Clinical and Neuropathological Characterization of Parkinsonism Related to TBI in Veterans (CANPARK-TBI)

退伍军人与 TBI 相关的帕金森病的临床和神经病理学特征 (CANPARK-TBI)

• 批准号: 10368321
• 负责人: MELISSA J NIRENBERG
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10368321
• 关键词: Address; Age of Onset; Alzheimer' s Disease; Amyloid beta-Protein; Autopsy; Behavioral; Biological Markers; Brain; Brain Injuries; Caring; Characteristics; Chronic; Clinic; Clinical; Code; Cognitive; Cognitive deficits; Collection; Complication; Conflict (Psychology); Core Protein; Craniocerebral Trauma; Data; Dementia; Deposition; Development; Diagnosis; Diffuse; Diffuse Lewy Body Disease; Disease; Economic Burden; Environmental Exposure; Epidemiology; Family member; Freedom; Frequencies; Health; Human; Impaired cognition; Incidence; Individual; Injury; Interview; Knowledge; Lead; Light; Literature; Malignant - descriptor; Measures; Mechanical Stress; Medical Records; Motor; Movement Disorder Society Unified Parkinson' s Disease Rating Scale; Nature; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurologic; Neurologic Symptoms; Neurology; Neurotransmitters; Orthostatic Hypotension; Paralysed; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathology; Patients; Pattern; Phenotype; Physical shape; Play; Population; Prevalence; Process; Prognosis; Progressive Supranuclear Palsy; Prospective cohort; Proteins; Qualitative Evaluations; Quantitative Evaluations; Questionnaires; REM Sleep Behavior Disorder; Recording of previous events; Reporting; Research; Resources; Risk Factors; Role; Serum; Severities; Severity of illness; Symptoms; Tauopathies; Therapeutic Intervention; Time; Tissues; Traumatic Brain Injury; United States Department of Veterans Affairs; Veterans; abnormally phosphorylated tau; agent orange; alpha synuclein; base; brain tissue; chronic traumatic encephalopathy; cigarette smoking; clinical development; clinical diagnostics; clinical examination; clinical phenotype; cohort; combat; diagnostic biomarker; dopaminergic neuron; experience; insight; long-term sequelae; mild traumatic brain injury; military veteran; neurofilament; neuroinflammation; neuropsychiatric symptom; novel diagnostics; operation; phenotypic biomarker; prion-like; progressive neurodegeneration; prophylactic; prospective; protein TDP-43; psychiatric symptom; psychologic; rational design; recruit; social; subconcussion; synuclein; synucleinopathy; tau Proteins; tau-1

The long-term sequelae of brain injury are being increasingly recognized, and are a major focus of current research. While severe traumatic brain injury (TBI) has immediate and obvious consequences, even mild traumatic brain injury (mTBI) and repetitive subconcussive injury can lead to devastating complications, sometimes decades later. Brain injury plays a significant role in the health of a large number of veterans, especially those from recent conflicts (Operation Enduring Freedom and Operation Iraqi Freedom) and can cause a spectrum of neuropsychiatric symptoms that include parkinsonism, psychiatric symptoms, and dementia. A number of reports have documented an increased prevalence of parkinsonism in those who have previously suffered brain injury, but the clinical and neuropathological characteristics of parkinsonism in these individuals is poorly understood. Until recently, parkinsonism related to TBI was presumed to be due to Parkinson’s disease (PD), with an associated characteristic pattern of abnormal accumulation of alpha- synuclein protein. More recent evidence, however, suggests that TBI-related parkinsonism may be clinically and pathologically distinct from PD. Some cases of parkinsonism related to TBI, for example, have been associated with atypical clinical and pathological features related to abnormal synuclein deposition, or with clinical features and a distinct pattern of abnormal deposition of tau protein characteristic of chronic traumatic encephalopathy. Other cases have shown overlapping clinical or pathological features of more than one neurodegenerative disease. In this proposal, we will examine the role that brain injury plays in the development of parkinsonism in veterans. We will recruit subjects with parkinsonism, with and without a history of head injury who are followed by the co-PIs in the neurology clinic at the James J. Peters VAMC. The nature, frequency, and severity of the head injury will be defined by medical record review combined with a validated prospective brain injury questionnaire. Subjects will undergo rigorous characterization of neurological, psychiatric, and cognitive symptoms, including measures of severity of parkinsonism, atypical motor and non-motor features, and environmental exposures (such as Agent Orange and cigarette smoking). We will analyze these data to characterize the features of parkinsonism in veterans with a history of brain injury. In addition, we will measure TBI-related serum biomarkers (including neurofilament light chain and tau levels) that have been associated with neurodegenerative disease severity, to determine the relationship between these biomarkers and clinical presentation. Subjects from this cohort will be recruited for brain donation; tissue from brains collected prospectively will then be studied in combination with existing postmortem brain tissue from parkinsonism and TBI cases in the Mount Sinai Brain Bank. Brain injury history from postmortem subjects will be determined through review of medical records and interviews of family members. All post mortem brain tissue will undergo qualitative and quantitative analysis focusing on alpha-synuclein and tau, the key proteins involved in PD, CTE, and other forms of degenerative parkinsonism. In each case we will examine the distribution and severity of deposition of these and other proteins associated with neurodegenerative disease, such as beta-amyloid, and neurotransmitter markers, and correlate them with the clinical features and brain injury history. We anticipate that TBI-related parkinsonism will be associated with more severe and atypical clinical features, more widely- distributed neuropathological changes, and atypical patterns of abnormal protein deposition. These findings will shed light on the chronic neuropathological processes underlying degenerative parkinsonism associated with brain injury.

脑损伤的长期后遗症越来越受到人们的认识，并且是当前的一个主要焦点 研究。虽然严重的创伤性脑损伤 (TBI) 会产生直接且明显的后果，甚至是轻微的后果 创伤性脑损伤（mTBI）和重复性脑震荡损伤可能导致毁灭性的并发症， 有时几十年后。脑损伤对大量退伍军人的健康起着重要作用， 特别是最近发生的冲突（持久自由行动和伊拉克自由行动），并且可以 引起一系列神经精神症状，包括帕金森病、精神症状和 失智。 许多报告记录了患有帕金森病的人中帕金森病患病率的增加 既往曾遭受过脑损伤，但这些患者帕金森病的临床和神经病理学特征 个人了解甚少。直到最近，与 TBI 相关的帕金森病被认为是由于 帕金森病 (PD)，具有 α- 异常积累的相关特征模式 突触核蛋白。然而，最近的证据表明，与 TBI 相关的帕金森症可能在临床上 并且在病理上与PD不同。例如，一些与 TBI 相关的帕金森病病例已被 与异常突触核蛋白沉积相关的非典型临床和病理特征相关，或与 慢性创伤的临床特征和 tau 蛋白异常沉积的独特模式 脑病。其他病例表现出多种重叠的临床或病理特征 神经退行性疾病。 在本提案中，我们将研究脑损伤在帕金森病的发展中所起的作用 退伍军人。我们将招募患有帕金森症、有或没有头部受伤史的受试者，并对其进行随访 由 James J. Peters VAMC 神经科诊所的联合 PI 负责。的性质、频率和严重性 头部损伤将通过医疗记录审查结合经过验证的预期脑损伤来定义 调查问卷。受试者将接受严格的神经学、精神病学和认知特征描述 症状，包括帕金森病严重程度、非典型运动和非运动特征的测量，以及 环境暴露（例如橙剂和吸烟）。我们将分析这些数据 描述有脑损伤史的退伍军人帕金森病的特征。此外，我们还会测量 与 TBI 相关的血清生物标志物（包括神经丝轻链和 tau 水平） 与神经退行性疾病的严重程度，以确定这些生物标志物与临床之间的关系 推介会。 该队列中的受试者将被招募进行大脑捐赠；前瞻性收集的大脑组织 然后将结合帕金森病和 TBI 病例的现有死后脑组织进行研究 西奈山脑库。死后受试者的脑损伤史将通过审查来确定 医疗记录和家庭成员的访谈。所有死后脑组织都将进行定性和 重点关注 α-突触核蛋白和 tau 蛋白（参与 PD、CTE 等的关键蛋白）的定量分析 退行性帕金森病的各种形式。在每种情况下，我们都会检查沉积物的分布和严重程度 这些和其他与神经退行性疾病相关的蛋白质，例如β-淀粉样蛋白，以及 神经递质标记物，并将其与临床特征和脑损伤史相关联。我们预计 TBI 相关的帕金森症将与更严重和非典型的临床特征、更广泛的症状相关 分布的神经病理变化和异常蛋白质沉积的非典型模式。这些发现将 揭示与退行性帕金森病相关的慢性神经病理过程 脑损伤。