Characterizing Neurobehavioral Dysregulation Among Former American Football Players: Findings From the DIAGNOSE CTE Research Project.

OBJECTIVE: Neurobehavioral dysregulation (NBD), a core clinical feature of traumatic encephalopathy syndrome, encompasses neuropsychiatric symptoms reported among individuals with a history of repetitive head impact exposure, including contact sport athletes. The objective of this study was to examine the construct and subconstructs of NBD through a series of factor and cluster analyses. METHODS: Six clinician-scientists selected self-report questionnaire items relevant to NBD from seven available neuropsychiatric scales through a blinded voting process. These items were subjected to confirmatory factor analyses in a sample of 178 former college and professional American football players and 60 asymptomatic individuals without a history of repetitive head impact exposure. All participants were enrolled in the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Factor scores were generated on the basis of the optimal expert-informed model for NBD. Construct validity was assessed with neuropsychiatric scales not included in generation of the factor scores. Cluster analyses with NBD factor scores were used to examine symptom profiles. RESULTS: Factor analyses confirmed that NBD was composed of four subconstructs: explosivity, emotional dyscontrol, impulsivity, and affective lability. Cluster analyses indicated four distinct symptom profiles of NBD in this group of former football players: asymptomatic (N=80, 45%), short fuse (N=33, 19%), high affective lability (N=34, 19%), and high NBD (N=31, 17%). CONCLUSIONS: These findings characterize NBD as a multifaceted clinical construct with a heterogeneous presentation, providing a foundation for empirical work on the diagnostic criteria for traumatic encephalopathy syndrome and research on the neurobiological underpinnings of NBD.

An Introduction to the Human Connectome Project for Early Psychosis.

BACKGROUND: The time following a recent onset of psychosis is a critical period during which intervention may be maximally effective. Studying individuals in this period also offers an opportunity to investigate putative brain biomarkers of illness prior to the long-term effects of chronicity and medication. The Human Connectome Project for Early Psychosis (HCP-EP) was funded by the National Institutes of Mental Health (NIMH) as an extension of the original Human Connectome Project's approach to understanding the human brain and its structural and functional connections. DESIGN: The HCP-EP data were collected at 3 sites in Massachusetts (Beth Israel Deaconess Medical Center, McLean Hospital, and Massachusetts General Hospital), and one site in Indiana (Indiana University). Brigham and Women's Hospital served as the data coordination center and as an imaging site. RESULTS: The HCP-EP dataset includes high-quality clinical, cognitive, functional, neuroimaging, and blood specimen data acquired from 303 individuals between the ages of 16-35 years old with affective psychosis (n = 75), non-affective psychosis (n = 148), and healthy controls (n = 80). Participants with early psychosis were within 5 years of illness onset (mean duration = 1.9 years, standard deviation = 1.4 years). All data and novel or modified analytic tools developed as part of the study are publicly available to the research community through the NIMH Data Archive (NDA) or GitHub (https://github.com/pnlbwh). CONCLUSIONS: This paper provides an overview of the specific HCP-EP procedures, assessments, and protocols, as well as a brief characterization of the study participants to make it easier for researchers to use this rich dataset. Although we focus here on discussing and comparing affective and non-affective psychosis groups, the HCP-EP dataset also provides sufficient information for investigators to group participants differently.

Robust Brain Correlates of Cognitive Performance in Psychosis and its Prodrome.

BACKGROUND: Neurocognitive impairment is a well-known phenomenon in schizophrenia that begins prior to psychosis onset. Connectome-wide association studies have inconsistently linked cognitive performance to resting-state fMRI. We hypothesized a carefully selected cognitive instrument and refined population would allow identification of reliable brain-behavior associations with connectome-wide association studies. To test this hypothesis, we first identified brain-cognition correlations via a connectome-wide association study in early psychosis. We then asked, in an independent dataset, if these brain-cognition relationships would generalize to individuals who develop psychosis in the future. METHODS: The Seidman Auditory Continuous Performance Task (ACPT) effectively differentiates healthy participants from those with psychosis. Our connectome-wide association study used the Human Connectome Project for Early Psychosis (n=183) to identify links between connectivity and ACPT performance. We then analyzed the North American Prodrome Longitudinal Study 2 (n=345), a multi-site prospective study of individuals at risk for psychosis. We tested the connectome-wide association study-identified cognition-connectivity relationship in both individuals at risk for psychosis and controls. RESULTS: Our connectome-wide association study in early-course psychosis identified robust associations between better ACPT performance and higher prefrontal-somatomotor connectivity (p<.005). Prefrontal-somatomotor connectivity was also related to ACPT performance in at-risk individuals who would develop psychosis (n=17). This finding was not observed in nonconverters (n=196) or controls (n=132). CONCLUSIONS: This connectome-wide association study identified reproducible links between connectivity and cognition in separate samples of psychosis and at-risk individuals who would later develop psychosis. A carefully selected task and population improves the ability of connectome-wide association studies to identify reliable brain-phenotype relationships.

Excessive interstitial free-water in cortical gray matter preceding accelerated volume changes in individuals at clinical high risk for psychosis.

Recent studies show that accelerated cortical gray matter (GM) volume reduction seen in anatomical MRI can help distinguish between individuals at clinical high risk (CHR) for psychosis who will develop psychosis and those who will not. This reduction is suggested to represent atypical developmental or degenerative changes accompanying an accumulation of microstructural changes, such as decreased spine density and dendritic arborization. Detecting the microstructural sources of these changes before they accumulate into volume loss is crucial. Our study aimed to detect these microstructural GM alterations using diffusion MRI (dMRI). We tested for baseline and longitudinal group differences in anatomical and dMRI data from 160 individuals at CHR and 96 healthy controls (HC) acquired in a single imaging site. Of the CHR individuals, 33 developed psychosis (CHR-P), while 127 did not (CHR-NP). Among all participants, longitudinal data was available for 45 HCs, 17 CHR-P, and 66 CHR-NP. Eight cortical lobes were examined for GM volume and GM microstructure. A novel dMRI measure, interstitial free water (iFW), was used to quantify GM microstructure by eliminating cerebrospinal fluid contribution. Additionally, we assessed whether these measures differentiated the CHR-P from the CHR-NP. In addition, for completeness, we also investigated changes in cortical thickness and in white matter (WM) microstructure. At baseline the CHR group had significantly higher iFW than HC in the prefrontal, temporal, parietal, and occipital lobes, while volume was reduced only in the temporal lobe. Neither iFW nor volume differentiated between the CHR-P and CHR-NP groups at baseline. However, in many brain areas, the CHR-P group demonstrated significantly accelerated changes (iFW increase and volume reduction) with time than the CHR-NP group. Cortical thickness provided similar results as volume, and there were no significant changes in WM microstructure. Our results demonstrate that microstructural GM changes in individuals at CHR have a wider extent than volumetric changes or microstructural WM changes, and they predate the acceleration of brain changes that occur around psychosis onset. Microstructural GM changes, as reflected by the increased iFW, are thus an early pathology at the prodromal stage of psychosis that may be useful for a better mechanistic understanding of psychosis development.

Intimate partner violence perpetration among veterans: associations with neuropsychiatric symptoms and limbic microstructure.

Background: Intimate partner violence (IPV) perpetration is highly prevalent among veterans. Suggested risk factors of IPV perpetration include combat exposure, post-traumatic stress disorder (PTSD), depression, alcohol use, and mild traumatic brain injury (mTBI). While the underlying brain pathophysiological characteristics associated with IPV perpetration remain largely unknown, previous studies have linked aggression and violence to alterations of the limbic system. Here, we investigate whether IPV perpetration is associated with limbic microstructural abnormalities in military veterans. Further, we test the effect of potential risk factors (i.e., PTSD, depression, substance use disorder, mTBI, and war zone-related stress) on the prevalence of IPV perpetration. Methods: Structural and diffusion-weighted magnetic resonance imaging (dMRI) data were acquired from 49 male veterans of the Iraq and Afghanistan wars (Operation Enduring Freedom/Operation Iraqi Freedom; OEF/OIF) of the Translational Research Center for TBI and Stress Disorders (TRACTS) study. IPV perpetration was assessed using the psychological aggression and physical assault sub-scales of the Revised Conflict Tactics Scales (CTS2). Odds ratios were calculated to assess the likelihood of IPV perpetration in veterans with either of the following diagnoses: PTSD, depression, substance use disorder, or mTBI. Fractional anisotropy tissue (FA) measures were calculated for limbic gray matter structures (amygdala-hippocampus complex, cingulate, parahippocampal gyrus, entorhinal cortex). Partial correlations were calculated between IPV perpetration, neuropsychiatric symptoms, and FA. Results: Veterans with a diagnosis of PTSD, depression, substance use disorder, or mTBI had higher odds of perpetrating IPV. Greater war zone-related stress, and symptom severity of PTSD, depression, and mTBI were significantly associated with IPV perpetration. CTS2 (psychological aggression), a measure of IPV perpetration, was associated with higher FA in the right amygdala-hippocampus complex (r = 0.400, p = 0.005). Conclusion: Veterans with psychiatric disorders and/or mTBI exhibit higher odds of engaging in IPV perpetration. Further, the more severe the symptoms of PTSD, depression, or TBI, and the greater the war zone-related stress, the greater the frequency of IPV perpetration. Moreover, we report a significant association between psychological aggression against an intimate partner and microstructural alterations in the right amygdala-hippocampus complex. These findings suggest the possibility of a structural brain correlate underlying IPV perpetration that requires further research.

Posttraumatic survivor guilt is associated with white matter microstructure alterations.

BACKGROUND: Military veterans with posttraumatic stress disorder (PTSD) commonly experience posttraumatic guilt. Guilt over commission or omission evolves when responsibility is assumed for an unfortunate outcome (e.g., the death of a fellow combatant). Survivor guilt is a state of intense emotional distress experienced by the weight of knowing that one survived while others did not. METHODS: This study of the Translational Research Center for TBI and Stress Disorders (TRACTS) analyzed structural and diffusion-weighted magnetic resonance imaging data from 132 male Iraq/Afghanistan veterans with PTSD. The Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV) was employed to classify guilt. Thirty (22.7 %) veterans experienced guilt over acts of commission or omission, 34 (25.8 %) experienced survivor guilt, and 68 (51.5 %) had no posttraumatic guilt. White matter microstructure (fractional anisotropy, FA), cortical thickness, and cortical volume were compared between veterans with guilt over acts of commission or omission, veterans with survivor guilt, and veterans without guilt. RESULTS: Veterans with survivor guilt had significantly lower white matter FA compared to veterans who did not experience guilt (p < .001), affecting several regions of major white matter fiber bundles. There were no significant differences in white matter FA, cortical thickness, or volumes between veterans with guilt over acts of commission or omission and veterans without guilt (p > .050). LIMITATIONS: This cross-sectional study with exclusively male veterans precludes inferences of causality between the studied variables and generalizability to the larger veteran population that includes women. CONCLUSION: Survivor guilt may be a particularly impactful form of posttraumatic guilt that requires specific treatment efforts targeting brain health.

Clinical Outcomes and Tau Pathology in Retired Football Players: Associations With Diagnosed and Witnessed Sleep Apnea.

Background and Objectives: Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players. Methods: The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested. Results: Approximately 36.7% of NFL players had diagnosed SA compared with 30% of the former college football players and 16.7% of the controls. Former NFL players and college football players also had higher ESS scores compared with the controls. Years of football play was not associated with any of the sleep metrics. Among the former NFL players, diagnosed SA was associated with worse Executive Function and Psychomotor Speed factor scores, greater BDI-II scores, and higher flortaucipir PET standard uptake value ratios, independent of age, race, body mass index, and APOE ε4 gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup. Discussion: Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health.

Executive functioning, behavior, and white matter microstructure in the chronic phase after pediatric mild traumatic brain injury: results from the adolescent brain cognitive development study.

BACKGROUND: Mild traumatic brain injury (mTBI) is common in children. Long-term cognitive and behavioral outcomes as well as underlying structural brain alterations following pediatric mTBI have yet to be determined. In addition, the effect of age-at-injury on long-term outcomes is largely unknown. METHODS: Children with a history of mTBI (n = 406; Mage = 10 years, SDage = 0.63 years) who participated in the Adolescent Brain Cognitive Development (ABCD) study were matched (1:2 ratio) with typically developing children (TDC; n = 812) and orthopedic injury (OI) controls (n = 812). Task-based executive functioning, parent-rated executive functioning and emotion-regulation, and self-reported impulsivity were assessed cross-sectionally. Regression models were used to examine the effect of mTBI on these domains. The effect of age-at-injury was assessed by comparing children with their first mTBI at either 0-3, 4-7, or 8-10 years to the respective matched TDC controls. Fractional anisotropy (FA) and mean diffusivity (MD), both MRI-based measures of white matter microstructure, were compared between children with mTBI and controls. RESULTS: Children with a history of mTBI displayed higher parent-rated executive dysfunction, higher impulsivity, and poorer self-regulation compared to both control groups. At closer investigation, these differences to TDC were only present in one respective age-at-injury group. No alterations were found in task-based executive functioning or white matter microstructure. CONCLUSIONS: Findings suggest that everyday executive function, impulsivity, and emotion-regulation are affected years after pediatric mTBI. Outcomes were specific to the age at which the injury occurred, suggesting that functioning is differently affected by pediatric mTBI during vulnerable periods. Groups did not differ in white matter microstructure.

Brain morphometry in former American football players: Findings from the DIAGNOSE CTE research project.

Exposure to repetitive head impacts (RHIs) in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE) which currently can be diagnosed only at postmortem. American football players are at higher risk of developing CTE given their exposure to RHIs. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at postmortem in living individuals using structural magnetic resonance imaging (MRI). MRI brain morphometry was evaluated in 170 male former American football players ages 45-74 years (n = 114 professional; n = 56 college) and 54 same-age unexposed asymptomatic male controls (n = 58 age range 45-74). Cortical thickness and volume of regions of interest were selected based on established CTE pathology findings and were assessed using FreeSurfer. Group differences and interactions with age and exposure factors were evaluated using a generalized least squares model. A separate logistic regression and independent multinomial model were performed to predict each Traumatic Encephalopathy Syndrome (TES) diagnosis core clinical features and provisional level of certainty for CTE pathology using brain regions of interest. Former college and professional American football players (combined) showed significant cortical thickness and/or volume reductions compared to unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula temporal pole and superior frontal gyrus. Post-hoc analyses identified group-level differences between former professional players and unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula and superior frontal gyrus. Former college players showed significant volume reductions in the hippocampus amygdala and superior frontal gyrus compared to the unexposed asymptomatic controls. We did not observe age-by-group interactions for brain morphometric measures. Interactions between morphometry and exposure measures were limited to a single significant positive association between the age of first exposure to organized tackle football and right insular volume. We found no significant relationship between brain morphometric measures and the TES diagnosis core clinical features and provisional level of certainty for CTE pathology outcomes. These findings suggest that MRI morphometrics detects abnormalities in individuals with a history of RHI exposure that resemble the anatomic distribution of pathological findings from postmortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggests that brain morphometry must be complemented by other types of measures to characterize individuals with RHIs.

Isolation of Distinct Networks Driving Action and Cognition in Psychomotor Processes.

BACKGROUND: Psychomotor disturbances are observed across psychiatric disorders and often manifest as psychomotor slowing, agitation, disorganized behavior, or catatonia. Psychomotor function includes both cognitive and motor components, but the neural circuits driving these subprocesses and how they relate to symptoms have remained elusive for centuries. METHODS: We analyzed data from the HCP-EP (Human Connectome Project for Early Psychosis), a multisite study of 125 participants with early psychosis and 58 healthy participants with resting-state functional magnetic resonance imaging and clinical characterization. Psychomotor function was assessed using the 9-hole pegboard task, a timed motor task that engages mechanical and psychomotor components of action, and tasks assessing processing speed and task switching. We used multivariate pattern analysis of whole-connectome data to identify brain correlates of psychomotor function. RESULTS: We identified discrete brain circuits driving the cognitive and motor components of psychomotor function. In our combined sample of participants with psychosis (n = 89) and healthy control participants (n = 52), the strongest correlates of psychomotor function (pegboard performance) (p < .005) were between a midline cerebellar region and left frontal region and presupplementary motor area. Psychomotor function was correlated with both cerebellar-frontal connectivity (r = 0.33) and cerebellar-presupplementary motor area connectivity (r = 0.27). However, the cognitive component of psychomotor performance (task switching) was correlated only with cerebellar-frontal connectivity (r = 0.19), whereas the motor component (processing speed) was correlated only with cerebellar-presupplementary motor area connectivity (r = 0.15), suggesting distinct circuits driving unique subprocesses of psychomotor function. CONCLUSIONS: We identified cerebellar-cortical circuits that drive distinct subprocesses of psychomotor function. Future studies should probe relationships between cerebellar connectivity and psychomotor performance using neuromodulation.

Data-driven, connectome-wide analysis identifies psychosis-specific brain correlates of fear and anxiety.

Decades of psychosis research highlight the prevalence and the clinical significance of negative emotions, such as fear and anxiety. Translational evidence demonstrates the pivotal role of the amygdala in fear and anxiety. However, most of these approaches have used hypothesis-driven analyses with predefined regions of interest. A data-driven analysis may provide a complimentary, unbiased approach to identifying brain correlates of fear and anxiety. The aim of the current study was to identify the brain basis of fear and anxiety in early psychosis and controls using a data-driven approach. We analyzed data from the Human Connectome Project for Early Psychosis, a multi-site study of 125 people with psychosis and 58 controls with resting-state fMRI and clinical characterization. Multivariate pattern analysis of whole-connectome data was used to identify shared and psychosis-specific brain correlates of fear and anxiety using the NIH Toolbox Fear-Affect and Fear-Somatic Arousal scales. We then examined clinical correlations of Fear-Affect scores and connectivity patterns. Individuals with psychosis had higher levels of Fear-Affect scores than controls (p < 0.05). The data-driven analysis identified a cluster encompassing the amygdala and hippocampus where connectivity was correlated with Fear-Affect score (p < 0.005) in the entire sample. The strongest correlate of Fear-Affect was between this cluster and the anterior insula and stronger connectivity was associated with higher Fear-Affect scores (r = 0.31, p = 0.0003). The multivariate pattern analysis also identified a psychosis-specific correlate of Fear-Affect score between the amygdala/hippocampus cluster and a cluster in the ventromedial prefrontal cortex (VMPFC). Higher Fear-Affect scores were correlated with stronger amygdala/hippocampal-VMPFC connectivity in the early psychosis group (r = 0.33, p = 0.002), but not in controls (r = -0.15, p = 0.28). The current study provides evidence for the transdiagnostic role of the amygdala, hippocampus, and anterior insula in the neural basis of fear and anxiety and suggests a psychosis-specific relationship between fear and anxiety symptoms and amygdala/hippocampal-VMPFC connectivity. Our novel data-driven approach identifies novel, psychosis-specific treatment targets for fear and anxiety symptoms and provides complimentary evidence to decades of hypothesis-driven approaches examining the brain basis of threat processing.

Inflammatory biomarkers for neurobehavioral dysregulation in former American football players: findings from the DIAGNOSE CTE Research Project.

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)-1ß, 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.

More organized white matter is associated with positivity bias in older adults.

On average, healthy older adults prefer positive over neutral or negative stimuli. This positivity bias is related to memory and attention processes and is linked to the function and structure of several interconnected brain areas. However, the relationship between the positivity bias and white matter integrity remains elusive. The present study examines how white matter organization relates to the degree of the positivity bias among older adults. We collected imaging and behavioral data from 25 individuals (12 females, 13 males, and a mean age of 77.32). Based on a functional memory task, we calculated a Pos-Neg score, reflecting the memory for positively valenced information over negative information, and a Pos-Neu score, reflecting the memory for positively valenced information over neutral information. Diffusion-weighted magnetic resonance imaging data were processed using Tract-Based Spatial Statistics. We performed two non-parametric permutation tests to correlate whole brain white matter integrity and the Pos-Neg and Pos-Neu scores while controlling for age, sex, and years of education. We observed a statistically significant positive association between the Pos-Neu score and white matter integrity in multiple brain connections, mostly frontal. The results did not remain significant when including verbal episodic memory as an additional covariate. Our study indicates that the positivity bias in memory in older adults is associated with more organized white matter in the connections of the frontal brain. While these frontal areas are critical for memory and executive processes and have been related to pathological aging, more extensive studies are needed to fully understand their role in the positivity bias and the potential for therapeutic interventions.

Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former American Football Players.

BACKGROUND AND OBJECTIVES: Recent data link exposure to repetitive head impacts (RHIs) from American football with increased white matter hyperintensity (WMH) burden. WMH might have unique characteristics in the context of RHI beyond vascular risk and normal aging processes. We evaluated biological correlates of WMH in former American football players, including markers of amyloid, tau, inflammation, axonal injury, neurodegeneration, and vascular health. METHODS: Participants underwent clinical interviews, MRI, and lumbar puncture as part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Structural equation modeling tested direct and indirect effects between log-transformed total fluid-attenuated inversion recovery (FLAIR) lesion volumes (TLV) and the revised Framingham stroke risk profile (rFSRP), MRI-derived global metrics of cortical thickness and fractional anisotropy (FA), and CSF levels of amyloid ß1-42, p-tau181, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and neurofilament light. Covariates included age, race, education, body mass index, APOE ε4 carrier status, and evaluation site. Models were performed separately for former football players and a control group of asymptomatic men unexposed to RHI. RESULTS: In 180 former football players (mean age = 57.2, 36% Black), higher log(TLV) had direct associations with the following: higher rFSRP score (B = 0.26, 95% CI 0.07-0.40), higher p-tau181 (B = 0.17, 95% CI 0.01-0.43), lower FA (B = -0.28, 95% CI -0.42 to -0.13), and reduced cortical thickness (B = -0.25, 95% CI -0.45 to -0.08). In 60 asymptomatic unexposed men (mean age = 59.3, 40% Black), there were no direct effects on log(TLV) (rFSRP: B = -0.03, 95% CI -0.48 to 0.57; p-tau181: B = -0.30, 95% CI -1.14 to 0.37; FA: B = -0.07, 95% CI -0.48 to 0.42; or cortical thickness: B = -0.28, 95% CI -0.64 to 0.10). The former football players showed stronger associations between log(TLV) and rFSRP (1,069% difference in estimates), p-tau181 (158%), and FA (287%) than the unexposed men. DISCUSSION: Risk factors and biological correlates of WMH differed between former American football players and asymptomatic unexposed men. In addition to vascular health, p-tau181 and diffusion tensor imaging indices of white matter integrity showed stronger associations with WMH in the former football players. FLAIR WMH may have specific risk factors and pathologic underpinnings in RHI-exposed individuals.

Examination of parkinsonism in former elite American football players.

BACKGROUND: Former American football players are at risk for chronic traumatic encephalopathy (CTE) which may have parkinsonism as a clinical feature. OBJECTIVE: Former football players were prospectively assessed for parkinsonism. METHODS: 120 former professional football players, 58 former college football players, and 60 same-age asymptomatic men without repetitive head impacts, 45-74 years, were studied using the MDS-UPDRS to assess for parkinsonism, and the Timed Up and Go (TUG). Traumatic encephalopathy syndrome (TES), the clinical syndrome of CTE, was adjudicated and includes parkinsonism diagnosis. Fisher's Exact Test compared groups on parkinsonism due to small cell sizes; analysis of covariance or linear regressions controlling for age and body mass index were used otherwise. RESULTS: Twenty-two (12.4%) football players (13.3% professional, 10.3% college) met parkinsonism criteria compared with two (3.3%) in the unexposed group. Parkinsonism was higher in professional (p = 0.037) but not college players (p = 0.16). There were no differences on the MDS-UPDRS Part III total scores. Scores on the individual MDS-UPDRS items were low. TUG times were longer in former professional but not college players compared with unexposed men (13.09 versus 11.35 s, p < 0.01). There were no associations between years of football, age of first exposure, position or level of play on motor outcomes. TES status was not associated with motor outcomes. CONCLUSIONS: Parkinsonism rates in this sample of football players was low and highest in the professional football players. The association between football and parkinsonism is inconclusive and depends on factors related to sample selection, comparison groups, and exposure characteristics.

Flortaucipir tau PET findings from former professional and college American football players in the DIAGNOSE CTE research project.

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.

Structural connectivity of cytoarchitectonically distinct human left temporal pole subregions: a diffusion MRI tractography study.

The temporal pole (TP) is considered one of the major paralimbic cortical regions, and is involved in a variety of functions such as sensory perception, emotion, semantic processing, and social cognition. Based on differences in cytoarchitecture, the TP can be further subdivided into smaller regions (dorsal, ventrolateral and ventromedial), each forming key nodes of distinct functional networks. However, the brain structural connectivity profile of TP subregions is not fully clarified. Using diffusion MRI data in a set of 31 healthy subjects, we aimed to elucidate the comprehensive structural connectivity of three cytoarchitectonically distinct TP subregions. Diffusion tensor imaging (DTI) analysis suggested that major association fiber pathways such as the inferior longitudinal, middle longitudinal, arcuate, and uncinate fasciculi provide structural connectivity to the TP. Further analysis suggested partially overlapping yet still distinct structural connectivity patterns across the TP subregions. Specifically, the dorsal subregion is strongly connected with wide areas in the parietal lobe, the ventrolateral subregion with areas including constituents of the default-semantic network, and the ventromedial subregion with limbic and paralimbic areas. Our results suggest the involvement of the TP in a set of extensive but distinct networks of cortical regions, consistent with its functional roles.

Amyloid PET across the cognitive spectrum in former professional and college American football players: findings from the DIAGNOSE CTE Research Project.

BACKGROUND: Exposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-ß (Aß) plaque formation and increases the risk for Alzheimer's disease (AD). Although the Aß neuritic plaques characteristic of AD are observed in a minority of later-stage CTE cases, diffuse plaques are more common. This study examined whether former professional and college American football players, including those with cognitive impairment and dementia, have elevated neuritic Aß plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected. METHODS: We examined 237 men ages 45-74, including 119 former professional (PRO) and 60 former college (COL) football players, with and without cognitive impairment and dementia, and 58 same-age men without a history of contact sports or TBI (unexposed; UE) and who denied cognitive or behavioral symptoms at telephone screening. Former players were categorized into four diagnostic groups: normal cognition, subjective memory impairment, mild cognitive impairment, and dementia. Positive florbetapir PET was defined by cortical-cerebellar average SUVR of ≥ 1.10. Multivariable linear regression and analysis of covariance (ANCOVA) compared florbetapir average SUVR across diagnostic and exposure groups. Multivariable logistic regression compared florbetapir positivity. Race, education, age, and APOE4 were covariates. RESULTS: There were no diagnostic group differences either in florbetapir average SUVR or the proportion of elevated florbetapir uptake. Average SUVR means also did not differ between exposure groups: PRO-COL (p = 0.94, 95% C.I. = [- 0.033, 0.025]), PRO-UE (p = 0.40, 95% C.I. = [- 0.010, 0.029]), COL-UE (p = 0.36, 95% CI = [0.0004, 0.039]). Florbetapir was not significantly associated with years of football exposure, cognition, or daily functioning. CONCLUSIONS: Cognitive impairment in former American football players is not associated with PET imaging of neuritic Aß plaque deposition. These findings are inconsistent with a neuropathological diagnosis of AD in individuals with substantial RHI exposure and have both clinical and medico-legal implications. TRIAL REGISTRATION: NCT02798185.

Adverse Outcome Following Mild Traumatic Brain Injury Is Associated with Microstructure Alterations at the Gray and White Matter Boundary.

The gray matter/white matter (GM/WM) boundary of the brain is vulnerable to shear strain associated with mild traumatic brain injury (mTBI). It is, however, unknown whether GM/WM microstructure is associated with long-term outcomes following mTBI. The diffusion and structural MRI data of 278 participants between 18 and 65 years of age with and without military background from the Department of Defense INTRuST study were analyzed. Fractional anisotropy (FA) was extracted at the GM/WM boundary across the brain and for each lobe. Additionally, two conventional analytic approaches were used: whole-brain deep WM FA (TBSS) and whole-brain cortical thickness (FreeSurfer). ANCOVAs were applied to assess differences between the mTBI cohort (n = 147) and the comparison cohort (n = 131). Associations between imaging features and post-concussive symptom severity, and functional and cognitive impairment were investigated using partial correlations while controlling for mental health comorbidities that are particularly common among military cohorts and were present in both the mTBI and comparison group. Findings revealed significantly lower whole-brain and lobe-specific GM/WM boundary FA (p < 0.011), and deep WM FA (p = 0.001) in the mTBI cohort. Whole-brain and lobe-specific GM/WM boundary FA was significantly negatively correlated with post-concussive symptoms (p < 0.039), functional (p < 0.016), and cognitive impairment (p < 0.049). Deep WM FA was associated with functional impairment (p = 0.002). Finally, no significant difference was observed in cortical thickness, nor between cortical thickness and outcome (p > 0.05). Findings from this study suggest that microstructural alterations at the GM/WM boundary may be sensitive markers of adverse long-term outcomes following mTBI.

Investigation of brain iron in anorexia nervosa, a quantitative susceptibility mapping study.

BACKGROUND: Anorexia nervosa (AN) is a potentially fatal psychiatric condition, associated with structural brain changes such as gray matter volume loss. The pathophysiological mechanisms for these changes are not yet fully understood. Iron is a crucial element in the development and function of the brain. Considering the systemic alterations in iron homeostasis in AN, we hypothesized that brain iron would be altered as a possible factor associated with structural brain changes in AN. METHODS: In this study, we used quantitative susceptibility mapping (QSM) magnetic resonance imaging to investigate brain iron in current AN (c-AN) and weight-restored AN compared with healthy individuals. Whole-brain voxel wise comparison was used to probe areas with possible group differences. Further, the thalamus, caudate nucleus, putamen, nucleus accumbens, hippocampus, and amygdala were selected as the regions of interest (ROIs) for ROI-based comparison of mean QSM values. RESULTS: Whole-brain voxel-wise and ROI-based comparison of QSM did not reveal any differences between groups. Exploratory analyses revealed a correlation between higher regional QSM (higher iron) and lower body mass index, higher illness severity, longer illness duration, and younger age at onset in the c-AN group. CONCLUSIONS: This study did not find evidence of altered brain iron in AN compared to healthy individuals. However, the correlations between clinical variables and QSM suggest a link between brain iron and weight status or biological processes in AN, which warrants further investigation.