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

基本信息

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
项目类别：
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

项目摘要

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）是与暴露有关的神经退行性疾病重复的头部外伤，其特征是高磷酸化的tau蛋白（P-TAU）的积累。 P- 创伤后神经炎症和微血管损伤增强了CTE的TAU病理。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主义。其他与帕金森氏症相关的基于P-TAU的神经退行性疾病包括渐进性上麻痹（PSP）和皮质型变性（CBD），两种不同的偶发性tauopathies，尚无已知与头部创伤，神经炎症或微血管损伤。 CTE，PSP和CBD仅被明确诊断在验尸检查中。 CTE P-TAU包含三个重复（3R）和四个重复（4R）的TAU同工型 PSP和CBD仅是4R tauopathies。在PSP和CBD中，运动区域的P-TAU病理学（MRS）与帕金森氏症相关，但CTE中的帕金森主义知之甚少。这些知识差距使我们走向假设微血管损伤和感染在3R和4R P-TAU的积累中起关键作用 CTE的MRS，P-Tau Burnen先生将与CTE中的帕金森主义有关。我们进一步假设 CTE中的P-Tau Burnen先生将与先前头部创伤的持续时间和剂量呈正相关（以CTE为重复的头部撞击（RHI）测量。为了解决我们的假设，我们将使用验尸组织来自神经性确认的CTE，PSP和CBD的病例，用于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发展中的作用 CTE中的病理将通过包含rhi-ne parpecteds确定确定没有发展CTE的对照以及PSP和CBD病例。在AIM 1中，我们将定量3R和4R MR P-TAU 与PSP和CBD相比，CTE燃烧，并表征具有多重疾病特异性细胞病理学免疫荧光染色以确定CTE中P-TAU病理学的增加。在AIM 2中，我们将量化MR 与PSP，CBD相比使用免疫组织化学，组织清除和蛋白质免疫测定的rhi-na to和rhi-proc to对照确定CTE中MR炎症，微血管病理和多巴胺能细胞的丧失。在AIM 3中，我们将使用可用的临床数据来评估RHI暴露，P-TAU病理学先生和 CTE中的Anemontem帕金森氏症。 McKee Lab and Bu Cte Center的先前工作（赞助商和共同赞助商）和初步数据验证了所提出的技术。我们将描绘独特的 CTE中MRS中的炎症特征，微血管改变和P-TAU病理与PSP不同和CBD，以及CTE中P-Tau病理学和帕金森氏症之间的相关性，以帮助识别 CTE和其他tauopathies的诊断生物标志物和治疗靶标。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.