Depressive symptoms in the pathogenesis of preclinical Alzheimer's Disease

项目摘要/摘要： 应聘者是一名老年精神病学家，曾接受过分子神经变性的基础科学培训。 世卫组织正在申请K23指导患者导向职业发展奖，以过渡到完全 作为一名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)神经成像-临床相关性、临床研究方法和分析方法，以及 老年人的认知和行为评估--将使候选人成为一个完全的 在老年抑郁症和临床前的交界处的老年精神病学的独立临床科学家 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 重点探讨老年抑郁症状在临床前AD发病机制中的作用。尽管最近流行 生活抑郁症状与阿尔茨海默病、抑郁症状、体内淀粉样蛋白和tau之间的关系 阿尔茨海默病的早期临床表现(例如，主观认知能力下降，在敏感的认知测试中出现轻微下降) 还没有得到明确的确定。该项目将填补知识的一个关键空白，方法是确定 抑郁症状的存在(与不存在)预示着AD蛋白病、淀粉样蛋白的更大积聚 和tau，以及更快的临床进展。通过竞争性试点资金生成的初步数据 申请者在亚临床抑郁加重之间显示出适度的横断面关联 症状和下颞部tau增加(使用前景看好的tau PET配体Flortaucipir[ftp]测量) 在哈佛大学老龄化研究(HABS)中认知正常(CN)的老年人中，最典型的特征之一 临床前AD的纵向队列。然而，对更广泛的抑郁症进行了进一步的调查 症状和纵向随访需要更明确地解决这一问题。最重要的是 目前研究的假说是，抑郁症状，无论是AD病理的原因还是后果， 发生在临床前AD的晚期，是随着时间的推移tau积累和临床进展更大的标志。 为了验证这一假设，我们将调查抑郁症状和活体内的横截面关联。 皮质淀粉样蛋白使用匹兹堡化合物B(PIB)进行PET成像，tau使用FTPPET。我们还会另外 研究抑郁症状的基线严重程度和皮质淀粉样蛋白是否预示更大的tau 累积超过三年的随访时间。最后，我们将招募一个新的试点参赛者队列 对有中到重度抑郁症状的哈布斯的认知状况进行调查 抑郁症状严重程度改变tau与阿尔茨海默病临床表现的关系 三年的随访。这些目标加在一起，有望影响 对可能是AD风险最大的老年人进行预防试验，并将导致候选人的转变 作为老年精神病学的临床科学家，在老年抑郁症的界面上工作，走向独立 和AD。 好了！

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. !