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Background Patterns of cognitive impairment in former American football players are uncertain because objective neuropsychological data are lacking. This study characterized the neuropsychological test performance of former college and professional football players. Methods One hundred seventy male former football players (n=111 professional, n=59 college; 45–74 years) completed a neuropsychological test battery. Raw scores were converted to T-scores using age, sex, and education-adjusted normative data. A T-score ≤ 35 defined impairment. A domain was impaired if 2+ scores fell in the impaired range except for the language and visuospatial domains due to the limited number of tests. Results Most football players had subjective cognitive concerns. On testing, rates of impairments were greatest for memory (21.2% two tests impaired), especially for recall of unstructured (44.7%) versus structured verbal stimuli (18.8%); 51.8% had one test impaired. 7.1% evidenced impaired executive functions; however, 20.6% had impaired Trail Making Test B. 12.1% evidenced impairments in the attention, visual scanning, and psychomotor speed domain with frequent impairments on Trail Making Test A (18.8%). Other common impairments were on measures of language (i.e., Multilingual Naming Test [21.2%], Animal Fluency [17.1%]) and working memory (Number Span Backward [14.7%]). Impairments on our tasks of visuospatial functions were infrequent. Conclusions In this sample of former football players (most of whom had subjective cognitive concerns), there were diffuse impairments on neuropsychological testing with verbal memory being the most frequently impaired domain.

BackgroundThe pathognomonic lesion of chronic traumatic encephalopathy (CTE) is the perivascular deposition of neuronal phosphorylated tau (p‐tau). Patchy p‐tau deposits initially accumulate in frontotemporal cortices. Medial temporal lobes (MTL) become involved in late stage. Validated in vivo biomarkers for CTE p‐tau do not exist. 18F‐MK‐6240 is a second‐generation tau PET ligand with improved imaging properties compared with first‐generation ligands, but its utility in CTE is unknown. We report initial results from an ongoing proof‐of‐concept study investigating MK‐6240 in people at risk for CTE.MethodTen older adult male symptomatic former National Football League (NFL) players completed tau (MK‐6240) and amyloid (florbetapir) PET imaging and neuropsychological testing. MK‐6240 data were acquired from 36 cognitively unimpaired males without traumatic brain injury history (but unknown contact sport history) from the Wisconsin Registry for Alzheimer’s Prevention (mean age=66.3, SD=6.3; mean MMSE=29.6, SD=0.5). Using cerebellar gray matter reference, 70‐90 min MK‐6240 SUVR images were created. W‐score (age‐adjusted z‐scores) maps were generated using the control data and thresholded at w>1.65 to visualize high binding voxels. Images and scatter plots of uptake in NFL players and controls were qualitatively assessed due to the small sample size.ResultsSample characteristics are in Table 1 (age range:51‐72, 5/10 Black). All NFL players had a negative florbetapir PET. 9/10 were cognitively impaired, particularly in memory and executive functions (Table 2). One former NFL player (case 4) had MTL MK‐6240 uptake greater than all controls, along with focal low intensity uptake in the superior frontal cortex (Figure 1). Two NFL players (cases 6 and 9) had mildly elevated MTL MK‐6240 uptake, particularly in entorhinal cortex and parahippocampus, though similar binding was seen in some controls (Figure 2). There was minimal MTL uptake in the remaining NFL players. Cortical uptake was complicated by contamination from off‐target meningeal binding.ConclusionsExisting data suggests current radioligands (e.g., flortaucipir) developed for Alzheimer’s disease might have restricted utility to late stage CTE. This might be true for MK‐6240 and off‐target meningeal binding complicates detection of cortical p‐tau. Data collection is ongoing and the larger data set will inform on MK‐6240 as a biomarker for CTE.

BackgroundRepetitive head impacts (RHI) from American football and other sources are associated with the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Moderate‐to‐severe traumatic brain injury (msTBI) has been suggested to be sufficient to precipitate CTE. Yet, this evidence is based on small case series of msTBI and the interplay between msTBI and RHI on CTE risk is unknown. We modeled the associations between msTBI history and years of American football play (proxy for RHI exposure duration) on CTE neuropathology among deceased American football players.MethodsThe sample included 471 deceased male football players from the UNITE brain bank, all 40+ years old. Informants of donors were administered the Ohio State University TBI Identification Method to assess TBI history. Loss of consciousness (LOC) for 30+ minutes defined msTBI. CTE was neuropathologically diagnosed and staged using published criteria. Outcomes included CTE status, CTE severity (low vs high), and cumulative p‐tau burden—summary of semi‐quantitative ratings of p‐tau severity across 11 brain regions (n = 402). Binary or linear regressions tested the association between msTBI and each outcome, controlling for age and years of football. A years of play x msTBI history interaction term was examined.ResultsTables 1‐2 shows sample characteristics (mean age = 67.89, SD = 12.70; 15.7% Black). Of the sample, 114 (24.2%) had a msTBI history. Years since last TBI with LOC was 37.16 (SD = 18.66) years. 344 (73.0%) had autopsy‐confirmed CTE. There was no association between msTBI and CTE status (OR = 1.38, 95% CI = 0.81,2.33, p = 0.24), CTE severity (OR = 0.77, CI = 0.41,1.44, p = 0.41), or cumulative p‐tau burden (beta = ‐1.03, 95% CI = ‐2.77,0.71, p = 0.25). In contrast, years of football play was associated with CTE status (OR = 1.15, 95% CI = 1.10,1.21, p<0.01), CTE severity (OR = 1.14, 95% CI = 1.08,1.21, p<0.01), and cumulative p‐tau burden (beta = 0.44, 95% CI = 0.32,0.56, p<0.01). There were no years of play x msTBI interaction effects (ps>0.05).ConclusionsmsTBI history was not associated with CTE neuropathology, nor did it modify the effect of years of football play on CTE status and severity. These findings argue against msTBI as a contributor to CTE in the setting of RHI. Examination of age at msTBI and msTBI frequency, as well as non‐CTE neuropathological correlates of msTBI are next steps.

Background: Repetitive head impacts from American football have been associated with long-term cognitive symptoms. The late neuropsychological profiles of this population is not well-characterized. Research has relied on retrospective informant reports and/or has been small samples of former professional players. We describe objective neuropsychological test performance in former college and professional American football players. Methods: Male (45-74 years) former National Football League (n=107) and college football players (n=59) from the DIAGNOSE-CTE Research Project completed a neuropsychological test battery, Functional Activities Questionnaire (FAQ) and Quick Dementia Rating Scale (QDRS). Neuropsychological test scores were converted to Tscores using age, sex, and/or education-adjusted normative data. T-scores<35 defined impairment. Participants were enrolled across the spectrum of symptom severity (asymptomatic to dementia). Individuals without decisional capacity were excluded. Participants with missing data (n=4) and who scored <45 on Test of Memory Malingering Trial 2 (n=10) were excluded. Results: 108 (65.1%) identified as White and 53 (31.9%) as Black. Mean education years was 16.76 (SD=1.48). Fourteen (8.4%) and 6 (3.6%) reported diagnostic history of ADHD and learning disability, respectively. Average Montreal Cognitive Assessment score was 24.96 (SD=3.17); 85 (51.2%) scored <26. Impairment rates were highest for learning and episodic memory. On Neuropsychological Assessment Battery List Learning, 29.5% were impaired on Immediate recall, 36.1% on Short Delay, and 44.0% on Long Delay Recall. Impairment rates for Craft Story Immediate and Delayed Recall (Paraphrase) were 15.7% and 18.7%, respectively. 19.9% and 15.7% were impaired on learning and delayed recall of the Brief Visuospatial Memory Test-Revised. Impairments were frequent on the Multilingual Naming Test (20.5%), Trail Making Test Parts B (19.3%) and A (18.1%), Animal Fluency (15.7%), and Number Span Backward (15.1%).Impairments were less common (<10%) for phonemic fluency, planning, basic attention, and visual-perceptual abilities, Mean FAQ was 3.11 (SD=5.14); 23 (13.9%) had an