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

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.