Markers of transition to Alzheimer disease in veterans with MCI

描述（由申请人提供）： 许多研究表明，记忆缺陷和淀粉样蛋白和tau蛋白的脑脊液标志物是痴呆症的预测因素。这些标记物甚至被提议作为阿尔茨海默病的新诊断标准和临床试验中的结果测量。然而，这些研究在很大程度上是在健康、受过良好教育的白人老年人的同质样本中进行的。没有关于这些标志物在更典型的老龄化人群中的价值的信息，这些人群代表了广泛的人口统计学谱，通常患有多种合并症。鉴于退伍军人人口老龄化，以及他们对医疗保健的需求日益增加，开发准确的疾病诊断和预测模型至关重要，以便有针对性地治疗和疾病管理。该申请提出对老年退伍军人进行纵向研究，以确定特定的神经心理学和CSF标志物是否可以预测向阿尔茨海默氏痴呆症的转变以及认知、功能和整体衰退的速度。150名患有新发认知主诉的退伍军人参与者将接受神经心理学测试和腰椎穿刺，以收集tau和淀粉样蛋白的CSF标志物。根据严格的神经心理学标准，将其分为遗忘型轻度认知障碍和非遗忘型轻度认知障碍。将使用tau和淀粉样蛋白的CSF标志物来定义CSF的“阿尔茨海默特征”。关键合并症将作为协变量进行评估，包括载脂蛋白E4、血管风险因素、是否存在创伤后应激障碍和轻度创伤性脑损伤。参与者将被随访长达3年，并每隔6个月进行评估，以确定临床结果的变化率和向痴呆症的转变。我们假设遗忘和非遗忘域（即aMCI和naMCI）的新发认知缺陷将预测临床衰退和痴呆。我们还假设CSF生物标志物特征将预测认知缺陷（MCI）患者的临床衰退和痴呆，而不管是否存在记忆缺陷。将根据考克斯模型生成的生存曲线估计累积转换率。将使用广义估计方程技术比较遗忘组和非遗忘组之间以及CSF特征阳性组和特征阴性组之间的认知、功能和临床下降率。额外的分析将比较这些标记物单独和组合，以确定该队列中痴呆的最佳预测模型。这些结果提供了在具有复杂医疗需求的高风险退伍军人人群中评估这些标志物的机会。它将解决哪些测试和诊断方法在预测阿尔茨海默病和临床衰退方面具有最大价值的问题。

DESCRIPTION (provided by applicant): Many studies demonstrate that memory deficit and cerebrospinal fluid markers of amyloid and tau are predictive of incident dementia. These markers have even been proposed as new diagnostic criteria for Alzheimer's disease and as outcome measures in clinical trials. Yet these studies have largely been conducted in homogeneous samples of healthy, well educated, Caucasian elders. There is no information on the value of these markers in more typical aging populations representing the broad demographic spectrum who often have multiple comorbidities. Given the aging veteran population, and their increasing need for health care, it is critical to develop accurate diagnostic and predictive models of disease, in order to target treatment and disease management. This application proposes to conduct a longitudinal study of aging veterans to determine if specific neuropsychological and CSF markers can predict transition to Alzheimer dementia and the rate of cognitive, functional and global decline. 150 veteran participants with new onset cognitive complaint will undergo neuropsychological testing and lumbar puncture for the collection of CSF markers of tau and amyloid. They will be characterized by strict neuropsychological criteria as amnestic Mild Cognitive Impairment or nonmnestic Mild Cognitive Impairment. CSF markers of tau and amyloid will be used to define the "Alzheimer signature" of CSF. Key comorbidities will be assessed as covariates including Apolipoprotein E4, vascular risk factors, the presence of Post Traumatic Stress Disorder and mild Traumatic Brain Injury. Participants will be followed for up to 3 years and assessed at 6 month intervals to determine the rate of change on clinical outcomes and the transition to dementia. We hypothesize that new onset cognitive deficit in both amnestic and non-amnestic domains (i.e. aMCI and naMCI) will predict clinical decline and dementia. We also hypothesize that the CSF biomarker signature will predict clinical decline and dementia in those with cognitive deficits (MCI) regardless of the presence of memory deficit. Cumulative transition rates will be estimated based on the survival curves generated from the Cox models. Rates of cognitive, functional and clinical decline will be compared between amnestic and non amnestic groups and between CSF signature positive and signature negative groups using the generalized estimating equation technique. Additional analyses will compare these markers alone and in combination to determine the best predictor model for dementia in this cohort. These results offer the opportunity to evaluate these markers in a high risk population of veterans who have complex medical needs. It will address the question of which tests and diagnostic approaches have the greatest value in predicting Alzheimer disease and clinical decline.