Assessment of TBI-related ADRD Pathology Related to Cognitive Impairment and Dementia Outcomes (U01 - Clinical Trial Not Allowed)

RFA-NS-24-003

This NOFO intends to address knowledge gaps there were identified in the 2019 CTE conferences. Examples include but are not limited to:

1. Characterize the neuropathological features of cTBI associated with ADRD and neurocognitive decline and prevalence of cTBI-related ADRD diagnoses and CTE pathology
2. Elucidate how different neurodegenerative processes interact in cTBI 
3. Identify associations between ADRD neuropathological burden (presence and severity of any single or multiple pathologies) and antemortem clinicopathologic symptoms.

A comprehensive characterization of the neuropathological features and neurodegenerative processes include but are not limited to identification of 1) microscopic changes, including proteinopathies (tau, beta-amyloid, alpha-synuclein, TDP-43), inflammation, gliosis, and neuronal loss, including structural biology approaches to characterize the structures of protein aggregates found in cTBI-related pathologies, as well as 2) macroscopic changes, including vascular pathology, hemorrhage, and cortical and white matter atrophy. When present, abnormal protein deposition should lead to identification of the specific pathological protein isoforms. Applicants are encouraged to utilize advanced methods and techniques to dissociate potential differences in protein structures. Further, to better understand the prevalence of mixed pathologies associated with cTBI-dementias, characterization of mixed pathologies is expected to be included.

To assess the relationship between postmortem cTBI neuropathological burden and antemortem clinicopathology, applicants should propose methods to assess the antemortem symptomatology and clinical presentation including degree of cognitive impairment, memory dysfunction, psychiatric symptoms and neuromotor deficits using the NINDS/FITBIR Clinical History Neuropathology Common Data Elements (CDEs).  Each application is expected to include assessment of the relationships among TBI exposure (including repetitive head impacts, single and multiple traumatic brain injuries (TBIs) across TBI severity), length of survival after injury, co-morbidities (e.g., post-traumatic epilepsy), neuropathological burden, and risk for neuropathological dementia diagnoses.  Applicants are expected have access to two or more existing brain banks with extensive collections of AD/ADRD diagnosed tissue.  Each brain bank should specialize in collecting tissue related to a different AD/ADRD so that neuropathological comparisons can be made across a range of disorders.  The aggregate tissue inventory across these brain banks should include an extensive collection of AD/ADRD diagnosed tissue, CTE diagnosed tissue, and tissue from person's with and without a history of TBI (as cTBI controls).

Application budgets are limited to no more than $1,300,000 in direct costs per year and need to reflect the actual needs of the proposed project.

Not required

July 28, 2023

Nsini Umoh, PhD

National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-480-7036
Email: Nsini.Umoh@nih.gov