Cognitive, Clinical and Neural Markers of Late Life Depression

晚年抑郁症的认知、临床和神经标志物

• 批准号: 8840084
• 负责人: Sara L. Weisenbach
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840084
• 关键词: Age; Antidepressive Agents; Area; Behavior assessment; Behavioral; Brain region; Caring; Clinic; Clinical; Cognition; Cognitive; Comorbidity; Complex; Corpus striatum structure; Development; Diffusion Magnetic Resonance Imaging; Disease; Etiology; Executive Dysfunction; Family; Functional Magnetic Resonance Imaging; Gender; Goals; Impaired cognition; Individual; Investigation; Knowledge; Lead; Link; Maps; Measures; Medical Education; Neurobiology; Outcome; Participant; Pathway interactions; Patients; Phenotype; Prevalence; Prevention strategy; Regimen; Relative (related person); Research; Research Personnel; Resistance; Rest; Sampling; Scanning; Signal Transduction; Symptoms; Techniques; Translating; Treatment Protocols; Veterans; Visit; Work; behavior measurement; career; clinical care; design; endophenotype; follow-up; functional decline; geriatric depression; improved; knowledge base; neural circuit; neuroimaging; neuropsychological; relating to nervous system; tool; translational neuroscience; treatment strategy

DESCRIPTION (provided by applicant) The applicant is a clinical neuropsychologist whose long-term career goal is to become an independent researcher conducting work in the translational neuroscience of late life depression (LLD) using neuropsychological and neuroimaging tools. Individuals with LLD are thought to encompass a neurobiologically heterogeneous group. Previous studies with small samples and mixed etiologies of LLD subjects have been limited in their development of knowledge of the basis of the disorder and of sub-phenotypes, but have been important in taking first steps toward difficult goals. For example, individuals with LLD present with high rates of treatment resistance to typical antidepressant regimens, increased vulnerability to decline in cognition and function, and high rates of treatment non-adherence. Some initial efforts have been made to identify more accurate intermediate endophenotypes (IE) of individuals with LLD, which might improve prediction of who is most likely to display cognitive and functional decline and identify individuals most likely to respond to specific treatment regimens. To date, research on LLD has focused primary on executive functioning deficits, related to disruption of dorsolateral-striatal circuitry using small samples. Observations of executive functioning deficits and associated disruption to dorsolateral-striatal pathways among patients with LLD have been predictive of poor psychiatric outcomes, such as treatment resistance. In addition, there has been less investigation into the ability of baseline neuropsychological and neuroimaging measures to predict the course of broad cognitive and functional decline, despite the fact that prediction is precisely what clinicians and families might find most useful in planning and care. Furthermore, clinical measures such as apathy and the potential predictive validity of such measures in related neural circuitry, is as yet unknown. Establishing which neuropsychological and clinical measures are related to the neural circuitry underlying LLD can be of signal value toward developing treatment to protect and enhance the respective underlying neural circuits. Furthermore, if these measures and circuits are predictive of course and change in broad cognitive areas, clinical features, and everyday functioning, this knowledge could more readily be transferred to clinical care practices. Thus, the primary objective of this study is to probe two neural circuits implicated in the etiology of LLD. To achieve this objective, the candidate proposes to distinguish neural circuitry related to executive dysfunction (as defined by comprehensive baseline neuropsychological assessment) from circuitry related to symptoms of apathy using resting state functioning connectivity (rRSfC, a functional MRI technique that examines neural connectivity of brain regions during a resting state), as well as diffusion tensor imaging as a microstructural compliment. Furthermore, the project is designed as a longitudinal, predictive study. It uses neuropsychological, clinical, and neural circuitry measures to map and predict course of LLD, including changes in cognitive areas, clinical features, and everyday functioning. It is designed so that cognitive and behavioral features of LLD that predict decline can be effectively evaluated and easily translated into clinic settings. Participants will include 40 individuals with LLD, antidepressant-free at baseline, relative to 20 controls. The two groups will be matched for age, gender, education, and medical comorbidities. They will be re-assessed at one- and two-year follow-up visits with a neuropsychological battery, including symptom and behavioral measures, to better understand the extent to which baseline neuropsychological alterations can predict the course of cognition and function among individuals with LLD. Linking neurobiological circuitry with neuropsychological and behavioral measures will allow for the mechanistic definition of simplified, non-imaging measures, anchored on a background of neurobiological correlates that may predict the course of cognition and function of LLD, leading to more accurate assessments, the specification of more valid phenotypes in this complex illness, and a better targeting of preventive and treatment strategies.

描述(由申请人提供) 申请者是一名临床神经心理学家，其长期职业目标是成为一名独立研究员，使用神经心理学和神经成像工具在晚期抑郁症(LLD)的翻译神经科学领域开展工作。患有LLD的个体被认为包含了一个神经生物学上不同的群体。以前对LLD受试者的小样本和混合病因的研究一直局限于他们对疾病基础和亚表型的了解，但对于迈向困难目标的第一步是重要的。例如，LLD患者对典型的抗抑郁药物方案具有较高的治疗抵抗率，更容易出现认知和功能下降，以及较高的治疗不依从率。已经进行了一些初步的努力，以确定更准确的LLD患者的中间内表型(IE)，这可能会改善对谁最有可能表现出认知和功能下降的预测，并确定最有可能对特定治疗方案有反应的个人。到目前为止，对LLD的研究主要集中在执行功能缺陷上，这与使用小样本的背外侧纹状体回路中断有关。观察LLD患者的执行功能缺陷和相关的背外侧-纹状体通路中断，可以预测不良的精神结局，如治疗抵抗。此外，对基线神经心理学和神经成像指标预测认知和功能全面下降过程的能力的研究较少，尽管预测恰恰是临床医生和家庭可能认为在规划和护理中最有用的。此外，临床测量，如冷漠，以及这些测量在相关神经回路中的潜在预测有效性，目前尚不清楚。确定哪些神经心理学和临床措施与LLD潜在的神经回路有关，对于开发保护和增强各自潜在神经回路的治疗方法具有信号价值。此外，如果这些测量和回路可以预测广泛认知领域、临床特征和日常功能的进程和变化，这些知识可以更容易地转移到临床护理实践中。因此，这项研究的主要目的是探索与LLD病因学有关的两个神经回路。为了实现这一目标，候选人建议使用静息状态功能连通性(rRSfC，一种检查静息状态下大脑区域神经连通性的功能磁共振技术)以及扩散张量成像作为微观结构的补充，区分与执行功能障碍相关的神经回路(由全面的基线神经心理学评估定义)和与冷漠症状有关的回路。此外，该项目被设计为一项纵向的预测性研究。它使用神经心理学、临床和神经回路测量来绘制和预测LLD的进程，包括认知区域、临床特征和日常功能的变化。它的设计是为了能够有效地评估LLD预测下降的认知和行为特征，并容易地将其转化为临床环境。参与者将包括40名LLD患者，基线时不使用抗抑郁药，而对照组为20名。这两组人将在年龄、性别、教育程度和医疗并存方面进行匹配。在一年和两年的随访中，他们将接受包括症状和行为测量在内的神经心理单元的重新评估，以更好地了解基线神经心理变化可以在多大程度上预测LLD患者的认知和功能进程。将神经生物回路与神经心理和行为措施联系起来，将允许对简化的非成像措施进行机械性定义，这些措施建立在神经生物学相关性的背景上，可以预测LLD的认知和功能过程，导致更准确的评估，指定这种复杂疾病的更有效表型，并更好地针对预防和治疗策略。