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Tools used for the identification, evaluation, and monitoring of concussion have not been sufficiently studied in youth or real-world settings. Normative and reliability data on sideline concussion assessment measures in the youth athlete population is needed. Pre-season normative data for 515 athletes (93.5% male) aged 5 to 16 on the Standardized Assessment of Concussion (SAC/SAC-Child), modified Balance Errors Scoring System (mBESS), Timed Tandem Gait (TTG), and the King–Devick Test (KDT) are provided. A total of 212 non-injured athletes repeated the measures post-season to assess test–retest reliability. Mean performance on the SAC-C, mBESS, TTG, and KDT tended to improve with age. KDT was the only measure that demonstrated good to excellent stability across age ranges (ICC = 0.758 to 0.941). Concentration was the only SAC/SAC-C subtest to demonstrate moderate test–retest stability (ICC = 0.503 to 0.706). TTG demonstrated moderate to good (ICC = 0.666 to 0.811) reliability. mBESS demonstrated poor to moderate reliability (ICC = −0.309 to 0.651). Commonly used measures of concussion vary regarding test–retest reliability in youth. The data support the use of at least annual sport concussion baseline assessments in the pediatric population to account for the evolution in performance as the child ages. Understanding the variation in the stability and the evolution of baseline performance will enable improved identification of possible injury.

Background Exposure to repetitive head impacts (RHI) is associated with developing chronic traumatic encephalopathy (CTE) neuropathology. Cognitive and behavioral symptoms have been associated with CTE neuropathology, but efforts to define the specific clinical syndrome are ongoing. This study characterizes the current use of centrally acting medications (CAMs), chronic pain, and number of orthopedic surgeries in former American football players and evaluates for associations with cognitive and behavioral symptoms. Methods This study analyzed data from the DIAGNOSE CTE Research Project, which includes 120 former professional football players, 60 collegiate football players, and 56 asymptomatic men without history of RHI. Medical history was obtained by self‐report, and participants completed the Montreal Cognitive Assessment (MoCA), Brief Pain Inventory, Barratt Impulsiveness Scale‐11 (BIS‐11), BRIEF‐A Behavioral Regulation Index (BRI), Beck Depression Inventory‐II (BDI‐II), Beck Anxiety Index (BAI), and Brown‐Goodwin Lifetime History of Aggression adulthood score (BGLHA). Logistic regression assessed the association of CAMs, average pain score, and orthopedic surgeries on the cognitive impairment and neurobehavioral dysregulation components of the NINDS traumatic encephalopathy syndrome (TES) research criteria, in former American football players. Linear regression assessed the associations with MoCA and behavioral scales. Models were adjusted for age, education, race, and years of football played. Results Tables 1 and 2 describe the sample and CAM burden. More orthopedic surgeries, CAMs, and higher average pain were observed in former American football players. Number of CAMs was associated with neurobehavioral dysregulation (OR = 2.18), lower MoCA (β = ‐0.47), and higher BIS‐11 (β = 2.23), BDI‐II (β = 2.01), BRI (β = 3.71), BAI (β = 2.04), and BGLHA (β = 0.68) scores. Higher average pain was associated with neurobehavioral dysregulation (OR = 1.57) and higher BIS‐11 (β = 2.20), BDI‐II (β = 1.98), BRI (β = 2.20), BAI (β = 1.84), and BGLHA (β = 0.52) scores. No associations were observed with orthopedic surgeries. Conclusions In former American football players, the number of CAMs and higher average pain were associated with neurobehavioral dysregulation. No associations were observed with diagnosis of cognitive impairment by TES criteria, though the number of CAMs was associated with decreased MoCA.

INTRODUCTION Blood‐based biomarkers offer a promising approach for the detection of neuropathologies from repetitive head impacts (RHI). We evaluated plasma biomarkers of amyloid, tau, neurodegeneration, and inflammation in former football players. METHODS The sample included 180 former football players and 60 asymptomatic, unexposed male participants (aged 45–74). Plasma assays were conducted for beta‐amyloid (Aβ) 40, Aβ42, hyper‐phosphorylated tau (p‐tau) 181+231, total tau (t‐tau), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), interleukin‐6 (IL‐6), Aβ42/p‐tau181 and Aβ42/Aβ40 ratios. We evaluated their ability to differentiate the groups and associations with RHI proxies and traumatic encephalopathy syndrome (TES). RESULTS P‐tau181 and p‐tau231(padj = 0.016) were higher and Aβ42/p‐tau181 was lower(padj = 0.004) in football players compared to controls. Discrimination accuracy for p‐tau was modest (area under the curve [AUC] = 0.742). Effects were not attributable to AD‐related pathology. Younger age of first exposure (AFE) correlated with higher NfL (padj = 0.03) and GFAP (padj = 0.033). Plasma GFAP was higher in TES‐chronic traumatic encephalopathy (TES‐CTE) Possible/Probable (padj = 0.008). DISCUSSION Plasma p‐tau181 and p‐tau231, GFAP, and NfL may offer some usefulness for the characterization of RHI‐related neuropathologies. Highlights Former football players had higher plasma p‐tau181 and p‐tau231 and lower Aβ42/ptau‐181 compared to asymptomatic, unexposed men. Younger age of first exposure was associated with increased plasma NfL and GFAP in older but not younger participants. Plasma GFAP was higher in participants with TES‐CTE possible/probable compared to TES‐CTE no/suggestive.

Background Traumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1β, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals. Methods Our cohort consisted of former American football players, with ( n  = 104) or without ( n  = 76) NBD diagnosis, as well as asymptomatic unexposed individuals ( n  = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, ≥ 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES. Results CSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations. Conclusion Specific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.

Exposure to repetitive head impacts (RHI) is associated with developing chronic traumatic encephalopathy (CTE) neuropathology. Cognitive and behavioral symptoms have been associated with CTE neuropathology, but efforts to define the specific clinical syndrome are ongoing. This study characterizes the current use of centrally acting medications (CAMs), chronic pain, and number of orthopedic surgeries in former American football players and evaluates for associations with cognitive and behavioral symptoms. This study analyzed data from the DIAGNOSE CTE Research Project, which includes 120 former professional football players, 60 collegiate football players, and 56 asymptomatic men without history of RHI. Medical history was obtained by self-report, and participants completed the Montreal Cognitive Assessment (MoCA), Brief Pain Inventory, Barratt Impulsiveness Scale-11 (BIS-11), BRIEF-A Behavioral Regulation Index (BRI), Beck Depression Inventory-II (BDI-II), Beck Anxiety Index (BAI), and Brown-Goodwin Lifetime History of Aggression adulthood score (BGLHA). Logistic regression assessed the association of CAMs, average pain score, and orthopedic surgeries on the cognitive impairment and neurobehavioral dysregulation components of the NINDS traumatic encephalopathy syndrome (TES) research criteria, in former American football players. Linear regression assessed the associations with MoCA and behavioral scales. Models were adjusted for age, education, race, and years of football played. Tables 1 and 2 describe the sample and CAM burden. More orthopedic surgeries, CAMs, and higher average pain were observed in former American football players. Number of CAMs was associated with neurobehavioral dysregulation (OR = 2.18), lower MoCA (β = -0.47), and higher BIS-11 (β = 2.23), BDI-II (β = 2.01), BRI (β = 3.71), BAI (β = 2.04), and BGLHA (β = 0.68) scores. Higher average pain was associated with neurobehavioral dysregulation (OR = 1.57) and higher BIS-11 (β = 2.20), BDI-II (β = 1.98), BRI (β = 2.20), BAI (β = 1.84), and BGLHA (β = 0.52) scores. No associations were observed with orthopedic surgeries. In former American football players, the number of CAMs and higher average pain were associated with neurobehavioral dysregulation. No associations were observed with diagnosis of cognitive impairment by TES criteria, though the number of CAMs was associated with decreased MoCA.

INTRODUCTION Tau 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. METHOD We 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). RESULTS Significantly 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. DISCUSSION Additional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.

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 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. Method 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. Result 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. Conclusion 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.

Traumatic encephalopathy syndrome (TES) is the proposed clinical syndrome of chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impacts in contact/collision sports. A core clinical feature of TES is cognitive impairment, particularly in memory and executive functions. Cognitive intraindividual variability (IIV) is the extent of variability in neuropsychological test performance (i.e., dispersion of test scores) and is believed to be an indicator of disruption in executive control, linked to altered fronto-subcortical circuits. Here, we examined cognitive IIV as a method to detect subtle executive dysfunction in TES that may not be captured by traditional neuropsychological measures. The sample included former American football players (120 professional, 60 college); participants were males, aged 45-74. Participants completed a baseline neuropsychological test battery (n = 8 excluded for suboptimal performance validity). A multidisciplinary diagnostic consensus conference classified participants using the 2021 NINDS Consensus Diagnostic Criteria for TES (see Table-1): (1) No-TES (n = 62); (2) TES-CTE Suggestive (n = 35); (3) TES-CTE Possible (n = 21); (4) TES-CTE Probable (n = 54). TES-CTE Possible and Probable were combined. The coefficient of variation (CoV) was used to measure cognitive IIV (CoV = iSD/iOTBM, iOTBM = average T-score across neuropsychological tests; iSD = standard deviation of iOTBM). A higher CoV indicates greater score dispersion. To avoid circularity, memory and executive tests used for classifying TES groups were intentionally excluded from the CoV calculation. Analysis of covariance compared the TES groups on CoV, controlling for age, education, and race. Results showed a significant difference in CoV between TES groups, F(2, 165) = 8.20 p<.001, partial η2 = .09. The TES-CTE Possible/Probable group had the highest CoV (M = .226, SE = .007), compared with the TES-no (M = .192, SE = .008, p<.001) and TES-CTE Suggestive groups (M = .178, SE = .011, p<.001). CoV did not significantly differ between the TES-no and TES-CTE suggestive groups (Mdiff = 0.014, SE = .013, p = .293). The TES-CTE possible/probable group had the highest cognitive IIV with ∼23% dispersion (vs. ∼18-19% in TES-no and TES-CTE suggestive groups), suggesting greater cognitive variability in those with the greatest likelihood for having underlying CTE (based on TES criteria). This finding emphasizes the potential utility of exploring cognitive IIV as a method for detecting nuanced executive dysfunction in TES.

Clinically meaningful cognitive impairment has typically been defined as a single impaired test score, but this approach is prone to false-positive errors. Examining two test scores at a lower threshold (i.e., using neuropsychological criteria) can improve diagnostic reliability and has shown stronger associations with biomarkers of Alzheimer's disease. Cognitive impairment in episodic memory and/or executive functioning is a core feature of traumatic encephalopathy syndrome (TES). However, there remains a need to improve the specificity of TES criteria. We applied 1- vs. 2-test criteria for cognitive impairment in former American football players to examine whether 2-test criteria showed stronger associations with biomarkers of tau, axonal injury, and neurodegeneration. 169 male former American football players from the DIAGNOSE CTE Research Project completed neuropsychological assessment, lumbar puncture, and MRI (see Table). Episodic memory measures were delayed recall from Craft Story, Brief Visuospatial Memory Test, and NAB List Learning. Executive functioning measures were FAS, Stroop Interference, NAB Mazes, and Trails B. Cerebrospinal fluid (CSF) was measured using Lumipulse technology (p-tau, t-tau) and an in-house ELISA (neurofilament light [NfL]). Hippocampal volumes were extracted from structural MRI using Freesurfer 7.1. Cognitive impairment was identified by 1-test criteria (≥1.5 SD below norms on one test in either domain) and 2-test criteria (>1 SD below norms on two tests within a domain). Regressions adjusting for age, race, education, and APOE ε4 status assessed whether meeting 1- or 2-test criteria, separately, predicted log-transformed CSF p-tau , p-tau , t-tau, and NfL, and hippocampal volumes. 37 of the 99 football players that were impaired by 1-test criteria did not meet 2-test criteria, and four uniquely met 2-test but not 1-test criteria (see Figure). Cognitive impairment by 2-test but not 1-test criteria predicted higher log-CSF NfL (2-test: B = 0.24, p = .007; 1-test: B = 0.06, p = .53), smaller left hippocampal volume (2-test: B = -195.84, p = .01; 1-test: B = -131.52, p = .08), and smaller right hippocampal volume (2-test: B = -161.19, p = .045; 1-test: B = -134.88, p = .08). Neither criterion predicted p-tau , p-tau , or t-tau. 2-test criteria demonstrated stronger associations between cognitive impairment and markers of axonal injury and neurodegeneration. Incorporating multiple test scores to identify cognitive impairment could improve diagnostic specificity in TES.