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

<b>Objective:</b> 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. <b>Method:</b> 169 participants from the DIAGNOSE CTE Research Project completed neuropsychological tests of memory and executive functioning. Cognitive impairment was identified by single-test criteria (<i>z</i>≤-1.5 on one test) and two-test criteria (<i>z</i>&lt;-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). <b>Results:</b> 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 (<i>p</i>=.04). Two-test criteria were ­associated with higher CSF p-tau₁₈₁/Aβ_1-42 (<i>q</i>=.02) and CSF NfL (<i>q</i>=.02). The association between two-test criteria and CSF NfL remained after excluding amyloid-positive participants (<i>q</i>=.04). Single-test criteria were not associated with any biomarkers (<i>q</i>’s&gt;.05). <b>Conclusions:</b> 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.