Stern, Robert A.

Abstract Background : Traumatic encephalopathy syndrome (TES) is a clinical research construct used to identify individuals at risk for chronic traumatic encephalopathy (CTE) following exposure to repetitive head impacts (RHI). Adjudication of TES relies on clinical features such as progressive cognitive impairment and neurobehavioral dysregulation. Blood-based biomarkers and structural neuroimaging abnormalities have been associated with TES but are not part of the criteria. This study evaluated whether TES identification was associated with the combined contribution of cognitive performance, blood biomarkers, and structural neuroimaging measures across two well-characterized cohorts. Methods : Participants included 158 professional fighters from the Professional Athletes Brain Health Study and 149 former American football players from The DIAGNOSE CTE Research Project. Three indices were constructed representing complementary domains: a cognitive index reflecting cohort-specific cognitive features, a blood biomarker index including plasma neurofilament light chain, glial fibrillary acidic protein, total tau, tau phosphorylated at amino acid 231, and APOE -ε4 carrier status, and an imaging index comprising volumetric MRI measures of subcortical structures, ventricles, and corpus callosum subregions. Grouped weighted quantile sum regression models were estimated within each cohort to evaluate associations between these indices and TES while adjusting for age, race, competition status, and RHI exposure. Results : Multidomain models demonstrated improved model performance compared with single-domain models in both cohorts (PABHS: AUC=0.91, PPV=0.80; DIAGNOSE CTE: AUC=0.84, PPV=0.85). Biomarker and imaging indices contributed additional information across cohorts, although imaging contributions were more prominent in fighters whereas blood biomarker associations were stronger in football players. Conclusion : TES in RHI-exposed athletes was associated with a convergent clinicobiological profile observed across two independent cohorts with distinct exposure patterns. These findings support multidomain analytic frameworks for evaluating correlated biological signals in RHI-exposed populations and may inform future studies of TES and CTE.

Abstract Repetitive head impacts are common in contact and collision sports and are linked to structural brain changes and an elevated risk of neurodegenerative diseases such as Chronic Traumatic Encephalopathy. Identifying early in vivo structural markers remains challenging. Although diagnosis currently requires post-mortem confirmation, clinical symptoms, including cognitive impairment and behavioural changes, are reflected in the diagnosis of Traumatic Encephalopathy Syndrome. These symptoms align with dysfunction in key brain regions—amygdala, hippocampus and thalamus—which support memory, emotion and behaviour and commonly show tau pathology in Chronic Traumatic Encephalopathy. This study uses shape analysis to examine structural differences in these regions between former American football players and unexposed asymptomatic controls and evaluates the influence of age, head impact exposure and clinical diagnosis on brain structure. We analyzed brain morphology in former American football players (n = 163) and unexposed, asymptomatic controls (n = 53). Structural segmentation was performed with FreeSurfer 7.1, and the shape analysis pipeline was used to generate subregional reconstructions. Vertex-level morphometry, based on the logarithm of the Jacobian determinant and radial distance, quantified local surface area dilation and thickness. Group differences were examined with covariate-adjusted linear regression models contrasting football players and controls, as well as participants with and without a Traumatic Encephalopathy Syndrome diagnosis. Partial correlations examined the influence of age, age of first football exposure and cumulative head impact index metrics, including frequency, linear acceleration and rotational force. Models were adjusted accordingly for age, body mass index, education, race, imaging site, apolipoprotein ϵ4 status and total intracranial volume. Former football players exhibited bilateral surface area contractions in the hippocampus and amygdala, along with reduced amygdala thickness, compared to controls. Older age was associated with widespread surface contractions and thinning across all regions, except for preserved thickness in the left hippocampus. An earlier age of first exposure to football correlated with surface contractions in the thalamus and left hippocampus. Greater cumulative linear acceleration was linked to bilateral hippocampal surface contractions and reduced thickness in the left thalamus, while greater rotational force exposure was associated with hippocampal thinning. No significant structural differences were found between players with and without a diagnosis of Traumatic Encephalopathy Syndrome. These findings extend volume-based research by revealing localized alterations in surface area dilation and thickness and emphasize the roles of age and repetitive head impact exposure in long-term brain changes.

Abstract Repetitive head impacts are associated with structural brain changes and an increased risk for chronic traumatic encephalopathy, a progressive neurodegenerative disease that can only be diagnosed after death. Chronic traumatic encephalopathy is defined by the abnormal accumulation of phosphorylated tau protein, particularly at the depths of the superior frontal sulci, suggesting that sulcal morphology may serve as a relevant structural biomarker. Contact sport athletes, such as former football players, are at elevated risk due to their prolonged exposure to repetitive head impacts. Cortical atrophy linked to underlying tau accumulation may result in shallower and wider sulci, potentially making sulcal morphology an imaging marker for identifying individuals at risk for this disease. This study investigated sulcal morphological differences in former football players and examined associations with age, football-related exposure, clinical diagnosis of traumatic encephalopathy syndrome, levels of certainty for chronic traumatic encephalopathy pathology, neuropsychological performance, and positron emission tomography imaging using flortaucipir. We analysed structural magnetic resonance imaging data from 169 male former football players (mean age 57.2 (8.2) years, range 45–74) and 54 age-matched, unexposed asymptomatic male controls (mean age 59.4 (8.5) years, range 45–74). Sulcal depth and width were quantified using the CalcSulc, focusing on two regions in each hemisphere commonly affected by chronic traumatic encephalopathy pathology: the superior frontal and occipitotemporal sulci. Generalized least squares models were used to assess group differences and interactions with age and football exposure variables, including age of first exposure, total years played, and cumulative head impact exposure. An analysis of covariance evaluated relationships between sulcal morphology, clinical measures, and flortaucipir uptake, adjusting for age, race, body mass index, education, imaging site, apolipoprotein E4 status, and total intracranial volume. Former football players demonstrated significantly shallower sulcal depth in the left superior frontal sulcus compared to unexposed controls. Earlier age of first exposure and longer football careers were associated with greater widening of the left occipitotemporal sulcus. Higher cumulative head impact exposure was linked to reduced sulcal depth in the left superior frontal region. However, sulcal morphology was not associated with clinical diagnosis, levels of certainty, neuropsychological test performance, or flortaucipir imaging. These findings suggest that sulcal morphology may reflect cumulative exposure to repetitive head impacts, particularly in brain regions vulnerable to chronic traumatic encephalopathy pathology. Future ante- and post-mortem validation studies are needed to determine whether sulcal morphology can serve as a reliable in vivo biomarker of risk.

AbstractBackgroundTraumatic encephalopathy syndrome (TES) is the proposed clinical syndrome of the neurodegenerative disease chronic traumatic encephalopathy (CTE). As part of the 2021 TES NINDS consensus diagnostic criteria, certainty levels of underlying CTE neuropathology can be determined (i.e., suggestive, possible, probable) partially based on the presence/absence of supportive psychiatric features including but not limited to depression, anxiety, and apathy. These are ‘supportive’ because of their non‐specificity and unclear biological correlates in this setting. We examined the association between CSF biomarkers of amyloid, tau, neurodegeneration, microglial activation and neuroinflammation and supportive psychiatric features of TES in former American football players.MethodThe sample included 180 male former football players (120 professional, 60 college) from the DIAGNOSE CTE Research Project. Participants completed a lumbar puncture, and CSF assays were conducted for biomarkers of amyloid (Aβ40, Aβ42), p‐tau (p‐tau181, p‐tau231, p‐tau217), neurodegeneration (total tau), axonal degeneration (NfL), microglial activation (strem2) and neuroinflammation (GFAP, IL‐6). Biomarkers were log‐transformed. The Apathy Evaluation Scale (AES), Beck Depression Inventory‐II (BDI‐II) and the Beck Anxiety Inventory (BAI) self‐report questionnaires were completed by participants. Multivariable regression models tested the association between each CSF biomarker and each scale, controlling for age, race, body mass index, revised Framingham stroke risk profile and Alcohol Use Disorders Identification Test. P‐values were adjusted for multiple comparisons using false discovery rate methods.Result140 participants had successful LPs and available CSF for assays. 33(22%) reported moderate/severe anxiety, 34(22%) reported moderate/severe depression, and 51(33%) had an elevated AES score. Higher CSF concentrations of IL‐6 were associated with higher scores on the BAI (unstandardized‐β=0.016, 95%CI [0.017, 0.026], padj=0.004), BDI‐II (unstandardized‐β=0.013, 95%CI [0.004, 0.021], padj=0.008) and AES (unstandardized‐β=0.014, 95%CI [0.006,0.022], padj=0.002). There were no significant relationships between other biomarkers with the BDI‐II, BAI or AES.ConclusionIn this sample of former American football players, there were significant associations between IL‐6 (a proinflammatory cytokine) and reported symptoms of depression, anxiety, and apathy. CSF biomarkers of amyloid, tau and neurodegeneration had no associations, highlighting the role of neuroinflammatory processes in the manifestation of psychiatric symptoms of TES. Continued research on the biological correlates of TES features will inform future iterations of the criteria.