Deep Phenotypic Characterization of Prodromal Dementia with Lewy Bodies

路易体前驱痴呆的深层表型特征

• 批准号: 10670501
• 负责人: James E Galvin
• 金额: $ 317.14万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670501
• 关键词: Alzheimer' s Disease; Amyloid; Apolipoprotein E; Attention; Autopsy; Behavioral; Biological; Biological Markers; Caregivers; Clinical; Cognition; Cognitive; Collaborations; Consensus; Consent; Constitutional; DSM-V; Data; Data Collection; Data Set; Delirium; Dementia; Dementia with Lewy Bodies; Detection; Diagnosis; Dorsal; Early Diagnosis; Electroencephalography; Functional Magnetic Resonance Imaging; Funding; Future; Genetic; Goals; Hallucinations; Image; Impaired cognition; Individual; Industry; Lead; Lewy Bodies; Lewy Body Dementia; Longitudinal Studies; Longitudinal cohort; Magnetic Resonance Imaging; Mental disorders; Modeling; Motor; National Institute of Neurological Disorders and Stroke; Neuropsychology; Parkinson Disease; Parkinson' s Dementia; Parkinsonian Disorders; Pathology; Patients; Persons; Phenotype; Physicians; Plasma; Publishing; REM Sleep Behavior Disorder; Research; Rest; Risk; Science; Signs and Symptoms; Site; Sleep; Specificity; Spinal Puncture; Standardization; Symptoms; Testing; United States; Vascular Dementia; Visual; Work; aging brain; archive data; archived data; base; biomarker signature; clinical diagnosis; cognitive ability; cognitive performance; cohort; comorbidity; comparison group; cost; dopamine system; executive function; experience; improved; innovation; mild cognitive impairment; multimodality; neurodegenerative dementia; neuroimaging; neurophysiology; new therapeutic target; novel; pre-clinical; programs; progression marker; public health relevance; recruit; sex; sleep behavior; synuclein; tau Proteins; white matter

Approximately 1.4 million people in the United States have Lewy body dementia, which includes both dementia with Lewy bodies (DLB) and Parkinson's disease (PD) dementia (PDD). Patients with DLB experience cognitive decline similar to Alzheimer's disease (AD), motor changes seen in PD5, behavioral and psychotic features associated with DSM5 Axis I psychiatric disorders, and constitutional and autonomic features that are often missed as early warning signs. Importantly, recent efforts have described prodromal DLB subtypes according to presenting symptoms (e.g., cognition, motor, sleep, behavior). Both AD and PD have benefited from large longitudinal studies that have advanced research, but few have DLB as a focus. Unfortunately, the diagnosis of DLB and its prodromal states can be difficult, with patients seeing more than 3 physicians and experiencing an 18-month delay to diagnosis. While the DLB consensus criteria have excellent specificity, until recently there has been no standardized way to assess signs and symptoms to improve sensitivity. We have led recent efforts to improve diagnosis with the Lewy Body Composite Risk Score (LBCRS) and the DLB-Module (DLB-MOD) for the NIA-funded Alzheimer Disease Research Center Program. These advances hastened the ability to (a) characterize DLB, (b) discriminate DLB from cognitively normal controls and AD, and (c) discriminate mild cognitive impairment (MCI) due to DLB from MCI due to AD. This application will test the HYPOTHESIS that DLB-MCI has unique neuropsychological, neuroanatomic, and neurophysiologic signatures distinct from MCI due to AD or vascular dementia (VCID). We further posit that combining state-of-the-science plasma biomarkers (e.g., amyloid, tau, synuclein) improves detection and permits antemortem characterization of co-morbid pathology and how pathology may drive transition to DLB and rates of progression. We will leverage existing longitudinal cohorts (n=850) of healthy brain aging, MCI, AD, and VCID that use identical data collection platforms to provide robust comparison groups at no cost to this application. Our SPECIFIC AIMS are: (1) Recruit and deep phenotype a DLB-MCI cohort (n=300) systematically characterizing and validating clinical-cognitive-sleep-behavioral-autonomic features, MRI, DAT, qEEG, plasma and genetic DLB biomarkers; (2) Refine phenotypic presentations of prodromal DLB and their associated biomarker signatures to formally test the recently published clinical criteria and leverage archival data from the PI's existing cohorts using identical data platforms to differentiate DLB-MCI as a distinct clinical entity; and (3) Model clinical-cognitive features, genetic, imaging, qEEG, and plasma biomarkers to predict transition and characterize progression to DLB based on biological variables (e.g., sex, ApoE), comorbid pathologies (e.g., amyloid, tau), and symptom presentations (e.g., fluctuations, hallucinations). DLB is the second most common cause of neurodegenerative dementia, however prodromal states have not yet been fully validated, DLB biomarkers are not well established, and the contribution of co-existent pathologies to presentation and progression is not fully understood. Our long-term goal is to define a parsimonious set of DLB markers to replicate and validate in a future multi-site study.

在美国大约有140万人患有路易体痴呆症，包括痴呆症和 路易小体(DLB)和帕金森病(PD)痴呆(PDD)。DLB患者认知功能减退 与阿尔茨海默病(AD)类似，PD5中出现的运动变化，行为和精神特征与 DSM5轴I精神障碍，以及经常被遗漏的早期预警的体质和自主神经特征 有征兆。重要的是，最近的努力根据出现的症状描述了前驱DLB亚型(例如， 认知、运动、睡眠、行为)。AD和PD都受益于大型纵向研究，这些研究 先进的研究，但很少有DLB作为重点。不幸的是，DLB及其前驱状态的诊断可以 困难的是，患者看3个以上的医生，并经历18个月的延迟诊断。而当 DLB共识标准具有极好的特异性，直到最近还没有标准化的方法来评估征兆 和症状来提高敏感度。我们领导了最近的努力，以改善路易体复合材料的诊断 NIA资助的阿尔茨海默病研究中心的风险评分(LBCRS)和DLB模块(DLB-MOD) 程序。这些进展加速了以下能力：(A)确定DLB的特征；(B)区分DLB与认知正常 (C)区分DLB引起的轻度认知损害(MCI)和AD引起的MCI。这 应用程序将检验DLB-MCI具有独特的神经心理学、神经解剖学和 神经生理学特征不同于AD或血管性痴呆(VCID)所致的MCI。我们进一步假设 结合最先进的血浆生物标志物(例如，淀粉样蛋白、tau、突触核蛋白)可以改进检测并允许 共病病理的生前特征，以及病理如何推动向DLB的转变以及 进步。我们将利用现有的健康脑老化、MCI、AD和VCID纵向队列(n=850) 使用相同的数据收集平台来提供强大的对比组，而不会对此应用程序产生任何影响。我们的 具体目标是：(1)招募和深入表型DLB-MCI队列(n=300)系统地表征 并验证临床-认知-睡眠-行为-自主神经特征、MRI、DAT、qEEG、血浆和遗传DLB 生物标志物；(2)完善前驱DLb的表型表现及其相关的生物标志物特征，以 正式测试最近发布的临床标准，并利用PI现有队列中的档案数据 相同的数据平台以区分DLB-MCI作为一个不同的临床实体；以及(3)模型临床-认知 特征、遗传、成像、qEEG和血浆生物标记物，用于预测向DLB的过渡和特征进展 基于生物变量(如性别、载脂蛋白E)、共病病理(如淀粉样蛋白、tau)和症状 表现(例如，波动、幻觉)。DLB是导致神经退行性变的第二大常见原因 然而，痴呆的前驱状态尚未得到充分验证，DLB生物标志物还没有很好地建立起来，以及 共同存在的病理对表现和进展的贡献尚不完全清楚。我们的长期合作 目标是定义一组简约的DLB标记，以便在未来的多点研究中重复和验证。