Markers of transition to Alzheimer disease in veterans with MCI

描述(由申请人提供)： 许多研究表明，记忆缺陷和脑脊液中淀粉样蛋白和tau蛋白的标志物可以预测痴呆的发生。这些标志物甚至被建议作为阿尔茨海默病的新诊断标准，并在临床试验中作为结果衡量标准。然而，这些研究在很大程度上是在健康、受过良好教育的高加索老年人的同类样本中进行的。没有关于这些标记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谱，通常患有多种并存疾病。鉴于退伍军人人口老龄化，以及他们日益增长的医疗保健需求，开发准确的疾病诊断和预测模型至关重要，以便有针对性地进行治疗和疾病管理。这项应用建议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脑脊液标志物是否可以预测过渡到阿尔茨海默病以及认知、功能和全球衰退的比率。150名新发认知障碍的退伍军人参与者将接受神经心理测试和腰椎穿刺术，以收集脑脊液中tau和淀粉样蛋白的标志物。他们将以严格的神经心理学标准为特征，如健忘性轻度认知障碍或非记忆性轻度认知障碍。脑脊液中tau和淀粉样蛋白的标记物将被用来定义脑脊液的“阿尔茨海默病特征”。关键的合并症将被评估为协变量，包括载脂蛋白E4、血管风险因素、创伤后应激障碍的存在和轻度创伤性脑损伤。参与者将接受长达3年的跟踪调查，每隔6个月进行一次评估，以确定临床结果的变化率和向痴呆症的转变。我们假设新出现的遗忘性和非遗忘性领域的认知缺陷(即aMCI和NAMCI)将预测临床衰退和痴呆。我们还假设，无论是否存在记忆缺陷，脑脊液生物标记物的特征都将预测认知缺陷(MCI)患者的临床衰退和痴呆。累积转移率将基于由COX模型生成的生存曲线来估计。使用广义估计方程技术比较健忘组和非健忘组之间以及脑脊液信号阳性组和信号阴性组之间的认知、功能和临床减退率。其他分析将单独和联合比较这些标记物，以确定该队列中痴呆症的最佳预测模型。这些结果提供了在有复杂医疗需求的退伍军人高危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下降方面最有价值的问题。

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.