Role of impaired cognitive states & risk factors in conversion to mixed dementias

描述(申请人提供)：人口统计表明，随着与年龄相关的痴呆症的预期急剧增加，一场公共卫生危机正在迫在眉睫。目前的重点是疾病预防，重点是表现出一些认知障碍的老年人。我们建议权威性地确定老年人认知能力下降的风险和保护因素。我们已经展示了如何追溯定义这些受损状态，如何解释反向转变，如何区分流行率和发病率，以及如何使用唯一的统计(马尔可夫)模型来解释竞争风险。但目前还没有足够的纵向和神经病理学数据来区分不同类型的痴呆症。没有一个单独的阿尔茨海默病中心(ADC)或合作研究有足够的样本量来可靠地跟踪到痴呆症的转变，并将阿尔茨海默病(AD)与其他常见的脑部疾病区分开来，这些疾病包括血管性痴呆(VAD)和路易体病(LBD)。该项目将汇集来自六个成熟的纵向队列的数据，以确定(1)符合不同类型痴呆症和MCI的神经病理学标准的人保持完整认知的风险因素，以及(2)特定形式的痴呆症(临床和神经病理学)。这将提高我们对干预受损状态和促进抵抗临床症状的因素的理解，尽管存在神经病理。这些考虑导致了下面的具体目标。具体目标1：合并六个大型项目的数据库，跟踪认知完好的痴呆症受试者的队列，以便进行严格的、统计的、生物知情的分析，强调纵向随访：大脑(肯塔基大学)、修女研究(明尼苏达大学)、记忆和衰老项目(华盛顿大学)、Kuakini檀香山-亚洲老龄化研究、宗教秩序研究(ROS，拉什医科大学)和OHSC ADC(俄勒冈健康与科学大学)。该数据库将向公众开放。具体目标2：根据从这些中心收集的数据对认知和功能技能的定期评估，确定完整认知和痴呆症之间的适当干预状态。具体目标3：使用新的统计学方法研究转变及其相关的风险因素(例如，遗传、医疗、受损状态的时间)。具体目标4：使数据库中的神经病理结果标准化(包括定量的神经病理评估)，以便能够分析新的致病因素对结果的影响。这一目的使我们能够评估实际的脑病理(例如，微梗塞、路易体、海马体硬化症和混合病理)与来进行尸检的参与者子集的生前状态之间的关系。这一目的可以支持对痴呆和临床前痴呆条件下当前神经病理学和临床研究诊断标准的拟议修订。

DESCRIPTION (provided by applicant): Population demographics suggest that with the expected dramatic increase in age-associated dementias a public health crisis is looming. Current emphasis is on disease prevention with a focus on elderly individuals who express some cognitive impairment. We propose to identify authoritatively the risk and protective factors for cognitive decline in older persons. We have shown how to define these impaired states retrospectively, how to account for reverse transitions, how to distinguish prevalence from incidence, and how to account for competing risks by using a unique statistical (Markov) model. But sufficient longitudinal and neuropathological data is currently not available to distinguish among different types of dementia. No single Alzheimer's Disease Center (ADC) or cooperative study has an adequate sample size to reliably track transitions to dementia and differentiate Alzheimer's disease (AD) from other prevalent brain diseases that include vascular dementia (VaD) and Lewy body disease (LBD). This project will pool data from six well established longitudinal cohorts to identify risk factors for (1) preservation of intact cognition in those meeting neuropathological criteria for varying types of dementia and MCI and (2) specific forms of dementia (clinical and neuropathological). This will improve our understanding of intervening impaired states and factors that promote resistance to clinical symptoms despite the presence of neuropathology. These considerations lead to the specific aims below. Specific Aim 1: To merge databases from six large projects that follow cohorts of cognitively intact subjects to dementia, for the purpose of rigorous, statistical, biologically-informed analyses that accentuate longitudinal follow-up: BRAiNS (University of Kentucky), Nun Study (University of Minnesota), Memory and Aging Project (Washington U), Kuakini Honolulu-Asia Aging Study, Religious Orders Study (ROS, Rush Medical University), and the OHSC ADC (Oregon Health & Science University). The database would be made publicly accessible. Specific Aim 2: To identify appropriate intervening states between intact cognition and dementia based on periodic assessments of cognition and functional skills from data collected at these centers. Specific Aim 3: To study transitions and associated risk factors (e.g., genetic, medical, time in an impaired state) using novel statistical methods. Specific Aim 4: To standardize the neuropathological findings across databases (including quantitative neuropathological assessments) to enable the analysis of novel pathogenetic determinants of outcomes. This aim allows us to evaluate how actual brain pathology (e.g., microinfarcts, Lewy bodies, hippocampal sclerosis, and mixed pathologies) relates to antemortem states in the subset of participants coming to autopsy. This aim could support proposed revisions of current neuropathological and clinical research diagnostic criteria in dementia and preclinical dementia conditions.