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NIH grant 2I01RD001594-05A1: Clinical and Neuropathological Characterization of Parkinsonism Related to TBI in Veterans (CANPARK-TBI)
Institute: {'code': 'VA', 'abbreviation': 'VA', 'name': 'Veterans Affairs', 'admin_org_id': '12500964', 'admin_funding_url': ''}. PI: MELISSA J NIRENBERG. Award: $.
Start: 2026-10-01T00:00:00.
Significance to VA: United States military veterans are at high risk of traumatic brain injury (TBI), which is a
major risk factor for the future development of degenerative parkinsonism. Even a single, mild TBI has been
linked to a 56% increased risk of parkinsonism in the Veterans Administration (VA) population, making this one
of the major, devastating long-term consequences of head injury in veterans. Despite the importance of TBI-
related parkinsonism (TBI-P) to veterans, it is still not known whether these symptoms are caused by
Parkinson’s disease (PD); another type of degenerative parkinsonism; or a combination of different
neurodegenerative disorders (“co-pathology”). It is therefore critical to understand the clinical features,
biomarkers, and neuropathological changes specific to TBI-P and whether these differ depending on the
mechanism, severity, or frequency of brain injury.
Innovation and Impact: The proposed study combines deep clinical phenotyping, cutting-edge biomarker
approaches, and extensive neuropathological analysis to assess the characteristics of TBI-P related
parkinsonism. This information is crucial for the future development of therapies to help veterans and civilians
with TBI-P, as well as those with a history of TBI who are at risk of developing TBI-P in the future.
Specific Aims:
Aim 1 (prospective clinical phenotyping): To expand our deep phenotyping of TBI-P vs. noTBI-P to
include longitudinal analysis and a larger cohort so that we will be able to compare different
mechanisms, severity, and frequency of TBI. Our hypothesis is that TBI-P has a more rapidly progressive
and malignant clinical phenotype than noTBI-P, with combined features of synucleinopathy and tauopathy.
Aim 2 (biomarker profile): To identify novel biomarkers for TBI-P. Our hypothesis is that blood-based
biomarkers in TBI-P will reflect increased neuroinflammation; more rapid disease progression; and more
frequent co-pathology.
Aim 3 (post-mortem analysis): To extend our analysis of novel co-pathology in TBI-P vs noTBI-P. Our
hypothesis is that TBI-P is associated with increased frequency and burden of co-pathology with distinct
neuropathological features. We will assess this using a novel hierarchical framework that we developed to
define co-pathology subtypes at the brain, regional, cellular, and subcellular levels and more clearly delineate
clinically relevant changes and identify potential drivers of TBI-P.
Methodology: Veterans with TBI-P and a control group with parkinsonism and no history of brain injury
(noTBI-P group) will be recruited from the James J. Peters VAMC movement disorders clinic. The mechanism,
severity, and frequency of head injury will be determined by patient/caregiver interviews, medical records
review, and a validated prospective brain injury questionnaire. Subjects will undergo rigorous characterization
of neurological, psychiatric, and cognitive symptoms, and recruited for brain donation. Genetic testing and
blood-based biomarkers will be assessed using cutting-edge techniques including plasma-based alpha-
synuclein seed amplification assays and analysis of biomarkers in brain-derived extracellular vesicles. A
machine learning algorithm will be used to identify the unique clinical, pathological, and biomarker profile; rate
of disease progression; and biomarker trajectory in TBI-P (vs. noTBI-P) and in different TBI-P subtypes.
Path to Translation/Implementation: This proposal will significantly advance our understanding of TBI-P by
establishing its distinct clinical and biomarker features and trajectory and underlying neuropathology. These
findings will directly impact clinical practice by facilitating earlier and more accurate diagnosis of TBI-P and
guiding the development of therapeutic interventions. This work addresses a critical gap in TBI research and
has the potential to transform care for veterans and civilians suffering from TBI-induced neurodegeneration.document fetched 2026-10-24 02:46