Barr, William

ImportanceExposure to repetitive head impacts (RHI) is associated with increased risk for neurodegeneration. Accumulation of toxic proteins due to impaired brain clearance is suspected to play a role.ObjectiveTo investigate whether perivascular space (PVS) volume is associated with lifetime exposure to RHI in individuals at risk for RHI-associated neurodegeneration.Design, Setting, and ParticipantsThis cross-sectional study was part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project, a 7-year multicenter study consisting of 4 US study sites. Data were collected from September 2016 to February 2020 and analyses were performed between May 2021 and October 2023. After controlling for magnetic resonance image (MRI) and processing quality, former American football players and unexposed asymptomatic control participants were included in analyses.ExposurePrior exposure to RHI while participating in American football was estimated using the 3 cumulative head impact indices (CHII-G, linear acceleration; CHII-R, rotational acceleration; and CHII, number of head impacts).Main Outcomes and MeasuresIndividual PVS volume was calculated in the white matter of structural MRI. Cognitive impairment was based on neuropsychological assessment. Linear regression models were used to assess associations of PVS volume with neuropsychological assessments in former American football players. All analyses were adjusted for confounders associated with PVS volume.ResultsAnalyses included 224 participants (median [IQR] age, 57 [51-65] years), with 170 male former football players (114 former professional athletes, 56 former collegiate athletes) and 54 male unexposed control participants. Former football players had larger PVS volume compared with the unexposed group (mean difference, 0.28 [95% CI, 0.00-0.56]; P = .05). Within the football group, PVS volume was associated with higher CHII-R (β = 2.71 × 10−8 [95% CI, 0.50 × 10−8 to 4.93 × 10−8]; P = .03) and CHII-G (β = 2.24 × 10−6 [95% CI, 0.35 × 10−6 to 4.13 × 10−6]; P = .03). Larger PVS volume was also associated with worse performance on cognitive functioning in former American football players (β = −0.74 [95% CI, −1.35 to −0.13]; P = .04).Conclusions and RelevanceThese findings suggest that impaired perivascular brain clearance, as indicated by larger PVS volume, may contribute to the association observed between RHI exposure and neurodegeneration.

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease thought to be caused, in part, by repetitive head impact (RHI) exposure and characterized by phosphorylated tau deposition with varying patterns in the cerebral cortex. Flortaucipir tau PET data from the DIAGNOSE CTE Research Project was examined to investigate tau PET patterns and its relation to RHI exposure in former professional and college American football players.MethodIn this study, 218 DIAGNOSE CTE participants, ages 45‐74, with flortaucipir PET were included; 104 were former National Football League players (PRO), 58 were former college football players (COL), and 56 had no history of contact sports, other exposure to RHI, or traumatic brain injury (UE). Regional flortaucipir uptake was quantified using established procedures for three previously defined statistical regions (superior frontal, left parietal, and medial temporal) and compared across the three groups. Association analyses were also performed to examine the relationship between flortaucipir uptake and exposure to RHI using the cumulative head impact index for linear acceleration g‐force (CHII‐G). The potential clinical utility of flortaucipir PET for CTE was also investigated by examining its ability to differentiate participants meeting criteria for traumatic encephalopathy syndrome (TES) and probable or possible level of certainty for CTE pathology from those who do not meet those criteria.ResultSignificantly higher flortaucipir uptake was observed in former football players than in participants without RHI exposure, controlling for age and race for the superior frontal region (Fig. 1A), left parietal, and medial temporal regions. Association between regional flortaucipir uptake and CHII‐G was only observed in the superior frontal region in former players (PRO+COL) 60 years and older (Fig. 1B) and no association was observed in the full PRO+COL group. Flortaucipir PET was not able to differentiate TES groups in former football players (Fig. 1C).ConclusionElevated flortaucipir uptake was observed in former American football players to a group of unexposed men. The association between flortaucipir uptake and exposure to RHI may require a long latent period to manifest. Further investigation of more sensitive tau PET tracers and quantification techniques is warranted to better characterize CTE related tau pathology.

AbstractBackgroundRepetitive head impacts (RHI) from American football can lead to tau and non‐tau pathologies that might present as white matter hyperintensities (WMH) on FLAIR MRI. In 2022, we published a study in Alzheimer’s & Dementia that examined WMH and their association with risk factors and clinical function in former elite football players. That study will be presented during this symposium along with new unpublished data that used imaging and fluid biomarkers to examine etiological correlates (tau, amyloid, neurodegeneration, axonal injury, neuroinflammation) of WMH in the same cohort.MethodsThe multi‐site DIAGNOSE CTE Research Project recruited 180 football players and 60 asymptomatic males without RHI (“controls”), all 45‐74 years (Table 1). Participants completed MRI, lumbar puncture, and neuropsychological testing. Lesion Segmentation Toolbox estimated FLAIR WMH, FreeSurfer derived total cortical thickness, and a diffusion pipeline derived average global FA. CSF was analyzed for p‐tau181, Aβ1‐42, NfL, and sTREM2. Tobit regressions compared football players (n = 149) and controls (n = 53) on total and regional log‐WMH and estimated the effects of years of football and age of first exposure (AFE) to football on log‐WMH. Linear regressions evaluated log‐WMH and clinical associations in football players. Structural equation modeling (SEM) examined effects between log‐WMH and cortical thickness, FA, and the CSF biomarkers. Analyses accounted for age, race, revised Framingham Stroke Risk Profile (rFSRP), body mass index, APOE ε4, and evaluation site.ResultsAlosco et al. (2022) found older (i.e., 60+) but not younger football players had greater total, frontal, temporal and parietal log‐WMH compared to controls (FDR‐adjusted p‐values<0.05; Table 2). Among older football players, younger AFE was associated with greater log‐WMH (beta = ‐0.13, 95% CI = ‐0.23,‐0.02). Greater log‐WMH corresponded to worse Trails A‐B (beta = ‐4.32, 95% CI = ‐8.59,‐0.05) and List Learning Long Delay scores (beta = ‐0.56, 95% CI = ‐0.93,‐0.19). Subsequent unpublished SEM analyses in football players (Figure 1) showed the following direct effects on log‐WMH: higher rFSRP, higher CSF p‐tau181, lower FA, and reduced cortical thickness. There were no indirect effects. Compared to controls, SEM associations were stronger in football players exception for cortical thickness.ConclusionsFLAIR WMH might have unique imaging characteristics, risk factors, and pathological underpinnings in people exposed to RHI.

AbstractINTRODUCTIONTau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project.METHODWe compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same‐age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES).RESULTSSignificantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups.DISCUSSIONAdditional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is characterized by perivascular foci of phosphorylated tau (p‐tau) notably in the depths of sulci, with varying patterns in the cerebral cortex. Prior studies show elevated flortaucipir (FTP) PET binding in former American professional football players(PRO). However, the association of p‐tau with clinical measures remains unclear using regional FTP SUVR as early signs of CTE related tau pathology. Graph theory (GT) takes advantages of the spatial variability in p‐tau load and allows the integration of regional measures to define GT based measures. Here we examine the GT based measures in two CTE cohorts to evaluate their utility in assessing p‐tau related pathology in CTE.MethodThe graph procedure was optimized in FTP PET images in a group of 26 PRO with reported cognitive and/or behavorial symptoms and 30 asymptomatic controls without a history of traumatic brain injury (the DETECT Study) and identified the GT measure, entorhinal tau strength, as the target metric with the best group separation between PRO and controls. The optimized graph procedures were then applied to the DIAGNOSE CTE Research Project dataset (99 former PRO, 51 former college football players [COL], and 52 controls without exposure to repetitive head impacts [CTL]) and we examined entorhinal tau strength’s ability to differentiate the exposure groups and relationship to consensus based diagnoses of Traumatic Encephalopathy Syndrome (TES), the clinical syndrome associated with CTE.ResultEntorhinal tau strength was significantly different among the three exposure groups (p=0.0001) similar to regional SUVR measures (Figure 1). Regional SUVR did not differentiate players (PRO+COL) with and without TES, while entorhinal tau strength approached although did not reach significance (Figure 2). Entorhinal tau strength is the only FTP measure that showed significant differences (p=0.006) between those players with cognitive impairment and players without (Figure 3).ConclusionWhile there is still considerable overlap in between‐group measurements, GT based entorhinal tau strength, is potentially more sensitive in detecting tau changes in players with and without TES. Additional studies are necessary to clarify the value of this new measure in detecting underlying CTE pathology.

AbstractIntroductionThe presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of WMH, and their association with years of play, age of first exposure, and clinical function in former American football players.MethodsA total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45–74 years) completed fluid‐attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self‐report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60.ResultsIn older but not younger participants, former football players had greater total, frontal, temporal, and parietal log‐WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log‐WMH was associated with younger age of first exposure to football and worse executive function.DiscussionIn older former football players, WMH may have unique presentations, risk factors, and etiologies.Highlights Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same‐age asymptomatic unexposed men. Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players. In former football players, greater WMH was associated with worse executive function and verbal memory.

AbstractBackgroundRepetitive 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.MethodsMale (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 T‐scores 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.Results108 (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 FAQ >9. Based on QDRS scores, 66 (39.8%) had mild cognitive impairment, 44 (26.5%) mild dementia, and 6 (3.6%) moderate dementia.ConclusionsIn these former American football players, neuropsychological impairments were most frequent in episodic memory, followed by confrontation naming and executive function. Further research is needed to delineate this population’s unique neuropsychological profile.

Using the Minnesota Multiphasic Personality Inventory (MMPI), this study investigated preoperative and postoperative emotional and personality adjustment of temporal lobectomy patients from two major epilepsy surgery centers. Temporal lobectomy patients were included only if they were without evidence of lesional pathology on magnetic resonance imaging (MRI; other than evidence of mesial temporal sclerosis), were left-hemisphere language-dominant, and had Wide Range Achievement Test-Revised (WRAT-R) reading achievement standard scores of 70 or higher. The MMPI was completed by 175 patients before and after a temporal lobectomy. There were no significant preoperative differences on any MMPI scale between right temporal (n = 79) and left temporal (n = 96) lobectomy patients. Analysis of MMPI data from one of the surgical centers revealed significant effects for postoperative seizure control. Minimal effects of laterality of seizure onset on preoperative or postoperative psychological adjustment were found. Adequacy of preoperative psychological adjustment and postoperative seizure control have a greater impact on preoperative to postoperative psychological adjustment than side of seizure onset.