The Role of Alzheimer’s Disease Pathology in Cognition, Brain Volume, and Plasma Biomarker Concentrations in Traumatic Encephalopathy Syndrome

Abstract

AbstractBackgroundPatients with a history of repetitive head impacts (RHI) risk progressive memory loss and executive dysfunction consistent with traumatic encephalopathy syndrome (TES). TES is a clinical phenotype sensitive but non‐specific to underlying chronic traumatic encephalopathy (CTE). Cognitive symptoms overlap with Alzheimer’s disease (AD), and features of AD pathology like beta‐amyloid (Aβ) plaques often co‐occur with CTE. We investigated whether Alzheimer’s neuropathological changes influences cognition, brain volume, and plasma biomarkers in patients with RHI or TES.MethodsWe studied 154 patients who underwent Aβ‐PET, including 33 with RHI/TES (age 61.5±11.5, 100% male, 11/33 Aβ[+]), 62 with AD and no prior RHI (age 67.1±10.2, 48% male, 62/62 Aβ[+]), and 59 healthy controls without RHI (HC; age 73.0±6.2, 40% male, 0/59 Aβ[+]). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (regions of interest: frontal, temporal, parietal, occipital, hippocampus) and provided plasma samples analyzed for GFAP and NfL. Patients with RHI/TES were stratified as Aβ[+] or Aβ[‐] and compared to each other and with AD and HC groups (ANCOVA adjusting for age and sex).ResultsCognitively, Aβ[+] RHI/TES performed worse than Aβ[‐] RHI/TES on visuospatial (p = .04, d = 0.86) and memory testing (p = .07, d = 0.74). Comparing brain volume, Aβ[+] RHI/TES, but not Aβ[‐] RHI/TES, had lower parietal volume than HC (p = .003, d = 1.3). Conversely, Aβ[‐] RHI/TES had lower hippocampal volume than patients with AD (p = .03, d = 0.77). Comparing plasma biomarkers, Aβ[+] RHI/TES had higher plasma GFAP than HC (p = .01, d = 0.88) and similar GFAP levels to patients with AD (p = .26, d = 0.38). Conversely, Aβ[‐] RHI/TES had higher NfL than HC (p = .004, d = 0.93) and a trend towards higher plasma NfL than Aβ[+] RHI/TES (p = .11; d = 0.61).ConclusionsPatients with RHI/TES and positive Aβ‐PET have cognitive, brain volume, and plasma biomarker changes that more closely align to patients with AD than patients with Aβ[‐] RHI/TES. Visuospatial impairment and associated parietal atrophy may suggest the presence of AD pathology in participants with RHI. The suggestion of greater neuronal injury in patients with Aβ[‐] RHI/TES warrants further evaluation in supporting a diagnosis of TES due to suspected underlying CTE. Measuring these biomarkers in patients with RHI/TES could guide precise clinical management.