Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to Repetitive Head Impacts

Background and Objectives:Late neuropathologies of repetitive head impacts from contact sports can include chronic traumatic encephalopathy (CTE) and white matter degeneration. White matter hyperintensities (WMH) on fluid attenuated inversion recovery (FLAIR) MRI scans are often viewed as microvascular disease from vascular risk, but might have unique underlying pathologies and risk factors in the setting of repetitive head impacts. We investigated the neuropathological correlates of antemortem WMH in brain donors exposed to repetitive head impacts. The association between WMH, and repetitive head impact exposure and informant-reported cognitive and daily function were tested.Methods:This imaging-pathological correlation study included symptomatic deceased men exposed to repetitive head impacts. Donors had antemortem FLAIR scans from medical records and were without evidence of CNS neoplasm, large vessel infarcts, hemorrhage, and/or encephalomalacia. WMH were quantified using log-transformed values for total lesion volume (TLV), calculated using the lesion prediction algorithm from the Lesion Segmentation Toolbox. Neuropathological assessments included semi-quantitative ratings of white matter rarefaction, cerebrovascular disease, p-tau severity (CTE stage, dorsolateral frontal cortex), and Aβ. Among football players, years of play was a proxy for repetitive head impact exposure. Retrospective informant-reported cognitive and daily function were assessed using the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ). Regression models controlled for demographics, diabetes, hypertension, and MRI resolution. Statistical significance was defined as p<0.05.Results:The sample included 75 donors: 67 football players and 8 non-football contact sport athletes and/or military veterans. Dementia was the most common MRI indication (64%). Fifty-three (70.7%) had CTE at autopsy. Log-TLV was associated with white matter rarefaction (OR=2.32, 95% CI=1.03,5.24, p=0.04), arteriolosclerosis (OR=2.38, 95% CI=1.02,5.52, p=0.04), CTE stage (OR=2.58, 95% CI=1.17,5.71, p=0.02), and dorsolateral frontal p-tau severity (OR=3.03, 95% CI=1.32,6.97, p=0.01). There was no association with Aβ. More years of football play was associated with log-TLV (b=0.04, 95% CI=0.01,0.06, p=0.01). Greater log-TLV correlated with higher FAQ (unstandardized beta=4.94, 95% CI=0.42,8.57, p=0.03) and CDS scores (unstandardized beta=15.35, 95% CI=-0.27,30.97, p=0.05).Discussion:WMH might capture long-term white matter pathologies from repetitive head impacts, including those from white matter rarefaction and p-tau, in addition to microvascular disease. Prospective imaging-pathological correlation studies are needed.Classification of Evidence:This study provides Class IV evidence of associations between FLAIR white matter hyperintensities, and neuropathological changes (white matter rarefaction, arteriolosclerosis, p-tau accumulation), years of American football play, and reported cognitive symptoms in symptomatic brain donors exposed to repetitive head impacts.

Detecting a History of Repetitive Head Impacts from a Short Voice Recording

Repetitive head impacts (RHI) are associated with an increased risk of developing various neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and most notably, chronic traumatic encephalopathy (CTE). While the clinical presentation of AD and PD is well established, CTE can only be diagnosed post-mortem. Therefore, a distinction can be made between the pathologically defined CTE and RHI-related functional or structural brain changes (RHI-BC) which may result in CTE. Unfortunately, there are currently no accepted biomarkers of CTE nor RHI-BC, a major hurdle to achieving clinical diagnoses. Interestingly, speech has shown promise as a potential biomarker of both AD and PD, being used to accurately classify individuals with AD and PD from those without. Given the overlapping symptoms between CTE, RHI-BC, PD and AD, we aimed to determine if speech could be used to identify individuals with a history of RHI from those without. We therefore created the Verus dataset, consisting of 13 second voice recordings from 605 professional fighters (RHI group) and 605 professional athletes in non-contact sports (control group) for a total of 1210 recordings. Using a deep learning approach, we achieved 85% accuracy in detecting individuals with a history of RHI from those without. We then used our model trained on the Verus dataset to fine-tune on publicly available AD and PD speech datasets and achieved new state-of-the-art accuracies of 84.99% on the AD dataset and 89% on the PD dataset. Finding a biomarker of CTE and RHI-BC that presents early in disease progression is critical to improve risk management and patient outcome. Our study is the first we are aware of to investigate speech as such a candidate biomarker of RHI-BC.

REPIMPACT - a prospective longitudinal multisite study on the effects of repetitive head impacts in youth soccer

Repetitive head impacts (RHI) are common in youth athletes participating in contact sports. RHI differ from concussions; they are considered hits to the head that usually do not result in acute symptoms and are therefore also referred to as “subconcussive” head impacts. RHI occur e.g., when heading the ball or during contact with another player. Evidence suggests that exposure to RHI may have cumulative effects on brain structure and function. However, little is known about brain alterations associated with RHI, or about the risk factors that may lead to clinical or behavioral sequelae. REPIMPACT is a prospective longitudinal study of competitive youth soccer players and non-contact sport controls aged 14 to 16 years. The study aims to characterize consequences of exposure to RHI with regard to behavior (i.e., cognition, and motor function), clinical sequelae (i.e., psychiatric and neurological symptoms), brain structure, function, diffusion and biochemistry, as well as blood- and saliva-derived measures of molecular processes associated with exposure to RHI (e.g., circulating microRNAs, neuroproteins and cytokines). Here we present the structure of the REPIMPACT Consortium which consists of six teams of clinicians and scientists in six countries. We further provide detailed information on the specific aims and the design of the REPIMPACT study. The manuscript also describes the progress made in the study thus far. Finally, we discuss important challenges and approaches taken to overcome these challenges.

Assessing Clinical Change in Individuals Exposed to Repetitive Head Impacts: The Repetitive Head Impact Composite Index

Background: There is a current lack of any composite measure for the effective tracking and monitoring of clinical change in individuals exposed to repetitive head impacts (RHI). The aim of this study is to create a composite instrument for the purposes of detecting change over time in cognitive and behavioral function in individuals exposed to RHI.Methods: The data to derive the composite instrument came from the Professional Fighters Brain Health Study (PFBHS), a longitudinal study of active and retired professional fighters [boxers and mixed martial arts (MMA) fighters] and healthy controls. Participants in the PFBHS underwent assessment on an annual basis that included computerized cognitive testing and behavioral questionnaires. Multivariate logistic regression models were employed to compare active fighters (n = 117) with controls (n = 22), and retired fighters (n = 26) with controls to identify the predictors that could be used to differentiate the groups over time. In a second step, linear discriminant analysis was performed to derive the linear discriminant coefficients for the three groups by using the predictors from the two separate logistic regression models.Results: The composite scale is a weighted linear value of 12 standardized scores consisting of both current and yearly change scores in domains including: processing speed, choice reaction time, semantic fluency, letter fluency, and Barrett Impulsiveness Scale. Because the weighting of values differed between active and retired fighters, two versions emerged. The mean and standard deviation ratio (MSDR) showed that the new index had better sensitivity compared to the individual measures, with the ratio of MSDR of the new index to that of the existing measures of at least 1.84.Conclusion: With the increasing need for tools to follow individuals exposed to RHI and the potential of clinical trials on the horizon for CTE, the RHICI is poised to serve as an initial approach to a composite clinical measure.

SPORT TYPE AND BASELINE NEUROCOGNITIVE SCORES AMONG HEALTHY HIGH SCHOOL ATHLETES

Background: Athletes who participate in collision sports may experience more repetitive head impacts than other sport types. These repetitive head impacts have been theorized as a potential catalyst for cognitive problems later in life. It is unknown, however, if sport type influences neurocognitive performance. Hypothesis/Purpose: Our purpose was to investigate the association between sport type and baseline neurocognitive scores in a high school athletic population. We hypothesized that athletes participating in collision sports would demonstrate worse scores on baseline neurocognitive tests compared to those in contact or non-contact sports. Methods: We conducted a cross-sectional, observational study using baseline computerized neurocognitive scores of 186,117 high school student-athletes (age: 15.47±2.28 years, height: 168.53±10.77 cm, weight: 63.02±14.83 kg, 45% female) in the state of Massachusetts. The dependent variables were five composite scores (verbal memory, visual memory, visual motor, reaction time, and impulse control) and total symptom score. The independent variables included sport type (collision, contact, non-contact), age, sex, and concussion history. We used univariable one-way ANOVAS to compare composite scores between sport type. We conducted a series of multivariable regression models, controlling for age, sex, and number of previous concussions, to examine the independent association between sport type and composite scores. Results: There was a minimal but statistically significant association between sport type and composite scores, with collision sport athletes performing slightly worse than other athletes on most composite scores. Collision sport athletes had a slightly lower symptom burden. (Tables 1 and 2) Conclusion: While statistically significant, the differences in neurocognitive function and symptom burden between sport type are of questionable clinical significance. In fact, all of them fall within the reliable change index values of each respective score. As participants were in high school at the time of the study, we cannot determine the potential for associations later in life. Tables/Figures: [Table: see text][Table: see text]

Repetitive head impacts in a collegiate football season: Exposure and effects

This study describes exposure to repetitive head impacts (RHI) by player position and activity during a collegiate football season, and investigates the relationship between RHI and acute (i.e., daily and weekly) and short-term (i.e., pre- to post-season) changes in balance, reaction time, symptoms, and cognition. We recorded RHI exposure in twenty Division I collegiate American football players during a single season using the Riddell InSite system. Participants sustained 4,586 impacts (4.20% high impact, i.e., >63 g; 95.79% low impact, i.e., 20–63 g). Greatest exposure to RHI was observed in running backs and defensive ends during games, and tight ends and defensive ends during practices. Running plays and team drills placed players at greatest risk for exposure during practice. Cumulative RHI exposure across the season was associated with short-term declines in reaction time (p = 0.045), but not balance or cognition. Acute decline in balance was associated with the number of impacts sustained in the past week (p < 0.05), but not the past 24 hours (p > 0.05). Acute increase in total symptom score was also associated with the number of impacts sustained in the past week (p < 0.01), but not the past 24 hours (p > 0.05). Reaction time did not decline based on impact exposure in the past 24 hours or week. This study identifies activities and positions that may put players at risk for RHI exposure, and demonstrates that RHI sustained during the course of typical American football play by non-concussed individuals may result in small changes in balance, reaction time, and symptoms, but not cognition.

The relation between neck strength and psychological distress: preliminary evidence from collegiate soccer athletes

Aim: To examine whether neck strength and symmetry are associated with psychological function in athletes with exposure to repetitive head impacts. Methods: Collegiate soccer (n = 29) and limited/noncontact (n = 63) athletes without a history of concussion completed the Brief Symptom Inventory 18 and assessments of isometric neck strength. Neck strength symmetry was calculated as the difference in strength between opposing muscle groups. Results: The results demonstrated that lower neck strength was associated with more symptoms of anxiety, whereas asymmetry in neck strength was associated with more symptoms of somatization and depression in soccer athletes only. Conclusion: These preliminary results suggest that greater neck strength/symmetry is related to better psychological function in athletes who have higher exposure to repetitive head impacts.