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

项目总结 65岁以上的成年人中有10%患有阿尔茨海默病(AD)，这一数字预计到2020年将翻一番 2050年。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，终生抑郁会导致 AD风险，尽管晚年抑郁也可能是痴呆症前驱症状的一部分。临床病理研究 为淀粉样β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，以及 有证据支持β与抑郁症之间的联系。然而，大多数研究都考察了 MDD与Aβ的关系包括轻度认知障碍患者， 使我们对MDD和Aβ之间的关系的理解复杂化。可溶性A-β水平受到影响 由于Aβ的存在，我们的初步数据表明，它们也与严重程度有关 抑郁症的症状。使用多个抑郁评分表，我们的数据也显示残差的变化 没有明显认知功能减退的老年抑郁症患者的症状与 A-β在脑脊液和血浆中均有变化。然而，因果关系的方向和性质 MDD症状和A-β多肽水平之间的关系尚不清楚。给出了一个β与 和AD风险，阐明淀粉样蛋白动力学和抑郁症状之间的关系将使我们 为了更好地了解MDD增加AD风险的机制。既然因果关系的方向 抑郁症和β之间的关系尚不清楚，了解病因和相关风险的唯一方法是治疗 抑郁症状和检测与抗抑郁治疗相关的AD生物标志物的影响 回应。我们建议对90名认知正常的老年人进行研究，他们目前患有MDD，但没有证据 一项使用SSRI的为期8周的平行组、双盲、安慰剂对照随机研究 抗抑郁药埃西妥普兰。假设是抑郁症状的减少和治疗反应 将与脑脊液Aβ40和Aβ42水平增加以及血管减少有关 功能障碍标记物，包括血小板激活。拟议的临床试验结果将建立在我们的 了解MDD症状与AD所涉及的生物变量之间的关系，以及 从而为降低AD风险提供了一个重要的目标。如果成功，这种方法可能会带来更有效的 通过更有效地治疗晚年MDD来降低AD风险的策略。

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.