Repetitive Head Research Articles

The effects of subconcussive head impacts on cerebral vascular reactivity

Purpose: One bout of repetitive subconcussive head impacts (SHI) can increase biomarkers of neurological injury, decrease neurovascular coupling, and alter cerebral autoregulation. It is unclear whether a bout of repetitive SHI alters cerebral vascular reactivity to carbon dioxide (CVR). We tested the hypotheses that CVR to hypercapnia (CVRhyper) and hypocapnia (CVRhypo) will decrease after a bout of repetitive SHI in healthy participants. Methods: Eight healthy participants (age: 20±2 y; BMI: 23±3 kg/m2; 2 women) completed four CVR tests: one prior to a bout of SHI (PRE), and three follow-up tests at 2 h, 24 h, and 72 h after the SHI. SHI were induced by 20 soccer headers projected from a soccer JUGS machine (1 header/30 s at 40 km/h and from 12.2 m). Mean arterial pressure (MAP), heart rate (HR), end tidal carbon dioxide tension (PETCO2), middle cerebral artery blood velocity (MCAV) and posterior cerebral artery blood velocity (PCAV) were measured prior to and during each CVR test. MCA conductance (MCAcon) and PCA conductance (PCAcon) were calculated as the quotient of MCAv and PCAv to MAP, respectively. During the CVRhyper test, participants inhaled 6% CO2, 21% O2, 73% N2 gas for 2 min or until PETCO2 was 10 mmHg greater than baseline. 3 min after the CVRhyper test, participants hyperventilated until PETCO2 was 10 mmHg less than baseline for 2 min (CVRhypo). PETCO2 values were plotted against MCAV, PCAV, MCAcon, and PCAcon at baseline and the last 10 s of each CVR test. The slopes of these linear regression lines were calculated for each variable and for both CVR tests. Data are presented as mean±SD. Results: There were no differences from PRE to post SHI for resting HR, PETCO2, MCAV, PCAV, MCAcon, or PCAcon (all p>0.13). A time effect was found for resting MAP (PRE: 90±10; 2 h: 101±8; 24 h: 86±4; 72 h: 88±10 mmHg; p=0.02). There were no differences from PRE to post SHI for the CVRhyper test for MCAV (PRE: 0.10±0.20; 2 h: 0.27±0.17; 24 h: 0.24±0.31; 72 h: 0.24±0.31 cm/s/mmHg; p=0.13), MCAcon (PRE: -0.0009±0.0014; 2 h: -0.0001±0.0023; 24 h: -0.0002±0.0017; 72 h: -0.0011±0.0017 cm/s/mmHg/mmHg; p=0.36), PCAV (PRE: 0.02±0.13; 2 h: 0.07±0.07; 24 h: 0.12±0.18; 72 h: 0.14±0.13 cm/s/mmHg; p=0.26), or PCAcon (PRE: 0.0018±0.0011; 2 h: 0.0014±0.0007; 24 h: 0.0033±0.0033; 72 h: 0.0012±0.0007 cm/s/mmHg/mmHg; p=0.18). There were also no differences from PRE to post SHI for the CVRhypo test for MCAV (PRE: 0.10±0.20; 2 h: 0.27±0.17; 24 h: 0.24±0.31; 72 h: 0.24±0.31 cm/s/mmHg; p=0.13), MCAcon (PRE: 0.0006±0.0019; 2 h: 0.0019±0.0011; 24 h: 0.004±0.0049; 72 h: 0.0025±0.0016 cm/s/mmHg/mmHg; p=0.10), PCAV (PRE: 0.02±0.13; 2 h: 0.07±0.07; 24 h: 0.12±0.18; 72 h: 0.14±0.13 cm/s/mmHg; p=0.26), or PCAcon (PRE: 0.0018±0.0016; 2 h: 0.0019±0.0007; 24 h: 0.004±0.0033; 72 h: 0.0037±0.0014; p=0.09). Conclusion: These preliminary data indicate that a bout of soccer headings does not change CVR to carbon dioxide in the MCA or PCA in healthy adults. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

7T MRI Versus 3T MRI of the Brain in Professional Fighters and Patients With Head Trauma.

Many studies have investigated the imaging sequelae of repetitive head trauma with mixed results, particularly with regard to the detection of intracranial white matter changes (WMCs) and cerebral microhemorrhages (CMHs) on ≤3 Tesla (T) field magnetic resonance imaging (MRI). 7T MRI, which has recently been approved for clinical use, is more sensitive at detecting lesions associated with multiple neurological diagnoses. In this study, we sought to determine whether 7T MRI would detect more WMCs and CMHs than 3T MRI in 19 professional fighters, 16 patients with single TBI, versus 82 normal healthy controls (NHCs). Fighters and patients with TBI underwent both 3T and 7T MRI; NHCs underwent either 3T (n = 61) or 7T (n = 21) MRI. Readers agreed on the presence/absence of WMCs in 88% (84 of 95) of 3T MRI studies (Cohen's kappa, 0.76) and in 93% (51 of 55) of 7T MRI studies (Cohen's kappa, 0.79). Readers agreed on the presence/absence of CMHs in 96% (91 of 95) of 3T MRI studies (Cohen's kappa, 0.76) and in 96% (54 of 56) of 7T MRI studies (Cohen's kappa, 0.88). The number of WMCs detected was greater in fighters and patients with TBI than NHCs at both 3T and 7T. Moreover, the number of WMCs was greater at 7T than at 3T for fighters, patients with TBI, and NHCs. There was no difference in the number of CMHs detected with 7T MRI versus 3T MRI or in the number of CMHs observed in fighters/patients with TBI versus NHCs. These initial findings suggest that fighters and patients with TBI may have more WMCs than NHCs and that the improved voxel size and signal-to-noise ratio at 7T may help to detect these changes. As 7T MRI becomes more prevalent clinically, larger patient populations should be studied to determine the cause of these WMCs.

Effects of repetitive head trauma on symptomatology of subsequent sport-related concussion.

Adolescent participation in athletics continues to grow, leading to an increasing incidence of sports-related concussion (SRC). The current literature suggests that a greater number of prior concussions positively correlates with a greater number of total symptoms, but the specific concussion-related symptoms are not as well defined. The current study investigated the effects of prior recurrent head injury on the symptom profiles of student-athletes after another suspected concussion. A multicenter database consisting of 25,815 Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) results was filtered for student-athletes aged 12-22 years old who competed in 21 different sports. Patients were separated into 2 cohorts: athletes reporting a single prior concussion (SRC1) and athletes reporting 2 or more prior concussions (SRC2+). Comparisons were assessed for differences in 22 symptoms and 4 symptom clusters at baseline, first postinjury test (PI1), and second postinjury test (PI2) by using univariate and multivariate analyses. No differences were seen between SRC1 (n = 2253) and SRC2+ (n = 976) at baseline. At PI1, the SRC2+ group (n = 286) had lower severity of headaches (p = 0.04) but increased nervousness (p = 0.042), irritability (p = 0.028), sadness (p = 0.028), visual problems (p = 0.04), and neuropsychiatric symptoms (p = 0.009) compared with SRC1 (n = 529). Multivariate analysis revealed decreased headache severity with increased prior concussion (β = -0.27,95% CI -0.45 to -0.09, p = 0.003). Multivariate analysis at PI2 demonstrated the SRC2+ cohort (n = 130) had increased cognitive (β = 1.22, 95% CI 0.27-2.18, p = 0.012), sleep (β = 0.63, 95% CI 0.17-1.08, p = 0.007), and neuropsychiatric (β = 0.67,95% CI 0.14-1.2,0.014) symptoms compared with SRC1 (n = 292). At longitudinal follow-up, patients with a history of recurrent concussions reported greater symptom burden in cognitive, sleep, and neuropsychiatric symptom clusters but not migraine symptoms. This is an important distinction because migraine symptoms are often more easily distinguishable to patients, parents, and physicians. Careful assessment of specific symptoms should be considered in patients with a history of recurrent head injury prior to return to play.

Brain glucose metabolism and gray matter volume in retired professional soccer players: a cross-sectional [18F]FDG-PET/MRI study.

Professional soccer athletes are exposed to repetitive head impacts and are at risk of developing chronic traumatic encephalopathy. To evaluate regional brain glucose metabolism (rBGM) and gray matter (GM) volume in retired soccer players (RSPs). Male RSPs and age and sex-matched controls prospectively enrolled between 2017 and 2019 underwent neurological and neuropsychological evaluations, brain MRI and [18F]FDG-PET in a 3.0-Tesla PET/MRI scanner. Visual analysis was performed by a blinded neuroradiologist and a blinded nuclear physician. Regional brain glucose metabolism and GM volume were assessed using SPM8 software. Groups were compared using appropriate statistical tests available at SPM8 and R. Nineteen RSPs (median [IQR]: 62 [50-64.5] years old) and 20 controls (60 [48-73] years old) were included. Retired soccer players performed worse on mini-mental state examination, digit span, clock drawing, phonemic and semantic verbal fluency tests, and had reduced rBGM in the left temporal pole (pFDR = 0.008) and the anterior left middle temporal gyrus (pFDR = 0.043). Semantic verbal fluency correlated with rBGM in the right hippocampus, left temporal pole, and posterior left middle temporal gyrus (p ≤ 0.042). Gray matter volume reduction was observed in similar anatomic regions but was less extensive and did not survive correction for multiple comparisons (pFDR ≥ 0.085). Individual [18F]FDG-PET visual analysis revealed seven RSPs with overt hypometabolism in the medial and lateral temporal lobes, frontal lobes, and temporoparietal regions. Retired soccer players had a higher prevalence of septum pellucidum abnormalities on MRI. Retired soccer players had reduced rBGM and GM volume in the temporal lobes and septum pellucidum abnormalities, findings possibly related to repetitive head impacts.

Screening for Brain Injury Sustained in the Context of Intimate Partner Violence (IPV): Measure Development and Preliminary Utility of the Brain Injury Screening Questionnaire IPV Module.

Abstract Intimate partner violence (IPV) is associated with risk for multi-etiology brain injury (BI), including repetitive head impacts, isolated traumatic brain injuries (TBI), and anoxic/hypoxic injury secondary to nonfatal strangulation (NFS). IPV-related injuries are often unreported, but evidence suggests that survivors are more likely to report when asked directly. There are currently no validated tools for screening of brain injury related to IPV that meet World Health Organization guidelines for this population. Here, we describe measure development methods and preliminary utility of the Brain Injury Screening Questionnaire IPV (BISQ-IPV) module. We culled items from existing IPV and TBI screening tools and sought two rounds of stakeholder feedback regarding content coverage, terminology, and safety of administration. The resulting stakeholder-informed BISQ-IPV module is a seven-item self-report measure that uses contextual cues (e.g., being shoved, shaken, strangled) to query lifetime history of IPV-related head/neck injury. We introduced the BISQ-IPV module into the Late Effects of TBI (LETBI) study to investigate rates of violent and IPV-specific head/neck injury reporting in a TBI sample. Among those who completed the BISQ-IPV module (n = 142), 8% of the sample (and 20% of women) reported IPV-related TBI, and 15% of the sample (34% of women) reported IPV-related head or neck injury events that did not result in loss or alteration of consciousness. No men reported NFS; one woman reported inferred BI secondary to NFS, and 6% of women reported NFS events. Those who endorsed IPV-BI were all women, many were highly educated, and many reported low incomes. We then compared reporting of violent TBIs and head/neck injury events among individuals who completed the core BISQ wherein IPV is not specifically queried (administered from 2015-2018; n = 156) to that of individuals who completed the core BISQ preceded by the BISQ-IPV module (BISQ+IPV, administered from 2019-2021; n = 142). We found that 9% of those who completed the core BISQ reported violent TBI (e.g., abuse, assault), whereas 19% of those who completed the BISQ+IPV immediately preceding the core BISQ reported non-IPV-related violent TBI on the core BISQ. These findings suggest that standard TBI screening tools are inadequate for identifying IPV-BI and structured cueing of IPV-related contexts yields greater reporting of both IPV- and non-IPV-related violent BI. When not queried directly, IPV-BI remains a hidden variable in TBI research studies.

Salt diet Induces Neuroinflammatory Response, Microbiome Dysregulation and Associated with Long-term Anxiety Following Repetitive Closed Head Injury. (S28.003)

<h3>Objective:</h3> Investigate the effects of salt diet on neuroinflammatory response, behavior, and microbiome dysregulation following repetitive closed head injury model. <h3>Background:</h3> Concussions continue to be a prominent public health concern, with an estimated 1.6–3.8 million incidences annually in the United States. Younger populations are experiencing the highest rates of concussion and nearly all athletic endeavors have some risk of concussive injury. Concerns surrounding the potential risks of long-term cognitive and medical outcomes made adolescent traumatic brain injury (TBI) a central focus of public attention. Coupled to these events, recent clinical studies have shown that lifestyle factors, including salt diet, constitute additional risk affecting TBI consequences and neuropathophysiological outcomes. However, the impact of salt diet on the pathophysiology of TBI and whether it exacerbates post-injury outcomes is still largely unknown. <h3>Design/Methods:</h3> We investigated if the exposure to a high salt diet (HSD) would alter hemodynamics, behavior, innate immune response and microbiome diversity after repetitive mild closed head injury in adolescent mice. Mice were injured with a three hit model (3HD) and then maintained on a HSD or standard diet (STD) for 12 weeks. <h3>Results:</h3> We found that HSD didn’t change systolic and diastolic blood pressure, and heart rate compared with STD group. HSD group was associated with worsening anxiety-like behavior at 12 weeks post diet administration. HSD induced microgliosis and proinflammatory microglial transcriptomic signature including upregulation in interferon gamma, Interferon beta, T cells proliferation pathways. Consistently, we found upregulation of proinflammatory Tumor necrotic factor (TNF) in brain compared to Sham-HSD and TBI-STD groups. HSD was the main driver of microbiome dysregulation in both TBI and Sham groups. We found that Eubacterium xylanophilum and Lachnospiraceae bacterium associated with an anxiety phenotype following injury at 12 weeks post diet administration. <h3>Conclusions:</h3> Salt diet associated with increasing risk of worsening anxiety and exacerbating chronic neuroinflammation post repetitive head injury. <b>Disclosure:</b> Dr. Izzy has received publishing royalties from a publication relating to health care. Taha Yahya has nothing to disclose. Dr. Cao has nothing to disclose. Mr. Albastaki has nothing to disclose. Dr. Waed has nothing to disclose. Ms. Chopra has nothing to disclose. Miss EKWUDO has nothing to disclose. Miss Kurdeikaite has nothing to disclose. Ms. Moraes Verissimo has received personal compensation for serving as an employee of Brigham and Women’s Hospital. Ms. Moraes Verissimo has received personal compensation for serving as an employee of Brigham and Women’s Hospital and Harvard Medical School. Ms. Moraes Verissimo has received personal compensation for serving as an employee of Von Medical, Inc.. Ms. Moraes Verissimo has received personal compensation for serving as an employee of Nova Southeastern University. Ms. Moraes Verissimo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Montachem Company. Dr. Cox has received personal compensation for serving as an employee of Anaerobe Systems. The institution of Dr. Cox has received research support from Infectious Disease Society. The institution of Dr. Cox has received research support from BrightFocus Foundation. Dr. Cox has received intellectual property interests from a discovery or technology relating to health care. Dr. Zafonte has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MYOMO. Dr. Zafonte has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Kisbee. Dr. Zafonte has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers in Neurology. The institution of Dr. Zafonte has received research support from NIDILRR. The institution of Dr. Zafonte has received research support from NIH. The institution of Dr. Zafonte has received research support from FPHS study. Dr. Zafonte has received publishing royalties from a publication relating to health care. Michael J. Whalen has nothing to disclose.

An Examination of Visual Quality of Life and Functional Vision Among Collision and Non-Collision Athletes Over a Competitive Season.

Repetitive head impacts (RHIs) experienced during sports are gaining attention due to potential long-term neurological dysfunction, absent of a diagnosed concussion. One area susceptible to dysfunction is vision. The goal of this study was to evaluate changes in visual quality of life (VQOL) and functional vision scores from pre- to post-season among collision and non-collision athletes. The Visual Functioning Questionnaire-25 and Neuro-Ophthalmic Supplement (NOS), as well as functional vision testing (Mobile Universal Lexicon Evaluation System - MULES) were completed pre- and post-season by three groups: collision athletes, non-collision athletes, and minimally active controls (MACs). There were 42 participants, with 41 (21 male, 20 female) completing both testing sessions, with a mean (standard deviation [SD]) age of 21 (2.46) years (collision group, n = 14; non-collision group, n = 13, MACs, n = 14). Baseline analyses revealed no significant differences between groups for VQOL or MULES scores. However, those with a family history of psychiatric disorder scored significantly worse on NOS. Post-season/follow-up testing revealed no significant differences between groups for VQOL scores. Non-collision athletes significantly improved on the MULES test by 2.46 ± 3.60 (SD) s (35.0 [95% confidence interval, 0.29-4.63]; p = .03). Change score results from pre- to post-season were not significant. Although the groups were not significantly different from one another, non-collision athletes significantly improved MULES scores, whereas collision athletes performed the worst, suggesting exposure to RHIs may impact functional vision. Thus, further evaluation of RHIs and their impact on vision is warranted.

Soccer heading immediately alters brain function and brain-muscle communication.

There is growing evidence of a link between repetitive soccer heading and the increased incidence of neurodegenerative disease. Even a short bout of soccer heading has been shown to impair cognitive performance and disrupt movement control. However, a greater understanding of the mechanisms behind these immediate impairments is needed. The current study attempted to identify how a short bout of soccer heading alters brain function and brain-muscle communication during a movement task. Sixty soccer players were exposed to either an acute bout (i.e., 20 balls thrown underarm) of soccer heading (n = 30) or a control condition where participants (n = 30) headed soccer balls in virtual reality (VR). Before and after heading, we measured cognitive performance on the King-Devick test, as well as electromyography (EMG), electroencephalography (EEG) and brain-muscle communication (i.e., corticomuscular coherence; CMC) during a force precision task. Following the heading protocol, the VR group improved their cognitive performance whereas the Heading group showed no change. Both groups displayed more precise force contractions at post-test. However, the VR group displayed elevated frontal theta activity and global increases in alpha and beta activity during the contraction task, whereas the Heading group did not. Contrary to our expectations, the Heading group displayed elevated CMC, whereas the VR group showed no change. Our findings indicate a short bout of soccer heading may impair cognitive function and disrupt the organization of efficient neural processes that typically accompany motor skill proficiency. Soccer heading also induced corticomuscular hyperconnectivity, which could represent compensatory brain-muscle communication and an inefficient allocation of increased task-related neuromuscular resources. These initial findings offer insights to the mechanisms behind the impairments experienced after a short bout of repetitive soccer heading.

Chronic traumatic encephalopathy (CTE)—features and forensic considerations

Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition, in which the only known cause is exposure to repeated episodes of blunt head trauma. It most often occurs in professional and amateur athletes who have had frequent and repetitive cranial impacts during contact sports, but may also be found in victims of domestic violence, military personnel exposed to explosive devices and in individuals with severe epilepsy. The pathognomonic pathological findings are of neurofibrillary tangles and pretangles in the depths of the cerebral sulci caused by perivascular accumulation of phosphorylated Tau (pTau). Cases may be high profile requiring an evaluation of whether the neuropathological findings of CTE can be related to injuries previously sustained on the sporting field. Failure to examine the brain or to adequately sample appropriate areas at autopsy may lead to cases being overlooked and to an underestimation of the incidence of this condition in the community. Performing immunohistochemical staining for pTau in three areas from the neocortex has been found to be a useful screening tool for CTE. Ascertaining whether there is a history of head trauma, including exposure to contact sports, as a standard part of forensic clinical history protocols will help identify at-risk individuals so that Coronial consideration of the need for brain examination can be appropriately informed. Repetitive head trauma, particularly from contact sport, is being increasingly recognized as a cause of significant preventable neurodegeneration.

190 Prion Protein Knockout Leads to Differential RNA Expression Following Head Injury

INTRODUCTION: It is not well understood why repetitive head injury causes the behavioral and pathologic sequelae associated with Chronic Traumatic Encephalopathy. Cellular prion protein (PrPC) is associated with several neurodegenerative diseases including Alzheimer’s disease and Creutzfeldt-Jakob disease and we have previously demonstrated that PrPC is required for the pathology and behavior associated with CTE after TBI. We show that Prpc knockout leads to differential mice cortex gene expression in a murine repetitive head injury model. METHODS: Experimental groups consisted of PrPC-knockout (Prnp-/-) and PrPC wild type (WT) mice. Bilateral close head injury consisted of daily impactions over 10 days with appropriate unimpacted control. All animals were allowed to recover for 6 weeks. Mice were sacrificed and brain cortexes rapidly dissected and flash frozen for RNA extraction, sequencing, and quantification. RESULTS: We identified 52 upregulated and 134 downregulated genes in WT impacted compared to unimpacted WT mice. 301 genes were upregulated and 85 downregulated in Prnp-/- impacted mice compared to Prnp-/- mice without impactions. We identified 85 upregulated and 86 downregulated genes in Prnp-/- impacted mice compared to WT impacted mice. RNA expression of KLK6 is upregulated by a factor of 2.3 and KChip3 is downregulated by a factor of 1.3 in Prnp-/- impacted mice compared to WT impacted mice. CONCLUSIONS: Deletion of PrPc in a murine model of CTE leads to differential expression of multiple gene clusters. Deletion of Prpc in impacted mice upregulates KLK6 and downregulates KCHip3 which have been implicated in neurodegenerative processes and neuroinflammation including Alzheimer’s disease. We have previously demonstrated that Prpc is required for cognitive deficits and standard histologic pathology following head injury who's biochemical mechanism may implicate KLK6 and KCHip3.

Quantifying the Magnitude and Longevity of the Effect of Repetitive Head Impacts in Adolescent Soccer Players: Deleterious Effect of Long Headers Extend Beyond a Month.

There is growing interest in the effects of sports-related repetitive head impacts (RHIs) on athletes' cognitive capabilities. This study examines the effect of RHIs in data collected from adolescent athletes to estimate the magnitude and longevity of RHIs on sensorimotor and cognitive performance. A non-linear regression model estimated the longevity of RHI effects by adding a half-life parameter embedded in an exponential decay function. A model estimate of this parameter allows the possibility of RHI effects to attenuate over time and introduces a mechanism to study the cumulative effect of RHIs. The posterior distribution of the half-life parameter associated with short-distance headers (<30 m) is centered around 6 days, whereas the posterior distribution of the half-life parameter associated with long-distance headers extends beyond a month. Additionally, the magnitude of the effect of each short header is around 3 times smaller than that of a long header. The results indicate that, on both tasks, response time (RT) changes after long headers are bigger in magnitude and last longer compared to the effects of short headers. Most important, we demonstrate that deleterious effects of long headers extend beyond 1 month. Although estimates are based on data from a relatively short-duration study with a relatively small sample size, the proposed model provides a mechanism to estimate long-term behavioral slowing from RHIs, which may be helpful to reduce the risk of additional injury. Finally, differences in the longevity of the effects of short and long RHIs may help to explain the large variance found between biomechanical input and clinical outcome in studies of concussion tolerance.

Mechanistic Insights into the Binding of Different Positron Emission Tomography Tracers to Chronic Traumatic Encephalopathy Tau Protofibrils.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts, and it is neuropathologically defined as the accumulation of abnormally hyperphosphorylated tau (p-tau). Early detection of p-tau in the brain is of great value in the prevention and treatment of CTE. Previous experimental studies reported that positron emission tomography (PET) technique using several tau tracers are available for imaging certain neurodegenerative diseases. However, few studies have focused on the development of CTE tau tracers. In this work, we performed conventional molecular docking and molecular dynamics simulations to address the binding properties and mechanisms of PET tracers (18F-PM-PBB3, 18F-CBD-2115, 18F-PI-2620, 18F-RO-948, 18F-MK-6240, and 18F-flortaucipir) to CTE tau protofibrils. The results show that the hydrophobic cavity and the top of the concave structure of CTE tau protofibrils are the preferred binding sites for the six tracers, and 18F-PM-PBB3 has the most competitive binding affinity to CTE tau protofibrils. Further investigation into the binding patterns of the six tracers to the CTE tau protofibrils showed that 18F-CBD-2115 and 18F-PM-PBB3 have a high number of H-bonds and hydrophobic contacts with tau protofibrils, resulting in strong hydrogen bonding and hydrophobic interactions; 18F-flortaucipir/18F-PI-2620 and 18F-PI-2620/18F-RO-948 form more intense π-π and cation-π interactions with tau protofibrils, respectively. Subsequently, we conducted a detailed analysis of the binding mechanism of 18F-PM-PBB3 to CTE tau protofibrils. The benzothiazole ring of 18F-PM-PBB3 exhibits stronger π-π stacking and cation-π interactions with tau protofibrils than the pyridine ring and forms a more concentrated T-shaped π-π stacking pattern. This study contributes to understanding the binding mechanism of PET tracers to CTE tau protofibrils and provides new insights into the design of potential novel tracers.

Association of Nonconcussive Repetitive Head Impacts and Intense Physical Activity With Levels of Phosphorylated Tau181 and Total Tau in Plasma of Young Elite Soccer Players

Head impacts resulting in traumatic brain injury (TBI) lead to the elevation of phosphorylated tau protein (p-tau181) in plasma. To our knowledge, this study is the first to investigate dynamics of p-tau181 levels and the ratio of p-tau181 to total tau in individuals after nonconcussive head impacts. To determine the association of repetitive low-intensity head impacts on p-tau181 and total tau protein levels in the plasma of young adult elite soccer players and assess the possible association of head impacts with focused attention and cognitive flexibility. In this cohort study, young elite soccer players performed intense physical activity with and without heading the ball. The study was conducted at a university facility in Slovakia from October 1, 2021, to May 31, 2022. Eligible participants were selected based on similarities in demographic variables, excluding those with a history of TBI. The primary study outcomes were the levels of total tau protein and p-tau181 in plasma samples and the cognitive status of the study participants. A total of 37 male athletes participated in the study (mean [SD] age: exercise group, 21.6 [1.6] years; heading group, 21.2 [1.5] years). We found significantly elevated levels of total tau and p-tau181 in the plasma of soccer players 1 hour after physical exercise (tau, 1.4-fold; 95% CI, 1.2-1.5; P < .001; p-tau181, 1.4-fold; 95% CI, 1.3-1.5, P < .001) and repetitive head impacts (tau, 1.3-fold; 95% CI, 1.2-1.4; P < .001; p-tau181, 1.5-fold; 95% CI, 1.4-1.7 P < .001). The ratio of p-tau181 to tau was significantly higher 1 hour after exercise and heading training, and remained elevated specifically in the heading group even after 24 hours (1.2-fold; 95% CI, 1.1-1.3; P = .002). Performance in cognitive tests revealed a significant decline in focused attention and cognitive flexibility after physical exercise and heading training; physical exercise of higher intensity without heading training was associated with a greater negative cognitive performance than heading only. In this cohort study of young elite soccer players, the elevation of p-tau181 and tau was observed after acute intense physical activity and nonconcussive repetitive head impacts. The increase of p-tau181 levels relative to tau after 24 hours indicated an acute enrichment of phosphorylated tau fraction in the periphery when compared with preimpact levels; an imbalance of tau proteins may have long-lasting consequences in the brain of head-impacted individuals.

Sparring and the Brain: The Associations between Sparring and Regional Brain Volumes in Professional Mixed Martial Arts Fighters.

Mixed martial arts (MMA) fighters, due to exposure to repetitive head impacts, are at risk for brain atrophy and neurodegenerative sequelae. Simultaneously, motor skills training and cognition-rich activities have been linked with larger regional brain volumes. The majority of an MMA fighter's sporting activity occurs during practice (e.g., sparring) rather than formal competition. This study, therefore, aims to be the first to explore regional brain volumes associated with sparring in MMA fighters. Ninety-four active, professional MMA fighters from the Professional Fighters Brain Health Study met inclusion criteria for this cross-sectional analysis. Adjusted multivariable regression analyses were utilized to examine the relationship between the number of sparring practice rounds per week during typical training and a select number of regional brain volumes (i.e., caudate, thalamus, putamen, hippocampus, amygdala). A higher number of weekly sparring rounds during training was significantly associated with larger left (beta = 13.5µL/round, 95%CI 2.26-24.8) and right (beta = 14.9µL/round, 95%CI 3.64-26.2) caudate volumes. Sparring was not significantly associated with left or right thalamus, putamen, hippocampus, or amygdala volumes. More weekly rounds of sparring was not significantly associated with smaller volumes in any of the brain regions studied in active, professional MMA fighters. Sparring's significant association with larger caudate volume raises questions about whether fighters who spar more experience attenuated trauma-related decreases in caudate volume relative to fighters who spar less, whether fighters who spar more experience minimal or even positive changes to caudate volume, whether baseline differences in caudate size may have mediated results, or whether some other mechanism may be at play. Given limitations inherent to the cross-sectional study design, more research is needed to further explore the brain effects of sparring in MMA.

Former participation in professional football as an occupation in patients with isolated REM sleep behavior disorder leading to a synucleinopathy: a case-control study.

Contact sports such as football are associated with late development of neurodegenerative diseases, in part due to the deleterious effect of repetitive head impacts during participation. Isolated REM sleep behavior disorder (IRBD) represents an early manifestation of neurodegenerative diseases including Parkinson disease (RBD) and dementia with Lewy bodies (DLB). We hypothesized that former professional football participation would be overrepresented in IRBD. To assess former participation in professional football as an occupation in IRBD. In a case-control retrospective study, having played football as a professional occupation in the Spanish Football Professional Leagues was examined interviewing polysomnographically confirmed IRBD patients and matched controls without IRBD. Among 228 Caucasian Spanish IRBD patients with 68.5 ± 7.2years, six (2.63%) were retired professional footballers. Length professional football career ranged between 11 and 16years. Interval between football retirement and IRBD diagnosis was 39.5 ± 6.4years. At IRBD diagnosis, the six footballers had synucleinopathy biomarkers including pathologic synuclein in the CSF and tissues, nigrostriatal dopaminergic deficit and hyposmia. Follow-up showed that three footballers developed PD and two DLB. None of the controls was a professional footballer. The percentage of professional footballers was higher in IRBD patients than in controls (2.63% versus 0.00%; p = 0.030) and among the general Spanish population (2.63% versus 0.62%; p < 0.0001). We found an overrepresentation of former professional footballers in IRBD patients who later developed PD and DLB after four decades from professional retirement. In professional footballers the development of a neurodegenerative disease may be first manifested by IRBD. Screening for IRBD in former footballers might identify individuals with underlying synucleinopathies. Further studies with larger samples are needed to confirm our observations.

Contact or Collision Sport History, Repetitive Neurotrauma, and Patient-Reported Outcomes in Early to Midadulthood.

Data on the early to midlife effects of repetitive neurotrauma on patient-reported outcomes have been delimited to homogeneous samples of male athletes without comparison groups or accounting for modifying factors such as physical activity. To determine the effect of contact or collision sport participation and repetitive neurotrauma on patient-reported outcomes among early to middle-aged adults. Cross-sectional study. Research laboratory. A total of 113 adults (53 [46.9%] men, 60 [53.1%] women; age = 34.88 ± 11.80 years) in 4 groups: (1) physically inactive individuals with no repetitive head impact (RHI) exposure (NON); (2) noncontact sport athletes and nonathletes with no RHI exposure who were currently physically active (NCA); (3) former high-risk sport athletes with an RHI history who were physically active (HRS); and (4) former rugby players with prolonged RHI exposure who remained physically active. The 12-Item Short-Form Health Survey (SF-12), Apathy Evaluation Scale-self-rated version (AES-S), Satisfaction With Life Scale (SWLS), and Sport Concussion Assessment Tool-5th Edition (SCAT5) Symptom and Symptom Severity Checklist. The NON group had worse self-rated physical function than the NCA group as assessed by the SF-12 physical component summary (P = .03) and worse self-rated apathy (AES-S) and satisfaction with life (SWLS) than the NCA (P = .03 for both) and HRS groups (P = .03 and P = .040, respectively). We observed no group differences for self-rated mental health (SF-12 mental component summary; P = .26) or symptoms (SCAT5; P = .42). Career duration was not associated with any patient-reported outcomes. A history of contact or collision sport participation and career duration did not negatively affect patient-reported outcomes in physically active, early to middle-aged adults. However, physical inactivity status was negatively associated with patient-reported outcomes in these individuals in the absence of an RHI history.

Head Impact Exposure in Youth Soccer: Comparing across Activity Types

Soccer is a popular youth sport in the United States, but the effect of repetitive head impacts experienced during training on neurocognitive outcomes is not well understood. Modifying practice structure may be an avenue for reducing head impact exposure and concussion risk in soccer, but research has yet to characterize head impact exposure across common soccer activities. The objective of this study was to compare head impact exposure across common training activities in soccer. Eight female soccer players practicing on an age 15 and under (U15) club team participated in this study for two soccer seasons. Players wore an instrumented mouthpiece sensor during all practice and game sessions. Research personnel recorded duration of all activities performed by each player to characterize player-specific exposure time. Film review was performed to identify head contact events during each session and classify events according to the activity and drill the player was performing. Head impact exposure for each athlete was quantified in terms of peak kinematics and impact rate. Mixed effects models were used to compare peak kinematics and generalized linear models were used to compare impact rates across drills and activity type. Drill and activity type were associated with peak kinematics and impact rate. Technical training activities accounted for the second-highest exposure time and were associated with higher impact rates and lower mean kinematics than other activity types. Team interaction activities and game play were associated with the highest rotational kinematics but the lowest impact rates. Head impact exposure in female youth soccer is influenced by the type of activity in which the athlete is engaged. Interventions designed to reduce head impact frequency in female youth soccer can benefit from targeting technical training activities; whereas, interventions designed to reduce head impact magnitude should target team interaction and game activities.

A sensor-enabled cloud-based computing platform for computational brain biomechanics

Background and ObjectivesDriven by the risk of repetitive head trauma, sensors have been integrated into mouthguards to measure head impacts in contact sports and military activities. These wearable devices, referred to as “instrumented” or “smart” mouthguards are being actively developed by various research groups and organizations. These instrumented mouthguards provide an opportunity to further study and understand the brain biomechanics due to impact. In this study, we present a brain modeling service that can use information from these sensors to predict brain injury metrics in an automated fashion. MethodsWe have built a brain modeling platform using several of Amazon's Web Services (AWS) to enable cloud computing and scalability. We use a custom-built cloud-based finite element modeling code to compute the physics-based nonlinear response of the intracranial brain tissue and provide a frontend web application and an application programming interface for groups working on head impact sensor technology to include simulated injury predictions into their research pipeline. ResultsThe platform results have been validated against experimental data available in literature for brain-skull relative displacements, brain strains and intracranial pressure. The parallel processing capability of the platform has also been tested and verified. We also studied the accuracy of the custom head surfaces generated by Avatar 3D. ConclusionWe present a validated cloud-based computational brain modeling platform that uses sensor data as input for numerical brain models and outputs a quantitative description of brain tissue strains and injury metrics. The platform is expected to generate transparent, reproducible, and traceable brain computing results.

Inflammation and neuronal gene expression changes differ in early versus late chronic traumatic encephalopathy brain

BackgroundOur understanding of the molecular underpinnings of chronic traumatic encephalopathy (CTE) and its associated pathology in post-mortem brain is incomplete. Factors including years of play and genetic risk variants influence the extent of tau pathology associated with disease expression, but how these factors affect gene expression, and whether those effects are consistent across the development of disease, is unknown.MethodsTo address these questions, we conducted an analysis of the largest post-mortem brain CTE mRNASeq whole-transcriptome dataset available to date. We examined the genes and biological processes associated with disease by comparing individuals with CTE with control individuals with a history of repetitive head impacts that lack CTE pathology. We then identified genes and biological processes associated with total years of play as a measure of exposure, amount of tau pathology present at time of death, and the presence of APOE and TMEM106B risk variants. Samples were stratified into low and high pathology groups based on McKee CTE staging criteria to model early versus late changes in response to exposure, and the relative effects associated with these factors were compared between these groups.ResultsSubstantial gene expression changes were associated with severe disease for most of these factors, primarily implicating diverse, strongly involved neuroinflammatory and neuroimmune processes. In contrast, low pathology groups had many fewer genes and processes implicated and show striking differences for some factors when compared with severe disease. Specifically, gene expression associated with amount of tau pathology showed a nearly perfect inverse relationship when compared between these two groups.ConclusionsTogether, these results suggest the early CTE disease process may be mechanistically different than what occurs in late stages, that total years of play and tau pathology influence disease expression differently, and that related pathology-modifying risk variants may do so via distinct biological pathways.

Design Considerations for the Attenuation of Translational and Rotational Accelerations in American Football Helmets.

Participants in American football experience repetitive head impacts that induce negative changes in neurocognitive function over the course of a single season. This study aimed to quantify the transfer function connecting the force input to the measured output acceleration of the helmet system to provide a comparison of the impact attenuation of various modern American football helmets. Impact mitigation varied considerably between helmet models and with location for each helmet model. The current data indicate that helmet mass is a key variable driving force attenuation, however flexible helmet shells, helmet shell cutouts, and more compliant padding can improve energy absorption.