Single- versus two-test criteria for cognitive impairment: associations with CSF and imaging markers in former American football players

Clin Neuropsychol. 2025 Jan 20:1-25. doi: 10.1080/13854046.2025.2451828. Online ahead of print.

ABSTRACT

Objective: Cognitive impairment is a core feature of traumatic encephalopathy syndrome (TES), the putative clinical syndrome of chronic traumatic encephalopathy-a neuropathological disease associated with repetitive head impacts (RHI). Careful operationalization of cognitive impairment is essential to improving the diagnostic specificity and accuracy of TES criteria. We compared single- versus two-test criteria for cognitive impairment in their associations with CSF and imaging biomarkers in male former American football players. Method: 169 participants from the DIAGNOSE CTE Research Project completed neuropsychological tests of memory and executive functioning. Cognitive impairment was identified by single-test criteria (z≤-1.5 on one test) and two-test criteria (z<-1 on two tests within a domain). ANCOVAs adjusting for age, race, education, body mass index, word-reading score, and APOE ε4 status assessed whether single- or two-test criteria predicted CSF markers (Aβ_1-42, p-tau₁₈₁, p-tau₁₈₁/Aβ_1-42, total tau, neurofilament light [NfL], glial fibrillary acidic protein [GFAP]) and MRI markers (hippocampal volume, cortical thickness, white matter hyperintensities). Results: Ninety-nine participants met single-test criteria for cognitive impairment. Sixty-six met two-test criteria. Participants who met two-test criteria had greater exposure to RHI than those who did not (p=.04). Two-test criteria were -associated with higher CSF p-tau₁₈₁/Aβ_1-42 (q=.02) and CSF NfL (q=.02). The association between two-test criteria and CSF NfL remained after excluding amyloid-positive participants (q=.04). Single-test criteria were not associated with any biomarkers (q's>.05). Conclusions: Two-test but not single-test criteria for cognitive impairment were associated with markers of neurodegeneration. Future clinical research in TES may benefit from applying two-test criteria to operationalize cognitive impairment.

PMID:39834028 | DOI:10.1080/13854046.2025.2451828