Deep Phenotypic Characterization of Prodromal Dementia with Lewy Bodies

在美国，大约有140万人患有路易体痴呆症，其中包括痴呆症和痴呆症。 路易体（DLB）和帕金森病（PD）痴呆（PDD）。DLB患者出现认知功能下降 类似于阿尔茨海默病（AD），在PD 5中观察到的运动改变，与PD 5相关的行为和精神病特征， DSM 5轴I精神疾病，以及经常作为早期预警而错过的体质和自主神经特征 信号装置.重要的是，最近的努力已经根据表现症状描述了前驱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， 先进的研究，但很少有DLB作为重点。不幸的是，诊断DLB及其前驱状态， 这是困难的，患者看到3名以上的医生，并经历了18个月的诊断延迟。而 DLB共识标准具有极好的特异性，直到最近才有标准化的方法来评估体征 和症状来提高敏感性。最近，我们通过Lewy Body Composite， 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（a）表征DLB，（B）区分DLB与认知正常的能力 对照和AD，以及（c）区分由于DLB引起的轻度认知障碍（MCI）和由于AD引起的MCI。这 应用程序将测试假设，DLB-MCI具有独特的神经心理学，神经解剖学， 神经生理特征与AD或血管性痴呆（VCID）引起的MCI不同。我们进一步重申， 结合科学水平的血浆生物标志物（例如，淀粉样蛋白、tau蛋白、突触核蛋白）改善检测并允许 共病病理学的死前表征以及病理学如何驱动向DLB的转变以及 进展我们将利用现有的健康脑老化、MCI、AD和VCID的纵向队列（n=850）， 使用相同的数据收集平台，以提供可靠的比较组，而无需为此应用程序付费。我们 具体目的是：（1）招募和深表型DLB-MCI队列（n=300）系统表征 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 （2）细化前驱DLB的表型呈现及其相关的生物标志物特征， 正式测试最近发表的临床标准，并利用PI现有队列的存档数据， 将DLB-MCI区分为不同临床实体的相同数据平台;以及（3）模拟临床认知 特征、遗传、成像、qEEG和血浆生物标志物，以预测向DLB的转变和表征进展 基于生物变量（例如，性别，ApoE），共病病理（例如，淀粉样蛋白、tau蛋白）和症状 呈现（例如，波动、幻觉）。DLB是神经退行性疾病的第二大常见原因。 然而，前驱状态尚未得到充分验证，DLB生物标志物尚未得到很好的建立， 共存的病理对表现和进展的贡献还没有完全理解。我们的长期 目的是定义一组简约的DLB标记，以在未来的多地点研究中重复和验证。

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.