In vivo biomarkers that can detect long-term neuropathologies from repetitive head impact (RHI) exposure are needed, especially for the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Here, we evaluated plasma p -tau217 as a potential biomarker for CTE p -tau pathology, and examined the concordance between plasma p -tau217 and Aβ pathology in an at-risk for CTE sample. The sample included 180 male former football players (120 professional, 60 college), and 56 asymptomatic men without RHI (i.e., controls). Participants completed blood draws, 18F-florbetapir (Aβ+=SUVR≥1.10), and 18F-flortaucipir PET. Traumatic encephalopathy syndrome (TES) diagnoses were made. Single molecule array for plasma p -tau217 (ALZpath) was performed (≥0.6 cutoff used to maximize sensitivity). Nine participants had post-mortem tissue. ANCOVA examined group differences in p -tau217 (football vs controls; TES-CTE no, TES-CTE suggestive, TES-CTE possible/probable). Multivariable regression models tested associations between p -tau217 and florbetapir/flortaucipir PET. Covariates included age, race and APOE e4 . Sample characteristics are in Table 1. p -tau217 concentrations were higher in former football players compared to controls (est. marginal mean difference=-0.217, p  = 0.005). There were no group differences in Aβ-PET SUVR. No differences were found across TES-CTE certainty levels. In football players, higher p -tau217 was associated with higher Aβ-PET SUVR (B=1.380, 95%CI[0.597-2.155], p  = 0.001) but not when Aβ+ ( n  = 17) participants and those with kidney/liver disease ( n  = 5) were excluded. Aβ+ participants had the highest p -tau217 (Figure 1). When compared against Aβ-PET, several false Aβ-positives (high p -tau217, Aβ-) were identified, including one extreme outlier (assay related) and a cluster of Aβ- participants with p -tau217 between 0.60–1.0. There were no associations with flortaucipir SUVR (frontal, mesial temporal, left parietal). Two extreme p -tau217 outliers had autopsy-confirmed CTE stage III (AD-, Table 2). Of the remaining donors, all were AD- and four had CTE (stages II-IV) with ptau217 between 0.125-0.449. Plasma p -tau217 has usefulness in quantifying Aβ pathology but restricted utility for detection of CTE. In this at-risk for CTE sample, p -tau217 and Aβ-PET were associated at the group level. At the individual level, false Aβ-positives (and negatives) existed, including Aβ- participants with high p -tau217. We will explore whether this discrepancy is due to disease or peripheral interference with the N-terminal binding in p -tau assays.

BACKGROUND:Childhood maltreatment (CM), encompassing abuse and neglect, is highly prevalent and associated with elevated risk for major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and other related conditions. However, the extent to which neuroanatomical alterations in MDD and PTSD are attributable to CM is uncertain. METHODS:Here, we analyzed CM and whole-brain magnetic resonance imaging (MRI) data from 3711 participants in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) MDD and PTSD Working Groups (25 sites; mean age = 33.3 ± 13.0 years; 59.9% female). Normative modeling estimated deviation z scores for 14 subcortical volume, 68 cortical thickness (CT), and 68 surface area (SA) measures. To identify transdiagnostic effects, associations between CM and brain deviation scores were evaluated across all participants (patients and healthy control participants) stratified by sex and 3 age bins (pediatric, young adult, older adult). RESULTS:In young adults (ages 18-35), abuse was associated with larger volumes in the thalamus and pallidum, thinner isthmus cingulate and middle frontal regions, and thicker medial orbitofrontal cortex; there were no significant effects in pediatric (≤18 years) participants. The strongest effects were observed in young female adults (|β| = 0.07-0.22, q < .05): Greater abuse and neglect were correlated with smaller hippocampus and putamen volumes, thinner entorhinal cortex, and smaller SA in fusiform/inferior parietal regions and with larger SA in the orbitofrontal and occipital cortices. In males, abuse had widespread effects on CT and SA (|β| = 0.1-0.18, q < .05); effects for neglect were minimal. CONCLUSIONS:Our findings of age- and sex-specific instantiations of CM on brain morphometry highlight the importance of developmental context in understanding how adverse experiences shape neurobiological vulnerability to MDD and PTSD.

Large language models (LLMs) are increasingly deployed to assess, diagnose, and predict clinical symptoms and outcomes from textual data. However, prior work has shown that LLMs are susceptible to hallucinations. To date, it remains unclear whether, how, and why such hallucinations arise when LLMs are applied to clinical data situated in diverse real-world contexts. In this work, we systematically quantify the prevalence and types of hallucinations across different LLMs and examine the utility of LLMs-as-judges (LLJs) for automated hallucination assessment using real-world clinical data situated in diverse real-world contexts. Specifically, we analyzed transcripts obtained from both community controls and populations at higher risk of developing schizophrenia. Across ground-truth hallucination analyses, we find that hallucination rates vary widely, from 0.3% to 76.3%, depending on transcript type, prompting strategy, and the LLM used for classification. Diagnostic hallucinations are the most prevalent subtype, accounting for up to 50.4% of observed hallucinations. Across automated hallucination detection, LLJs demonstrate reasonable alignment with human raters, achieving up to 65.7% agreement on hallucination presence and 64.7% agreement on hallucination subcategorization. Finally, we identify that hallucinations most commonly arise when there is insufficient contextual grounding.

Evidence suggests extracellular free-water (FW) is a potential marker of neuroinflammation. In psychosis spectrum disorders (PSD), neuroinflammation has been associated with cognition deficits, but findings are heterogeneous. Thus, we derived FW and cognition-based subgroups in PSD. PSD (n = 166) and healthy (n = 50) individuals underwent diffusion magnetic resonance imaging, cognitive testing, and clinical assessments. Canonical correlation analysis (CCA) was performed using statistically significant measures, including 8 FW regions (anterior corona radiata, body, genu, and splenium of corpus callosum, fornix/stria terminalis, inferior and superior fronto-occipital fasciculus, and superior longitudinal fasciculus) and 13 cognitive measures. Permutation testing and cross validation quantified CCA significance and reliability. PSD subgroups were identified by hierarchical clustering of CCA projections. Random sampling and bootstrapping assessed clustering significance and reliability. Analysis of variance, general linear models, and Cohen's effect sizes tested for differences between groups. The false discovery rate corrected for multiple comparisons. The first latent variate (r = 0.45) identified two clusters: cluster 1 demonstrated lower FW (n = 110, 66%) while cluster 2 showed higher FW (n = 56, 34%). Both displayed cognitive deficits compared to controls. Cluster 2 showed greater FW in all regions tested (p < 0.05), exhibited cognitive impairment across multiple cognitive domains (p < 0.01), and higher depressive, manic, general and total psychosis symptoms (p < 0.05) compared to cluster 1. However, they did not differ with regard to medication, functioning, or potential inflammatory confounds. Results support previous research indicating that a high neuroinflammatory subgroup of PSD exists and is related to cognition and brain structure, but the translational impact remains to be determined.

OBJECTIVE:Subjective cognitive complaints (SCC) can precede cognitive decline and are associated with demographic, exposure, lifestyle, and psychological factors. Prevalences of SCC and their correlates in individuals with repetitive head impacts (RHI) are poorly understood. This study characterized SCC in former elite American football players by frequency, mood and behavioral correlates, concordance with informant reports, and associations with neuropsychological test performance, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) markers of neurodegeneration. METHOD:Former American football players (n = 180) completed measures of global and domain-specific SCC, neuropsychiatric symptom questionnaires, neuropsychological testing, lumbar puncture, and MRI. Elastic net regression evaluated the relative importance of potential SCC correlates. Intraclass correlation coefficients measured concordance between self and informant reports. Multiple linear regressions tested associations between SCC and verbal memory and executive functioning scores. CSF Aβ1-42, p-tau181, t-tau, neurofilament light (NfL), hippocampal volume, and regional cortical thickness were examined for their potential associations with SCC. RESULTS:Rates of SCC ranged from 43 to 77% depending on the domain. Symptoms of depression, impulsivity, and anxiety were strongly associated with SCC. Self- and informant-reported SCC showed moderate inter-rater agreement. Adjusting for age, race, education, APOE ϵ4 carrier status, and depressive symptoms, SCC were associated with lower objective verbal memory and executive functioning performance. SCC were associated with lower parahippocampal cortical thickness but not with hippocampal volume or any of the measured CSF tests. CONCLUSIONS:SCC are strongly associated with neuropsychiatric factors in former American football players. SCC may also be a marker of cognitive decline and neurodegeneration.

White matter (WM) alterations are well documented in individuals at clinical high-risk for psychosis (CHR-P) and with recent-onset psychosis (ROP), yet it remains unclear whether they reflect vulnerability, psychosis-related symptom severity, or general impairments shared with other disorders such as depression. To disentangle these correlates, we analyzed diffusion MRI data from 882 individuals (457 females) of the multisite Personalized Prognostic Tools for Early Psychosis Management (PRONIA) study, including 183 CHR-P, 206 ROP, 298 healthy controls, and 195 individuals with depression who were assessed as a clinical comparison group of observed associations. Fractional anisotropy (FA) was extracted from 25 WM regions. Analyses of covariance tested group differences across CHR-P, ROP, and healthy controls. Canonical correlation analysis then identified multivariate correlation components between FA and a broad set of twelve clinical, two cognitive, and two risk-related measures in CHR-P and ROP, restricted to regions with group effects. To identify if these findings are not specific to psychosis, we additionally tested whether the correlation components were expressed in the depression comparison group. Group differences emerged in 17 of 25 regions. Canonical correlation analysis identified two significant correlation components. Component 1 linked widespread lower FA with impaired cognition and functioning, representing general impairment. Component 2 linked focal lower FA with more severe psychosis-related symptoms and absence of familial risk. Component 1, but not Component 2, showed also a significant association in the depression group emphasizing its relevance for general impairment. Disentangling general impairment from psychosis-related symptom severity suggests potentially different underlying processes. Developing imaging biomarkers accounting for these processes may guide early detection strategies and targeted interventions.

Posttraumatic stress disorder (PTSD) is a psychiatric condition that may develop after trauma exposure. PTSD is characterized by considerable clinical heterogeneity. The amygdala's key role in fear conditioning makes it an important focus for investigating the neurobiology of PTSD. However, associations between amygdala volume and PTSD have been inconsistent. The amygdala consists of functionally distinct nuclei. Specific associations between amygdala nuclei volumes and PTSD may account for previous discrepancies between PTSD and whole amygdala volume. This study investigates the associations between amygdala nuclei volumes, PTSD diagnosis, severity, symptom cluster scores, age of onset and childhood trauma. Individuals with a PTSD diagnosis (n = 771) and controls (n = 1 081, 72% trauma-exposed) were sourced from the Enhancing Neuro-Imaging Genetics through Meta-Analysis and Psychiatric Genomics Consortium (mean age = 32.4 years, (SD = 13 years), 60% male). Nine amygdala nuclei volumes were compared to PTSD diagnosis, age of onset, overall severity, symptom cluster scores (re-experiencing, arousal, and avoidance/emotional numbing), and childhood trauma subscales. Analyses were performed using ordinary least-squares regression, corrected for age, sex, intracranial volume, and whole amygdala volume. PTSD diagnosis was not significantly associated with amygdala nuclei volumes. PTSD severity scores were associated with smaller right lateral nucleus volume (β = -0.26, pBON = 0.01). Smaller right lateral nucleus volume was also associated with re-experiencing (β = -1.01, pBON = 0.04) and arousal (β = -0.9, pBON = 0.04), smaller left paralaminar nucleus volume was associated with re-experiencing (β = -0.1, pBON = 0.04), smaller left corticoamygdaloid transition area volume was associated with avoidance (β = -0.31, pBON = 0.02). Larger left and right central nucleus volumes were significantly associated with childhood physical abuse (β = 0.24, pBON = 9 × 10-3) and neglect (β = 0.29, pBON = 0.04), respectively. Differences in select amygdala nuclei volumes among adults are associated with PTSD severity, symptom cluster scores, and childhood physical abuse and neglect. These findings demonstrate nuclei-specific patterns consistent with their functional roles in fear learning and expression.

INTRODUCTION:Chronic traumatic encephalopathy (CTE) is a tauopathy linked to repetitive head impacts. Factors influencing brain regional susceptibility to tau deposition and spreading remain unclear. METHODS:We used three datasets: [18F]flortaucipir positron emission tomography (PET) in 157 former professional American football players and 53 controls (DIAGNOSE CTE); cortical myelin water fractions (MWF) in 50 healthy individuals (Myelin Water Atlas); and white matter (WM) tract MWF and functional connectivity (FC) in 100 healthy individuals (Human Connectome Project). We tested associations between tau-PET uptake and covariance in football players and typical cortical gray matter (GM) MWF, WM tract MWF, and FC. RESULTS:Cortical regions with lower typical GM MWF showed higher tau-PET uptake (β = -0.399, p = 0.001). WM tracts with lower typical MWF were associated with higher tau-PET covariance (β = -0.238, p < 0.001). Higher typical FC was associated with higher tau-PET covariance (β = 0.447, p < 0.001). DISCUSSION:In former football players at risk for CTE, regional susceptibility to tau deposition may be driven by low myelin and high FC.

INTRODUCTION:Repetitive head impacts (RHIs) have been linked to later life neurodegeneration, yet the in vivo structural correlates of cumulative biomechanical loading remain unclear. We examined whether regional ventricular morphology in former American football players reflects exposure burden and traumatic encephalopathy syndrome (TES) classification. METHODS:Participants included 170 male former football players and 54 age-matched asymptomatic male controls from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Subject-specific manual segmentation quantified lateral ventricle, inferior horn, third ventricle, and fourth ventricle volumes. Group and exposure associations were tested using generalized least squares models. RESULTS:Former players showed larger left inferior lateral ventricle volume than controls, with the largest effects among professional players. Greater cumulative linear and rotational acceleration exposure was associated with enlargement across lateral ventricular and inferior horn regions. DISCUSSION:Regional ventricular enlargement may represent an in vivo marker of cumulative biomechanical loading after RHI exposure.

Abstract Background Cognitive impairment is the leading cause of disability in schizophrenia with limited treatments. A major barrier to treatment development is the absence of reproducible, mechanistically grounded neural targets. Cross-sectional studies have identified dorsomedial prefrontal cortex (DMPFC)-somatomotor connectivity as a neural marker of cognitive performance on the Auditory Continuous performance task (ACPT), a measure of attention. To test the stability of this marker, we tested the relationship between DMPFC-somatomotor connectivity and ACPT performance in a longitudinal psychosis sample. Methods Individuals with early psychosis (n=251) and matched controls (n=90) were enrolled and underwent resting-state neuroimaging and neurocognitive assessment. A subset completed longitudinal assessments over 2-4 years. We calculated DMPFC-somatomotor resting-state functional connectivity using a previously identified DMPFC region and a seed in the somatomotor cortex. We performed linear mixed effects models to predict ACPT performance based on connectivity, time, psychosis type, and their interaction. Results In the psychosis sample, time (p=.0037) and affective psychosis diagnosis (p<.0001) predicted better ACPT performance. In a model predicting ACPT performance, we observed a significant interaction effect of DMPFC-somatomotor connectivity*psychosis subtype (p=.0079) such that DMPFC-somatomotor connectivity predicted ACPT performance only in individuals with non-affective psychosis (p=.0051). We then tested the specificity of this connectivity-cognitive performance relationship. In a model predicting DMPFC-somatomotor connectivity, only ACPT performance (p=.017), but not fluid cognition, was a significant predictor. Conclusions DMPFC-somatomotor connectivity is longitudinally associated with cognitive performance in early psychosis. This relationship is strongest in nonaffective psychosis, suggesting a novel, reliable target for intervention for cognitive deficits in early psychosis.

Importance:In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed. Objective:To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample. Design, Setting, and Participants:This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data. Exposures:RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty. Main Outcomes and Measures:Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ-positron emission tomography (PET; 18F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET (18F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status. Results:Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET-positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217-negative and Aβ-PET-positive; 7 participants were p-tau217-positive and Aβ-PET-negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing. Conclusions and Relevance:The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.

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.

Background:Self-disorders, or anomalous disturbances in the basic sense of self, have been described in psychosis-risk states and may contribute to social cognitive impairment and functioning. This study examined self-disorder severity and associations with social cognition and functioning across individuals at clinical high risk for psychosis (CHR-P), autism spectrum disorder (ASD), and controls. ASD was included due to overlapping difficulties in social cognition/functioning with CHR-P. We hypothesized a graded pattern of self-disorders (CHR-P > ASD > controls) and stronger associations between self-disorders and social cognition in CHR-P. Methods:We included 39 CHR-P, 39 ASD, and 30 controls (mean age ≈24 years; 51% female). Self-disorders were assessed with the Inventory of Psychotic-Like Anomalous Self-Experiences (IPASE). Social cognitive domains included social cognitive bias and theory of mind alongside measures of social functioning. Analyses of covariance and bootstrapped regression models with IPASE as predictor were used, adjusting for age, sex, and IQ. Multiple comparisons were Benjamini-Hochberg corrected. Results:Self-disorders followed a graded distribution (CHR-P > ASD > controls) across all IPASE subscores. Both clinical groups showed elevated social cognitive bias and reduced social functioning compared to controls. Self-disorders were associated with social cognitive bias in ASD (B = 0.392, 95%CI 0.236-0.544, p < 0.001), but not in CHR P. Group differences in associations between self-disorders and social cognition/functioning did not survive correction for multiple comparisons. Conclusion:Self-disorders showed a graded distribution across groups but was only associated with social cognitive deficits in ASD. Findings suggest that shared symptom profiles may reflect divergent experiential processes across groups. Further research is needed to clarify clinical implications and generalizability.

The prevalence of behavioral and cognitive difficulties in children is high and often remains undetected. Evidence suggests that poor motor coordination may be an early indicator of these difficulties. However, the underlying mechanisms are unknown. This study investigates whether motor coordination is associated with behavioral and cognitive outcomes, and whether white matter microstructure characteristics mediate these relationships. Data from 9342 children participating in the Adolescent Brain Cognitive Development (ABCD) study was analyzed. Children were categorized in two groups: normal (n = 8239; mean age = 9.93; 48.5

The medical adoption of NLP tools requires interpretability by end users, yet traditional explainable AI (XAI) methods are misaligned with clinical reasoning and lack clinician input. We introduce CHiRPE (Clinical High-Risk Prediction with Explainability), an NLP pipeline that takes transcribed semi-structured clinical interviews to: (i) predict psychosis risk; and (ii) generate novel SHAP explanation formats co-developed with clinicians. Trained on 944 semi-structured interview transcripts across 24 international clinics of the AMP-SCZ study, the CHiRPE pipeline integrates symptom-domain mapping, LLM summarisation, and BERT classification. CHiRPE achieved over 90% accuracy across three BERT variants and outperformed baseline models. Explanation formats were evaluated by 28 clinical experts who indicated a strong preference for our novel concept-guided explanations, especially hybrid graph-and-text summary formats. CHiRPE demonstrates that clinically-guided model development produces both accurate and interpretable results. Our next step is focused on real-world testing across our 24 international sites.

BACKGROUND AND OBJECTIVES:The link between repetitive head impact (RHI) exposure, later-life cognitive decline, and neurobehavioral dysregulation (NBD) is not well understood. Recent work has implicated inflammation and limbic dysfunction as relevant RHI correlates. Our goal was to integrate plasma and CSF inflammatory biomarkers, structural brain imaging, and clinical measures in former elite American football players to better understand reasons for RHI-related cognitive and neurobehavioral changes. METHODS:Participants were from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project, which recruited male former college/professional football players with RHI and asymptomatic unexposed (UE) controls with no history of contact sports, military combat, or traumatic brain injury/concussion. Our study focused on plasma/CSF inflammatory biomarkers (interleukin [IL]-6, tumor necrosis factor [TNF]-α, glial fibrillary acidic protein), limbic white matter (WM) microstructure (diffusion tensor imaging: fractional anisotropy [FA], mean diffusivity [MD]), and clinical measures (memory, executive function, NBD). Hierarchical linear regressions assessed change in variance explained (ΔR2) among inflammation, WM, and clinical outcomes in former football players. Post hoc analyses tested whether associations differed by group (football vs UE; group interactions) or were stronger in football players considered at highest risk of CTE. RESULTS:Our sample included 223 men (n = 170 football players: age 57.2 ± 8.1 years, 33% non-Hispanic/Black; n = 53 UE participants: age 59.4 ± 8.6 years, 34% non-Hispanic/Black). In football players, higher inflammation was associated with lower limbic FA (plasma IL-6: ΔR2 = 0.03 [0.001-0.09], p = 0.03; CSF IL-6: ΔR2 = 0.03 [-0.01 to 0.11], p = 0.03; plasma TNF-α: ΔR2 = 0.05 [0.01-0.11], p = 0.003) and higher limbic MD (CSF IL-6: ΔR2 = 0.06 [0.007-0.15], p = 0.01). Inflammation was more strongly related to limbic WM microstructure in football players than in UE participants. Worse WM microstructure was associated with worse memory in football players (FA: ΔR2 = 0.05 [0.003-0.14], p = 0.007; MD: ΔR2 = 0.07, p = 0.003 [0.008-0.16]). Most of the observed associations were stronger in the CTE probable subgroup. There were no direct associations between plasma or CSF markers of inflammation and cognition. DISCUSSION:In former elite football players, elevated plasma and CSF inflammatory markers were associated with poorer limbic WM microstructure, which in turn related to worse cognition. Given the limbic system's role in cognition and behavior, inflammation may be a modifiable target for RHI-related neurodegeneration. Limitations include the cross-sectional design and limited generalizability to other contact sports, lower levels of play, female athletes, or other RHI sources.

Repetitive head impacts sustained during American football have been associated with neuropathological changes such as white matter shear injuries. However, the impact of specific factors, such as age of first exposure and cumulative head impact burden, on white matter integrity remains unclear. This study investigated in vivo white matter microstructural changes using diffusion tensor imaging and tract-based spatial statistics in 165 male former American football players (mean age 57.3 years, range 45-74) and 52 unexposed asymptomatic male controls (mean age 59.4 years, range 45-74) in the DIAGNOSE CTE Research Project. Compared to controls, former football players exhibited significantly higher fractional anisotropy (FA) in 1.97% of the white matter skeleton (1552 voxels; Cohen's d = 0.587) and higher tissue-corrected FA (FAt) in 1.48% of the white matter skeleton (1004 voxels; Cohen's d = 0.616). No significant differences were observed for mean diffusivity, axial diffusivity, radial diffusivity, or free water between football players and controls. Among football players, there were no significant differences in the white matter microstructure between players diagnosed with traumatic encephalopathy syndrome and those without the diagnosis. Lower FA was significantly associated with older age (P < 0.00001) and an earlier age of first exposure to tackle football (P < 0.01), while lower FAt was associated with greater cumulative head impact burden, specifically higher linear acceleration (P < 0.04) and rotational force (P < 0.02). This study highlights the influential role of exposure factors on white matter microstructure in former American football players, as well as the utility of diffusion tensor imaging to aid in characterizing the long-term effects of repetitive head impacts in contact sport athletes.

Importance:Repetitive head impacts (RHIs) are associated with later-life neurodegeneration. Because soccer is the most widely played sport among youth worldwide, identifying early changes associated with RHI is important. Objective:To determine whether participation in 1 season of youth soccer is associated with changes in cognition, behavior, balance, brain structure or function, or blood biomarkers compared with noncontact sports. Design, Setting, and Participants:Prospective longitudinal cohort study at European centers (Munich, Germany; Leuven, Belgium; and Oslo, Norway). Male adolescent soccer players and noncontact athletes were each studied across a single competitive season with assessments at preseason, postseason, and 2 months later. Data were analyzed from January 2023 to March 2025. Exposures:Soccer players were compared with noncontact athletes. In addition, self-reported heading of a soccer ball was assessed among soccer players as a measure of RHI. Main Outcomes and Measures:Cognition, behavior, balance, magnetic resonance imaging (brain structure, function, and biochemistry), and plasma biomarkers. Results:Male adolescent soccer players (n = 82; mean [SD] age, 14.8 [0.6] years) did not differ from noncontact sport athletes (n = 47; mean [SD] age, 14.7 [0.7] years) in cognition, behavior, balance, cortical thickness, brain volumes, white-matter microstructure, or functional connectivity. At preseason, soccer players had higher total N-acetylaspartate (tNAA; β, -0.379 [95% CI, -0.627 to -0.131]; P = .003), glial fibrillary acidic protein (GFAP; β, -0.055 [95% CI, -0.103 to -0.006]; P = .03), and neurofilament light chain (NfL; β, -0.071 [95% CI, -0.122 to -0.020]; P = .01) than noncontact sport controls. Across the season, tNAA (β, 0.047 [95% CI, 0.020-0.074]; P = .001) declined in soccer players and increased in controls, converging by postseason. Group trajectories of GFAP and NfL did not differ between groups. Within soccer players, heading exposure was not significantly associated with changes in any outcome. Conclusions and Relevance:In this cohort study of adolescent males, no statistically significant differences were detected over 1 season between soccer players and noncontact sport athletes in cognition, behavior, or brain structure and function. Group differences in GFAP and NfL may represent early signs of exposure, but lack of association with heading exposure warrants further investigation. These results highlight the need for large, multiyear studies to inform health policy.