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: 10626805
• 负责人: Daniel A Kirsch
• 金额: $ 4.77万
• 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/10626805
• 关键词: Address; Astrocytes; Autopsy; Basal Ganglia; Binding; Blood Vessels; Brain; Cd68; Cells; Clinic; Clinical; Clinical Data; Craniocerebral Trauma; Cytopathology; Data; Dentate nucleus; Deposition; Development; Diagnosis; Disease; Disease stratification; 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; 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; Phenotype; Play; Populations at Risk; 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; behavior change; biomarker identification; 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; neuropathology; novel diagnostics; pars compacta; persistent symptom; tau Proteins; tau aggregation; tau-1; therapeutic target; therapeutically effective; vascular abnormality; vascular inflammation; 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，其特征在于过度磷酸化的tau蛋白（p-tau）的积累。那个... CTE的tau病理学通过创伤后神经炎症和微血管损伤而增强。共同 CTE的临床症状包括认知损害、情绪和行为改变以及帕金森综合征。其他 与帕金森综合征相关的基于p-tau的神经变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 头部创伤神经炎症或微血管损伤CTE，PSP和CBD仅被明确诊断 在验尸时CTE p-tau含有具有三个重复（3R）和四个重复（4 R）的tau同种型， PSP和CBD是唯一的4 R tau蛋白病。在PSP和CBD中，运动区（MR）中的p-tau病理学 与帕金森症相关，但对CTE中的帕金森症了解较少。这种知识差距导致我们 假设微血管损伤和炎症在3R和4 R p-tau蛋白积聚中起关键作用， CTE中的MR，并且MR p-tau负荷将与CTE中的帕金森症相关。我们进一步假设 CTE中的MR p-tau负荷与既往头部创伤的持续时间和剂量呈正相关 （测量为重复头部撞击（RHI））。为了证实我们的假设，我们将使用死后组织 从神经病理学证实的CTE、PSP和CBD病例中进行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发生中的作用 CTE的病理学将通过纳入RHI初治对照、RHI暴露对照来明确确定 未发生CTE的对照组，以及PSP和CBD病例。在目标1中，我们将定量3R和4 R MR p-tau 与PSP和CBD相比，CTE的负担，并用多重 免疫荧光染色以确定CTE中增加的MR p-tau病理学。在目标2中，我们将定量MR 与PSP，CBD， 使用免疫组织化学、组织清除和蛋白质免疫测定， 确定CTE中MR炎症、微血管病理学和多巴胺能细胞损失增加。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中的死前帕金森症McKee实验室和BU CTE中心（赞助商和合作伙伴）之前的工作 申办者）和初步数据已经验证了所提出的技术。我们将描绘出 CTE中MR的炎症特征、微血管改变和p-tau病理与PSP不同 和CBD，以及CTE中MR p-tau病理学和帕金森症之间的相关性，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标。

项目成果

Neuropathologic and Clinical Findings in Young Contact Sport Athletes Exposed to Repetitive Head Impacts.

• DOI: 10.1001/jamaneurol.2023.2907
• 发表时间: 2023-10-01
• 期刊: JAMA NEUROLOGY
• 影响因子: 29
• 作者: Mckee, Ann C.;Mez, Jesse;Abdolmohammadi, Bobak;Butler, Morgane;Huber, Bertrand Russell;Uretsky, Madeline;Babcock, Katharine;Cherry, Jonathan D.;Alvarez, Victor E.;Martin, Brett;Tripodis, Yorghos;Palmisano, Joseph N.;Cormier, Kerry A.;Kubilus, Caroline A.;Nicks, Raymond;Kirsch, Daniel;Mahar, Ian;Mchale, Lisa;Nowinski, Christopher;Cantu, Robert C.;Stern, Robert A.;Daneshvar, Daniel;Goldstein, Lee E.;Katz, Douglas I.;Kowall, Neil W.;Dwyer, Brigid;Stein, Thor D.;Alosco, Michael L.
• 通讯作者: Alosco, Michael L.