Late Pathologies of Exposure to Repetitive Head Impacts from Contact Sports: White Matter and Vascular Contributions to Cognitive Impairment, Dementia, and Neuropsychiatric Symptoms

接触性运动造成的重复性头部撞击的晚期病理学：白质和血管对认知障碍、痴呆和神经精神症状的影响

• 批准号: 10276270
• 负责人: Michael Alosco
• 金额: $ 230.95万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10276270
• 关键词: Affect; Age; Agreement; Alzheimer' s Disease; Alzheimer' s disease related dementia; American; Amyloid beta-42; Amyloid beta-Protein; Anterior; Axon; Biological Markers; Blood; Blood Vessels; Boston; Brain; California; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Clinical; Cognition; Cognitive; Cognitive deficits; Collaborations; Data; Data Set; Dementia; Deposition; Diffusion Magnetic Resonance Imaging; Disease Marker; Dose; Elderly; Enrollment; Enzyme-Linked Immunosorbent Assay; Etiology; Evaluation; Executive Dysfunction; Exposure to; Female; Frequencies; Immunofluorescence Immunologic; Impaired cognition; Impairment; Injury; Intervention; Interview; Iron; Late Effects; Light; Literature; Magnetic Resonance Imaging; Manufactured football; Memory; Mental Depression; Myelin; Myelin Basic Proteins; Neurodegenerative Disorders; Oligodendroglia; Outcome; Participant; Pathologic; Pathology; Plasma; Play; Positioning Attribute; Predisposition; Protocols documentation; Race; Recording of previous events; Reporting; Research; Risk; Risk Factors; Sampling; San Francisco; Severities; Spin Labels; Spinal Puncture; Sports; Subgroup; Symptoms; Syndrome; Telephone; Testing; Thick; Traumatic Brain Injury; Universities; Vascular Cell Adhesion Molecule-1; Vascular Cognitive Impairment; Vascular Endothelial Growth Factors; White Matter Hyperintensity; apolipoprotein E-4; axon injury; base; blood-brain barrier disruption; chronic traumatic encephalopathy; cohort; contact sports; dementia risk; density; dosage; executive function; head impact; hypoperfusion; in vivo; indexing; informant; male; microvascular pathology; neurobehavioral; neurofilament; neuropsychiatric symptom; neuropsychiatry; novel; ranpirnase; recruit; response; sex; symposium; tau Proteins; tau-1; vascular contributions; vascular risk factor; white matter

Each year, millions of Americans are exposed to repetitive head impacts (RHI) through contact sport participation and may be at risk for chronic traumatic encephalopathy (CTE). The clinical presentation of CTE is ill-defined and includes deficits in executive function and memory, dementia, neurobehavioral dysregulation and depression. While these clinical features have been attributed to phosphorylated tau (p-tau) pathology, our data show p-tau is not related to neuropsychiatric symptoms and does not account for all cognitive deficits in CTE. The etiology of these clinical features is thus unclear and likely multifactorial. Our data in small samples of male football players show that white matter (WM) degeneration and cerebrovascular disease (CBVD) are common and affect cognition. Yet, the vascular contributions to neuropsychiatric syndromes and cognitive impairment and dementia (VCID) in former contact sport athletes are unknown and a topic that our existing studies do not address. This R01 will conduct sophisticated in vivo and ex vivo assessments of WM integrity and CBVD and examine risk factors for, and the cognitive and neuropsychiatric effects of WM degeneration and CBVD in living and deceased former contact sport athletes. In a collaborative effort between the Boston University (BU) and Univ. of California, San Francisco (UCSF) Alzheimer's Disease Research Centers (ADRCs), we will recruit 200 former contact sport athletes (>50 years), males and females from different sports, and 100 age- and race- matched people with no history of RHI or traumatic brain injury (TBI). Groups will span the cognitive continuum. Participants will enroll into the BU or UCSF ADRC to complete cognitive and neuropsychiatric tests, advanced MRI protocols of WM integrity and CBVD, and blood draw for plasma biomarker analysis of WM integrity and CBVD. A subgroup (50 former contact sport athletes, 25 non-RHI/TBI) will undergo lumbar puncture to test plasma-CSF analyte concordance and examine novel CSF microvascular markers. We will expand our U54 of 7 harmonized brain banks studying RHI and AD/ADRD risk by adding novel ELISA, multiplex immunofluorescence, and CLARITY pathological assessments of WM integrity (myelin integrity and thickness, oligodendrocyte and axonal loss) and CBVD (vessel density, size, and branch points) on 200 deceased contact sport athletes (varying in RHI exposure and age) and 100 age-/race-matched non-RHI/TBI donors. Harmonized pathological protocols, informant interviews and clinicopathological conferences are done across all brain banks. Data from this R01 will be used to test our hypotheses that RHI exposure is associated with WM degeneration and CBVD; these pathologies independently contribute to executive dysfunction, neurobehavioral dysregulation and depression; and RHI (e.g., type of sport played) and non-RHI (e.g., vascular risk) factors are effect modifiers. This R01 will lead to unprecedented data sets to increase understanding of the risk for cognitive and neuropsychiatric impairment from WM degeneration and CBVD in former contact sport athletes. Data will inform on symptom etiology and open the door to intervention and preventative targets for the millions exposed to RHI.

每年，数以百万计的美国人通过接触性运动参与暴露于重复性头部撞击（RHI） 并且可能有慢性创伤性脑病（CTE）的风险。CTE的临床表现不明确 包括执行功能和记忆缺陷、痴呆、神经行为失调和 萧条虽然这些临床特征归因于磷酸化tau（p-tau）病理学，但我们的数据显示， 显示p-tau与神经精神症状无关，并且不能解释CTE中的所有认知缺陷。 因此，这些临床特征的病因尚不清楚，可能是多因素的。我们在男性小样本中的数据 足球运动员显示，白色物质（WM）变性和脑血管疾病（CBVD）是常见的 并影响认知。然而，血管对神经精神综合征和认知障碍的作用 和痴呆症（VCID）在前接触性运动员是未知的，我们现有的研究没有一个主题 地址.该R01将对WM完整性和CBVD进行复杂的体内和离体评估， 检查生活中WM变性和CBVD的风险因素以及认知和神经精神影响 和已故的前身体接触运动员在波士顿大学（BU）和 Univ.在加州旧金山弗朗西斯科（UCSF）阿尔茨海默病研究中心（ADRC），我们将招募200名 前接触性运动员（> 50岁），来自不同运动的男性和女性，以及100名年龄和种族- 没有RHI或创伤性脑损伤（TBI）病史的人。群体将跨越认知连续体。 参与者将进入BU或UCSF ADRC完成认知和神经精神测试，高级 WM完整性和CBVD的MRI方案，以及用于WM完整性和CBVD的血浆生物标志物分析的抽血 CBVD。一个亚组（50名前接触性运动员，25名非RHI/TBI）将接受腰椎穿刺检查 血浆-CSF分析物一致性并检查新的CSF微血管标志物。我们将扩大我们的U54 7个统一的脑库，通过增加新型ELISA，多重ELISA，研究RHI和AD/ADRD风险 WM完整性的免疫荧光和免疫病理学评估（髓鞘完整性和厚度， 少突胶质细胞和轴突损失）和CBVD（血管密度、大小和分支点） 运动员（RHI暴露和年龄不同）和100名年龄/种族匹配的非RHI/TBI供体。统一 所有脑库都进行病理学协议、知情人访谈和临床病理学会议。 来自R01的数据将用于检验我们的假设，即RHI暴露与WM变性相关 和CBVD;这些病理独立地导致执行功能障碍、神经行为失调 和抑郁症;和RHI（例如，所进行的运动类型）和非RHI（例如，血管风险）因素是效应调节剂。 这一R01将产生前所未有的数据集，以增加对认知和 前接触性运动员WM变性和CBVD的神经精神损害。数据将告知 症状病因学，并为数百万暴露于RHI的人打开干预和预防目标的大门。