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Purpose: Flourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer's disease. Human imaging studies have begun to investigate its use in chronic traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association between end-of-life flortaucipir PET and postmortem neuropathological measurements of CTE-related tau in six former American football players., Methods: Three former National Football League players and three former college football players who were part of the DIAGNOSE CTE Research Project died and agreed to have their brains donated. The six players had flortaucipir (tau) and florbetapir (amyloid) PET prior to death. All brains from the deceased participants were neuropathologically evaluated for the presence of CTE. On average, the participants were 59.0 (SD = 9.32) years of age at time of PET. PET scans were acquired 20.33 (SD = 13.08) months before their death. Using Spearman correlation analyses, we compared flortaucipir standard uptake value ratios (SUVRs) to digital slide-based AT8 phosphorylated tau (p-tau) density in a priori selected composite cortical, composite limbic, and thalamic regions-of-interest (ROIs)., Results: Four brain donors had autopsy-confirmed CTE, all with high stage disease (n = 3 stage III, n = 1 stage IV). Three of these four met criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES). Two did not have CTE at autopsy and one of these met criteria for TES. Concomitant pathology was only present in one of the non-CTE cases (Lewy body) and one of the CTE cases (motor neuron disease). There was a strong association between flortaucipir SUVRs and p-tau density in the composite cortical (ρ = 0.71) and limbic (ρ = 0.77) ROIs. Although there was a strong association in the thalamic ROI (ρ = 0.83), this is a region with known off-target binding. SUVRs were modest and CTE and non-CTE cases had overlapping SUVRs and discordant p-tau density for some regions., Conclusions: Flortaucipir-PET could be useful for detecting high stage CTE neuropathology, but specificity to CTE p-tau is uncertain. Off-target flortaucipir binding in the hippocampus and thalamus complicates interpretation of these associations. In vivo biomarkers that can detect the specific p-tau of CTE across the disease continuum are needed., (© 2022. The Author(s).)

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been neuropathologically diagnosed in brain donors exposed to repetitive head impacts, including boxers and American football, soccer, ice hockey, and rugby players. CTE cannot yet be diagnosed during life. In December 2015, the National Institute of Neurological Disorders and Stroke awarded a seven-year grant (U01NS093334) to fund the "Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project." The objectives of this multicenter project are to: develop in vivo fluid and neuroimaging biomarkers for CTE; characterize its clinical presentation; refine and validate clinical research diagnostic criteria (i.e., traumatic encephalopathy syndrome [TES]); examine repetitive head impact exposure, genetic, and other risk factors; and provide shared resources of anonymized data and biological samples to the research community. In this paper, we provide a detailed overview of the rationale, design, and methods for the DIAGNOSE CTE Research Project., Methods: The targeted sample and sample size was 240 male participants, ages 45-74, including 120 former professional football players, 60 former collegiate football players, and 60 asymptomatic participants without a history of head trauma or participation in organized contact sports. Participants were evaluated at one of four U.S. sites and underwent the following baseline procedures: neurological and neuropsychological examinations; tau and amyloid positron emission tomography; magnetic resonance imaging and spectroscopy; lumbar puncture; blood and saliva collection; and standardized self-report measures of neuropsychiatric, cognitive, and daily functioning. Study partners completed similar informant-report measures. Follow-up evaluations were intended to be in-person and at 3 years post-baseline. Multidisciplinary diagnostic consensus conferences are held, and the reliability and validity of TES diagnostic criteria are examined., Results: Participant enrollment and all baseline evaluations were completed in February 2020. Three-year follow-up evaluations began in October 2019. However, in-person evaluation ceased with the COVID-19 pandemic, and resumed as remote, 4-year follow-up evaluations (including telephone-, online-, and videoconference-based cognitive, neuropsychiatric, and neurologic examinations, as well as in-home blood draw) in February 2021., Conclusions: Findings from the DIAGNOSE CTE Research Project should facilitate detection and diagnosis of CTE during life, and thereby accelerate research on risk factors, mechanisms, epidemiology, treatment, and prevention of CTE., Trial Registration: NCT02798185., (© 2021. The Author(s).)

Younger age at first exposure (AFE) to repetitive head impacts while playing American football increases the risk for later-life neuropsychological symptoms and brain alterations. However, it is not known whether AFE is associated with cortical thickness in American football players. Sixty-three former professional National Football League players (55.5 ± 7.7 years) with cognitive, behavioral, and mood symptoms underwent neuroimaging and neuropsychological testing. First, the association between cortical thickness and AFE was tested. Second, the relationship between clusters of decreased cortical thickness and verbal and visual memory, and composite measures of mood/behavior and attention/psychomotor speed was assessed. AFE was positively correlated with cortical thickness in the right superior frontal cortex (cluster-wise P value [CWP] = 0.0006), the left parietal cortex (CWP = 0.0003), and the occipital cortices (right: CWP = 0.0023; left: CWP = 0.0008). A positive correlation was found between cortical thickness of the right superior frontal cortex and verbal memory (R = 0.333, P = 0.019), and the right occipital cortex and visual memory (R = 0.360, P = 0.012). In conclusion, our results suggest an association between younger AFE and decreased cortical thickness, which in turn is associated with worse neuropsychological performance. Furthermore, an association between younger AFE and signs of neurodegeneration later in life in symptomatic former American football players seems likely., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts. CTE has been linked to disruptions in cognition, mood, and behavior. Unfortunately, the diagnosis of CTE can only be made post-mortem. Neuropathological evidence suggests limbic structures may provide an opportunity to characterize CTE in the living. Using 3 T magnetic resonance imaging, we compared select limbic brain regional volumes - the amygdala, hippocampus, and cingulate gyrus - between symptomatic former National Football League (NFL) players (n = 86) and controls (n = 22). Moreover, within the group of former NFL players, we examined the relationship between those limbic structures and neurobehavioral functioning (n = 75). The former NFL group comprised eighty-six men (mean age = 55.2 ± 8.0 years) with at least 12 years of organized football experience, at least 2 years of active participation in the NFL, and self-reported declines in cognition, mood, and behavior within the last 6 months. The control group consisted of men (mean age = 57.0 ± 6.6 years) with no history of contact-sport involvement or traumatic brain injury. All control participants provided neurobehavioral data. Compared to controls, former NFL players exhibited reduced volumes of the amygdala, hippocampus, and cingulate gyrus. Within the NFL group, reduced bilateral cingulate gyrus volume was associated with worse attention and psychomotor speed (r = 0.4 (right), r = 0.42 (left); both p < 0.001), while decreased right hippocampal volume was associated with worse visual memory (r = 0.25, p = 0.027). Reduced volumes of limbic system structures in former NFL players are associated with neurocognitive features of CTE. Volume reductions in the amygdala, hippocampus, and cingulate gyrus may be potential biomarkers of neurodegeneration in those at risk for CTE.

Background: Repetitive head impacts (RHI) from contact sports have been associated with cognitive and neuropsychiatric disorders. However, not all individuals exposed to RHI develop such disorders. This may be explained by the reserve hypothesis. It remains unclear if the reserve hypothesis accounts for the heterogenous symptom presentation in RHI-exposed individuals. Moreover, optimal measurement of reserve in this population is unclear and likely unique from non-athlete populations.Objective: We examined the association between metrics of reserve and cognitive and neuropsychiatric functioning in 89 symptomatic former National Football League players.Methods: Individual-level proxies (e.g., education) defined reserve. We additionally quantified reserve as remaining residual variance in 1) episodic memory and 2) executive functioning performance, after accounting for demographics and brain pathology. Associations between reserve metrics and cognitive and neuropsychiatric functioning were examined.Results: Higher reading ability was associated with better attention/information processing (β=0.25; 95% CI, 0.05-0.46), episodic memory (β=0.27; 95% CI, 0.06-0.48), semantic and phonemic fluency (β=0.24; 95% CI, 0.02-0.46; β=0.38; 95% CI, 0.17-0.59), and behavioral regulation (β=-0.26; 95% CI, -0.48, -0.03) performance. There were no effects for other individual-level proxies. Residual episodic memory variance was associated with better attention/information processing (β=0.45; 95% CI, 0.25, 0.65), executive functioning (β=0.36; 95% CI, 0.15, 0.57), and semantic fluency (β=0.38; 95% CI, 0.17, 0.59) performance. Residual executive functioning variance was associated with better attention/information processing (β=0.44; 95% CI, 0.24, 0.64) and episodic memory (β=0.37; 95% CI, 0.16, 0.58) performance.Conclusion: Traditional reserve proxies (e.g., years of education, occupational attainment) have limitations and may be unsuitable for use in elite athlete samples. Alternative approaches of reserve quantification may prove more suitable for this population. [ABSTRACT FROM AUTHOR]

Background: Exposure to repetitive head impacts (RHI) is associated with an increased risk of later‐life neurobehavioral dysregulation and neurodegenerative disease. The underlying pathomechanisms are largely unknown. Purpose: To investigate whether RHI exposure is associated with later‐life corpus callosum (CC) microstructure and whether CC microstructure is associated with plasma total tau and neuropsychological/neuropsychiatric functioning. Study Type: Retrospective cohort study. Population: Seventy‐five former professional American football players (age 55.2 ± 8.0 years) with cognitive, behavioral, and mood symptoms. Field Strength/Sequence: Diffusion‐weighted echo‐planar MRI at 3 T. Assessment: Subjects underwent diffusion MRI, venous puncture, neuropsychological testing, and completed self‐report measures of neurobehavioral dysregulation. RHI exposure was assessed using the Cumulative Head Impact Index (CHII). Diffusion MRI measures of CC microstructure (i.e., free‐water corrected fractional anisotropy (FA), trace, radial diffusivity (RD), and axial diffusivity (AD)) were extracted from seven segments of the CC (CC1‐7), using a tractography clustering algorithm. Neuropsychological tests were selected: Trail Making Test Part A (TMT‐A) and Part B (TMT‐B), Controlled Oral Word Association Test (COWAT), Stroop Interference Test, and the Behavioral Regulation Index (BRI) from the Behavior Rating Inventory of Executive Function, Adult version (BRIEF‐A). Statistical Tests: Diffusion MRI metrics were tested for associations with RHI exposure, plasma total tau, neuropsychological performance, and neurobehavioral dysregulation using generalized linear models for repeated measures. Results: RHI exposure was associated with increased AD of CC1 (correlation coefficient (r) = 0.32, P < 0.05) and with increased plasma total tau (r = 0.34, P < 0.05). AD of the anterior CC1 was associated with increased plasma total tau (CC1: r = 0.30, P < 0.05; CC2: r = 0.29, P < 0.05). Higher trace, AD, and RD of CC1 were associated with better performance (P < 0.05) in TMT‐A (trace, r = 0.33; AD, r = 0.31; and RD, r = 0.28) and TMT‐B (trace, r = 0.31; RD, r = 0.34). Higher FA and AD of CC2 were associated with better performance (P < 0.05) in TMT‐A (FA, r = 0.36; AD, r = 0.28), TMT‐B (FA, r = 0.36; AD, r = 0.27), COWAT (FA, r = 0.36; AD, r = 0.32), and BRI (AD, r = 0.29). Data Conclusion: These results suggest an association among RHI exposure, CC microstructure, plasma total tau, and clinical functioning in former professional American football players. Level of Evidence: 3 Technical Efficacy Stage: 1 [ABSTRACT FROM AUTHOR]

Background: Factors of increased prevalence among individuals with Black racial identity (e.g., cardiovascular disease, CVD) may influence the association between exposure to repetitive head impacts (RHI) from American football and later-life neurological outcomes. Here, we tested the interaction between racial identity and RHI on neurobehavioral outcomes, brain volumetric measures, and cerebrospinal fluid (CSF) total tau (t-tau), phosphorylated tau (p-tau181), and Aβ1–42 in symptomatic former National Football League (NFL) players. Methods: 68 symptomatic male former NFL players (ages 40–69; n = 27 Black, n = 41 White) underwent neuropsychological testing, structural MRI, and lumbar puncture. FreeSurfer derived estimated intracranial volume (eICV), gray matter volume (GMV), white matter volume (WMV), subcortical GMV, hippocampal volume, and white matter (WM) hypointensities. Multivariate generalized linear models examined the main effects of racial identity and its interaction with a cumulative head impact index (CHII) on all outcomes. Age, years of education, Wide Range Achievement Test, Fourth Edition (WRAT-4) scores, CVD risk factors, and APOE ε4 were included as covariates; eICV was included for MRI models. P -values were false discovery rate adjusted. Results: Compared to White former NFL players, Black participants were 4 years younger (p = 0.04), had lower WRAT-4 scores (mean difference = 8.03, p = 0.002), and a higher BMI (mean difference = 3.09, p = 0.01) and systolic blood pressure (mean difference = 8.15, p = 0.03). With regards to group differences on the basis of racial identity, compared to White former NFL players, Black participants had lower GMV (mean adjusted difference = 45649.00, p = 0.001), lower right hippocampal volume (mean adjusted difference = 271.96, p = 0.02), and higher p-tau181/t-tau ratio (mean adjusted difference = −0.25, p = 0.01). There was not a statistically significant association between the CHII with GMV, right hippocampal volume, or p-tau181/t-tau ratio. However, there was a statistically significant Race x CHII interaction for GMV (b = 2206.29, p = 0.001), right hippocampal volume (b = 12.07, p = 0.04), and p-tau181/t-tau ratio concentrations (b = −0.01, p = 0.004). Conclusion: Continued research on racial neurological disparities could provide insight into risk factors for long-term neurological disorders associated with American football play. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether or not automated FreeSurfer segmentation of brain regions considered important in repetitive head trauma can be analyzed accurately without manual correction. Materials and methods 3 T MR neuroimaging was performed with automated FreeSurfer segmentation and manual correction of 11 brain regions in former National Football League (NFL) players with neurobehavioral symptoms and in control subjects. Automated segmentation and manually-corrected volumes were compared using an intraclass correlation coefficient (ICC). Linear mixed effects regression models were also used to estimate between-group mean volume comparisons and to correlate former NFL player brain volumes with neurobehavioral factors. Results: Eighty-six former NFL players (55.2 ± 8.0 years) and 22 control subjects (57.0 ± 6.6 years) were evaluated. ICC was highly correlated between automated and manually-corrected corpus callosum volumes (0.911), lateral ventricular volumes (right 0.980, left 0.967), and amygdala-hippocampal complex volumes (right 0.713, left 0.731), but less correlated when amygdalae (right −0.170, left −0.090) and hippocampi (right 0.539, left 0.637) volumes were separately delineated and also less correlated for cingulate gyri volumes (right 0.639, left 0.351). Statistically significant differences between former NFL player and controls were identified in 8 of 11 regions with manual correction but in only 4 of 11 regions without such correction. Within NFL players, manually corrected brain volumes were significantly associated with 3 neurobehavioral factors, but a different set of 3 brain regions and neurobehavioral factor correlations was observed for brain region volumes segmented without manual correction. Conclusions: Automated FreeSurfer segmentation of the corpus callosum, lateral ventricles, and amygdala-hippocampus complex may be appropriate for analysis without manual correction. However, FreeSurfer segmentation of the amygdala, hippocampus, and cingulate gyrus need further manual correction prior to performing group comparisons and correlations with neurobehavioral measures.

Chronic traumatic encephalopathy ( CTE) is a neurodegenerative disease confirmed at postmortem. Those at highest risk are professional athletes who participate in contact sports and military personnel who are exposed to repetitive blast events. All neuropathologically confirmed CTE cases, to date, have had a history of repetitive head impacts. This suggests that repetitive head impacts may be necessary for the initiation of the pathogenetic cascade that, in some cases, leads to CTE. Importantly, while all CTE appears to result from repetitive brain trauma, not all repetitive brain trauma results in CTE. Magnetic resonance imaging has great potential for understanding better the underlying mechanisms of repetitive brain trauma. In this review, we provide an overview of advanced imaging techniques currently used to investigate brain anomalies. We also provide an overview of neuroimaging findings in those exposed to repetitive head impacts in the acute/subacute and chronic phase of injury and in more neurodegenerative phases of injury, as well as in military personnel exposed to repetitive head impacts. Finally, we discuss future directions for research that will likely lead to a better understanding of the underlying mechanisms separating those who recover from repetitive brain trauma vs. those who go on to develop CTE. [ABSTRACT FROM AUTHOR]

Introduction: The goal was to identify which neurochemicals differ in professional athletes with repetitive brain trauma (RBT) when compared to healthy controls using a relatively new technology, in vivo Localized COrrelated SpectroscopY (L-COSY). Methods: To achieve this, L-COSY was used to examine five former professional male athletes with 11 to 28 years of exposure to contact sports. Each athlete who had had multiple symptomatic concussions and repetitive sub concussive trauma during their career was assessed by an experienced neuropsychologist. All athletes had clinical symptoms including headaches, memory loss, confusion, impaired judgment, impulse control problems, aggression, and depression. Five healthy men, age and weight matched to the athlete cohort and with no history of brain trauma, were recruited as controls. Data were collected from the posterior cingulate gyrus using a 3 T clinical magnetic resonance scanner equipped with a 32 channel head coil. Results: The variation of the method was calculated by repeated examination of a healthy control and phantom and found to be 10% and 5%, respectively, or less. The L-COSY measured large and statistically significant differences (P =0.05), between healthy controls and those athletes with RBT. Men with RBT showed higher levels of glutamine/ glutamate (31%), choline (65%), fucosylated molecules (60%) and phenylalanine (46%). The results were evaluated and the sample size of five found to achieve a significance level P = 0.05 and a power of 90%. Differences in N-acetyl aspartate and myo-inositol between RBT and controls were small and were not statistically significance. Conclusions: A study of a small cohort of professional athletes, with a history of RBT and symptoms of chronic traumatic encephalopathy when compared with healthy controls using 2D L-COSY, showed elevations in brain glutamate/glutamine and choline as recorded previously for early traumatic brain injury. For the first time increases in phenylalanine and fucose are recorded in the brains of athletes with RBT. Larger studies utilizing the L-COSY method may offer an in-life method of diagnosis and personalized approach for monitoring the acute effects of mild traumatic brain injury and the chronic effects of RBT. [ABSTRACT FROM AUTHOR]

Thalamic atrophy has been associated with exposure to repetitive head impacts (RHI) in professional fighters. The aim of this study is to investigate whether or not age at first exposure (AFE) to RHI is associated with thalamic volume in symptomatic former National Football League (NFL) players at risk for chronic traumatic encephalopathy (CTE). Eighty-six symptomatic former NFL players (mean age = 54.9 ± 7.9 years) were included. T1-weighted data were acquired on a 3T magnetic resonance imager, and thalamic volumes were derived using FreeSurfer. Mood and behavior, psychomotor speed, and visual and verbal memory were assessed. The association between thalamic volume and AFE to playing football and to number of years playing was calculated. Decreased thalamic volume was associated with more years of play (left: p = 0.03; right: p = 0.03). Younger AFE was associated with decreased right thalamic volume ( p = 0.014). This association remained significant after adjusting for total years of play. Decreased left thalamic volume was associated with worse visual memory ( p = 0.014), whereas increased right thalamic volume was associated with fewer mood and behavior symptoms ( p = 0.003). In our sample of symptomatic former NFL players at risk for CTE, total years of play and AFE were associated with decreased thalamic volume. The effect of AFE on right thalamic volume was almost twice as strong as the effect of total years of play. Our findings confirm previous reports of an association between thalamic volume and exposure to RHI. They suggest further that younger AFE may result in smaller thalamic volume later in life. [ABSTRACT FROM AUTHOR]