LAUSR

Traumatic encephalopathy syndrome (TES) criteria were developed to aid diagnosis of chronic traumatic encephalopathy (CTE) pathology during life. Interpreting clinical and biomarker findings in patients with TES during life requires autopsy-based determination of the neuropathological profile. We report a clinico-pathological series of 9 patients with prior repetitive head impacts (RHI) classified retrospectively using the TES research framework (100% male and white/Caucasian, age at death 49-84) who completed antemortem neuropsychological evaluations, T1-weighted MRI, diffusion tensor imaging (N=6), (18)F-fluorodeoxyglucose-PET (N=5), and plasma measurement of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau (N=8). Cognitively, low test scores and longitudinal decline were relatively consistent for memory and executive function. Medial temporal lobe atrophy was observed in all 9 patients. Poor white matter integrity was consistently found in the fornix. Glucose hypometabolism was most common in the medial temporal lobe and thalamus. Most patients had elevated plasma GFAP, NfL, and total tau at their initial visit and a subset showed longitudinally increasing concentrations. Neuropathologically, 5 of the 9 patients had CTE pathology (N=4 "High CTE", N=1 "Low CTE"). Primary neuropathological diagnoses (i.e., the disease considered most responsible for symptoms) were frontotemporal lobar degeneration (N=2 FTLD-TDP, N=1 FTLD-tau), Alzheimer's disease (N=3), CTE (N=2), and primary age-related tauopathy (N=1). Hippocampal sclerosis was a common neuropathological comorbidity (N=5) and associated with limbic-predominant TDP-43 proteinopathy (N=4) or FTLD-TDP (N=1). Memory and executive function decline, limbic system changes (atrophy, decreased white matter integrity, hypometabolism), and plasma biomarker alterations are common in RHI or TES but may reflect multiple neuropathologies. In particular, the neuropathologic differential for TES presenting with medial temporal atrophy and memory loss should include limbic TDP-43. Researchers and clinicians should be cautious in attributing cognitive, neuroimaging, or other biomarker changes solely to CTE tau pathology based on prior RHI or a TES diagnosis alone.