Depressive symptoms in the pathogenesis of preclinical Alzheimer's Disease

临床前阿尔茨海默病发病机制中的抑郁症状

• 批准号: 10116242
• 负责人: Jennifer Rose Gatchel
• 金额: $ 20.02万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116242
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Anhedonia; Award; Basic Science; Behavior assessment; Characteristics; Clinical; Clinical Research; Cognitive; Data; Disease; Doctor of Philosophy; Early Intervention; Early identification; Elderly; Episodic memory; Funding; Future; General Hospitals; Geriatric Psychiatry; Goals; Impaired cognition; Inferior; Intervention; Investigation; K-Series Research Career Programs; Knowledge; Lateral; Left; Ligands; Longitudinal cohort; Longitudinal cohort study; Measures; Memory; Memory Loss; Mental Depression; Mentors; Molecular; Morbidity - disease rate; Nerve Degeneration; Neurobehavioral Manifestations; Participant; Pathogenesis; Pathologic; Pattern; Performance; Phenotype; Physicians; Pilot Projects; Pittsburgh Compound-B; Positioning Attribute; Positron-Emission Tomography; Prefrontal Cortex; Prevalence; Prevention trial; Prognosis; Psychiatrist; Public Health; Research Methodology; Resources; Retrieval; Risk; Scientist; Severities; Symptoms; Temporal Lobe; Testing; Time; Training; Work; aging brain; analytical method; career; cognitive development; cognitive testing; cohort; depressive symptoms; design; entorhinal cortex; executive function; follow-up; geriatric depression; improved; in vivo; innovation; mortality; multidisciplinary; negative affect; neuroimaging; patient oriented; pre-clinical; preclinical study; recruit; success; tau Proteins; tau aggregation

PROJECT SUMMARY/ABSTRACT: The candidate is a geriatric psychiatrist with previous basic science training in molecular neurodegeneration who is applying for a K23 Mentored Patient-Oriented Career Development Award to transition to full independence as a clinical research scientist. The training goals—gaining expertise in positron emission tomography (PET) neuroimaging-clinical correlations, clinical research methodology and analytic methods, and cognitive and behavioral assessments in older adults—will together enable the candidate to emerge as a fully independent clinician scientist in geriatric psychiatry at the interface of late life depression and preclinical Alzheimer’s Disease (AD).These training goals are aligned with the aims of the proposed project, which focuses on late life depressive symptoms in the pathogenesis of preclinical AD. Despite the prevalence of late life depressive symptoms and AD, the associations among depressive symptoms, in vivo amyloid and tau, and early clinical manifestations of AD (e.g., subjective cognitive decline, subtle decline on sensitive cognitive tests) have not been clearly established. This project will fill a critical gap in knowledge by determining whether the presence (vs absence) of depressive symptoms predicts greater accumulation of AD proteinopathies, amyloid and tau, and more rapid clinical progression. Preliminary data generated through competitive pilot funding to the applicant showed a modest cross-sectional association between increased subclinical depressive symptoms and increased inferior temporal tau (measured using a promising tau PET ligand Flortaucipir [FTP]) in cognitively normal (CN) older adults in the Harvard Aging Study (HABS), one of the best characterized longitudinal cohorts of preclinical AD. However, further investigation across a wider range of depressive symptoms and with longitudinal follow up is needed to more definitively address this question. The overarching hypothesis of the current study is that depressive symptoms, whether cause or consequence of AD pathology, occur late in preclinical AD and are a marker for greater tau accumulation and clinical progression over time. To test this hypothesis, we will investigate the cross-sectional association of depressive symptoms and in vivo cortical amyloid using Pittsburgh compound B (PiB) PET imaging and tau using FTP PET. We will additionally investigate whether baseline severity of depressive symptoms and cortical amyloid predict greater tau accumulation over three-year follow up. Finally, we will recruit a new pilot cohort of participants of comparable cognitive status to HABS but with moderate to severe depressive symptoms in order to investigate whether depressive symptom severity modifies the relationship between tau and clinical manifestations of AD over three-year follow up. Together, these aims have promise to impact the design and future success of prevention trials in older adults who may be at greatest risk for AD, and will result in the candidate’s transition to independence as a clinician-scientist in geriatric psychiatry working at the interface of late life depression and AD. !

项目摘要/摘要： 候选人是一位老年精神科医生，之前接受过分子神经变性方面的基础科学培训 正在申请 K23 指导的以患者为中心的职业发展奖以过渡到全面 作为临床研究科学家的独立性。培训目标——获得正电子发射方面的专业知识 断层扫描 (PET) 神经影像与临床的相关性、临床研究方法和分析方法，以及 对老年人的认知和行为评估——将共同使候选人成为一个全面的人 老年精神病学独立临床科学家，研究晚年抑郁症和临床前疾病的交叉点 阿尔茨海默病 (AD)。这些培训目标与拟议项目的目标一致，该项目 重点关注临床前 AD 发病机制中的晚年抑郁症状。尽管晚期流行 生活抑郁症状和 AD，抑郁症状、体内淀粉样蛋白和 tau 蛋白之间的关联，以及 AD 的早期临床表现（例如主观认知能力下降、敏感认知测试的轻微下降） 尚未明确规定。该项目将通过确定是否 抑郁症状的存在（与不存在）预示着 AD 蛋白病、淀粉样蛋白的更多积累 和 tau 蛋白，并且临床进展更快。通过竞争性试点资金生成的初步数据 申请人表现出亚临床抑郁症增加之间存在适度的横断面关联 症状和下颞 tau 蛋白增加（使用有前景的 tau PET 配体 Flortaucipir [FTP] 测量） 哈佛衰老研究 (HABS) 中认知正常 (CN) 的老年人是最有特征的研究之一 临床前 AD 的纵向队列。然而，针对更广泛的抑郁症的进一步调查 需要症状和纵向随访才能更明确地解决这个问题。首要的 当前研究的假设是，抑郁症状，无论是 AD 病理的原因还是结果， 发生在临床前 AD 的晚期，是随着时间的推移 tau 蛋白积累和临床进展的标志。 为了检验这一假设，我们将研究抑郁症状与体内的横断面关联。 使用匹兹堡化合物 B (PiB) PET 成像检测皮质淀粉样蛋白，使用 FTP PET 成像检测 tau 蛋白。我们还将另外 研究抑郁症状和皮质淀粉样蛋白的基线严重程度是否预示着更高的 tau 蛋白 三年随访积累。最后，我们将招募一批新的试点参与者，其参与者具有可比性 HABS 的认知状态，但有中度至重度抑郁症状，以调查是否 抑郁症状的严重程度改变了 tau 蛋白与 AD 临床表现之间的关系 三年随访。这些目标共同有望影响设计和未来的成功 针对 AD 风险最大的老年人进行预防试验，并将导致候选人的过渡 作为老年精神病学临床医生科学家的独立性，致力于晚年抑郁症的研究 和广告。 ！