Tau Pathology in Motor Regions and Parkinsonism in Chronic Traumatic Encephalopathy: A Comparison to Progressive Supranuclear Palsy and Corticobasal Degeneration

慢性创伤性脑病运动区 Tau 蛋白病理学和帕金森病：与进行性核上性麻痹和皮质基底节变性的比较

• 批准号: 10464173
• 负责人: Daniel A Kirsch
• 金额: $ 4.68万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464173
• 关键词: Address; Astrocytes; Autopsy; Basal Ganglia; Binding; Biological Markers; Brain; Cells; Clinic; Clinical; Clinical Data; Craniocerebral Trauma; Cytopathology; Data; Dentate nucleus; Deposition; Development; Diagnosis; Diagnostic; Disease; Dopaminergic Cell; Dose; Etiology; Exposure to; Extravasation; Fibrinogen; Fibroblast Growth Factor; Fresh Tissue; Glial Fibrillary Acidic Protein; Goals; ICAM1 gene; Immunoassay; Immunohistochemistry; Impaired cognition; Individual; Inflammation; Inflammatory; Injury; Interview; Knowledge; Label; Life; Link; Measures; Microscopy; Microtubules; Mission; Moods; Morbidity - disease rate; Motor; Motor Cortex; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oligodendroglia; Parkinsonian Disorders; Pathologic; Pathology; Pattern; Persons; Phenotype; Play; Positioning Attribute; Prognostic Marker; Progressive Supranuclear Palsy; Protein Isoforms; Proteins; Proteomics; Public Health; Recording of previous events; Red nucleus structure; Research; Resources; Risk; Role; Serum Albumin; Spatial Distribution; Stains; Standardization; Structural defect; Substantia nigra structure; Symptoms; Tauopathies; Techniques; Testing; Tissues; Trauma; Traumatic Brain Injury; Tyrosine 3-Monooxygenase; United States National Institutes of Health; Vascular Endothelial Growth Factors; Work; base; behavior change; brain tissue; cell type; chronic traumatic encephalopathy; cohort; contact sports; corticobasal degeneration; diagnostic biomarker; dopaminergic neuron; dosage; effective therapy; experience; head impact; hyperphosphorylated tau; indexing; inflammatory marker; informant; microvascular pathology; military service; military veteran; mortality; neuroinflammation; novel diagnostics; pars compacta; persistent symptom; tau Proteins; tau aggregation; tau-1; therapeutic target; therapeutically effective; vascular injury

Abstract: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head trauma and characterized by accumulation of hyperphosphorylated tau protein (p-tau). The p- tau pathology of CTE is enhanced by post-traumatic neuroinflammation and microvascular damage. Common clinical symptoms of CTE include cognitive impairment, mood and behavior changes, and parkinsonism. Other p-tau based neurodegenerative disorders associated with parkinsonism include progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), two distinct sporadic tauopathies with no known association with head trauma, neuroinflammation, or microvascular damage. CTE, PSP, and CBD are definitively diagnosed only at postmortem examination. CTE p-tau contains tau isoforms with three repeats (3R) and four repeats (4R) while PSP and CBD are exclusively 4R tauopathies. In PSP and CBD, p-tau pathology in motor regions (MRs) correlates with parkinsonism, but parkinsonism in CTE is less well understood. This knowledge gap led us to hypothesize that microvascular injury and inflammation play critical roles in accumulation of 3R and 4R p-tau in MRs in CTE, and that MR p-tau burden will be associated with parkinsonism in CTE. We further hypothesize that MR p-tau burden in CTE will be positively associated with duration and dose of previous head trauma (measured as repetitive head impacts (RHI)) in CTE. To address our hypotheses, we will use postmortem tissue from neuropathologically confirmed cases of CTE, PSP, and CBD for immunohistological and proteomic analysis, as well as corresponding clinical data. The role of RHI exposure in the development of MR p-tau pathology in CTE will be definitively established through the inclusion of RHI-naïve controls, RHI-exposed controls that did not develop CTE, and cases of PSP and CBD. In Aim 1, we will quantitate 3R and 4R MR p-tau burden in CTE compared to PSP and CBD, and characterize disease-specific cytopathology with multiplex immunofluorescent staining to determine increased MR p-tau pathology in CTE. In Aim 2, we will quantitate MR neuroinflammation and microvascular pathology and nigral dopaminergic cells in CTE compared to PSP, CBD, RHI-naïve and RHI-exposed controls using immunohistochemistry, tissue clearing, and protein immunoassay to establish increased MR inflammation, microvascular pathology and loss of dopaminergic cells in CTE. In Aim 3, we will use available clinical data to assess associations among RHI exposure, MR p-tau pathology, and antemortem parkinsonism in CTE. Previous work by the McKee Lab and BU CTE Center (Sponsor and Co- Sponsor) and preliminary data have validated the proposed techniques. We will delineate the unique inflammatory features, microvascular alterations, and p-tau pathology in MRs in CTE that are distinct from PSP and CBD, and the correlation between MR p-tau pathology and parkinsonism in CTE, in order to help identify diagnostic biomarkers and therapeutic targets for CTE and other tauopathies.

【摘要】：慢性创伤性脑病(CTE)是一种与暴露相关的神经退行性疾病。 重复性头部创伤，其特征是过度磷酸化 tau 蛋白 (p-tau) 的积累。该 p- CTE 的 tau 蛋白病理学因创伤后神经炎症和微血管损伤而增强。常见的 CTE 的临床症状包括认知障碍、情绪和行为改变以及帕金森症。其他 与帕金森病相关的基于 p-tau 的神经退行性疾病包括进行性核上性麻痹 （PSP）和皮质基底节变性（CBD），两种不同的散发性 tau蛋白病，与 头部外伤、神经炎症或微血管损伤。仅明确诊断 CTE、PSP 和 CBD 在尸检时。 CTE p-tau 包含具有三个重复 (3R) 和四个重复 (4R) 的 tau 亚型，而 PSP 和 CBD 完全是 4R tau蛋白病。在 PSP 和 CBD 中，运动区 (MR) 的 p-tau 病理学 与帕金森症相关，但 CTE 中的帕金森症尚不清楚。这种知识差距导致我们 假设微血管损伤和炎症在 3R 和 4R p-tau 的积累中起关键作用 CTE 中的 MR，并且 MR p-tau 负担将与 CTE 中的帕金森病相关。我们进一步假设 CTE 中的 MR p-tau 负荷与先前头部外伤的持续时间和剂量呈正相关 （以重复头部撞击 (RHI) 的形式测量）CTE。为了验证我们的假设，我们将使用死后组织 来自神经病理学确诊的 CTE、PSP 和 CBD 病例，用于免疫组织学和蛋白质组学研究 分析，以及相应的临床数据。 RHI 暴露在 MR p-tau 发展中的作用 CTE 的病理学将通过纳入未接触过 RHI 的对照、暴露于 RHI 的对照来明确建立 未发生 CTE 的对照，以及 PSP 和 CBD 的案例。在目标 1 中，我们将定量 3R 和 4R MR p-tau 与 PSP 和 CBD 相比，CTE 的负担，并通过多重表征疾病特异性细胞病理学 免疫荧光染色以确定 CTE 中 MR p-tau 病理学的增加。在目标 2 中，我们将量化 MR 与 PSP、CBD 相比，CTE 中的神经炎症和微血管病理学以及黑质多巴胺能细胞 使用免疫组织化学、组织透明化和蛋白质免疫测定法进行 RHI 未接触和 RHI 暴露对照 建立 CTE 中 MR 炎症、微血管病理学和多巴胺能细胞损失的增加。在目标 3 中， 我们将使用现有的临床数据来评估 RHI 暴露、MR p-tau 病理学和 CTE 中的生前帕金森病。 McKee 实验室和 BU CTE 中心（赞助商和合作者）之前的工作 赞助商）和初步数据验证了所提出的技术。我们将描绘出独一无二的 CTE 中 MR 的炎症特征、微血管改变和 p-tau 病理学与 PSP 不同 和 CBD，以及 MR p-tau 病理学与 CTE 帕金森病之间的相关性，以帮助识别 CTE 和其他 tau蛋白病的诊断生物标志物和治疗靶点。