3/5 Neurocognitive and neuroimaging biomarkers: predicting progression towards dementia in patients with treatment resistant late-life depression

项目摘要 描述：痴呆症，尤其是阿尔茨海默氏痴呆症（AD），是一个日益严重的公共卫生问题， 仅在美国的患病率为5 M（全球为33 M）。尽管发病率有所下降，但随着年龄的增长， 在美国，痴呆症的患病率预计将增加到1600万（全球1.15亿）， 相关成本上升至1 T美元。将美国老年人的长期护理延迟1个月将节省600亿美元 每年的直接护理费用。预防或延迟痴呆症的努力在很大程度上是不成功的。然而，在这方面， 老年抑郁症（“晚年抑郁症”，LLD）已被确定为六种可治疗的风险之一 痴呆症，特别是AD和血管性痴呆的因素。抑郁与痴呆的关系可能是 在对抗抑郁药物治疗无反应并出现持续症状的老年人中，这种情况会被放大。 因此，解决那些患有难治性晚年抑郁症（TRLLD）的人是否有更高的风险， 与治疗反应性LLD患者相比， 重要. 利用以患者为中心的结局研究所（PCARI）资助的治疗研究，N=1500 在5个地点的LLD患者中，我们建议全面描述神经认知和神经成像 与患有持续性LLD的人进展为痴呆相关的生物标志物（即，TRLLD）相比， 那些LLD通过治疗缓解的人。我们预计将招募750名患有LLD的长者， 24个月的症状轨迹。我们将在三个时间点评估每位参与者的神经认知功能， 和先进的神经成像技术我们假设，执行功能和执行控制的变化 网络，以及情景记忆和默认模式/皮质边缘网络的变化，将在 与TRLLD相比，那些对治疗有反应并保持良好的人。我们还假设， 两年的执行功能和情景记忆将与执行功能的变化特别相关， 控制和皮质边缘电路。 根据我们最近的发现，炎症和相关分子标记物可以区分那些与 神经认知功能障碍和LLD从那些与LLD单独，我们将建立一个预测多变量模型 结合基线神经认知，神经影像学和血浆蛋白数据，以确定谁是最大的风险， 认知能力下降和痴呆。最后，我们还将探讨抑郁症患者的潜在阶级轨迹是否 症状可以超越缓解/不缓解的二分法，以确定LLD的老年人亚群， 认知能力下降、神经回路改变和进展为痴呆症的风险最高。 这项工作将为神经回路靶向预防性护理奠定基础，以延缓老年患者亚群的痴呆症 与LLD如果成功，我们的工作可以加速针对抑郁症的治疗努力和创新- 痴呆症的途径，并减少大量老年人及其家人的痛苦。

PROJECT SUMMARY DESCRIPTION: Dementia, especially Alzheimer's dementia (AD), is a growing public health problem with a prevalence of 5M in the US alone (33M worldwide). Despite a decrease in incidence rates, with the aging of the population, the prevalence of dementia is expected to increase to 16M in the US (115M worldwide) with associated costs rising to $1T. Delaying long-term care by 1 month for older Americans would save $60B annually in direct care cost. Efforts to prevent or delay dementia have been largely unsuccessful. However, major depressive disorder in late life (“late-life depression”, LLD) has been identified as one of six treatable risk factors for dementia, especially AD and vascular dementia. The depression-dementia relationship may be magnified in elders who do not respond to antidepressant treatment and experience persistent symptoms. Thus, resolving whether those with treatment-resistant late-life depression (TRLLD) are at higher risk of cognitive decline and progression to dementia compared to those with treatment-responsive LLD is critically important. Leveraging a Patient-Centered Outcomes Research Institute (PCORI)-funded treatment study of N=1500 people with LLD, across 5 sites, we propose to comprehensively delineate neurocognitive and neuroimaging biomarkers associated with progression to dementia in people with persistent LLD (i.e., TRLLD) compared to those whose LLD remits with treatment. We anticipate enrolling 750 elders with LLD and characterizing their symptomatic trajectory over 24 months. We will assess each participant at three time points with neurocognitive and advanced neuroimaging. We hypothesize that changes in executive functions and the executive control network, as well as changes in episodic memory and the default mode/cortico-limbic network, will be greater in those with TRLLD than in those who respond to treatment and stay well. We also hypothesize that changes over two years in executive function and episodic memory will be specifically associated with changes in executive- control and cortico-limbic circuitry, respectively. Based on our recent findings that inflammatory and related molecular markers can differentiate those with neurocognitive impairment and LLD from those with LLD alone, we will build a predictive multivariate model combining baseline neurocognitive, neuroimaging, and plasma protein data to determine who is at greatest risk for cognitive decline and dementia. Finally, we will also explore whether latent class trajectories of depressive symptoms can go beyond the dichotomy of remission/non-remission to identify subsets of elders with LLD at highest risk of cognitive decline, neural circuit change, and progression to dementia. This work will set the stage for neural circuit- targeted preventive care to delay dementia in subsets of older patients with LLD. If successful, our work can accelerate therapeutic efforts and innovation targeting the depression- dementia pathway and reduce suffering for large numbers of elders and their families.