Functional connectivity changes in neurodegenerative biomarker-positive athletes with repeated concussions.

Multimodal biomarkers may identify former contact sports athletes with repeated concussions and at risk for dementia. Our study aims to investigate whether biomarker evidence of neurodegeneration in former professional athletes with repetitive concussions (ExPro) is associated with worse cognition and mood/behavior, brain atrophy, and altered functional connectivity. Forty-one contact sports athletes with repeated concussions were divided into neurodegenerative biomarker-positive (n = 16) and biomarker-negative (n = 25) groups based on positivity of serum neurofilament light-chain. Six healthy controls (negative for biomarkers) with no history of concussions were also analyzed. We calculated cognitive and mood/behavior composite scores from neuropsychological assessments. Gray matter volume maps and functional connectivity of the default mode, salience, and frontoparietal networks were compared between groups using ANCOVAs, controlling for age, and total intracranial volume. The association between the connectivity networks and sports characteristics was analyzed by multiple regression analysis in all ExPro. Participants presented normal-range mean performance in executive function, memory, and mood/behavior tests. The ExPro groups did not differ in professional years played, age at first participation in contact sports, and number of concussions. There were no differences in gray matter volume between groups. The neurodegenerative biomarker-positive group had lower connectivity in the default mode network (DMN) compared to the healthy controls and the neurodegenerative biomarker-negative group. DMN disconnection was associated with increased number of concussions in all ExPro. Biomarkers of neurodegeneration may be useful to detect athletes that are still cognitively normal, but with functional connectivity alterations after concussions and at risk of dementia.

Self-managing symptoms of Long COVID: an education and strategies research protocol.

Post-acute sequelae of SARS-COV-2 (PASC) is growing in prevalence, and involves symptoms originating from the central neurological, cardiovascular, respiratory, gastrointestinal, autonomic nervous, or immune systems. There are non-specific symptoms such as fatigue, headaches, and brain fog, which cannot be ascribed to a single system. PASC places a notable strain on our healthcare system, which is already laden with a large number of acute-COVID-19 patients. Furthermore, it impedes social, academic and vocational functioning, and impacts family life, relationships, and work/financial life. The treatment for PASC needs to target this non-specific etiology and wide-ranging sequelae. In conditions similar to PASC, such as "chemo brain," and prolonged symptoms of concussion, the non-specific symptoms have shown to be effectively managed through education and strategies for self-management and Mindfulness interventions. However, such interventions have yet to be empirically evaluated in PASC to our knowledge. In response to this gap, we have developed a virtual education intervention synthesized by psychiatrists and clinical psychologists for the current study. We will undertake a two-phase randomized controlled trial to determine the feasibility (Phase 1; N = 90) and efficacy (Phase 2; sample sized based on phase 1 results) of the novel 8 week Education and Self-Management Strategies group compared to a mindfulness skills program, both delivered virtually. Main outcomes include confidence/ability to self-manage symptoms, quality of life, and healthcare utilization. This study stands to mitigate the deleterious intrusiveness of symptoms on everyday life in patients with PASC, and may also help to reduce the impact of PASC on the healthcare system. Clinical trial registration:https://classic.clinicaltrials.gov/ct2/show/NCT05268523; identifier NCT05268523.

Feasibility of group telerehabilitation for individuals with chronic acquired brain injury: integrating clinical care and research.

BACKGROUND: Acquired brain injury (ABI) is a leading cause of lifelong disability, but access to treatment in the chronic stages has significant barriers. Group-based, remotely delivered neurorehabilitation reduces costs, travel barriers, and infection risk; however, its feasibility for patients with ABI is not well-established. OBJECTIVES: To investigate the feasibility of remotely group-based cognitive and mood therapies for persons with chronic ABI. METHODS: Three hundred and eighty-eight adults with chronic ABI participated in group tele-neurorehabilitation modules comprising Cognitive Behavioral Therapy, Goal Management Training®, Relaxation and Mindfulness Skills Training, and/or a novel Concussion Education & Symptom Management program. Assessments comprised quantitative metrics, surveys, as well as qualitative semi-structured interviews in a subset of participants. RESULTS: High retention, adherence, and satisfaction were observed. Facilitators of treatment included accessibility, cost-effectiveness, and convenience. Adoption of technology was high, but other people's technological interruptions were a barrier. Self-reported benefits specific to group-based format included improved mood, stress management, coping, interpersonal relationships, cognitive functioning, and present-mindedness. CONCLUSIONS: The present study examined chronic ABI patients' perceptions of telerehabilitation. Patients found remotely delivered, group-based mood, and cognitive interventions feasible with easy technology adoption. Group format was considered a benefit. Recommendations are provided to inform design of remotely delivered ABI programs.

Group-based mood and cognitive telerehabilitation is feasible for persons with chronic acquired brain injury, with high reported satisfaction.Screening for technical proficiency and providing ongoing technical support improves therapy adherence and retention.Integration of clinical care and research is feasible for delivering remote therapies to persons with brain injury.

Moderate-Severe TBI as a Progressive Disorder: Patterns and Predictors of Cognitive Declines in the Chronic Stages of Injury.

BACKGROUND: Moderate-severe traumatic brain injury (TBI) has been associated with progressive cognitive decline in the chronic injury stages in a small number of studies. OBJECTIVE: This study aimed to (i) replicate our previous findings of decline from 1 to 3+ years post-injury in a larger, non-overlapping sample and (ii) extend these findings by examining the proportion of decliners in 2 earlier time windows, and by investigating novel predictors of decline. METHODS: N = 48 patients with moderate-severe TBI underwent neuropsychological assessment at 2, 5, 12 months, and 30+ months post-injury. We employed the Reliable Change Index (RCI) to evaluate decline, stability and improvement across time and logistic regression to identify predictors of decline (demographic/cognitive reserve; injury-related). RESULTS: The proportions of patients showing decline were: 12.5% (2-5 months post-injury), 17% (5-12 months post-injury), and 27% (12-30+ months post-injury). Measures of verbal retrieval were most sensitive to decline. Of the predictors, only left progressive hippocampal volume loss from 5 to 12 months post-injury significantly predicted cognitive decline from 12 to 30+ months post-injury. CONCLUSIONS: Identical to our previous study, 27% of patients declined from 12 to 30+ months post-injury. Additionally, we found that the further from injury, the greater the proportion of patients declining. Importantly, earlier progressive hippocampal volume loss predicted later cognitive decline. Taken together, the findings highlight the need for ongoing research and treatment that target these deleterious mechanisms affecting patients in the chronic stages of moderate-severe TBI.

Misfolded α-Synuclein in Cerebrospinal Fluid of Contact Sport Athletes.

BACKGROUND: Misfolded α-synuclein in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) can be detected using the real-time quaking-induced conversion (RT-QuIC) technique in cerebrospinal fluid (CSF). OBJECTIVES: The objectives are (1) to examine misfolded CSF α-synuclein incidence, and (2) to compare clinical presentation, sports history, brain volumes, and RT-QuIC α-synuclein positivity in former athletes. METHODS: Thirty former athletes with magnetic resonance imaging, neuropsychological testing, and CSF analyzed for phosphorylated tau 181 (p-tau), total tau (t-tau), amyloid-ß 42 (Aß42), and neurofilament light chain (NfL). CSF α-synuclein was detected using RT-QuIC. RESULTS: Six (20%) former athletes were α-synuclein positive. α-Synuclein positive athletes were similar to α-synuclein negative athletes on demographics, sports history, clinical features, CSF p-tau, t-tau, Aß42, and NfL; however, had lower grey matter volumes in the right inferior orbitofrontal, right anterior insula and right olfactory cortices. CONCLUSIONS: α-Synuclein RT-QuIC analysis of CSF may be useful as a prodromal biofluid marker of PD and DLB. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Preliminary efficacy and predictors of response to a remotely-delivered symptom self-management program for persistent symptoms after concussion.

BACKGROUND: More than a quarter of adults with concussion endure prolonged symptoms of >3 months. We developed the Concussion Education Self-Management program to help people manage persisting symptoms. Here, we assess feasibility, preliminary efficacy, and correlates of response. METHODS: N = 80 adults participated in the program; ages ranged from 18 to 65 years and time post-injury ranged from 6 months to 18 years. Weekly sessions, delivered remotely and in groups, comprised education and strategies for management of cognitive, emotional, and physical symptoms. Primary outcome: Confidence to self-manage symptoms. Secondary outcomes: Quality of life; mood/anxiety/stress. Predictors of response: Self-reported cognitive, emotional and physical symptoms at intake. RESULTS: Pre- to post-program improvements were observed in confidence to self-manage, p < 0.03; quality of life, p < 0.001; depression, p < 0.001; anxiety, p < 0.001; and stress, p < 0.001. Considering confidence to self-manage, those with fewer cognitive and physical symptoms benefitted more (p's < 0.0005 and p < 0.01, respectively). DISCUSSION: This program shows promise for improving self-management of prolonged symptoms. Those with high symptom burden may need extra sessions to benefit. This is a cost-effective and scalable program that can reach people regardless of geographic location or impediments to travel.

Predictors and Functional Outcomes Associated With Longitudinal Trajectories of Anxiety and Depression from 2 to ≥36 Months After Moderate to Severe Traumatic Brain Injury.

This study investigated longitudinal trajectories of anxiety and depressive symptoms following moderate-severe traumatic brain injury (TBI), predictors of the trajectories, and associations with 1-year return to productivity. One hundred forty-eight patients with moderate-severe TBI were assessed at 2, 5, 12, and ≥36 months post-injury on the Beck Anxiety Inventory and the Beck Depression Inventory. Clinical interviews obtained information about demographics, injury characteristics, and 1-year return to productivity. Latent growth mixture modeling identified trajectories of anxiety and depression across time. The three-step method identified predictors of trajectories, and χ2 analyses determined associations between trajectories and 1-year return to productivity. Analyses revealed that four-class models of anxiety and depression best fit the data. Most individuals had stable minimal (67%) or low (18%) levels of anxiety over time. Two other subsets of individuals were classified by anxiety that worsened rapidly (7%) or improved in the 1st year but worsened by 3 years post-injury (9%). Similarly for the depression trajectories, most individuals had stable minimal (70%) or low (10%) levels of depression over time. Others had depression that worsened rapidly (12%) or was delayed, with onset 1-year post-injury (8%). Predictors of worsening anxiety and depression included younger age, less education, and male gender. Those with worsening anxiety or depression were less likely to return to productivity by 1-year post-injury. There is a significant burden of anxiety (15%) and depression (20%) in the 3 years after moderate-severe TBI. Future research targeting at-risk patients may help to improve quality of life and functional recovery.

Longitudinal Patterns of Functional Connectivity in Moderate-to-Severe Traumatic Brain Injury.

Longitudinal neuroimaging studies aid our understanding of recovery mechanisms in moderate-to-severe traumatic brain injury (TBI); however, there is a dearth of longitudinal functional connectivity research. Our aim was to characterize longitudinal functional connectivity patterns in two clinically important brain networks, the frontoparietal network (FPN) and the default mode network (DMN), in moderate-to-severe TBI. This inception cohort study of prospectively collected longitudinal data used resting-state functional magnetic resonance imaging (fMRI) to characterize functional connectivity patterns in the FPN and DMN. Forty adults with moderate-to-severe TBI (mean ± standard deviation [SD]; age = 39.53 ± 16.49 years, education = 13.92 ± 3.20 years, lowest Glasgow Coma Scale score = 6.63 ± 3.24, sex = 70% male) were scanned at approximately 0.5, 1-1.5, and 3+ years post-injury. Seventeen healthy, uninjured participants (mean ± SD; age = 38.91 ± 15.57 years, education = 15.11 ± 2.71 years, sex = 29% male) were scanned at baseline and approximately 11 months afterwards. Group independent component analyses and linear mixed-effects modeling with linear splines that contained a knot at 1.5 years post-injury were employed to investigate longitudinal network changes, and associations with covariates, including age, sex, and injury severity. In patients with TBI, functional connectivity in the right FPN increased from approximately 0.5 to 1.5 years post-injury (unstandardized estimate = 0.19, standard error [SE] = 0.07, p = 0.009), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.21, SE = 0.11, p = 0.009), and marginally declined afterwards (estimate = -0.10, SE = 0.06, p = 0.079). Functional connectivity in the DMN increased from approximately 0.5 to 1.5 years (estimate = 0.15, SE = 0.05, p = 0.006), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.19, SE = 0.08, p = 0.021), and was estimated to decline from 1.5 to 3+ years (estimate = -0.04, SE = 0.04, p = 0.303). Similarly, the left FPN increased in functional connectivity from approximately 0.5 to 1.5 years post-injury (estimate = 0.15, SE = 0.05, p = 0.002), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.18, SE = 0.07, p = 0.008), and was estimated to decline thereafter (estimate = -0.04, SE = 0.03, p = 0.254). At approximately 0.5 years post-injury, patients showed hypoconnectivity compared with healthy, uninjured participants at baseline. Covariates were not significantly associated in any of the models. Findings of early improvement but a tapering and possible decline in connectivity thereafter suggest that compensatory effects are time-limited. These later reductions in connectivity mirror growing evidence of behavioral and structural decline in chronic moderate-to-severe TBI. Targeting such declines represents a novel avenue of research and offers potential for improving clinical outcomes.

Investigating the use of plasma pTau181 in retired contact sports athletes.

BACKGROUND: Considering the wide range of outcomes following sport-related concussions, biomarkers are needed to detect underlying pathological changes. The objective was to analyze the use of plasma phosphorylated tau 181 (pTau181) as a non-invasive measure of underlying brain changes in a cohort of retired contact sports athletes at risk of neurodegeneration. METHODS: Fifty-four retired contact sport athletes and 27 healthy controls whose blood plasma was analyzed for pTau181 were included. A portion (N = 21) of retired athletes had a 2-years follow-up visit. All participants had completed a neuropsychological battery and MRI imaging. RESULTS: Plasma pTau181 was significantly higher in retired athletes compared to healthy controls (8.94 ± 5.08 pg/mL vs. 6.00 ± 2.53 pg/mL, respectively; 95% BCa CI 1.38-4.62; p = 0.02); and was significantly associated with fornix fractional anisotropy values only in the athletes group (ß = - 0.002; 95% BCa CI - 0.003 to - 0.001; p = 0.002). When the retired athletes cohort was divided into high vs. normal pTau181 groups, the corpus callosum (CC) volume and white-matter integrity was significantly lower in high pTau181 compared to older healthy controls (CC volume: 1.57 ± 0.19 vs. 2.02 ± 0.32, p = 0.002; CC medial diffusivity: 0.96 ± 0.04 × 10-3 mm2/s vs. 0.90 ± 0.03 × 10-3 mm2/s, p = 0.003; CC axial diffusivity: 1.49 ± 0.04 × 10-3 mm2/s vs. 1.41 ± 0.02 × 10-3 mm2/s, p < 0.001, respectively). CONCLUSIONS: Although high plasma pTau181 levels were associated with abnormalities in CC and fornix, baseline pTau181 did not predict longitudinal changes in regional brain volumes or white-matter integrity in the athletes. pTau181 may be useful for identifying those with brain abnormalities related to repeated concussion but not for predicting progression.

Functional brain activity constrained by structural connectivity reveals cohort-specific features for serum neurofilament light chain.

Background: Neuro-axonal brain damage releases neurofilament light chain (NfL) proteins, which enter the blood. Serum NfL has recently emerged as a promising biomarker for grading axonal damage, monitoring treatment responses, and prognosis in neurological diseases. Importantly, serum NfL levels also increase with aging, and the interpretation of serum NfL levels in neurological diseases is incomplete due to lack of a reliable model for age-related variation in serum NfL levels in healthy subjects. Methods: Graph signal processing (GSP) provides analytical tools, such as graph Fourier transform (GFT), to produce measures from functional dynamics of brain activity constrained by white matter anatomy. Here, we leveraged a set of features using GFT that quantified the coupling between blood oxygen level dependent signals and structural connectome to investigate their associations with serum NfL levels collected from healthy subjects and former athletes with history of concussions. Results: Here we show that GSP feature from isthmus cingulate in the right hemisphere (r-iCg) is strongly linked with serum NfL in healthy controls. In contrast, GSP features from temporal lobe and lingual areas in the left hemisphere and posterior cingulate in the right hemisphere are the most associated with serum NfL in former athletes. Additional analysis reveals that the GSP feature from r-iCg is associated with behavioral and structural measures that predict aggressive behavior in healthy controls and former athletes. Conclusions: Our results suggest that GSP-derived brain features may be included in models of baseline variance when evaluating NfL as a biomarker of neurological diseases and studying their impact on personality traits.

Brain Connectivity Changes in Postconcussion Syndrome as the Neural Substrate of a Heterogeneous Syndrome.

Background: Postconcussion syndrome (PCS) or persistent symptoms of concussion refers to a constellation of symptoms that persist for weeks and months after a concussion. To better capture the heterogeneity of the symptoms of patients with PCS, we aimed to separate patients into clinical subtypes based on brain connectivity changes. Methods: Subject-specific structural and functional connectomes were created based on diffusion weighted and resting state functional magnetic resonance imaging, respectively. Following an informed dimensionality reduction, a Gaussian mixture model was used on patient-specific structural and functional connectivity matrices to find potential patient clusters. For validation, the resulting patient subtypes were compared in terms of cognitive, neuropsychiatric, and postconcussive symptom differences. Results: Multimodal analyses of brain connectivity were predictive of behavioral outcomes. Our modeling revealed two patient subtypes: mild and severe. The severe subgroup showed significantly higher levels of depression, anxiety, aggression, and a greater number of symptoms than the mild patient subgroup. Conclusion: This study suggests that structural and functional connectivity changes together can help us better understand the symptom severity and neuropsychiatric profiles of patients with PCS. This work allows us to move toward precision medicine in concussions and provides a novel machine learning approach that can be applicable to other heterogeneous conditions.

Progressive Neurodegeneration Across Chronic Stages of Severe Traumatic Brain Injury.

OBJECTIVE: To examine the trajectory of structural gray matter changes across 2 chronic periods of recovery in individuals who have sustained severe traumatic brain injury (TBI), adding to the growing literature indicating that neurodegenerative processes occur in the months to years postinjury. PARTICIPANTS: Patients who experienced posttraumatic amnesia of 1 hour or more, and/or scored 12 or less on the Glasgow Coma Scale at the emergency department or the scene of the accident, and/or had positive brain imaging findings were recruited while receiving inpatient care, resulting in 51 patients with severe TBI. METHODS: Secondary analyses of gray matter changes across approximately 5 months, 1 year, and 2.5 years postinjury were undertaken, using an automated segmentation protocol with improved accuracy in populations with morphological anomalies. We compared patients and matched controls on regions implicated in poorer long-term clinical outcome (accumbens, amygdala, brainstem, hippocampus, thalamus). To model brain-wide patterns of change, we then conducted an exploratory principal component analysis (PCA) on the linear slopes of all regional volumes across the 3 time points. Finally, we assessed nonlinear trends across earlier (5 months-1 year) versus later (1-2.5 years) time-windows with PCA to compare degeneration rates across time. Chronic degeneration was predicted cortically and subcortically brain-wide, and within specific regions of interest. RESULTS: (1) From 5 months to 1 year, patients showed significant degeneration in the accumbens, and marginal degeneration in the amygdala, brainstem, thalamus, and the left hippocampus when examined unilaterally, compared with controls. (2) PCA components representing subcortical and temporal regions, and regions from the basal ganglia, significantly differed from controls in the first time-window. (3) Progression occurred at the same rate across both time-windows, suggesting neither escalation nor attenuation of degeneration across time. CONCLUSION: Localized yet progressive decline emphasizes the necessity of developing interventions to offset degeneration and improve long-term functioning.

Patterns of change in cortical morphometry following traumatic brain injury in adults.

Progressive cortical volumetric loss following moderate-severe traumatic brain injury (TBI) has been observed; however, regionally specific changes in the structural determinants of cortical volume, namely, cortical thickness (CT) and cortical surface area (CSA), are unknown and may inform the patterns and neural substrates of neurodegeneration and plasticity following injury. We aimed to (a) assess differences in CT and CSA between TBI participants and controls in the early chronic stage post-injury, (b) describe longitudinal changes in cortical morphometry following TBI, and (c) examine how regional changes in CT and CSA are associated. We acquired magnetic resonance images for 67 participants with TBI at up to 4 time-points spanning 5 months to 7 years post-injury, and 18 controls at 2 time-points. In the early chronic stage, TBI participants displayed thinner cortices than controls, predominantly in frontal regions, but no CSA differences. Throughout the chronic period, TBI participants showed widespread CT reductions in posterior cingulate/precuneus regions and moderate CT increase in frontal regions. Additionally, CSA showed a significant decrease in the orbitofrontal cortex and circumscribed increase in posterior regions. No changes were identified in controls. Relationships between regional cortical changes in the same morphological measure revealed coordinated patterns within participants, whereas correlations between regions with CT and CSA change yielded bi-directional relationships. This suggests that these measures may be differentially affected by neurodegenerative mechanisms such as transneuronal degeneration following TBI and that degeneration may be localized to the depths of cortical sulci. These findings emphasize the importance of dissecting morphometric contributions to cortical volume change.

Remotely delivered environmental enrichment intervention for traumatic brain injury: Study protocol for a randomised controlled trial.

INTRODUCTION: Individuals with moderate-severe traumatic brain injury (m-sTBI) experience progressive brain and behavioural declines in the chronic stages of injury. Longitudinal studies found that a majority of patients with m-sTBI exhibit significant hippocampal atrophy from 5 to 12 months post-injury, associated with decreased cognitive environmental enrichment (EE). Encouragingly, engaging in EE has been shown to lead to neural improvements, suggesting it is a promising avenue for offsetting hippocampal neurodegeneration in m-sTBI. Allocentric spatial navigation (ie, flexible, bird's eye view approach), is a good candidate for EE in m-sTBI because it is associated with hippocampal activation and reduced ageing-related volume loss. Efficacy of EE requires intensive daily training, prohibitive within most current health delivery systems. The present protocol is a novel, remotely delivered and self-administered intervention designed to harness principles from EE and allocentric spatial navigation to offset hippocampal atrophy and potentially improve hippocampal functions such as navigation and memory for patients with m-sTBI. METHODS AND ANALYSIS: Eighty-four participants with chronic m-sTBI are being recruited from an urban rehabilitation hospital and randomised into a 16-week intervention (5 hours/week; total: 80 hours) of either targeted spatial navigation or an active control group. The spatial navigation group engages in structured exploration of different cities using Google Street View that includes daily navigation challenges. The active control group watches and answers subjective questions about educational videos. Following a brief orientation, participants remotely self-administer the intervention on their home computer. In addition to feasibility and compliance measures, clinical and experimental cognitive measures as well as MRI scan data are collected pre-intervention and post-intervention to determine behavioural and neural efficacy. ETHICS AND DISSEMINATION: Ethics approval has been obtained from ethics boards at the University Health Network and University of Toronto. Findings will be presented at academic conferences and submitted to peer-reviewed journals. TRIAL REGISTRATION NUMBER: Version 3, ClinicalTrials.gov Registry (NCT04331392).

Interaction of APOE4 alleles and PET tau imaging in former contact sport athletes.

BACKGROUND: Genetic polymorphisms like apolipoprotein E (APOE) and microtubule-associated protein tau (MAPT) genes increase the risk of neurodegeneration. METHODS: 38 former players (age 52.63±14.02) of contact sports underwent neuroimaging, biofluid collection, and comprehensive neuropsychological assessment. The [F-18]AV-1451 tracer signal was compared in the cortical grey matter between APOE4 allele carriers and non-carriers as well as carriers of MAPT H1H1 vs non-H1H1. Participants were then divided into the high (N = 13) and low (N = 13) groups based on cortical PET tau standard uptake value ratios (SUVRs) for comparison. FINDINGS: Cortical grey matter PET tau SUVR values were significantly higher in APOE4 carriers compared to non-carriers (p = 0.020). In contrast, there was no significant difference in SUVR between MAPT H1H1 vs non-H1H1 carrier genes (p = 1.00). There was a significantly higher APOE4 allele frequency in the high cortical grey matter PET tau group, comparing to low cortical grey matter PET tau group (p = 0.048). No significant difference in neuropsychological function was found between APOE4 allele carriers and non-carriers. INTERPRETATION: There is an association between higher cortical grey matter tau burden as seen with [F-18]AV-1451 PET tracer SUVR, and the APOE4 allele in former professional and semi-professional players at high risk of concussions. APOE4 allele may be a risk factor for tau accumulation in former contact sports athletes at high risk of neurodegeneration. FUNDING: Toronto General and Western Hospital Foundations; Weston Brain Institute; Canadian Consortium on Neurodegeneration in ageing; Krembil Research Institute. There was no role of the funders in this study.

Prognostic-factors for neurodegeneration in chronic moderate-to-severe traumatic brain injury: a systematic review protocol.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability. Recently, a paradigm shift in our understanding of moderate-to-severe TBI has led to its reconceptualization as a progressive neurodegenerative disorder. Widespread progressive atrophy is observed in the months and years post-injury, long after the acute effects of the injury have resolved. Some studies have begun to examine prognostic demographic, injury-related, and post-injury risk factors that contribute to these declines. A synthesis of this information, and in particular, an increased understanding of post-injury factors that may be modifiable, would improve our ability to design interventions to reduce neurodegeneration in moderate-to-severe TBI. This systematic review aims to identify prognostic factors for neural deterioration in moderate-to-severe TBI, and thereby inform future intervention research in this population. METHODS: This review protocol was informed by and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) guidelines. Search strategies (designed to identify literature on prognostic factors of neurodegeneration in adults with moderate-to-severe TBI) optimized for MEDLINE, EMBASE PsychINFO, CINAHL, SportDiscus, and Cochrane Central Register of Controlled Trials will be developed with the assistance of a health sciences librarian. Retrieved studies will be screened by two team members. Studies must report on longitudinal neuroimaging (i.e., two or more scans in the same cohort) or neuroimaging in a cross-sectional study and potential prognostic factors for neurodegeneration, such as demographics (e.g., gender, age, education), injury (e.g., severity, etiology), or post-injury characteristics (e.g., type and length of therapy, activity level, mood). DISCUSSION: By identifying prognostic factors for neurodegeneration, this systematic review can help inform injury management, as well as intervention research designed to offset the effects of modifiable prognostic factors, such as low levels of cognitive or physical activity. In turn, this systematic review can increase our understanding of how to improve outcome following moderate-to-severe TBI. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019122389.

The scale of neurodegeneration in moderate-to-severe traumatic brain injury: a systematic review protocol.

BACKGROUND: Our understanding of recovery after moderate-to-severe traumatic brain injury (TBI) has shifted. Until recently, it was presumed that following a period of acute neurological vulnerability, the brain remained stable in the chronic stages of injury. However, recent research has shown neurodegeneration in the chronic stages of moderate-to-severe TBI, challenging the assumption of neurological stability. While there is extensive evidence that neurodegeneration occurs, debate remains regarding the scale and timing. This systematic review will evaluate the scale and timelines of neurodegeneration in adult patients with moderate-to-severe TBI. METHODS: Literature searches will be conducted in six electronic databases (from inception onwards), including MEDLINE, EMBASE, PsycINFO, CINAHL, SportDiscus, and Cochrane Central Register of Controlled Trials. We will include observational studies that examine neurodegenerative changes within a single sample of TBI patients or studies that compare neuroimaging outcomes between TBI patients and healthy controls. Our primary outcome is structural neuroimaging, and our secondary outcome is diffusion tensor imaging for detection of post-injury white matter changes. All screening, data extraction, and study quality appraisal will be performed independently by the same two study members. It is expected that a narrative summary of the literature will be produced. If feasible, we will conduct a random-effects meta-analysis. However, given the expected heterogeneity between studies (with respect to, for example, timing of imaging, regions imaged) we do not expect to perform a meta-analysis; rather, a narrative synthesis of our findings is expected to be performed. DISCUSSION: Understanding the scale and timelines of neurodegeneration in moderate-to-severe TBI (as well as which brain areas are most vulnerable to chronic declines) can inform intervention research designed to offset such changes. This may help improve patient outcome following moderate-to-severe TBI and, in turn, reduce the burden of the injury. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019117548.

Comprehensive Neuropsychiatric and Cognitive Characterization of Former Professional Football Players: Implications for Neurorehabilitation.

Objectives: To identify novel targets for neurorehabilitation of people with a remote history of multiple concussions by: (1) comprehensively characterizing neuropsychiatric and cognitive functioning in former professional football players, with a focus on executive functions; (2) distinguishing concussion-related findings from pre-morbid/cohort characteristics of professional football players; and, (3) exploring the relationship between executive functions and neuropsychiatric symptoms. Participants: Sixty-one high-functioning former professional football players and 31 age- and sex-matched control participants without history of concussion or participation in contact sports. Design: Between-groups analyses. Main measures: Neuropsychiatric. Personality Assessment Inventory (PAI) clinical scales plus the Aggression treatment consideration scale; the Mini International Neuropsychiatric Interview (MINI). Cognitive. Comprehensive clinical neuropsychological battery assessing domains of verbal and visuospatial attention; speed of processing and memory; current and estimated pre-morbid IQ; and, executive functioning, including two experimental measures that were novel for this population (i.e., response inhibition and inconsistency of responding on a go/no-go task). Results: (1) Compared to control participants, former professional football players scored significantly higher on the PAI Depression, Mania, and Aggression scales, and significantly lower on response inhibition. (2) Relative to controls, former players with >3 concussions ( x ¯ = 6 . 1 ), but not former players with ≤ 3 concussions ( x ¯ = 2 . 0 ), showed (i) significantly higher scores on the PAI Depression scale, (ii) significantly more MINI clinical diagnoses overall, and manic/hypomanic episodes specifically, and (iii) significantly poorer executive function. (3) Mediation analysis revealed that concussion exposure had a significant indirect effect on PAI Depression, Mania, and Aggression via inconsistency of responding on the go/no-go task. Conclusions: Notable impairments to neuropsychiatric functioning and worse performance on a sensitive experimental measure of executive function were observed; these were related to both concussion history and pre-morbid (cohort) factors. Therefore, neuropsychiatric and executive functioning should be carefully assessed in those with a remote history of multiple concussions. Moreover, former players' neuropsychiatric symptoms were associated with inconsistency of responding; this suggests that treatments targeted at response inconsistency could help to mitigate neuropsychiatric dysfunction.

Elevated cerebrospinal fluid total tau in former professional athletes with multiple concussions.

OBJECTIVE: To identify CSF biomarkers that are related to decreased white matter (WM) integrity and poor cognitive performance in former professional athletes with a history of multiple concussions. METHODS: Concentrations of phosphorylated tau181, total tau (t-tau), and ß-amyloid in the CSF were measured in 3 groups: 22 former professional athletes with multiple concussions (mean ± SD age 55.9 ± 12.2 years), 5 healthy controls (age 57.4 ± 5.2 years), and 12 participants (age 60.0 ± 6.6 years) diagnosed with Alzheimer disease (AD). All participants in the former athletes group underwent diffusion tensor imaging to determine WM tract integrity and completed neuropsychological testing. We divided the former athletes group into those with normal (<300 pg/mL) and high (>300 pg/mL) CSF t-tau. RESULTS: CSF t-tau in the former athletes group was significantly higher than in the healthy control group (349.3 ± 182.6 vs 188.8 ± 39.9 pg/mL, p = 0.003) and significantly lower than in the patients with AD (349.3 ± 182.6 vs 857.0 ± 449.3 pg/mL, p = 0.007). Fractional anisotropy values across all the tracts were significantly lower in the high CSF t-tau group compared to the normal CSF t-tau group (p = 0.036). Participants in the high CSF t-tau group scored significantly lower on the Trail Making Test (TMT) Part B compared to the normal CSF t-tau group (t scores 45.6 ± 18.8 vs 62.3 ± 10.1, p = 0.017). CONCLUSION: Our findings indicate that former athletes with multiple concussions are at increased risk of elevated levels of CSF t-tau and that high CSF t-tau is associated with reduced WM integrity and worse scores on the TMT Part B.

The relationship between brain atrophy and cognitive-behavioural symptoms in retired Canadian football players with multiple concussions.

Multiple concussions, particularly in contact sports, have been associated with cognitive deficits, psychiatric impairment and neurodegenerative diseases like chronic traumatic encephalopathy. We used volumetric and deformation-based morphometric analyses to test the hypothesis that repeated concussions may be associated with smaller regional brain volumes, poorer cognitive performance and behavioural symptoms among former professional football players compared to healthy controls. This study included fifty-three retired Canadian Football League players, 25 age- and education-matched healthy controls, and controls from the Cambridge Centre for Aging and Neuroscience database for validation. Volumetric analyses revealed greater hippocampal atrophy than expected for age in former athletes with multiple concussions than controls and smaller left hippocampal volume was associated with poorer verbal memory performance in the former athletes. Deformation-based morphometry confirmed smaller bilateral hippocampal volume that was associated with poorer verbal memory performance in athletes. Repeated concussions may lead to greater regional atrophy than expected for age.