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: 10657335
• 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/10657335
• 关键词: 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; 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; 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; brain tissue; chronic traumatic encephalopathy; cigarette smoking; clinical biomarkers; 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; neuropathology; neuropsychiatric symptom; novel diagnostics; operation; 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被认识到，并且是当前研究的主要焦点。 research.虽然严重的创伤性脑损伤（TBI）有立即和明显的后果，即使是轻微的 创伤性脑损伤（mTBI）和重复性亚震荡损伤可导致毁灭性的并发症， 有时是几十年后。脑损伤在大量退伍军人的健康中起着重要作用， 特别是最近的冲突（持久自由行动和伊拉克自由行动）， 引起一系列神经精神症状，包括帕金森综合征，精神症状， 痴呆 一些报告已经记录了帕金森症在那些患有帕金森病的人中的患病率增加。 以前遭受脑损伤，但在这些帕金森氏症的临床和神经病理学特征， 个人知之甚少。直到最近，与TBI相关的帕金森症被认为是由于 帕金森病（PD），伴随着一种相关的特征性模式，即α- 突触核蛋白然而，最近的证据表明，TBI相关的帕金森病可能是临床上的， 并且在病理学上与PD不同。例如，一些与TBI有关的帕金森症病例已经被证实是脑外伤。 与异常突触核蛋白沉积相关的非典型临床和病理学特征相关，或与 慢性创伤性结肠炎的临床特征和tau蛋白异常沉积的独特模式 脑病其他病例显示出一种以上的临床或病理特征重叠 神经退行性疾病 在这个建议中，我们将研究脑损伤在帕金森病发展中的作用， 老兵我们将招募患有帕金森症的受试者，无论有无头部受伤史，都会对其进行随访 由詹姆斯·J·彼得斯VAMC的神经科诊所的联合私家侦探的性质、频率和严重程度。 头部损伤将通过医疗记录审查结合经验证的前瞻性脑损伤来定义 问卷受试者将接受神经、精神和认知方面的严格表征。 症状，包括帕金森综合征的严重程度、非典型运动和非运动特征的测量，以及 环境暴露（如橙子剂和吸烟）。我们将分析这些数据， 描述有脑损伤史的退伍军人帕金森综合征的特征。此外，我们将测量 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 演示文稿. 将招募该队列的受试者进行脑捐献;前瞻性采集脑组织 然后将结合帕金森综合征和TBI病例的现有死后脑组织进行研究， 西奈山脑库尸检受试者的脑损伤史将通过审查 医疗记录和家庭成员的面谈。所有死后的脑组织将进行定性和 定量分析集中在α-突触核蛋白和tau，参与PD，CTE和其他疾病的关键蛋白质， 退化性帕金森综合症在每一种情况下，我们将研究沉积的分布和严重程度， 这些和其他与神经退行性疾病相关的蛋白质，如β-淀粉样蛋白， 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相关的帕金森综合征将与更严重和非典型的临床特征相关，更广泛- 分布的神经病理改变和异常蛋白沉积的非典型模式。这些发现将 揭示了慢性神经病理学过程的基础退行性帕金森病与 脑损伤