老年痴呆症的病理生理学的理解，并延伸到预防性治疗。本PPG的目的是进一步了解老年人中两种最常见的病理（血管疾病和AD）的症状前（或亚临床）动态过程与认知的关系。为了纵向研究这一动态过程，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，其中认知综合征的发生率非常高，2）集中于风险评估的心脏策略（心脏评分）队列，更年轻（65-75岁），认知综合征的预期发生率要低得多。通过这个频繁的临床变化的晚期阶段扩展我们对GEMS队列的观察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，它使我们能够看到亚临床水平的显著变化（即，认知能力下降，但未达到MCI/痴呆状态）。如果我们在心脏评分队列中观察到血管疾病、AD病理学和认知下降之间的关联，这将强烈支持GEMS队列产生的假设。这种设计使我们能够在5年内收集关于血管疾病，AD病理学和认知之间关联的深入信息，否则需要十多年才能积累。这些GEMS队列研究（项目-1）和心脏评分队列通过将其与项目3中进行的详细神经病理学评价和新应用的tau正电子发射断层扫描（PET）技术的药代动力学研究相结合，（项目-4），旨在同时增加缺失的成分，以表征tau-PET，并提高准确性和价值的tau-在此PPG中采集的PET数据-一般由现场采集。

 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.