Depression treatment and Aβ dynamics: A study of Alzheimer’s disease risk

抑郁症治疗和 Aβ 动态：阿尔茨海默病风险研究

• 批准号: 10681339
• 负责人: Nunzio Pomara
• 金额: $ 78.24万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681339
• 关键词: Adult; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Antidepressive Agents; Biological; Biological Markers; Blood; Blood Platelets; Blood Vessels; Brain; Cerebrospinal Fluid; Cerebrovascular Disorders; Clinical Trials; Cognitive; Cognitive deficits; Data; Dementia; Deposition; Development; Double-Blind Method; Elderly; Epidemiology; Escitalopram; Etiology; Evaluation; Frequencies; Goals; Homocysteine; Impaired cognition; Individual; Knowledge; Lead; Link; Longevity; MMP2 gene; MMP9 gene; Magnetic Resonance Imaging; Major Depressive Disorder; Measures; Mediating; Mediator; Mental Depression; Monitor; Nature; P-Selectin; Pathogenesis; Patients; Persons; Plasma; Platelet Activation; Population; Positron-Emission Tomography; Randomized; Reporting; Research; Residual state; Risk; Risk Factors; Risk Reduction; Selective Serotonin Reuptake Inhibitor; Severities; Study models; Symptoms; Testing; Vascular Diseases; White Matter Hyperintensity; abeta deposition; cardiovascular risk factor; cognitive testing; dementia risk; depressive symptoms; disorder risk; effective therapy; geriatric depression; in vivo; inflammatory marker; mild cognitive impairment; modifiable risk; novel therapeutic intervention; prevent; prodromal Alzheimer' s disease; randomized placebo controlled study; reduce symptoms; research clinical testing; response; single episode major depressive disorder; tau Proteins; tau-1; treatment response

PROJECT SUMMARY Ten percent of adults over 65 suffer from Alzheimer’s disease (AD), and this number is projected to double by 2050. Thus, understanding and reducing AD risk factors is of critical importance, particularly in the absence of an effective treatment. Epidemiological evidence suggests that depression throughout the lifespan contributes to AD risk, although depression in late life also may be part of the dementia prodrome. Clinicopathological studies have provided robust support for the importance of amyloid-beta (Aβ) deposition in the pathogenesis of AD, and evidence supports an association between Aβ and depression. However, most studies that have examined the relationship between MDD and Aβ have included individuals with mild cognitive impairment (MCI), complicating our understanding of the relationship between MDD and Aβ. Levels of soluble Aβ are influenced by the presence of deposited Aβ and our preliminary data suggests that they also are associated with the severity of depression symptoms. Using a number of depression rating scales, our data also show that changes in residual symptoms in people with geriatric depression who do not have significant cognitive decline are correlated with Aβ changes in both cerebrospinal fluid (CSF) and plasma. However, the direction and nature of the causal relationship between MDD symptoms and Aβ peptide levels are unknown. Given the relationship between Aβ and AD risk, elucidating the relationship between amyloid dynamics and depression symptoms would allow us to better understand the mechanism for heightened AD risk imparted by MDD. Since the direction of causation between depression and Aβ is unknown, the only way to understand cause and associated risk is to treat the depressive symptoms and examine the effects on AD biomarkers in relation to antidepressant treatment response. We propose to study 90 cognitively-normal older adults with current episode of MDD and no evidence of MCI in an 8-week, parallel-group, double-blind, placebo-controlled randomized study using the SSRI antidepressant escitalopram. The hypothesis is that a reduction in depressive symptoms and treatment response will be associated with an increase in the levels of CSF Aβ40 and Aβ42, as well as a reduction in vascular dysfunction markers, including platelet activation. The results of the proposed clinical trial will build on our understanding of the relationship between MDD symptoms and the biological variables implicated in AD, and thus provide a significant target for reducing AD risk. If successful, this approach might lead to more effective strategies for reducing the risk of developing AD through more effective treatment of late-life MDD.

项目摘要 65岁以上的成年人中有10%患有阿尔茨海默病（AD），预计到2020年这一数字将翻一番。 2050.因此，了解和减少AD风险因素至关重要，特别是在缺乏 有效的治疗方法。流行病学证据表明，抑郁症在整个生命周期有助于 AD风险，尽管晚年抑郁也可能是痴呆前驱症状的一部分。临床病理学研究 为β淀粉样蛋白（Aβ）沉积在AD发病机制中的重要性提供了强有力的支持， 证据支持Aβ与抑郁症之间存在联系。然而，大多数研究已经检查了 MDD和Aβ之间的关系包括轻度认知障碍（MCI）患者， 这使我们对MDD和Aβ之间关系的理解变得复杂。可溶性Aβ水平受到影响 我们的初步数据表明，Aβ沉积的存在也与严重程度有关， 抑郁症的症状。使用一些抑郁等级量表，我们的数据还显示， 老年抑郁症患者的症状，没有明显的认知能力下降， 脑脊液（CSF）和血浆中的Aβ变化。然而，因果关系的方向和性质 MDD症状与Aβ肽水平之间的关系尚不清楚。考虑到Aβ与 和AD风险之间的关系，阐明淀粉样蛋白动力学和抑郁症状之间的关系将使我们 更好地了解MDD引起AD风险升高的机制。因为因果关系的方向 抑郁症和Aβ之间的关系尚不清楚，了解原因和相关风险的唯一方法是治疗抑郁症。 抑郁症状，并检查与抗抑郁药治疗相关的AD生物标志物的影响 反应我们建议研究90名认知正常的老年人，他们目前患有MDD，并且没有证据表明 在一项使用SSRI的8周、平行组、双盲、安慰剂对照随机化研究中， 抗抑郁药艾司西酞普兰假设抑郁症状的减轻和治疗反应 将与CSF Aβ40和Aβ42水平的增加以及血管内皮细胞的减少相关。 功能障碍标志物，包括血小板活化。拟议的临床试验的结果将建立在我们的基础上， 了解MDD症状与AD相关生物学变量之间的关系，以及 从而为降低AD风险提供了重要的靶点。如果成功，这种方法可能会导致更有效的 通过更有效地治疗晚期MDD来降低AD风险的策略。