Risk and Resilience, Clinical presentation, and Biomarker Profiles of Chronic Traumatic Encephalopathy and Related Dementias: The DIAGNOSE CTE Research Project II

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease diagnosed postmortem in people exposed to repetitive head impacts (RHI) from football and other contact sports. NINDS consensus research diagnostic criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES), were

published in 2021. However, we cannot diagnose CTE in life due to the following knowledge gaps: 1) TES criteria do not include biomarkers, limiting disease specificity; (2) longitudinal studies are lacking; (3) biomarkers and clinical features that distinguish CTE from other AD/ADRDs are unknown; and (4) risk/resilience factors of TES

are unclear, particularly social determinants of health (SDOH). In 2015, we were awarded a NINDS funded 7- year U01 known as the DIAGNOSE CTE Research Project (DIAGNOSE), designed in part to develop biomarkers of CTE. It enrolled 180 former football players (120 professional, 60 college) and 60 non-RHI controls, all males

ages 45-74. Baseline clinical exams, MRI, tau (flortaucipir) and amyloid PET, and blood draws were completed in 2020. Four-year remote follow-ups, including in-home blood draws, were finished in Nov. 2023. We had a 90% retention rate. The goals of this R01 are to retain and grown DIAGNOSE and examine the clinical and biomarker

course and profiles of TES (Aim 1); investigate risk/resilience factors of TES (Aim 2); and compare biomarkers of amyloid (Aβ), p-tau, neurodegeneration, neuroinflammation, and white matter injury between TES and AD syndromes (Aims 3-4). Our hypotheses are that TES has unique clinical and biomarker profiles, and RHI and

non-RHI risk factors influence the development of TES. There will be 3 groups: (1) Retention, 150 former football players and 50 controls retained from DIAGNOSE; (2) Expansion, we will grow DIAGNOSE by newly recruiting 75 former college and professional football players and 25 controls; (3) AD, 50 Aβ+ participants with cognitive

impairment. In total, we will study 225 former football players, 75 controls, and 50 AD. Groups will be similar in age (50+), sex (males), and race (40% Black). Participants will complete a single visit, including clinical exams, SDOH measures, MRI, blood draw, and tau PET, at 1 of 5 P30 AD Research Centers: BU, UCSF, Arizona,

1Florida, or South Texas. Retention Cohort will have flortaucipir PET to study its longitudinal value. Expansion Cohort will have MK-6240 PET to build on our R21. A subset of Retention (n=20) will have flortaucipir and MK- 6240 for tracer comparison. Blood will be analyzed for 6 p-tau epitopes, Aβ40/42, neuroinflammation, and white

matter injury. Retention Cohort will have legacy data for longitudinal study of outcomes (2-3 timepoints over 6-8-years). Expansion will contribute to pooled cross-sectional analyses. DIAGNOSE participants were asked for brain donation; 8 have donated. This R01 will permit continued brain donation and clinical-pathological validation

studies. This R01 will retain and grow a unique, deeply phenotyped, longitudinal cohort of people at risk for CTE. Results will help refine the TES criteria and differentiate it from other AD/ADRDs. This R01 will provide insight into the detection, diagnosis, and prognosis for people living with CTE, paving the way for treatment trials.