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

摘要：慢性创伤性脑病是一种与暴露相关的神经退行性疾病。 反复头部创伤，以过度磷酸化的tau蛋白(p-tau)积聚为特征。P- 创伤后神经炎和微血管损伤可增强CTE的tau病理改变。普普通通 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 与帕金森综合征相关的基于P-tau的神经退行性疾病包括进行性核上性瘫痪 (PSP)和皮质基底膜退行性变(CBD)是两种不同的散发性神经病，尚未发现与 头部创伤、神经炎症或微血管损伤。CTE、PSP和CBD只能明确诊断 在验尸时。CTE p-tau含有带有三个重复(3R)和四个重复(4R)的tau亚型，而 PSP和CBD完全是4R牛皮病。在PSP和CBD中，运动区的p-tau病理(MRS) 与帕金森病有关，但对CTE中的帕金森病了解较少。这一知识鸿沟使我们 假设微血管损伤和炎症在3R和4R p-tau的积聚中起关键作用 P-tau先生的负担将与CTE中的帕金森病有关。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 (以重复头部撞击(RHI)衡量)，以CTE表示。为了解决我们的假设，我们将使用尸检组织 来自神经病理确诊的CTE、PSP和CBD患者的免疫组织学和蛋白质组学 分析，以及相应的临床数据。RHI暴露在MR p-tau发病中的作用 CTE的病理学将通过纳入RHI-幼稚对照、暴露于RHI的 未发生CTE的对照组，以及PSP和CBD病例。在目标1中，我们将对3R和4R MR p-tau进行量化 CTE与PSP和CBD的负担比较，并用多重方法表征疾病特异性细胞病理学 免疫荧光染色确定CTE患者MR p-tau病理改变。在目标2中，我们将对MR进行量化 CTE患者的神经炎症和微血管病理及黑质多巴胺能细胞与PSP，CBD， 使用免疫组织化学、组织透明和蛋白质免疫分析的RHI-NAIVE和RHI暴露对照 在CTE中建立增加的MR炎症、微血管病理和多巴胺能细胞丢失。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病理和 CTE中的生前帕金森综合征。麦基实验室和北卡罗来纳大学CTE中心之前的工作(赞助商和联合 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 与PSP不同的CTE MRS的炎症特征、微血管改变和p-tau病理 和CBD，以及MR p-tau病理与CTE中帕金森病的相关性，以帮助识别 CTE和其他牛皮病的诊断生物标志物和治疗靶点。

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.