Sandy R. Shultz

Stroke remains a predominant cause of death and long-term disability among adults worldwide. Emerging evidence suggests that proteinopathies, characterized by the aggregation and accumulation of misfolded proteins, may play a significant role in the aftermath of stroke and the progression of neurodegenerative disorders. In this review, we explore preclinical and clinical research on key proteinopathies associated with stroke, including tau, Aβ (amyloid-β), TDP-43 (TAR DNA-binding protein 43), α-synuclein, and UCH-L1 (ubiquitin C-terminal hydrolase-L1). We focus on their potential as biomarkers for recovery management and as novel treatment targets that may enhance neuronal repair and mitigate secondary neurodegeneration. The involvement of these proteinopathies in various aspects of stroke, including neuroinflammation, oxidative stress, neuronal damage, and vascular dysfunction, underscores their potential. However, further investigations are essential to validate the clinical utility of these biomarkers, elucidate the mechanisms connecting proteinopathies to poststroke neurodegeneration, and develop targeted interventions. Identifying specific protein signatures associated with stroke outcomes could facilitate the advancement of precision medicine tailored to individual patient needs, significantly enhancing the quality of life for stroke survivors.

Mild traumatic brain injuries (mTBIs) are caused by biomechanical forces being transmitted to the brain, causing neuronal connections to be subjected to sheering forces. The injury severity can be affected by a number of factors that include age and sex, however, there remains a paucity of data on how repeated mTBI (r-mTBI) impacts the female brain. In these studies, male and female juvenile rats [postnatal day (PND) 25-26] were administered a total of eight mTBIs over a 2-day period. Following each mTBI, rats were immediately assessed for acute neurological impairment. After eight mTBIs were completed, the Barnes maze was used to assess spatial learning and memory. Axonal injury was assessed using silver stain histological analyses. We found that injured females exhibited less acute neurological impairment than males. Three days after the final r-mTBI, no significant differences were observed in spatial learning and memory, with all animals showing similar times to locate the escape platform on the reversal trial, additionally there was no main effect of sex in the Barnes maze. Silver stain uptake was significantly increased in the optic tract, corpus callosum, and cortex compared with sham animals at seven days postinjury in a sex-specific manner. Females showed significant increase in all three regions following r-mTBI, whereas males only showed a significant increase in staining in the optic tract. Overall, these findings show that females may be more susceptible to axonal damage than males, and that cognitive deficits were not evident in this population following r-mTBI. These results indicate that there may be benefits in examining biomarkers that reflect axonal injury and the therapies that target reducing axonal degradation.NEW & NOTEWORTHY Diffuse axonal injury is a hallmark feature of all severities of traumatic brain injury (TBI) yet, in preclinical mild (m)TBI research no studies have yet investigated axonal damage with silver stain immunohistochemistry in female animals. This is a critical gap in the literature as recent studies suggest that females experience mTBI more frequently than males. We found that repeated mTBI (r-mTBI) caused significant diffuse axonal injury that was more pronounced in females compared with males.

Objective: Previous studies on sport-related concussion (SRC) may have measured brain injury blood-based biomarker, glial fibrillary acidic protein (GFAP), either before or after its peak, potentially underestimating the diagnostic value. The primary aim of this study was to evaluate the diagnostic performance of serum GFAP at 24 hours post-SRC. Secondary objectives included assessing whether the timing of sample collection relative to an Australian football match (with or without SRC) affected GFAP levels, evaluating if combining GFAP with symptoms improved discrimination of SRC compared with symptoms alone, and determining the diagnostic utility of serum neurofilament light (NfL) levels at 24 hours post-SRC. Methods: In a prospective cohort study, adult male and female Australian football players of the Victorian Amateur Football Association (Melbourne, Australia) with and without SRC had blood sampled around 24 hours postinjury/postmatch. GFAP and NfL levels were quantified using Simoa assays, and area under the curve (AUC) values were calculated for time bins of 16-24 hours, 24-32 hours, and 36-52 hours. Symptom severity at blood collection was assessed using the Sport Concussion Assessment Tool 5 (SCAT). Results: A total of 151 athletes with SRC (median age 22.5 years; 85% male) and 97 controls (median age 24.3 years; 86% male) were sampled at a median of 24.5 hours (interquartile range [IQR] 21.7-28.0; min-max 16-51.5). Time to sample postmatch did not affect GFAP levels in controls; however, higher GFAP levels correlated with shorter time post-SRC (Spearman r = -0.25, 95% CI -0.40 to -0.09). Median GFAP concentrations were 65.9 pg/mL (IQR 49.1-81.3) in controls, and for SRC, 124.6 pg/mL (IQR 86.7-190.7) at 16-24 hours, 94.5 pg/mL (IQR 61.6-163.9) at 24-32 hours, and 59.9 pg/mL (IQR 49.1-94.7) at 36-52 hours. AUC values at 16-24 and 24-32 hours were 0.83 (95% CI 0.76-0.90) and 0.72 (95% CI 0.64-0.80), respectively. Furthermore, combining GFAP with SCAT symptoms at 16-24 hours enhanced discriminatory capability compared with SCAT symptoms alone (AUC increased from 0.91 to 0.97; z = 2.48, p = 0.01). Serum NfL had a limited diagnostic value (AUC ≤0.60). Conclusions: Serum GFAP measured at 16-24 hours following potential or suspected SRC may be a useful objective aid to SRC diagnosis.

Adverse childhood experiences (ACEs) alter brain development, leading to vulnerability for chronic pain, mental health disorders, and suicidality. These effects often emerge during adolescence. Importantly, ACEs can occur prenatally, including when exposed to in utero intimate partner violence (IPV) or postnatally as maternal neglect. Maternal social support has demonstrated promise in the mitigation of ACE-related deficits. Oxytocin, which has a role in social-bonding and stress regulation, serves as a suitable surrogate for social support in preclinical studies. Therefore, we aimed to explore the effects of oxytocin on alleviating social deficits, nociception, and epigenetic changes resulting from models that aimed to mimic the stress normally induced following exposure to two ACEs: IPV in utero and maternal neglect. During pregnancy, dams were randomly assigned to experience the model of IPV or a sham insult. Following birth, offspring from the IPV group underwent 10 days of maternal separation. Dams received three days of oxytocin therapy while nursing. In adolescence, half of the offspring underwent a plantar surgery to induce pain. Overall, in adolescence, rats exposed to the ACEs exhibited increased nociceptive sensitivity and aberrant social interactions, particularly among males, further suggesting that ACEs can increase an individual's risk for chronic pain. The ACEs changed gene expression related to social behaviour and neuroplasticity. Maternal oxytocin normalized pain, social, and gene changes, while oxytocin levels in offspring correlated with nociceptive sensitivity. Although ACEs have enduring consequences, the outcomes are modifiable, and oxytocin may be a robust and implementable therapeutic capable of attenuating early adversity.

Background: Advances in instrumented mouthguards (iMGs) allow for accurate quantification of single high-acceleration head impacts and cumulative head acceleration exposure in collision sports. However, relationships between these measures and risk of brain cell injury remain unclear. Objective: The purpose of this study was to quantify measures of non-concussive head impact exposure and assess their association with blood glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated-tau-181 (p-tau-181) levels in male Australian football players. Methods: A total of 31 athletes underwent in-season (24 h post-match) and post-season (> 5 weeks) blood collections and/or wore HITIQ Nexus A9 iMGs measuring peak linear (PLA) and rotational (PRA) acceleration. Match footage was used to verify and code impacts. Blood GFAP, NfL, and p-tau-181 were quantified using Simoa and natural log transformed for analysis. Associations between post-match biomarkers and within match maximum single impact and cumulative PLA/PRA were assessed with linear mixed models. Results: In-season versus post-season elevations were found for GFAP (mean difference 0.14, 95% CI 0.01-0.26, p = 0.033), NfL (mean difference = 0.21, 95% CI 0.09-0.32, p = 0.001) and p-tau-181 (mean difference = 0.49, 95% CI 0.33-0.65, p < 0.001). Post-match GFAP was associated with maximum single impact PLA (B = 0.003, 95% CI 0.0002-0.005, p = 0.036), cumulative PLA (B = 0.001, 95% CI 0.0002-0.002, p = 0.017), cumulative PRA (B = 0.01, 95% CI 0.002-0.02, p = 0.014), and impact number (B = 0.03, 95% CI 0.003-0.05, p = 0.029) within a single match. Change in NfL levels between two-matches correlated with cumulative PLA (r = 0.80, 95% CI 0.38-0.95, p = 0.005), PRA (r = 0.71, 95% CI 0.19-0.92, p = 0.019) and impact number (r = 0.63, 95% CI 0.05-0.89, p = 0.038). Conclusions: Maximum and cumulative head accelerations in Australian football, measured by iMGs, were associated with elevated blood biomarkers of brain injury, highlighting the potential of both technologies for head impact management in collision sports.