Clinicopathologic Studies of Lewy Body Disease

路易体病的临床病理学研究

• 批准号: 7491431
• 负责人: DENNIS WILLIAM DICKSON
• 金额: $ 13.27万
• 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/7491431
• 关键词: Abbreviations; Address; Anosmia; Anterior; Astrocytes; Autonomic Dysfunction; Autopsy; Biochemical; Brain; Brain Stem; Brain region; Case Study; Cell Nucleus; Classification; Clinical; Cognitive; Collaborations; Collection; Compatible; Count; Dementia; Descriptor; Diagnosis; Disease; Early identification; Environmental Risk Factor; Epidemiology; Etiology; Familial Dementias; Frequencies; Genetic; Genetic Risk; Genetic Variation; Glial Fibrillary Acidic Protein; Gliosis; Goals; HLA-DR Antigens; Image Analysis; Immunohistochemistry; In Vitro; Lesion; Lewy Bodies; Lewy Body Disease; Measures; Medical Genetics; Medical Record Linkage; Medical Records; Mental Depression; Mental disorders; Methods; Microglia; Motor; Motor Manifestations; Neurites; Neurologic; Neurons; Normalcy; Paralysed; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Progressive Supranuclear Palsy; Publishing; Resources; Sampling; Scheme; Series; Severities; Site; Sleep Disorders; Staging; Substantia nigra structure; System; Testing; alpha synuclein; basal forebrain; case control; clinically relevant; cohort; immunoreactivity; neuron loss; neuropathology; olfactory nuclei; pre-clinical; synuclein; tau Proteins; tau mutation

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.

帕金森病（PD）的最早阶段的识别对于了解其病因至关重要。Braak及其同事提出的路易体病（Lewy body disease，LBD）的解剖学分期挑战了黑质是PD病理学主要部位的观点，即黑质LB在中期被检测到，而神经元丢失在某些不确定的晚期被检测到。如果LBD分期方案得到验证，其含义是明确的。非运动表现是PD的最早体征（即临床前PD），而不是目前用于诊断PD的锥体外系体征。本提案的目的是使用临床病理学方法和马约病历链接系统（MMRLS）验证LBD分期方案。将对确定为偶发LB的病例的病历进行筛选，以确定与PD相关的临床、人口统计学和环境风险因素，并与无LB的匹配病例进行比较。LBD分期方案预测了几种非运动性 临床前PD的特征，包括嗅觉丧失、自主神经功能障碍、睡眠障碍和 萧条将查询MMRLS中符合这些临床描述符的尸检病例，并将研究其大脑和匹配对照的LB。拟议的LBD分期方案不包括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。具体而言，在发现具有偶然LB的大脑和具有更晚期阶段的大脑中，将在最早阶段脆弱的脑干和基底前脑核中测量神经元计数和神经胶质增生。与Yen项目合作，将在多个脑区测量异常α-突触核蛋白种类的生化指标，以比较生化和组织病理学分期。为了在一个独立的病理学队列中验证LBD分期，将对一系列进行性核上性麻痹（PSP）脑进行LB筛查，并将分布与非PSP病例的分期进行比较。LBD分期方案的适用性也将在通过神经病理学核心的各种资源获得的LBD病例中进行评估，包括临床和遗传核心研究的痴呆伴LBs、PD伴晚期痴呆和家族性LBD病例。最后，将评估tau病理学对LBD的可能贡献，因为遗传核心的研究表明TAU与PD有关。