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

描述（由申请人提供）：人口统计数据表明，随着年龄相关性痴呆的预期急剧增加，公共卫生危机迫在眉睫。目前的重点是疾病预防，重点是老年人谁表达一些认知障碍。我们建议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回顾性地定义这些受损状态，如何解释反向转换，如何区分患病率和发病率，以及如何通过使用独特的统计（马尔可夫）模型来解释竞争风险。但是，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向痴呆的转变，并将阿尔茨海默病（AD）与其他流行的脑部疾病（包括血管性痴呆（VaD）和路易体病（LBD））区分开来。该项目将汇集来自六个完善的纵向队列的数据，以确定（1）在满足不同类型痴呆和MCI的神经病理学标准的人群中保留完整认知的风险因素，以及（2）特定形式的痴呆（临床和神经病理学）。这将提高我们对干预受损状态和促进对临床症状抵抗的因素的理解，尽管存在神经病理学。这些考虑促成了以下具体目标。具体目标1：合并来自六个大型项目的数据库，这些项目跟踪认知完整受试者到痴呆症的队列，目的是进行严格的，统计的，生物学信息分析，强调纵向随访：大脑（肯塔基州大学），修女研究（明尼苏达大学），记忆和衰老项目（华盛顿U）、Kuakini Honolulu-Asia Aging Study、Religious Orders Study（ROS，Rush Medical University）和OHSC ADC（俄勒冈州健康与科学大学）。该数据库将向公众开放。具体目标二：根据这些中心收集的数据，定期评估认知和功能技能，确定完整认知和痴呆之间的适当干预状态。具体目标3：研究转型和相关风险因素（例如，遗传、医学、受损状态的时间）。具体目标4：标准化数据库中的神经病理学结果（包括定量神经病理学评估），以分析结局的新致病决定因素。这一目标使我们能够评估实际的大脑病理学（例如，微梗死、路易体、海马硬化和混合病理）与前来尸检的参与者亚组的死前状态有关。这一目标可以支持目前的神经病理学和临床研究诊断标准在痴呆症和临床前痴呆症条件的拟议修订。

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.