Blood biomarkers of traumatic brain injury and cognitive impairment in older veterans

Objective: To determine whether blood-based biomarkers can differentiate
older veterans with and without traumatic brain injury (TBI) and cognitive
impairment (CI). Methods: We enrolled 155 veterans from two veterans’
retirement homes: 90 without TBI and 65 with TBI history. Participants
were further separated into CI groups: Controls (no TBI, no CI), n=60; no
TBI with CI, n=30; TBI without CI, n=30; and TBI with CI, n=35. TBI was
determined by the Ohio State University TBI Identification Method. CI was
defined as impaired cognitive testing, dementia diagnosis, or use of
dementia medication. Blood specimens were enriched for CNS-derived
exosomes. Proteins [neurofilament light (NfL), total tau, glial fibrillary
acidic protein (GFAP), alpha synuclein, β-amyloid 42 (Aβ42), and
phosphorylated tau (pTAU)] and cytokines [tumor necrosis factor alpha
(TNFa), interleukin 6 (IL-6) and interleukin 10] were measured using
ultrasensitive immunoassays. Results: Veterans were, on average, 79 years
old. In participants with TBI history, 65% had mild TBI; average time from
most recent TBI was 37 years. In adjusted analyses, the TBI and CI groups
differed on CNS-enriched exosome concentration of pTAU, NfL, IL-6, TNFa
(all p<0.05), and GFAP (p=0.06), but not on Aβ42 or other markers.
Adjusted area under the curve (AUC) analyses found that all significantly
associated biomarkers combined separated TBI with/without CI (AUC = 0.85,
95% confidence interval 0.74-0.95) and CI with/without TBI (AUC = 0.88,
95% confidence interval 0.77-0.99). Conclusions:  Increased
levels of blood-based, CNS-enriched exosomal biomarkers associated with
TBI and CI can be detected, even decades after TBI. Classification of
Evidence: This study provides Class II evidence that in veterans with a
history of TBI, CNS-enriched exosome concentration of pTAU, NfL, IL-6,
TNFa are associated with cognitive impairment.