In Vivo Detection of Chronic Traumatic Encephalopathy with 18F-MK-6240 Tau PET - PROJECT ABSTRACT
Exposure to repetitive head impacts (RHI) through participation in contact sports can result in symptomatic
concussions and asymptomatic sub-concussions and may increase risk for the neurodegenerative disease
chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE is phosphorylated tau (p-tau)
deposition in neurons and other cell processes around small blood vessels, at the depths of the cortical sulci.
CTE can only be diagnosed at autopsy, severely limiting research on risk and resilience factors, mechanisms,
epidemiology and treatment. There is an urgent need for in vivo biomarkers that can accurately detect CTE
and differentiate it from other neurological disorders in living people. Tau positron emission tomography (PET)
imaging is a promising tool for detecting p-tau aggregates in Alzheimer’s disease (AD). Initial human imaging
studies using the tau PET ligand 18F-flortaucipir (18F-FTP) in individuals at high risk for CTE show low intensity
binding and modest correlations between antemortem imaging and post-mortem tau. 18F-MK-6240 is a second-
generation tau PET ligand that has improved in vivo imaging properties and reduced “off-target” (non-tau
related) binding compared to 18F-FTP. Our goal is to test the premise that the tau-PET ligand MK-6240 can
detect p-tau pathology in living people at high risk for CTE. We will compare MK-6240 standard uptake value
ratios (SUVR) in 30 male former National Football League (NFL) players with cognitive symptoms, ages 45-74,
and 10 matched male cognitively normal individuals without a TBI history (i.e., “controls”). We will leverage the
infrastructure of the NIA-funded Univ. of California, San Francisco AD Research Center (UCSF ADRC) and the
NIA-funded Boston University AD Research Center (BU ADRC) and the experience these centers have in the
evaluation of symptomatic former NFL players and with PET imaging. Former NFL players and controls will
enroll in the UCSF or BU ADRC, depending on their geographical location, and complete harmonized exams,
including neurological, neuropsychological, and self-report mood/behavior measures; MRI exams; and brain
donation consent. The resources from this proposal will supplement the Center visits with tau-PET (MK-6240)
and amyloid (18F-florbetapir) imaging. We will test the hypothesis that that compared to controls, former NFL
players at-risk for CTE will show increased MK-6240 retention in a distribution consistent with CTE
neuropathological staging, and tracer retention will correlate with worse cognitive and neuropsychiatric function
and greater exposure to RHI. This will be the first study to examine the usefulness of tau-PET MK-6240 in the
detection of CTE p-tau. If successful, it will provide preliminary data for larger proposals to examine MK-6240
as an accurate and reliable biomarker to support a clinical diagnosis of probable CTE and differentiate it from
other neurological disorders. The ability to accurately detect and diagnose CTE during life is a critical next step
in clinical research on the risk factors, mechanisms, and treatment of this brain disease.
