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

5/5 神经认知和神经影像生物标志物：预测治疗抵抗性晚年抑郁症患者的痴呆进展

• 批准号: 10219919
• 负责人: JOSHUA S SHIMONY
• 金额: $ 29.01万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219919
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; American; Antidepressive Agents; Biological Markers; Brain; Brain imaging; Chronic; Clinical; Clinical Trials; Cognitive; Data; Dementia; Disease remission; Education; Elderly; Enrollment; Episodic memory; Family; Funding; Gender; Goals; Image; Impaired cognition; Impairment; Incidence; Individual; Inflammatory; Infrastructure; Intervention; Lead; Link; Long-Term Care; Magnetic Resonance Imaging; Major Depressive Disorder; Medical; Memory Loss; Mental Depression; Modeling; Molecular; Molecular Profiling; Neurocognitive; Neurocognitive Deficit; Outcome; Participant; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral; Pharmacotherapy; Phenotype; Plasma Proteins; Population; Positioning Attribute; Prevalence; Preventive care; Proteins; Public Health; Randomized; Research Institute; Resistance; Risk; Sample Size; Site; Structure; Suicide; Testing; Therapeutic; Time; Vascular Dementia; Work; base; care costs; cognitive function; cognitive performance; cortico-limbic circuits; cost; dementia risk; depressive symptoms; design; effective therapy; executive function; experience; geriatric depression; high risk; high risk population; improved; indexing; innovation; learning strategy; molecular marker; neural circuit; neuroimaging; neuroimaging marker; novel; older patient; persistent symptom; predictive marker; predictive tools; prevent; recruit; relating to nervous system; senescence; treatment response; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; American; Antidepressive Agents; Biological Markers; Brain; Brain imaging; Chronic; Clinical; Clinical Trials; Cognitive; Data; Dementia; Disease remission; Education; Elderly; Enrollment; Episodic memory; Family; Funding; Gender; Goals; Image; Impaired cognition; Impairment; Incidence; Individual; Inflammatory; Infrastructure; Intervention; Lead; Link; Long-Term Care; Magnetic Resonance Imaging; Major Depressive Disorder; Medical; Memory Loss; Mental Depression; Modeling; Molecular; Molecular Profiling; Neurocognitive; Neurocognitive Deficit; Outcome; Participant; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral; Pharmacotherapy; Phenotype; Plasma Proteins; Population; Positioning Attribute; Prevalence; Preventive care; Proteins; Public Health; Randomized; Research Institute; Resistance; Risk; Sample Size; Site; Structure; Suicide; Testing; Therapeutic; Time; Vascular Dementia; Work; base; care costs; cognitive function; cognitive performance; cortico-limbic circuits; cost; dementia risk; depressive symptoms; design; effective therapy; executive function; experience; geriatric depression; high risk; high risk population; improved; indexing; innovation; learning strategy; molecular marker; neural circuit; neuroimaging; neuroimaging marker; novel; older patient; persistent symptom; predictive marker; predictive tools; prevent; recruit; relating to nervous system; senescence; treatment response

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.

项目摘要 描述：痴呆症，尤其是阿尔茨海默氏症的痴呆症（AD），是一个日益增长的公共卫生问题 仅美国（全球3300万）就有5M的患病率。尽管发病率降低，但随着年龄的衰老 人口，痴呆症的患病率预计在美国（全球1.15亿）的人口将增加到1600万 相关费用上涨至$ 1T。将长期护理延迟1个月的年长美国人将节省$ 60B 预防或延迟痴呆的努力在很大程度上没有成功。然而， 晚期重度抑郁症（“晚期抑郁症”，LLD）已被确定为六种可治疗风险之一 痴呆症的因素，尤其是AD和血管性痴呆。抑郁症的关系可能是 在不反应抗抑郁治疗和经历持续症状的长辈中放大了。 解决那些有耐药晚期抑郁症（TRLLD）的人是否有更高的风险 与接受治疗响应的LLD相比，认知能力下降和痴呆症的进展至关重要 重要的。 利用以患者为中心的结果研究所（PCORI）资助的治疗研究N = 1500 LLD的人，在5个站点上，我们建议全面描述神经认知和神经影像学 与持续性LLD（即TRLLD）相比的生物标志物与痴呆症的发展 那些在接受治疗的人。我们预计将招募750名老年人，并描述他们的表征 有症状的轨迹在24个月内。我们将以神经认知的三个时间点评估每个参与 和高级神经影像学。我们假设执行职能的变化和执行控制 网络以及情节内存和默认模式/Cortico-limbic网络的变化将更大 那些患有TRLLD的人比那些对待治疗并保持良好的人。我们还假设改变了 执行功能和情节记忆的两年将特别与执行的变化有关 对照和皮质膜电路分别。 根据我们最近的发现，炎症和相关的分子标记可以区分 神经认知障碍和仅来自LLD的神经认知障碍和LLD，我们将建立一个预测性多元模型 将基线神经认知，神经影像学和血浆蛋白数据结合在一起，以确定谁最大的风险 认知能力下降和痴呆症。最后，我们还将探索抑郁症的潜在类轨迹 症状可以超越缓解/不抑制的二分法，以识别患有LLD的长老子集 认知能力下降，神经回路变化和痴呆症的最高风险。 这项工作将为靶向预防性护理奠定阶段，以延迟老年患者子集的痴呆症 与lld。如果成功的话，我们的工作可以加快针对抑郁症的治疗努力和创新 - 痴呆症途径并减少大量长老及其家人的苦难。