Clinicopathologic Studies of Lewy Body Disease

路易体病的临床病理学研究

• 批准号: 7119706
• 负责人: DENNIS WILLIAM DICKSON
• 金额: $ 12.16万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7119706
• 关键词: Lewy body; Parkinson' s disease; alpha synuclein; anosmia; automated medical record system; autonomic nervous system; biochemistry; brain disorder diagnosis; brain stem; dementia; depression; disease /disorder classification; disease /disorder proneness /risk; early diagnosis; epidemiology; family genetics; gliosis; histopathology; human tissue; nervous system disorder; neural degeneration; neuropathology; pathologic process; patient oriented research; postmortem; progressive supranuclear palsy; prosencephalon; sleep disorders; tau proteins

Identification of the earliest stage of Parkinson's disease (PD) is critical to understanding its etiology. The idea that the substantia nigra is the primary site of pathology in PD is challenged by the anatomical staging for Lewy body disease (LBD) proposed by Braak and co-workers, in which substantia nigra LBs are detected at mid-stage and neuronal loss at some undefined later stage. If the LBD staging scheme is validated, the implications are clear. Non-motor manifestations are the earliest signs of PD (i.e. preclinical PD), not the extrapyramidal signs that are currently used to diagnose PD. The aim of this proposal is to validate the LBD staging scheme using clinicopathologic approaches and the Mayo Medical Records Linkage System (MMRLS). Medical records of cases determined to have incidental LBs will be screened for clinical, demographic and environmental risk factors that have been implicated in PD and compared to matched cases without LBs. The LBD staging scheme predicts several non-motor features of preclinical PD, including anosmia, autonomic dysfunction, sleep disorders and depression. The MMRLS will be queried for cases that have come to autopsy meeting these clinical descriptors and their brains and matched controls will be studied for LBs. The proposed LBD staging scheme does not include estimates of severity or neuronal loss, but these will be assessed with quantitative methods. Specifically, in brains found to have incidental LBs and those with more advanced stages, neuronal counts and gliosis will be measured in brainstem and basal forebrain nuclei that are vulnerable at the earliest stages. In collaboration with Project by Yen, biochemical measures of abnormal alpha-synuclein species will be measured in multiple brain regions to compare biochemical with histopathologic staging. To validate LBD staging in an independent pathologic cohort, a large series of progressive supranuclear palsy (PSP) brains will be screened for LBs, and the distribution will be compared to staging in non-PSP cases. The applicability of the LBD staging scheme will also be assessed in LBD cases acquired through various resources available to the Neuropathology Core, including cases of dementia with LBs, PD with later developing dementia and familial LBD cases studied by the Clinical and Genetic Cores. Finally, the possible contribution of tau pathology to LBD will be assessed since studies by the Genetic Core implicate TAU in PD.

帕金森氏病(PD)早期诊断是了解其病因的关键。Braak和他的同事提出的路易体病(LBD)的解剖学分期对黑质是PD的主要病理部位的观点提出了挑战，在LBD的解剖学分期中，黑质LBS在中期被发现，而神经元的丢失在一些不确定的后期被发现。如果LBD分期方案得到验证，其影响是显而易见的。非运动性表现是帕金森病最早的体征(即临床前帕金森病)，而不是目前用于诊断帕金森病的锥体外系体征。该提案的目的是使用临床病理方法和Mayo医疗记录链接系统(MMRLS)来验证LBD分期方案。将对确定为偶发性LBS的病例的医疗记录进行筛查，以确定与PD有关的临床、人口和环境风险因素，并将其与没有LBS的匹配病例进行比较。LBD分期方案预测了几个非电机 临床前帕金森病的特征，包括嗅觉障碍、自主神经功能障碍、睡眠障碍和 抑郁症。将向MMRLS查询符合这些临床描述的尸检病例，并研究他们的大脑和匹配的对照组是否存在LBS。建议的LBD分期方案不包括对严重程度或神经元丢失的估计，但这些将用定量方法进行评估。具体地说，在被发现患有偶发性LBS的大脑和那些处于更晚期的大脑中，将在脑干和基底前脑核团中测量神经元计数和胶质细胞增生，这些核团在最早的阶段就很脆弱。在与Yen Project By Yen的合作下，将在多个脑区测量异常α-突触核蛋白物种的生化测量，以比较生化与组织病理学分期。为了在独立的病理队列中验证LBD分期，将对大量进行性核上性瘫痪(PSP)脑进行LBS筛查，并将其分布与非PSP病例的分期进行比较。LBD分期计划的适用性也将在通过神经病理学核心可用的各种资源获得的LBD病例中进行评估，包括伴有LBS的痴呆症病例、后来发展为痴呆症的PD病例以及由临床和遗传核心研究的家族性LBD病例。最后，将评估tau病理对LBD的可能贡献，因为遗传核心的研究表明TAU与PD有关。