Clinicopathologic Studies of Lewy Body Disease

路易体病的临床病理学研究

• 批准号: 7687304
• 负责人: DENNIS WILLIAM DICKSON
• 金额: $ 11.8万
• 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/7687304
• 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.

鉴定帕金森氏病（PD）最早的阶段对于理解其病因至关重要。 Braak及其同事提出的Lewy身体疾病（LBD）的解剖学分期挑战了Nigra是PD中病理学的主要部位，在某些阶段中，在中期和神经元损失中，在某些未定义的阶段中检测到了黑质LBS。如果验证了LBD登台方案，则含义是明确的。非运动表现是PD的最早迹象（即临床前PD），而不是当前用于诊断PD的腹膜外符号。该提案的目的是使用临床病理学方法和Mayo病历连锁系统（MMRL）验证LBD分期计划。确定具有偶然磅的病例的病历将筛选为已与PD有关的临床，人口统计和环境风险因素，并将其与没有LB的匹配病例进行了比较。 LBD分期方案预测了几种非运动器 临床前PD的功能，包括厌食，自主功能障碍，睡眠障碍和 沮丧。 MMRL将询问针对这些临床描述符的尸检病例，将研究其大脑和匹配的对照组的LBS。拟议的LBD分期方案不包括严重性或神经元损失的估计值，但将通过定量方法进行评估。具体而言，在发现具有偶然LB的大脑中，具有更先进的阶段的大脑，神经元计数和神经胶质病将在脑干和基础前脑核中进行测量，这些核在最早的阶段很容易受到伤害。与日元的Project合作，将在多个大脑区域测量异常α-突触核蛋白物种的生化测量，以将生化与组织病理学分期进行比较。为了验证独立病理队列中的LBD分期，将筛选一大批进行性核上麻痹（PSP）大脑的大脑的LBS，并将分布与非PSP病例的分期进行比较。 LBD分期计划的适用性也将在通过可用于神经病理学核心的各种资源获得的LBD病例中进行评估，包括伴有LBS的痴呆症病例，PD，后来患有痴呆症和家族性LBD病例，由临床和遗传核心研究。最后，由于遗传核心的研究暗示了tau在PD中，因此将评估TAU病理对LBD的可能贡献。