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受到人们的重视，也是当前研究的一个主要焦点。 研究。而重型颅脑损伤(TBI)具有直接和明显的后果，即使是轻微的 创伤性脑损伤(MTBI)和反复的亚震荡损伤可导致毁灭性的并发症， 有时是几十年后。脑损伤对一大批退伍军人的健康起着重要作用， 特别是最近的冲突(持久自由行动和伊拉克自由行动)，并可以 引起一系列神经精神症状，包括帕金森症、精神症状和 痴呆症。 许多报告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。 曾遭受过脑损伤，但帕金森氏症的临床和神经病理特征 人们对个人的了解很少。直到最近，与脑外伤相关的帕金森症被认为是由于 帕金森病(PD)，伴随着与α-α异常堆积相关的特征模式 突触核蛋白。然而，最近的证据表明，与脑外伤相关的帕金森症可能在临床上 在病理上与帕金森病截然不同。例如，一些与脑外伤有关的帕金森症病例 与与异常突触核蛋白沉积有关的不典型临床和病理特征有关，或与 慢性创伤患者的临床特点和tau蛋白异常沉积的特点 脑病。其他病例表现出多个重叠的临床或病理特征。 神经退行性疾病。 在这项建议中，我们将研究脑损伤在帕金森病发展中所起的作用。 退伍军人。我们将招募有和没有头部损伤史的帕金森症受试者，并对他们进行追踪。 詹姆斯·J·彼得斯VAMC神经科诊所的合作PI。疾病的性质、频率和严重程度 头部损伤的定义将通过审查医疗记录和确认的未来脑损伤来确定 问卷调查。受试者将接受神经学、精神病学和认知学的严格描述。 症状，包括帕金森综合症的严重程度、不典型的运动和非运动特征，以及 环境暴露(如橙剂和吸烟)。我们将对这些数据进行分析以 描述有脑损伤病史的退伍军人帕金森症的特征。此外，我们还将测量 与脑损伤相关的血清生物标志物(包括神经丝轻链和tau水平) 根据神经退行性疾病的严重程度，确定这些生物标志物与临床的关系 演示文稿。 这一队列中的受试者将被招募用于脑捐赠；预期收集的脑组织 然后将结合现有的帕金森氏症和脑外伤病例的尸检脑组织进行研究 西奈山脑库。身体受试者的脑损伤病史将通过审查确定 医疗记录和对家属的面谈。所有的尸检脑组织都会进行定性和 定量分析侧重于阿尔法-突触核蛋白和tau蛋白，这是参与PD、CTE和其他疾病的关键蛋白 各种形式的退行性帕金森综合症。在每种情况下，我们将检查沉积的分布和严重程度 这些蛋白质和其他与神经退行性疾病有关的蛋白质，如β-淀粉样蛋白，以及 神经递质标记物，并与临床特征和脑损伤病史相关。我们期待着 与脑外伤相关的帕金森综合症将与更严重和不典型的临床特征有关，更广泛地- 分布广泛的神经病变和异常蛋白沉积的不典型模式。这些发现将 阐明退行性帕金森病相关的慢性神经病理过程 脑部受伤。