1/2 Phenotype Predictors of Cognitive Outcomes in Geriatric Depression

在老年人中，伴有认知障碍(CI)的严重抑郁障碍与 残疾、更高的医疗保健利用率和更高的痴呆症风险。从临床的角度来看， 关于最近(即5年内)认知不良结果预测因素的知识 抑郁的老年人对于对高危人群进行及时和有针对性的干预至关重要。从一个科学的 观点，识别与认知诊断结果相关的表型和基因类型-两者 积极和消极--将推进对机制、预防和治疗的研究。NIMH- 支持老年抑郁症的神经认知结果(NCode)研究在杜克大学和 康涅狄格大学(UConn)晚年抑郁症的神经生物学(NBOLD)研究是 很少有前瞻性研究同时包含纵向认知诊断结果和正式的临床研究 老年抑郁症的诊断(LLD)。此外，这些研究的共同特征与 临床和认知评估、神经成像和基因分析。与PAR-14-165一致， 拟议的临床协作的目标是完成一项认知功能的两个部位的前瞻性研究 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，将目前的两年制学习延长到五年制 临床随访期，以增加样本量以确定临床、神经影像和遗传学 我们的数据在五年内90%的认知诊断结果中发现了三种关键诊断的预测因素： 1)正常认知(CN)，2)无痴呆的持续性认知障碍(PCI)，3)阿尔茨海默氏症 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 在急性LLD期间与不同的临床、认知和神经表型相关，而这些表型又与不同的 基因类型相关。具体地说，报告称，与AD相比，CN患者首次出现抑郁症的时间更早 与AD和PCI相比，负性生活压力更大，脑白质完整性更强；此外，CN 将与COMTval158met的AA基因型相关，这可能赋予神经保护和 对压力的敏感性更高。与AD相比，经皮冠状动脉介入治疗将与抑郁症发病年龄更早、更大相关 脆弱，脑白质完整性不如NC。AD将与较晚的抑郁症发病年龄相关， 食欲/体重下降，焦虑程度降低，海马体体积变小，记忆力受损。我们打算测试一下 在我们的特定目标中，所有这些假定的联系。拟议的研究将确定和整合 与LLD(NIMH)近期认知诊断结果相关的生物学和行为标记物 战略目标1)，并有可能产生更好地定义和识别风险和保护的工具 老年抑郁症不良后果的因素(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).