Depressive symptoms in the pathogenesis of preclinical Alzheimer's Disease

项目总结/摘要： 候选人是一位老年精神病学家，曾接受过分子神经变性方面的基础科学培训。 谁正在申请K23指导以病人为导向的职业发展奖，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-将共同使候选人成为一个完全的 老年精神病学的独立临床科学家，在晚年抑郁症和临床前 这些培训目标与拟议项目的目标相一致， 侧重于临床前AD发病机制中的晚年抑郁症状。尽管最近流行 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） 尚未明确确立。该项目将填补知识的一个关键空白， 抑郁症状的存在（与不存在）预示着AD蛋白病、淀粉样蛋白 和tau蛋白，以及更快的临床进展。通过竞争性试点供资产生的初步数据， 申请人显示了增加的亚临床抑郁症 症状和颞下tau蛋白增加（使用有前景的tau PET配体Flortaucipir [FTP]测量） 在哈佛衰老研究（HABS）中，认知正常（CN）的老年人中， 临床前AD的纵向队列。然而，在更广泛的抑郁症患者中进行进一步的调查， 症状和纵向随访需要更明确地解决这个问题。总体 目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，并且是随时间推移更大的tau积累和临床进展的标志物。 为了验证这一假设，我们将调查抑郁症状和体内 皮质淀粉样蛋白使用匹兹堡化合物B（PiB）PET成像，tau使用FTP PET。我们还将 研究抑郁症状和皮质淀粉样蛋白的基线严重程度是否可预测更大的tau蛋白 三年随访的积累。最后，我们将招募一批新的试点参与者， 对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， 三年的后续行动。这些目标有望共同影响设计和未来的成功 在老年人中进行预防试验，他们可能是AD的最大风险，并将导致候选人的过渡 作为一名老年精神病学的临床科学家， 的AD。 !

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. !