1/2 Phenotype Predictors of Cognitive Outcomes in Geriatric Depression

在老年人中，伴有认知障碍（CI）的重度抑郁症与 残疾，更高的医疗保健利用率和痴呆症的风险增加。从临床角度来看， 关于邻近的知识（即，5年内）的不良认知结果的预测因素 抑郁的老年人是及时和有针对性的干预风险的人至关重要。从科学 观点，识别与认知诊断结果相关的表型和基因型， 积极的和消极的将推进机制，预防和治疗的研究。NIMH- 支持杜克大学的老年抑郁症神经认知结果（NCODE）研究， 康涅狄格大学（UConn）的晚年抑郁症神经生物学（NBOLD）研究是 一些前瞻性研究，包括纵向认知诊断结果和正式的临床研究， 晚年抑郁症（LLD）此外，这些研究具有以下共同特征： 临床和认知评估、神经成像和遗传分析。与PAR-14-165一致， 拟议的临床合作的目的是完成一项关于认知功能的两个地点的前瞻性研究， LLD的诊断结果，将利用组合数据的力量：1）识别临床和 预测认知诊断结果的生物表型，以及2）了解神经和遗传 与之相关的机制。我们寻求支持，以延长目前的2年学习注册到5年 临床随访期，以增加样本量，以确定临床，神经影像学和遗传学 三个关键诊断的预测因素，我们的数据在5年内发现了90%的认知诊断结果： 1)正常认知（CN），2）无痴呆的持续性认知损害（PCI），和3）阿尔茨海默病 疾病（AD）。我们的中心假设是，每个认知诊断结果的5年可能性是 与急性LLD期间不同的临床、认知和神经表型相关，而这些表型又具有不同的 基因型相关。具体来说，CN个人将有更早的抑郁症首次发作相对于AD，报告 与AD和PCI相比，更大的负生活压力，并且具有更大的白色完整性;此外，CN 将与COMTval 158 met的AA基因型相关，其可赋予神经保护和 对压力更敏感。PCI与抑郁症发病年龄早于AD相关， 虚弱，白色物质完整性低于NC。AD与抑郁症发病年龄晚相关， 食欲/体重减轻、焦虑降低、海马体积减小和记忆障碍。我们建议测试 所有这些在我们的具体目标中的假定关联。拟议的研究将确定和整合 与LLD（NIMH）的近认知诊断结果相关的生物学和行为学标志物 战略目标1），并有可能产生更好地定义和识别风险的工具， 抑郁症的不良后果的因素，通过以后的生活（NIMH战略目标2）。

Among older adults, major depressive disorder with cognitive impairment (CI) is associated with increased disability, higher healthcare utilization, and increased risk of dementia. From a clinical standpoint, gaining knowledge about proximate (i.e., within 5 years) predictors of adverse cognitive outcomes among currently depressed older adults is crucial to timely and targeted intervention for at-risk individuals. From a scientific standpoint, identifying phenotypes and genotypes associated with cognitive diagnostic outcomes—both positive and negative—will advance research on mechanisms, prevention, and treatment. The NIMH- supported Neurocognitive Outcomes of Depression in the Elderly (NCODE) Study at Duke University and Neurobiology of Late-life Depression (NBOLD) Study at the University of Connecticut (UConn) are among the few prospective studies that include both longitudinal cognitive diagnostic outcomes and a formal clinical diagnosis of major depression in late life (LLD). In addition, these studies share common features related to clinical and cognitive assessment, neuroimaging, and genetic analysis. Consistent with PAR-14-165, the objective of the proposed clinical collaboration is to complete a two-site prospective study of cognitive diagnostic outcomes of LLD that will capitalize on the power of the combined data to: 1) identify clinical and biological phenotypes that predict cognitive diagnostic outcomes, and 2) understand the neural and genetic mechanisms associated with them. We seek support to extend current 2-year study enrollments to a 5-year clinical follow-up period in order to increase sample sizes to identify clinical, neuroimaging and genetic predictors of three key diagnoses our data find in 90% of cognitive diagnostic outcomes over a 5-year period: 1) normal cognition (CN), 2) persistent cognitive impairment without dementia (PCI), and 3) Alzheimer’s disease (AD). Our central hypothesis is that the 5-year likelihood of each cognitive diagnostic outcome is associated with distinct clinical, cognitive, and neural phenotypes during acute LLD, which in turn have distinct genotypic correlates. Specifically, CN individuals will have earlier first onset of depression relative to AD, report greater negative life stress compared to AD and PCI, and have greater white matter integrity; additionally, CN will be associated with the AA genotype of COMTval158met, which may confer both neuroprotection and higher sensitivity to stress. PCI will be associated with earlier age of depression onset relative to AD, greater frailty, and lesser white matter integrity than NC. AD will be associated with later age of depression onset, appetite/weight loss, lower anxiety, smaller hippocampal volume, and memory impairment. We propose to test all of these putative associations in our Specific Aims. The proposed research will identify and integrate biological and behavioral markers associated with proximate cognitive diagnostic outcomes in LLD (NIMH Strategic Objective 1), and has the potential to yield tools that better define and identify risk and protective factors for adverse outcomes of depression through the course of later life (NIMH Strategic Objective 2).