4/5 Neurocognitive and neuroimaging biomarkers: predicting progression towards dementia in late-life depression

项目总结 描述：痴呆症，尤其是阿尔茨海默氏症(AD)，是一个日益严重的公共卫生问题， 仅在美国就有500万人流行(全球3300万人)。尽管发病率有所下降，但随着年龄的增长 在人口方面，痴呆症的患病率预计将在美国增加到1600万(全球1.15亿)， 相关成本上升至1T美元。将美国老年人的长期护理推迟1个月将节省600亿美元 每年的直接医疗费用。预防或推迟痴呆症的努力在很大程度上没有成功。然而， 老年抑郁症(“晚年抑郁症”)已被确定为六种可治疗的风险之一。 导致痴呆的因素，特别是阿尔茨海默病和血管性痴呆。抑郁症和痴呆症的关系可能是 在对抗抑郁药物治疗无效并经历持续症状的老年人中放大。 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 与那些对治疗有反应的LLD患者相比，认知能力下降和进展为痴呆症是至关重要的 很重要。 利用以患者为中心的结果研究所(PCORI)资助的N=1500治疗研究 LLD患者，覆盖5个地点，我们建议全面描述神经认知和神经成像 与持续性LLD(即TRLLD)患者进展为痴呆相关的生物标记物与 那些LLD缓解的人接受治疗。我们预计招收750名学习LLD的老年人，并描述他们的特征 症状轨迹超过24个月。我们将在三个时间点对每个参与者进行神经认知评估 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，以及情节记忆和默认模式/皮质-边缘网络的变化将在 那些患有TRLLD的人比那些对治疗有反应并留得很好的人更好。我们还假设改变了 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- 分别是控制回路和皮质-边缘回路。 根据我们最近的发现，炎症和相关的分子标志物可以区分那些 神经认知功能障碍与LLD的关系我们将建立一个预测性的多变量模型 结合基线神经认知、神经成像和血浆蛋白数据，确定谁患高血压的风险最大 认知功能衰退和痴呆症。最后，我们还将探索抑郁的潜在班级轨迹 症状可以超越缓解/未缓解的二分法来识别患有LLD的老年人亚群 认知衰退、神经回路改变和进展为痴呆症的最高风险。 这项工作将为针对神经回路的预防性护理奠定基础，以延缓老年患者亚群的痴呆 和LLD一起。如果成功，我们的工作可以加快针对抑郁症的治疗努力和创新- 治疗痴呆症，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.