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Lewy身体痴呆症，其中包括痴呆症 路易尸体（DLB）和帕金森氏病（PD）痴呆（PDD）。 DLB患者经历认知能力下降 与阿尔茨海默氏病（AD）类似，PD5中看到的运动变化，行为和精神病特征与 DSM5轴I精神疾病以及宪法和自主性特征通常会被视为预警 标志。重要的是，最近的努力描述了前瞻性DLB亚型，根据症状（例如， 认知，运动，睡眠，行为）。 AD和PD都受益于大型纵向研究 高级研究，但很少有人将DLB作为重点。不幸的是，DLB及其前驱状态的诊断可以 要困难，患者看到3名以上的医生，并且经历了18个月的诊断延迟。而 DLB共识标准具有良好的特异性，直到最近才有标准化的方法来评估迹象 和症状以提高灵敏度。我们采取了最近的努力来改善Lewy身体复合材料的诊断 NIA资助的阿尔茨海默氏病研究中心的风险评分（LBCR）和DLB模块（DLB模型） 程序。这些进步加速了（a）表征DLB的能力，（b）歧视DLB与认知正常 对照和AD，以及（c）由于AD引起的DLB而区分了轻度认知障碍（MCI）。这 应用将检验以下假设：DLB-MCI具有独特的神经心理学，神经解剖学和 由于AD或血管性痴呆（VCID），与MCI不同的神经生理特征（VCID）。我们进一步认为 结合科学等离子生物标志物（例如淀粉样蛋白，tau，Synclein）可改善检测和许可 联合病理学的动物质地表征以及病理学如何推动过渡到DLB和速率 进展。我们将利用健康的脑衰老，MCI，AD和VCID的现有纵向队列（n = 850） 使用相同的数据收集平台以无需与此应用程序无需提供可靠的比较组。我们的 具体目的是：（1）招募和深表型DLB-MCI队列（n = 300）系统地表征 并验证临床认知 - 脊椎行为自治特征，MRI，DAT，QEEG，血浆和遗传DLB 生物标志物； （2）前列型DLB及其相关的生物标志的精炼表型表现与 正式测试最近发布的临床标准，并利用PI现有同伙的档案数据 相同的数据平台将DLB-MCI区分开为独特的临床实体； （3）临床认知模型 特征，遗传，成像，QEEG和等离子体生物标志物，以预测过渡和表征到DLB 基于生物学变量（例如性别，apoE），合并症（例如淀粉样蛋白，tau）和症状 演示文稿（例如波动，幻觉）。 DLB是神经退行性的第二大最常见原因 然而，痴呆症尚未得到充分验证，DLB生物标志物的确定性尚未得到充分验证，并且 共存病理对表现和进展的贡献尚不完全了解。我们的长期 目的是定义一组简约的DLB标记，以在未来的多站点研究中复制和验证。