Single nucleotide polymorphisms in aquaporin-4 associate with cognitive impairment status in people with HIV.

Neurocognitive impairments are more frequent in people with HIV (PWH) compared to their uninfected counterparts. HIV-associated neurocognitive disorder (HAND) is a spectrum disorder and up to 50% of PWH are reported to suffer from HAND. Altered waste clearance from the brain, chronic neuroinflammation and impaired metabolic processes may contribute to abnormal aging in PWH and are more common among those who suffer from HAND. Thus, it is important to identify earlier predictors for development of HAND. A key contributor to cognitive impairment in HIV and in Alzheimer's disease (AD) is formation and accumulation of aberrant proteins including hyperphosphorylated Tau (pTau). Previous data from AD and traumatic brain injury studies report that impaired waste clearance from the brain contributes in part to cognitive impairments. Evidence suggests that the aquaporin 4 (aqp4) gene may have an important role in waste clearance from the brain as single nucleotide polymorphisms (SNPs) in aqp4 have been reported to associate with changes in cognitive decline in AD patients. Given some similarities between HAND and AD, we assessed potential associations of several aqp4 SNPS with cognitive impairment in PWH. Our data show that homozygous carriers of the minor allele in SNPs rs3875089 and rs3763040 had significantly lower neuropsychological test Z-scores in multiple domains compared to the other genotypes. Interestingly, this decrease in Z-scores was only observed in PWH and not in HIV-control participants. Conversely, homozygosity of the minor allele of rs335929 associated with better executive function in PWH. Based on these data, tracking large cohorts of PWH to determine if the presence of these SNPs associate with cognitive changes during disease progression is of interest. Furthermore, screening PWH for SNPs that may be associated with cognitive impairment risk after diagnosis could be considered in alignment with traditional treatment plans to potentially work on skills in areas shown to have cognitive decline with these SNPs present.

Sex Differences in Neck Strength Force and Activation Patterns in Collegiate Contact Sport.

The purpose of this study was to assess changes in cervical musculature throughout contact-heavy collegiate ice hockey practices during a regular season of NCAA Division III ice hockey teams. In this cross-sectional study, 36 (male n = 13; female n = 23) ice hockey players participated. Data were collected over 3 testing sessions (baseline; pre-practice; post-practice). Neck circumference, neck length, head-neck segment length, isometric strength and electromyography (EMG) activity for flexion and extension were assessed. Assessments were completed approximately 1h before a contact-heavy practice and 15 min after practice. For sternocleidomastoid (SCM) muscles, males had significantly greater peak force and greater time to peak force versus females. For both left and right SCMs, both sexes had significantly greater peak EMG activity pre-practice versus baseline, and right (dominant side) SCM time to peak EMG activity was decreased post-practice compared to pre-practice. There were no significant differences for EMG activity of the upper trapezius musculature, over time or between sexes. Sex differences observed in SCM force and activation patterns of the dominant side SCM may contribute to head stabilization during head impacts. Our study is the first investigation to report changes in cervical muscle strength in men's and women's ice hockey players in the practical setting.

Viruses, SUMO, and immunity: the interplay between viruses and the host SUMOylation system.

The conjugation of small ubiquitin-like modifier (SUMO) proteins to substrates is a well-described post-translational modification that regulates protein activity, subcellular localization, and protein-protein interactions for a variety of downstream cellular activities. Several studies describe SUMOylation as an essential post-translational modification for successful viral infection across a broad range of viruses, including RNA and DNA viruses, both enveloped and un-enveloped. These viruses include but are not limited to herpes viruses, human immunodeficiency virus-1, and coronaviruses. In addition to the SUMOylation of viral proteins during infection, evidence shows that viruses manipulate the SUMO pathway for host protein SUMOylation. SUMOylation of host and viral proteins greatly impacts host innate immunity through viral manipulation of the host SUMOylation machinery to promote viral replication and pathogenesis. Other post-translational modifications like phosphorylation can also modulate SUMO function. For example, phosphorylation of COUP-TF interacting protein 2 (CTIP2) leads to its SUMOylation and subsequent proteasomal degradation. The SUMOylation of CTIP2 and subsequent degradation prevents CTIP2-mediated recruitment of a multi-enzymatic complex to the HIV-1 promoter that usually prevents the transcription of integrated viral DNA. Thus, the "SUMO switch" could have implications for CTIP2-mediated transcriptional repression of HIV-1 in latency and viral persistence. In this review, we describe the consequences of SUMO in innate immunity and then focus on the various ways that viral pathogens have evolved to hijack the conserved SUMO machinery. Increased understanding of the many roles of SUMOylation in viral infections can lead to novel insight into the regulation of viral pathogenesis with the potential to uncover new targets for antiviral therapies.

Mitochondrial quality control in cardiac cells: Mechanisms and role in cardiac cell injury and disease.

Mitochondria play an important role in maintaining cardiac homeostasis by supplying the major energy required for cardiac excitation-contraction coupling as well as controlling the key intracellular survival and death pathways. Healthy mitochondria generate ATP molecules through an aerobic process known as oxidative phosphorylation (OXPHOS). Mitochondrial injury during myocardial infarction (MI) impairs OXPHOS and results in the excessive production of reactive oxygen species (ROS), bioenergetic insufficiency, and contributes to the development of cardiovascular diseases. Therefore, mitochondrial biogenesis along with proper mitochondrial quality control machinery, which removes unhealthy mitochondria is pivotal for mitochondrial homeostasis and cardiac health. Upon damage to the mitochondrial network, mitochondrial quality control components are recruited to segregate the unhealthy mitochondria and target aberrant mitochondrial proteins for degradation and elimination. Impairment of mitochondrial quality control and accumulation of abnormal mitochondria have been reported in the pathogenesis of various cardiac disorders and heart failure. Here, we provide an overview of the recent studies describing various mechanistic pathways underlying mitochondrial homeostasis with the main focus on cardiac cells. In addition, this review demonstrates the potential effects of mitochondrial quality control dysregulation in the development of cardiovascular disease.

Astrocyte activation and altered metabolism in normal aging, age-related CNS diseases, and HAND.

Astrocytes regulate local cerebral blood flow, maintain ion and neurotransmitter homeostasis, provide metabolic support, regulate synaptic activity, and respond to brain injury, insults, and infection. Because of their abundance, extensive connectivity, and multiple roles in the brain, astrocytes are intimately involved in normal functioning of the CNS and their dysregulation can lead to neuronal dysfunction. In normal aging, decreased biological functioning and reduced cognitive abilities are commonly experienced in individuals free of overt neurological disease. Moreover, in several age-related CNS diseases, chronic inflammation and altered metabolism have been reported. Since people with HIV (PWH) are reported to experience rapid aging with chronic inflammation, altered brain metabolism is likely to be exacerbated. In fact, many studies report altered metabolism in astrocytes in diseases such as Alzheimer's, Parkinson's, and HIV. This review will address the roles of astrocyte activation and altered metabolism in normal aging, in age-related CNS disease, and in HIV-associated neurocognitive disorders.

NFL blood levels are moderated by subconcussive impacts in a cohort of college football players.

INTRODUCTION: Repetitive subconcussive head impacts in contact/collision sports such as in US football are believed to contribute to long-term brain changes and chronic symptoms. However, the lack of tools to measure the effects of repeated subconcussion limits our understanding of potential contributions to neuropathological alterations including cellular damage. METHODS: We examined subconcussive head impacts using an accelerometer-embedded mouthguard on changes in blood levels of neurofilament light (NFL) chain in 18 Division I college football players. Plasma levels of NFL and clinical symptoms were assessed at pre-post practices. The frequency and linear and rotational head accelerations recorded via the mouthguard were examined in relation to NFL plasma changes. RESULTS: The frequency and magnitude of head impacts associated with increased NFL levels. The greater numbers of hits and head accelerations associated with greater pre- to post-practice NFL level increases (p < 0.05). Greater pre- to post-practice increases in NFL also associated with greater pre- to post-practice increases in S100ß (p < 0.001), but not with total tau. Years of football experience and concussion history did not associate with changes in NFL. CONCLUSION: Acute changes in NFL may be a clinically useful peripheral marker in tracking acute brain damage in collegiate football players, and other contact sports.

Network analysis of hippocampal neurons by microelectrode array in the presence of HIV-1 Tat and cocaine.

HIV-associated neurocognitive disorders affecting greater than 30% of patients are caused by HIV-1 infection of the CNS, and in part, include neurotoxic effects of the viral transactivator of transcription, Tat protein. In addition to increasing the risk for becoming HIV infected, cocaine abuse enhances the neuropathogenic impacts of HIV-1. To investigate the outcome of Tat and cocaine interference in the hippocampal neuronal network, cross-rank-corrlation was employed to develop a systematic framework to assess hippocampal neurons behavior cultured on multielectrode arrays. Tat and cocaine differentially disturbed neuronal spiking rates, amplitude, synchronous activity, and oscillations within the hippocampal neuronal network via potentiation of inhibitory neurotransmission. The Tat-mediated impairment of neuronal spiking was reversible by removal of Tat, which restored neuronal activity. The presence of astrocytes co-cultured with neuronal networks diminished the effects of Tat and cocaine on neuron function suggesting a role for astrocytes in stabilizing neuronal behavior and increasing neuronal spontaneous activities such as bursting amplitude, frequency, and wave propagation rate. Taken together, our studies indicate that the HIV protein Tat and cocaine impair hippocampal neuronal network functioning and that the presence of astrocytes alleviates network dysfunction pointing to a newly discovered pathway through which ionic homeostasis is maintained by neuron-glial crosstalk in the CNS.

Cocaine and HIV-1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV-associated neurocognitive disorders in cocaine user patients.

Cholesterol synthesis and clearance by astrocytes are tightly regulated to maintain constant levels within the brain. In this context, liver X receptors (LXRs) are the master regulators of cholesterol homeostasis in the central nervous system (CNS). Increasing levels of cholesterol in astrocytes trigger LXR activation leading to the transcription of target genes involved in cholesterol trafficking and efflux, including apolipoprotein E, cytochrome P450 enzymes, sterol regulatory binding protein, and several ATP-binding cassette transporter proteins. The disturbance of LXR signaling in the brain can lead to significant dysfunctions in cholesterol homeostasis, and disruptions in this pathway have been implicated in numerous neurological diseases including Alzheimer's disease and Huntington's disease. HIV infection of the CNS in combination with cocaine use is associated with astrocyte and neuronal energy deficit and damage. We propose that dysregulation in CNS cholesterol metabolism may be involved in the progression of HIV-associated neurocognitive disorders (HAND) and in cocaine-mediated neurocognitive impairments. We hypothesize that exposure of astrocytes to cocaine and the HIV protein Tat will disrupt LXR signaling. Alterations in these pathways will in turn, affect cholesterol bioavailability for neurons. Our data show that exposure of astrocytes to cocaine and HIV-Tat significantly decreases LXRß levels, downstream signaling and bioavailability of cholesterol. Taken together, these data uncover novel alterations in a bioenergetic pathway in astrocytes exposed to cocaine and the HIV protein Tat. Results from these studies point to a new pathway in the CNS that may contribute to HAND in HIV+ cocaine user individuals.

Cocaine-mediated activation of microglia and microglial MeCP2 and BDNF production.

The molecular substrates underlying cocaine reinforcement and addiction have been studied for decades, with a primary focus on signaling molecules involved in modulation of neuronal communication. Brain-derived neurotrophic factor (BDNF) is an important signaling molecule involved in neuronal dendrite and spine modulation. Methyl CpG binding protein 2 (MeCP2) binds to the promoter region of BDNF to negatively regulate its expression and cocaine can recruit MeCP2 to alter the expression of genes such as BDNF that are involved in synaptic plasticity. For several decades, BDNF has been implicated in mediating synaptic plasticity associated with cocaine abuse, and most studies report that neurons are the primary source for BDNF production in the brain. The current study assessed the effects of intravenous cocaine self-administration on microglial activation, and MeCP2 and BDNF expression in reward regions of the brain in vivo, as well as determined specific effects of cocaine exposure on MeCP2 and BDNF expression in human primary neurons and microglia. The results from this study highlight a distinct molecular pathway in microglia through which cocaine increases BDNF, including the phosphorylation of MeCP2 its subsequent translocation from the nucleus to the cytosol, which frees the BDNF promoter and permits its transcriptional activation. Results from these studies show for the first time that cocaine self-administration increases microglial activation, and that microglial MeCP2 is a sensitive target of cocaine resulting in increased release of BDNF from microglia, and possibly contributing to cocaine-induced synaptic plasticity.

Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model.

HIV-1 Tat is known to be neurotoxic and important for HIV/neuroAIDS pathogenesis. However, the overwhelming majority of the studies involved use of recombinant Tat protein. To understand the contributions of Tat protein to HIV/neuroAIDS and the underlying molecular mechanisms of HIV-1 Tat neurotoxicity in the context of a whole organism and independently of HIV-1 infection, a doxycycline-inducible astrocyte-specific HIV-1 Tat transgenic mouse (iTat) was created. Tat expression in the brains of iTat mice was determined to be in the range of 1-5 ng/ml and led to astrocytosis, loss of neuronal dendrites, and neuroinflammation. iTat mice have allowed us to define the direct effects of Tat on astrocytes and the molecular mechanisms of Tat-induced GFAP expression/astrocytosis, astrocyte-mediated Tat neurotoxicity, Tat-impaired neurogenesis, Tat-induced loss of neuronal integrity, and exosome-associated Tat release and uptake. In this review, we will provide an overview about the creation and characterization of this model and its utilities for our understanding of Tat neurotoxicity and the underlying molecular mechanisms.

Kaposi's Sarcoma-Associated Herpesvirus Infection of Neurons in HIV-Positive Patients.

Background: Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), one of the leading cancers in human immunodeficiency virus (HIV)-infected patients in Zambia. KSHV was detected in the human central nervous system (CNS) by polymerase chain reaction (PCR) analysis, but tissue location and cell tropism for KSHV infection has not been established. Given the neurotropism exhibited by other herpesviruses and the frequent coinfection of HIV-positive individuals by KSHV, we sought to determine whether the central nervous system (CNS) can be infected by KSHV in HIV-positive Zambian individuals. Methods: Postmortem brain tissue specimens were collected from individuals coinfected with KSHV and HIV. PCR and Southern blots were performed on DNA extracted from the brain tissue specimens to verify KSHV infection. Immunohistochemical analysis and immunofluorescent microscopy were used to localize and identify KSHV-infected cells. Tropism was further established by in vitro infection of primary human neurons with rKSHV.219. Results: KSHV DNA was detected in the CNS from 4 of 11 HIV-positive individuals. Immunohistochemical analysis and immunofluorescent microscopy demonstrated that KSHV infected neurons and oligodendrocytes in parenchymal brain tissues. KSHV infection of neurons was confirmed by in vitro infection of primary human neurons with rKSHV.219. Conclusion: Our study showed that KSHV infects human CNS-resident cells, primarily neurons, in HIV-positive Zambian individuals.

Regulation and Functional Implications of Opioid Receptor Splicing in Opioid Pharmacology and HIV Pathogenesis.

Despite the identification and characterization of four opioid receptor subtypes and the genes from which they are encoded, pharmacological data does not conform to the predications of a four opioid receptor model. Instead, current studies of opioid pharmacology suggest the existence of additional receptor subtypes; however, no additional opioid receptor subtype has been identified to date. It is now understood that this discrepancy is due to the generation of multiple isoforms of opioid receptor subtypes. While several mechanisms are utilized to generate these isoforms, the primary mechanism involves alternative splicing of the pre-mRNA transcript. Extensive alternative splicing patterns for opioid receptors have since been identified and discrepancies in opioid pharmacology are now partially attributed to variable expression of these isoforms. Recent studies have been successful in characterizing the localization of these isoforms as well as their specificity in ligand binding; however, the regulation of opioid receptor splicing specificity is poorly characterized. Furthermore, the functional significance of individual receptor isoforms and the extent to which opioid- and/or HIV-mediated changes in the opioid receptor isoform profile contributes to altered opioid pharmacology or the well-known physiological role of opioids in the exacerbation of HIV neurocognitive dysfunction is unknown. As such, the current review details constitutive splicing mechanisms as well as the specific architecture of opioid receptor genes, transcripts, and receptors in order to highlight the current understanding of opioid receptor isoforms, potential mechanisms of their regulation and signaling, and their functional significance in both opioid pharmacology and HIV-associated neuropathology.

Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice.

The ß-lactam antibiotic ceftriaxone (CTX) reduces cocaine reinforcement and relapse in preclinical assays through a mechanism involving activation of glutamate transporter subtype 1 (GLT-1). However, its poor brain penetrability and intravenous administration route may limit its therapeutic utility for indications related to CNS diseases. An alternative is clavulanic acid (CA), a structural analog of CTX that retains the ß-lactam core required for GLT-1 activity but displays enhanced brain penetrability and oral activity relative to CTX. Here, we tested the hypothesis that CA (1, 10 mg/kg ip) would enhance GLT-1 expression and decrease cocaine self-administration (SA) in mice, but at lower doses than CTX. Experiments revealed that GLT-1 transporter expression in the nucleus accumbens of mice treated with repeated CA (1, 10 mg/kg) was enhanced relative to saline-treated mice. Repeated CA treatment (1 mg/kg) reduced the reinforcing efficacy of cocaine (0.56 mg/kg/inf) in mice maintained on a progressive-ratio (PR) schedule of reinforcement but did not affect acquisition of cocaine SA under fixed-ratio responding or acquisition or retention of learning. These findings suggest that the ß-lactamase inhibitor CA can activate the cellular glutamate reuptake system in the brain reward circuit and reduce cocaine's reinforcing efficacy at 100-fold lower doses than CTX.

HIV-infected microglia mediate cathepsin B-induced neurotoxicity.

HIV-1-infected mononuclear phagocytes release soluble factors that affect the homeostasis in tissue. HIV-1 can prompt metabolic encephalopathy with the addition of neuronal dysfunction and apoptosis. Recently, we reported that HIV-1 enhances the expression and secretion of bioactive cathepsin B in monocyte-derived macrophages, ultimately contributing to neuronal apoptosis. In this research, we asked if microglia respond to HIV infection similarly by modifying the expression, secretion, and neurotoxic potential of cathepsin B and determined the in vivo relevance of these findings. HIV-1ADA-infected human primary microglia and CHME-5 microglia cell line were assessed for expression and activity of cathepsin B, its inhibitors, cystatins B and C, and the neurotoxicity associated with these changes. Human primary neurons were exposed to supernatants from HIV-infected and uninfected microglia in the presence of cathepsin B inhibitors and apoptosis was assessed by TUNEL. Microglial expression of cathepsin B was validated in brain tissue from HIV encephalitis (HIVE) patients. HIV-infected microglia secreted significantly greater levels of cathepsin B, cystatin B, and cystatin C compared to uninfected cells. Increased apoptosis was observed in neurons exposed to supernatants from HIV-1 infected microglia at day 12 post-infection. The cathepsin B inhibitor CA-074 and cathepsin B antibody prevented neuronal apoptosis. Increased microglia-derived cathepsin B, cystatin B, and cystatin C and caspase-3+ neurons were detected in HIVE brains compared to controls. Our results suggest that HIV-1-induced cathepsin B production in microglia contributes to neuronal apoptosis and may be an important factor in neuronal death associated with HIVE.

Changes in PINCH levels in the CSF of HIV+ individuals correlate with hpTau and CD4 count.

Several studies report associations between the particularly interesting new cysteine histidine-rich (PINCH) protein and HIV-associated CNS disease. PINCH is detected in the CSF of HIV patients, and changes in levels during disease may be indicative of changes in disease status over time. PINCH binds hyperphosphorylated Tau (hpTau) in the brain and CSF, but little is known about the relevance of these interactions to HIV CNS disease. In this study, PINCH and hpTau levels were assessed in three separate CSF samples collected longitudinally from 20 HIV+ participants before and after initiating antiretroviral therapy or before and after a change in the treatment regimen. The intervals were approximately 1 (T2) and 3-7 (T3) months from the initial visit (baseline, T1). Correlational analyses were conducted for CSF levels of PINCH and hpTau and other variables including blood CD4 T-cell count, plasma and CSF viral burden, CSF neopterin, white blood cell (WBC) count, and antiretroviral CNS penetration effectiveness (CPE). Values for PINCH and hpTau were determined for each patient by calculating the fold changes between the second (T2) and third measurements (T3) from the baseline measurement (T1). Statistical analyses showed that the fold changes in CSF PINCH protein from T1 to T2 were significantly higher in participants with CD4 counts >200 cells/mm(3) at T2 compared to those with CD4 counts <200 cells/mm(3) at T2. This trend persisted irrespective of plasma or CSF viral burden or antiretroviral therapy CPE scores. The fold changes in PINCH levels between T1 and T2, and T1 and T3 were highly correlated to the fold changes in hpTau at T2/T1 and T3/T1 (correlation coefficient = 0.69, p < 0.001; correlation coefficient = 0.83, p < 0.0001, respectively). In conclusion, in these HIV participants, changes in CSF levels of PINCH appear to correlate with changes in blood CD4 count and with changes in CSF hpTau levels, but not with plasma or CSF viral burden, neopterin, WBC, or antiretroviral regimen CPE.

Relationships between plasma neurofilament light chain protein, cognition, and brain aging in people with HIV.

OBJECTIVE: Neurofilament light chain protein (NfL) is a marker of neuronal injury and neurodegeneration. Typically assessed in cerebrospinal fluid, recent advances have allowed this biomarker to be more easily measured in plasma. This study assesses plasma NfL in people with HIV (PWH) compared with people without HIV (PWoH), and its relationship with cognitive impairment, cardiovascular risk, and a neuroimaging metric of brain aging [brain-age gap (BAG)]. DESIGN: One hundred and four PWH (HIV RNA <50 copies/ml) and 42 PWoH provided blood samples and completed a cardiovascular risk score calculator, neuroimaging, and cognitive testing. METHOD: Plasma NfL was compared between PWoH and PWH and assessed for relationships with age, HIV clinical markers, cardiovascular disease risk, cognition, and BAG (difference between a brain-predicted age and chronological age). RESULTS: Plasma NfL was not significantly different between PWoH and PWH. Higher NfL related to increasing age in both groups. Plasma NfL was not associated with typical HIV disease variables. Within PWH, NfL was higher with higher cardiovascular risk, cognitive impairment and a greater BAG. CONCLUSION: Virally suppressed PWH who are cognitively normal likely do not have significant ongoing neurodegeneration, as evidenced by similar plasma NfL compared with PWoH. However, NfL may represent a biomarker of cognitive impairment and brain aging in PWH. Further research examining NfL with longitudinal cognitive decline is needed to understand this relationship more fully.

Mechanisms of Injury Leading to Concussions in Collegiate Soccer Players: A CARE Consortium Study.

BACKGROUND: Few previous studies have investigated how different injury mechanisms leading to sport-related concussion (SRC) in soccer may affect outcomes. PURPOSE: To describe injury mechanisms and evaluate injury mechanisms as predictors of symptom severity, return to play (RTP) initiation, and unrestricted RTP (URTP) in a cohort of collegiate soccer players. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: The Concussion Assessment, Research and Education (CARE) Consortium database was used. The mechanism of injury was categorized into head-to-ball, head-to-head, head-to-body, and head-to-ground/equipment. Baseline/acute injury characteristics-including Sports Concussion Assessment Tool-3 total symptom severity (TSS), loss of consciousness (LOC), and altered mental status (AMS); descriptive data; and recovery (RTP and URTP)-were compared. Multivariable regression and Weibull models were used to assess the predictive value of the mechanism of injury on TSS and RTP/URTP, respectively. RESULTS: Among 391 soccer SRCs, 32.7% were attributed to a head-to-ball mechanism, 27.9% to a head-to-body mechanism, 21.7% to a head-to-head mechanism, and 17.6% to a head-to-ground/equipment mechanism. Event type was significantly associated with injury mechanism [χ2(3) = 63; P < .001), such that more head-to-ball concussions occurred in practice sessions (n = 92 [51.1%] vs n = 36 [17.1%]) and more head-to-head (n = 65 [30.8%] vs n = 20 [11.1]) and head-to-body (n = 76 [36%] vs n = 33 [18.3%]) concussions occurred in competition. The primary position was significantly associated with injury mechanism [χ2(3) = 24; P < .004], with goalkeepers having no SRCs from the head-to-head mechanism (n = 0 [0%]) and forward players having the least head-to-body mechanism (n = 15 [19.2%]). LOC was also associated with injury mechanism (P = .034), with LOC being most prevalent in head-to-ground/equipment. Finally, AMS was most prevalent in head-to-ball (n = 54 [34.2%]) and head-to-body (n = 48 [30.4%]) mechanisms [χ2(3) = 9; P = .029]. In our multivariable models, the mechanism was not a predictor of TSS or RTP; however, it was associated with URTP (P = .044), with head-to-equipment/ground injuries resulting in the shortest mean number of days (14 ± 9.1 days) to URTP and the head-to-ball mechanism the longest (18.6 ± 21.6 days). CONCLUSION: The mechanism of injury differed by event type and primary position, and LOC and AMS were different across mechanisms. Even though the mechanism of injury was not a significant predictor of acute symptom burden or time until RTP initiation, those with head-to-equipment/ground injuries spent the shortest time until URTP, and those with head-to-ball injuries had the longest time until URTP.

Cocaine-induced loss of white matter proteins in the adult mouse nucleus accumbens is attenuated by administration of a ß-lactam antibiotic during cocaine withdrawal.

We report significantly decreased white matter protein levels in the nucleus accumbens in an adult mouse model of chronic cocaine abuse. Previous studies from human cocaine abuse patients show disruption of white matter and myelin loss, thus supporting our observations. Understanding the neuropathological mechanisms for white matter disruption in cocaine abuse patients is complicated by polydrug use and other comorbid factors, hindering the development of effective therapeutic strategies to ameliorate damage or compliment rehabilitation programs. In this context, our data further demonstrate that cocaine-induced loss of white matter proteins is absent in mice treated with the ß-lactam antibiotic, ceftriaxone, during cocaine withdrawal. Other studies report that ceftriaxone, a glutamate transporter subtype-1 activator, is neuroprotective in murine models of multiple sclerosis, thereby demonstrating potential therapeutic properties for diseases with white matter loss. Cocaine-induced white matter abnormalities likely contribute to the cognitive, motor, and psychological deficits commonly afflicting cocaine abusers, yet the underlying mechanisms responsible for these changes remain unknown. Our observations describe an adult animal model for the study of cocaine-induced myelin loss for the first time, and highlight a potential pharmacological intervention to ameliorate cocaine-induced white matter loss.

Concussions in young adult athletes: No effect on cerebral white matter.

Introduction: The media's recent focus on possible negative health outcomes following sports- related concussion has increased awareness as well as anxiety among parents and athletes. However, the literature on concussion outcomes is equivocal and limited by a variety of diagnostic approaches. Methods: The current study used a rigorous, open- access concussion identification method-the Ohio State University Traumatic Brain Injury Identification method (OSU TBI-ID) to identify concussion and periods of repeated, subclinical head trauma in 108 young adult athletes who also underwent a comprehensive protocol of cognitive tests, mood/anxiety questionnaires, and high-angular-resolution diffusion-weighted brain imaging to evaluate potential changes in white matter microstructure. Results: Analyses showed that athletes with a history of repetitive, subclinical impacts to the head performed slightly worse on a measure of inhibitory impulse control and had more anxiety symptoms compared to those who never sustained any type of head injury but were otherwise the same as athletes with no history of concussion. Importantly, there were no group differences in cerebral white matter as measured by tract- based spatial statistics (TBSS), nor were there any associations between OSU TBI-ID measures and whole-brain principal scalars and free-water corrected scalars. Discussion: Our results provide support for the hypothesis that it is not concussion per se, but repetitive head impacts that beget worse outcomes.

Optimizing Concussion Care Seeking: A Longitudinal Analysis of Recovery.

BACKGROUND: Approximately half of concussions go undisclosed and therefore undiagnosed. Among diagnosed concussions, 51% to 64% receive delayed medical care. Understanding the influence of undiagnosed concussions and delayed medical care would inform medical and education practices. PURPOSE: To compare postconcussion longitudinal clinical outcomes among (1) individuals with no concussion history, all previous concussions diagnosed, and ≥1 previous concussion undiagnosed, as well as (2) those who have delayed versus immediate symptom onset, symptom reporting, and removal from activity after concussion. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Participants included 2758 military academy cadets and intercollegiate athletes diagnosed with concussion in the CARE Consortium. We determined (1) each participant's previous concussion diagnosis status self-reported at baseline (no history, all diagnosed, ≥1 undiagnosed) and (2) whether the participant had delayed or immediate symptom onset, symptom reporting, and removal from activity. We compared symptom severities, cognition, balance, and recovery duration at baseline, 24 to 48 hours, date of asymptomatic status, and date of unrestricted return to activity using tests of parallel profiles. RESULTS: The ≥1 undiagnosed concussion group had higher baseline symptom burdens (P < .001) than the other 2 groups and poorer baseline verbal memory performance (P = .001) than the all diagnosed group; however, they became asymptomatic and returned to activity sooner than those with no history. Cadets/athletes who delayed symptom reporting had higher symptom burdens 24 to 48 hours after injury (mean ± SE; delayed, 28.8 ± 0.8; immediate, 20.6 ± 0.7), took a median difference of 2 days longer to become asymptomatic, and took 3 days longer to return to activity than those who had immediate symptom reporting. For every 30 minutes of continued participation after injury, days to asymptomatic status increased 8.1% (95% CI, 0.3%-16.4%). CONCLUSION: Clinicians should expect that cadets/athletes who delay reporting concussion symptoms will have acutely higher symptom burdens and take 2 days longer to become asymptomatic. Educational messaging should emphasize the clinical benefits of seeking immediate care for concussion-like symptoms.