Return of intracranial beta oscillations and traveling waves with recovery from traumatic brain injury.

Traumatic brain injury (TBI) remains a pervasive clinical problem associated with significant morbidity and mortality. However, TBI remains clinically and biophysically ill-defined, and prognosis remains difficult even with the standardization of clinical guidelines and advent of multimodality monitoring. Here we leverage a unique data set from TBI patients implanted with either intracranial strip electrodes during craniotomy or quad-lumen intracranial bolts with depth electrodes as part of routine clinical practice. By extracting spectral profiles of this data, we found that the presence of narrow-band oscillatory activity in the beta band (12-30 Hz) closely corresponds with the neurological exam as quantified with the standard Glasgow Coma Scale (GCS). Further, beta oscillations were distributed over the cortical surface as traveling waves, and the evolution of these waves corresponded to recovery from coma, consistent with the putative role of waves in perception and cognitive activity. We consequently propose that beta oscillations and traveling waves are potential biomarkers of recovery from TBI. In a broader sense, our findings suggest that emergence from coma results from recovery of thalamo-cortical interactions that coordinate cortical beta rhythms.

Change in Enlarged Perivascular Spaces over Time and Associations with Outcomes After Traumatic Brain Injury.

Enlarged perivascular spaces (EPVs) can be seen on magnetic resonance imaging (MRI) scans in various neurological diseases, including traumatic brain injury (TBI). EPVs have been associated with cognitive dysfunction and sleep disturbances; however, their clinical significance remains unclear. The goal of this study was to identify MRI burden of EPVs over time following TBI and to explore their relationship with postinjury outcomes. Individuals with TBI underwent postinjury data collection at Day 1 (blood), 2 weeks (blood, MRI, outcomes), and 6 months (blood, MRI, outcomes). EPV burden was assessed using T1 and FLAIR sequences on representative slices in the centrum semiovale, basal ganglia, and midbrain. Serum blood was assayed to measure concentrations of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Thirty-two participants with TBI were included (mean age 36.8 years, 78% male, 50% White). Total EPVs count did not significantly change from 2 weeks (23.5 [95% confidence interval or CI = 22.0-32.0]) to 6 months (26.0 [95% CI = 22.0-30.0], p = 0.16). For self-reported measures of sleep, there were no significant associations between EPVs count and Insomnia Severity Index (2 weeks: ß = -0.004; 95% CI = -0.094, 0.086; 6 months: ß = 0.002; 95% CI = -0.122, 0.125) or the subset of sleep questions on the Rivermead Post-Concussion Symptoms Questionnaire (2 weeks: ß = -0.005; 95% CI = -0.049, 0.039; 6 months: ß = -0.019; 95% CI = -0.079, 0.042). Functional outcome, determined by 6 months incomplete recovery (Glasgow Outcome Scale-Extended [GOS-E < 8]) versus complete recovery (GOS-E = 8), was significantly associated with a higher number of EPVs at 2 weeks (odds ratio = 0.94, 95% CI = 0.88-0.99). Spearman correlations showed no significant relationship between EPVs count and GFAP or NfL. This study used commonly acquired MRI sequences to quantify EPVs and investigated their utility as a potential imaging biomarker in TBI. Given the minimal change in EPVs over time, this period may not be long enough for potential recovery or may indicate that EPVs are structural findings that do not significantly change over time.

Plasma von Willebrand Factor Is Elevated Hyperacutely After Mild Traumatic Brain Injury.

Each year in the United States, ∼2.7 million persons seek medical attention for traumatic brain injury (TBI), of which ∼85% are characterized as being mild brain injuries. Many different cell types in the brain are affected in these heterogeneous injuries, including neurons, glia, and the brain vasculature. Efforts to identify biomarkers that reflect the injury of these different cell types have been a focus of ongoing investigation. We hypothesized that von Willebrand factor (vWF) is a sensitive biomarker for acute traumatic vascular injury and correlates with symptom severity post-TBI. To address this, blood was collected from professional boxing athletes (n = 17) before and within 30 min after competition. Plasma levels of vWF and neuron-specific enolase were measured using the Meso Scale Discovery, LLC. (MSD) electrochemiluminescence array-based multi-plex format (MSD, Gaithersburg, MD). Additional symptom and outcome data from boxers and patients, such as the Rivermead symptom scores (Rivermead Post Concussion Symptoms Questionnaire [RPQ-3]), were collected. We found that, subsequent to boxing bouts, there was a 1.8-fold increase in vWF levels within 30 min of injury (p < 0.0009). Moreover, fold-change in vWF correlates moderately (r = 0.51; p = 0.03) with the number of head blows. We also found a positive correlation (r = 0.69; p = 0.002) between fold-change in vWF and self-reported post-concussive symptoms, measured by the RPQ-3. The receiver operating curve analysis of vWF plasma levels and RPQ-3 scoring yielded a sensitivity of 94.12% and a specificity of 76.5% with an area under the curve of 83% for boxers after a fight compared to the pre-bout baseline. This study suggests that vWF is a potential blood biomarker measurable in the hyperacute period after blunt mild TBI. This biomarker may prove to be useful in diagnosing and monitoring traumatic vascular injury.

Patients' Perspectives on Life and Recovery 1 Year After COVID-19 Hospitalization.

BACKGROUND: Many patients hospitalized for COVID-19 experience prolonged symptoms months after discharge. Little is known abou t patients' personal experiences recovering from COVID-19 in the United States (US), where medically underserved populations are at particular risk of adverse outcomes. OBJECTIVE: To explore patients' perspectives on the impact of COVID-19 hospitalization and barriers to and facilitators of recovery 1 year after hospital discharge in a predominantly Black American study population with high neighborhood-level socioeconomic disadvantage. DESIGN: Qualitative study utilizing individual, semi-structured interviews. PARTICIPANTS: Adult patients hospitalized for COVID-19 approximately 1 year after discharge home who were engaged in a COVID-19 longitudinal cohort study. APPROACH: The interview guide was developed and piloted by a multidisciplinary team. Interviews were audio-recorded and transcribed. Data were coded and organized into discrete themes using qualitative content analysis with constant comparison techniques. KEY RESULTS: Of 24 participants, 17 (71%) self-identified as Black, and 13 (54%) resided in neighborhoods with the most severe neighborhood-level socioeconomic disadvantage. One year after discharge, participants described persistent deficits in physical, cognitive, or psychological health that impacted their current lives. Repercussions included financial suffering and a loss of identity. Participants reported that clinicians often focused on physical health over cognitive and psychological health, an emphasis that posed a barrier to recovering holistically. Facilitators of recovery included robust financial or social support systems and personal agency in health maintenance. Spirituality and gratitude were common coping mechanisms. CONCLUSIONS: Persistent health deficits after COVID-19 resulted in downstream consequences in participants' lives. Though participants received adequate care to address physical needs, many described persistent unmet cognitive and psychological needs. A more comprehensive understanding of barriers and facilitators for COVID-19 recovery, contextualized by specific healthcare and socioeconomic needs related to socioeconomic disadvantage, is needed to better inform intervention delivery to patients that experience long-term sequelae of COVID-19 hospitalization.

Associations of Microvascular Injury-Related Biomarkers With Traumatic Brain Injury Severity and Outcomes: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot Study.

Traumatic brain injury (TBI) is characterized by heterogeneity in terms of injury severity, mechanism, outcome, and pathophysiology. A single biomarker alone is unlikely to capture the heterogeneity of even one injury subtype, necessitating the use of panels of biomarkers. Herein, we focus on traumatic cerebrovascular injury and investigate associations of a panel of 16 vascular injury-related biomarkers with indices of TBI severity and outcomes using data from 159 participants in the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot Study. Associations of individual biomarkers and clusters of biomarkers identified using non-linear principal components analysis with TBI severity and outcomes were assessed using logistic regression models and Spearman's correlations. As individual biomarkers, higher levels of thrombomodulin, angiopoietin (Ang)-2, von Willebrand factor, and P-selectin were associated with more severe injury; higher levels of Ang-1, Tie2, vascular endothelial growth factor (VEGF)-C, and basic fibroblast growth factor (bFGF) were associated with less severe injury (all p < 0.05 in age-adjusted models). After false discovery rate correction for multiple comparisons, higher levels of Ang-2 remained associated with more severe injury and higher levels of Ang-1, Tie2, and bFGF remained associated with less severe injury at a p < 0.05 level. In principal components analysis, principal component (PC)1, comprised of Ang1, bFGF, P-selectin, VEGF-C, VEGF-A, and Tie2, was associated with less severe injury (age-adjusted odds ratio [OR]: 0.63, 95% confidence interval [CI]: 0.44-0.88 for head computer tomography [CT] positive vs. negative) and PC2 (Ang-2, E-selectin, Flt-1, placental growth factor, thrombomodulin, and vascular cell adhesion protein 1) was associated with greater injury severity (age-adjusted OR: 2.29, 95% CI: 1.49-3.69 for Glasgow Coma Scale [GCS] 3-12 vs. 13-15 and age-adjusted OR 1.59, 95% CI: 1.11-2.32 for head CT positive vs. negative). Neither individual biomarkers nor PCs were associated with outcomes in adjusted models (all p > 0.05). In conclusion, in this trauma-center based population of acute TBI patients, biomarkers of microvascular injury were associated with TBI severity.

Structural brain network deviations predict recovery after traumatic brain injury.

OBJECTIVE: Traumatic brain injury results in diffuse axonal injury and the ensuing maladaptive alterations in network function are associated with incomplete recovery and persistent disability. Despite the importance of axonal injury as an endophenotype in TBI, there is no biomarker that can measure the aggregate and region-specific burden of axonal injury. Normative modeling is an emerging quantitative case-control technique that can capture region-specific and aggregate deviations in brain networks at the individual patient level. Our objective was to apply normative modeling in TBI to study deviations in brain networks after primarily complicated mild TBI and study its relationship with other validated measures of injury severity, burden of post-TBI symptoms, and functional impairment. METHOD: We analyzed 70 T1-weighted and diffusion-weighted MRIs longitudinally collected from 35 individuals with primarily complicated mild TBI during the subacute and chronic post-injury periods. Each individual underwent longitudinal blood sampling to characterize blood protein biomarkers of axonal and glial injury and assessment of post-injury recovery in the subacute and chronic periods. By comparing the MRI data of individual TBI participants with 35 uninjured controls, we estimated the longitudinal change in structural brain network deviations. We compared network deviation with independent measures of acute intracranial injury estimated from head CT and blood protein biomarkers. Using elastic net regression models, we identified brain regions in which deviations present in the subacute period predict chronic post-TBI symptoms and functional status. RESULTS: Post-injury structural network deviation was significantly higher than controls in both subacute and chronic periods, associated with an acute CT lesion and subacute blood levels of glial fibrillary acid protein (r = 0.5, p = 0.008) and neurofilament light (r = 0.41, p = 0.02). Longitudinal change in network deviation associated with change in functional outcome status (r = -0.51, p = 0.003) and post-concussive symptoms (BSI: r = 0.46, p = 0.03; RPQ: r = 0.46, p = 0.02). The brain regions where the node deviation index measured in the subacute period predicted chronic TBI symptoms and functional status corresponded to areas known to be susceptible to neurotrauma. CONCLUSION: Normative modeling can capture structural network deviations, which may be useful in estimating the aggregate and region-specific burden of network changes induced by TAI. If validated in larger studies, structural network deviation scores could be useful for enrichment of clinical trials of targeted TAI-directed therapies.

Imaging Approach to Concussion.

The acute and long-term neurobiological sequelae of concussion (mild traumatic brain injury [mTBI]) and sub-concussive head trauma have become increasingly apparent in recent decades in part due to neuroimaging research. Although imaging has an established role in the clinical management of mTBI for the identification of intracranial lesions warranting urgent interventions, MR imaging is increasingly employed for the detection of post-traumatic sequelae which carry important prognostic significance. As neuroimaging research continues to elucidate the pathophysiology of TBI underlying prolonged recovery and the development of persistent post-concussive symptoms, there is a strong motivation to translate these techniques into clinical use for improved diagnosis and therapeutic monitoring.

Clinical Updates in Mild Traumatic Brain Injury (Concussion).

Traumatic brain injury (TBI) affects > 3 million people in the United States annually. Although the number of deaths related to severe TBIs has stabalized, mild TBIs, often termed concussions, are increasing. As evidence indicates that a significant proportion of these mild injuries are associated with long-lasting functional deficits that impact work performance, social integration, and may predispose to later cognitive decline, it is important that we (a) recognize these injuries, (b) identify those at highest risk of poor recovery, and (c) initiate appropriate treatments promptly. We discuss the epidemiology of TBI, the most common persistent symptoms, and treatment approaches.

Adherence to Established Blood Pressure Targets and Associated Complications in Patients Presenting with Acute Intracerebral Hemorrhage.

BACKGROUND: Conflicting evidence exists surrounding systolic blood pressure (SBP) control in patients with acute intracerebral hemorrhage (ICH). The 2022 American Heart Association and American Stroke Association guidelines recommend targeting a SBP of 140 mm Hg while maintaining the range of 130-150 mm Hg. The current practice at our health system is to titrate antihypertensives to a SBP goal of < 160 mm Hg, which aligns with previous recommendations. We hypothesized that the prior lack of guidance to a specific SBP target range predisposed patients to hypotension leading to an increased risk of brain and renal adverse events. METHODS: This retrospective, multicenter, single health system cohort study included adults admitted to the neurointensive care unit or intermediate unit with acute ICH from June 2019 to June 2021. The primary objective evaluated the frequency of time within SBP range (140-160 mm Hg) in the first 48 h. Secondary and safety end points included the frequency of time above and below the established SBP range, episodes of hypotension (defined as a decrease in SBP < 140 mm Hg prompting discontinuation in antihypertensive[s] or the initiation of vasopressor[s]), the incidence of new brain or renal adverse events within 7 days, and modified Rankin Scale at discharge. RESULTS: A total of 80 patients (59% men; median age 62 years) were included. The majority of ICHs in this cohort were intraparenchymal (70%). Nearly one third were attributed to systemic hypertension (31%). During the first 48 h of admission, the frequency of time spent above, within, and below the target SBP range were 6 h (12%), 16 h (34%), and 26 h (54%), respectively. Hypotension was associated with renal adverse events (odds ratio [OR] 3.36, 95% confidence interval [CI] 1.10-11.44, p = 0.023). A relative SBP reduction > 20% in the first 48 h was associated with renal adverse events (OR 8.99, 95% CI 2.57-35.25, p < 0.001), brain ischemia (OR 22.5, 95% CI 1.92-300.11, p = 0.005), and an increased odd of a modified Rankin Scale of 4-6 at discharge (OR 11.79, 95% CI 2.79-57.02, p < 0.001). CONCLUSIONS: In individuals with nontraumatic/nonaneurysmal ICH, SBP measurements were observed to be < 140 mm Hg for > 50% of the initial 48 h following admission. Hypotension and relative SBP reduction > 20% were also independent predictors of renal adverse events. SBP reduction > 20% was also an independent predictor of brain ischemia. These data indicate that intensive SBP reduction following ICH predispose patients to secondary organ injury that may impact long-term outcomes. Our data suggest that a more modest lowering of the SBP within 48 h, as recommended in the most recent guidelines, may minimize the risk of further adverse events.

Longitudinal Abnormalities in White Matter Extracellular Free Water Volume Fraction and Neuropsychological Functioning in Patients with Traumatic Brain Injury.

Traumatic brain injury is a global public health problem associated with chronic neurological complications and long-term disability. Biomarkers that map onto the underlying brain pathology driving these complications are urgently needed to identify individuals at risk for poor recovery and to inform design of clinical trials of neuroprotective therapies. Neuroinflammation and neurodegeneration are two endophenotypes potentially associated with increases in brain extracellular water content, but the nature of extracellular free water abnormalities after neurotrauma and its relationship to measures typically thought to reflect traumatic axonal injury are not well characterized. The objective of this study was to describe the relationship between a neuroimaging biomarker of extracellular free water content and the clinical features of a cohort with primarily complicated mild traumatic brain injury. We analyzed a cohort of 59 adult patients requiring hospitalization for non-penetrating traumatic brain injury of all severities as well as 36 healthy controls. Patients underwent brain magnetic resonance imaging (MRI) at 2 weeks (n = 59) and 6 months (n = 29) post-injury, and controls underwent a single MRI. Of the participants with TBI, 50 underwent clinical neuropsychological assessment at 2 weeks and 28 at 6 months. For each subject, we derived a summary score representing deviations in whole brain white matter extracellular free water volume fraction (VF) and free water-corrected fractional anisotropy (fw-FA). The summary specific anomaly score (SAS) for VF was significantly higher in TBI patients at 2 weeks and 6 months post-injury relative to controls. SAS for VF exhibited moderate correlation with neuropsychological functioning, particularly on measures of executive function. These findings indicate abnormalities in whole brain white matter extracellular water fraction in patients with TBI and are an important step toward identifying and validating noninvasive biomarkers that map onto the pathology driving disability after TBI.

Associations of Preexisting Vascular Risk Factors With Outcomes After Traumatic Brain Injury: A TRACK-TBI Study.

OBJECTIVE: To evaluate associations of preinjury vascular risk factors with traumatic brain injury (TBI) outcomes. SETTING: The level 1 trauma center-based T ransforming R esearch a nd C linical K nowledge in TBI (TRACK-TBI) Study. PARTICIPANTS: A total of 2361 acute TBI patients 18 years or older who presented to the emergency department within 24 hours of head trauma warranting clinical evaluation with a noncontrast head CT between February 26, 2014, and August 8, 2018. DESIGN: A multicenter prospective cohort study. MAIN MEASURES: Vascular risk factors (hypertension, diabetes, hyperlipidemia, and smoking) were assessed at baseline by self- or proxy-report and chart review. The primary outcome was the 6-month Glasgow Outcome Scale-Extended TBI version (GOSE-TBI). Secondary 6-month outcomes included the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), the Satisfaction with Life Scale (SWLS), and the 18-item Brief Symptom Inventory Global Severity Index (BSI-18-GSI). RESULTS: Mean age of participants was 42 years, 31% were women, and 16% were Black. Current smoking was the most common vascular risk factor (29%), followed by hypertension (17%), diabetes (8%), and hyperlipidemia (6%). Smoking was the only risk factor associated with worse scores on all 4 outcome indices. Hypertension and diabetes were associated with worse RPQ scores, and hypertension was associated with worse BSI-18-GSI scores (all P < .05). Compared with individuals with no vascular risk factors, individuals with 1 but not 2 or more vascular risk factors had significantly worse GOSE-TBI and SWLS scores, while a higher burden of vascular risk factors was significantly associated with worse RPQ and BSI-18-GSI scores. CONCLUSION: Our study found that preinjury vascular risk factors, especially smoking, are associated with worse outcomes after TBI. Aggressive postinjury treatment of vascular risk factors may be a promising strategy to improve TBI outcomes.

Assessment of Resident Physician Comfort in Screening for Social Determinants of Health in a Specialty Clinic Population.

Through qualitative surveys, a team of law students, law professors, physicians, and residents explored the perceptions of neurology residents towards referral to appropriate legal resources in an academic training program. Respondents reported feeling uncomfortable screening their patients for health-harming legal needs, which many attributed to a lack of training in this area. These findings indicate that neurology residents would benefit from training on screening for social factors that may be impacting their patients' health.

Neurotrauma.

PURPOSE OF REVIEW: This review will highlight the latest research relevant to the clinical care of traumatic brain injury (TBI) patients over the last 2 years while underscoring the implications of these advances in the understanding of diagnosis, treatment, and prognosis of TBI. RECENT FINDINGS: Brain tissue oxygenation monitoring can identify hypoperfusion as an adjunct to intracerebral pressure monitoring. Multiple biomarker assays are now available to help clinicians screen for mild TBI and biomarker elevations correlate with the size of intracranial injury. Beta-blocker exposure following TBI has demonstrated a survival benefit in those with TBI though the mechanism for this remains unknown. The optimal timing for venous thromboembolism prophylaxis for TBI patients is still uncertain. SUMMARY: The current characterization of TBI as mild, moderate, or severe fails to capture the complexity of the disease process and helps little with prognostication. Molecular biomarkers and invasive monitoring devices including brain tissue oxygenation and measures of cerebral autoregulation are being utilized more commonly and can help guide therapy. Extracranial complications following TBI are common and include infection, respiratory failure, coagulopathy, hypercoagulability, and paroxysmal sympathetic hyperactivity.

Dynamic contrast enhanced MRI for characterization of blood-brain-barrier dysfunction after traumatic brain injury.

BACKGROUND AND PURPOSE: Dysfunction of the blood-brain-barrier (BBB) is a recognized pathological consequence of traumatic brain injury (TBI) which may play an important role in chronic TBI pathophysiology. We hypothesized that BBB disruption can be detected with dynamic contrast-enhanced (DCE) MRI not only in association with focal traumatic lesions but also in normal-appearing brain tissue of TBI patients, reflecting microscopic microvascular injury. We further hypothesized that BBB integrity would improve but not completely normalize months after TBI. MATERIALS AND METHODS: DCE MRI was performed in 40 adult patients a median of 23 days after hospitalized TBI and in 21 healthy controls. DCE data was analyzed using Patlak and linear models, and derived metrics of BBB leakage including the volume transfer constant (Ktrans) and the normalized permeability index (NPI) were compared between groups. BBB metrics were compared with focal lesion distribution as well as with contemporaneous measures of symptomatology and cognitive function in TBI patients. Finally, BBB metrics were examined longitudinally among 18 TBI patients who returned for a second MRI a median of 204 days postinjury. RESULTS: TBI patients exhibited higher mean Ktrans (p = 0.0028) and proportion of suprathreshold NPI voxels (p = 0.001) relative to controls. Tissue-based analysis confirmed greatest TBI-related BBB disruption in association with focal lesions, however elevated Ktrans was also observed in perilesional (p = 0.011) and nonlesional (p = 0.044) regions. BBB disruption showed inverse correlation with quality of life (rho = -0.51, corrected p = 0.016). Among the subset of TBI patients who underwent a second MRI several months after the initial evaluation, metrics of BBB disruption did not differ significantly at the group level, though variable longitudinal changes were observed at the individual subject level. CONCLUSIONS: This pilot investigation suggests that TBI-related BBB disruption is detectable in the early post-injury period in association with focal and diffuse brain injury.

Six-Month Impairment in Cognition, Mental Health, and Physical Function Following COVID-19-Associated Respiratory Failure.

To determine the prevalence and extent of impairments impacting health-related quality of life among survivors of COVID-19 who required mechanical ventilation, 6 months after hospital discharge. DESIGN: Multicenter, prospective cohort study, enrolling adults 18 years old or older with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection who received mechanical ventilation for 48 hours or more and survived to hospital discharge. Eligible patients were contacted 6 months after discharge for telephone-based interviews from March 2020 to December 2020. Assessments included: Montreal Cognitive Assessment-Blind, Hospital Anxiety and Depression Scale, Impact of Event Scale-6, EuroQOL 5 domain quality-of-life questionnaire, and components of the Multidimensional Dyspnea Profile. SETTING: Two tertiary academic health systems. PATIENTS: Of 173 eligible survivors, a random sample of 63 were contacted and 60 consented and completed interviews. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mean age was 57 + 13 years and mean duration of invasive mechanical ventilation was 14 + 8.2 days. Six months post-discharge, 48 patients (80%; 95% CI, 68-88%) met criteria for post-intensive care syndrome (PICS), with one or more domains impaired. Among patients with PICS, 28 (47%; 95% CI, 35-59%) were impaired in at least 2 domains, and 12 (20%; 95% CI, 12-32%) impaired in all three domains. Significant symptoms of post-traumatic stress were present in 20 patients (33%; 95% CI, 23-46%), anxiety in 23 (38%; 95% CI, 27-51%), and depression in 25 (42%; 95% CI, 30-54%). Thirty-three patients (55%; 95% CI, 42-67%) had impairments in physical activity; 25 patients (42%; 95% CI, 30-54%) demonstrated cognitive impairment. CONCLUSIONS: Eighty percent of COVID-19 survivors who required mechanical ventilation demonstrated PICS 6 months after hospital discharge. Patients were commonly impaired in multiple PICS domains as well as coexisting mental health domains.

Extracellular vesicles as distinct biomarker reservoirs for mild traumatic brain injury diagnosis.

Mild traumatic brain injury does not currently have a clear molecular diagnostic panel to either confirm the injury or to guide its treatment. Current biomarkers for traumatic brain injury rely mainly on detecting circulating proteins in blood that are associated with degenerating neurons, which are less common in mild traumatic brain injury, or with broad inflammatory cascades which are produced in multiple tissues and are thus not brain specific. To address this issue, we conducted an observational cohort study designed to measure a protein panel in two compartments-plasma and brain-derived extracellular vesicles-with the following hypotheses: (i) each compartment provides independent diagnostic information and (ii) algorithmically combining these compartments accurately classifies clinical mild traumatic brain injury. We evaluated this hypothesis using plasma samples from mild (Glasgow coma scale scores 13-15) traumatic brain injury patients (n = 47) and healthy and orthopaedic control subjects (n = 46) to evaluate biomarkers in brain-derived extracellular vesicles and plasma. We used our Track Etched Magnetic Nanopore technology to isolate brain-derived extracellular vesicles from plasma based on their expression of GluR2, combined with the ultrasensitive digital enzyme-linked immunosorbent assay technique, Single-Molecule Array. We quantified extracellular vesicle-packaged and plasma levels of biomarkers associated with two categories of traumatic brain injury pathology: neurodegeneration and neuronal/glial damage (ubiquitin C-terminal hydrolase L1, glial fibrillary acid protein, neurofilament light and Tau) and inflammation (interleukin-6, interleukin-10 and tumour necrosis factor alpha). We found that GluR2+ extracellular vesicles have distinct biomarker distributions than those present in the plasma. As a proof of concept, we showed that using a panel of biomarkers comprised of both plasma and GluR2+ extracellular vesicles, injured patients could be accurately classified versus non-injured patients.

Arterial Spin Labeling Reveals Elevated Cerebral Blood Flow with Distinct Clusters of Hypo- and Hyperperfusion after Traumatic Brain Injury.

Imaging detection of brain perfusion alterations after traumatic brain injury (TBI) may provide prognostic insights. In this study, we used arterial spin labeling (ASL) to quantify cross-sectional and longitudinal changes in cerebral blood flow (CBF) after TBI and correlated changes with clinical outcome. We analyzed magnetic resonance imaging scans from adult participants with TBI requiring hospitalization in the acute (2 weeks post-injury, n = 33) and chronic (6 months post-injury, n = 16) phases, with 13 participants scanned longitudinally at both time points. We also analyzed 18 age- and sex-matched healthy controls. Whole-brain CBF maps were derived using a three-dimensional pseudo-continuous arterial spin label technique. Mean CBF across tissue-based regions (whole brain, gray matter, and white matter) was compared cross-sectionally and longitudinally. In addition, individual-level clusters of abnormal perfusion were identified using voxel-based z-score analysis of relative CBF maps, and number and volume of abnormally hypo- and hyperperfused clusters were assessed cross-sectionally and longitudinally. Finally, all CBF measures were correlated with clinical outcome measures. Mean global and gray matter CBF were significantly elevated in acute and chronic TBI participants compared to controls. Participants with better outcome at 6 months post-injury tended to have higher CBF in the acute phase compared to those with poorer outcome. Acute TBI participants had a significantly greater volume of hypo- and hyperperfused brain tissue compared to controls, with these regions partially normalizing by the chronic phase. Our findings demonstrate global elevation of CBF with focal hypo- and hyperperfusion in the early post-injury period and suggest a reparative role for acute elevation in CBF post-TBI.

Imaging biomarkers of vascular and axonal injury are spatially distinct in chronic traumatic brain injury.

Traumatic Brain Injury (TBI) is associated with both diffuse axonal injury (DAI) and diffuse vascular injury (DVI), which result from inertial shearing forces. These terms are often used interchangeably, but the spatial relationships between DAI and DVI have not been carefully studied. Multimodal magnetic resonance imaging (MRI) can help distinguish these injury mechanisms: diffusion tensor imaging (DTI) provides information about axonal integrity, while arterial spin labeling (ASL) can be used to measure cerebral blood flow (CBF), and the reactivity of the Blood Oxygen Level Dependent (BOLD) signal to a hypercapnia challenge reflects cerebrovascular reactivity (CVR). Subjects with chronic TBI (n = 27) and healthy controls (n = 14) were studied with multimodal MRI. Mean values of mean diffusivity (MD), fractional anisotropy (FA), CBF, and CVR were extracted for pre-determined regions of interest (ROIs). Normalized z-score maps were generated from the pool of healthy controls. Abnormal ROIs in one modality were not predictive of abnormalities in another. Approximately 9-10% of abnormal voxels for CVR and CBF also showed an abnormal voxel value for MD, while only 1% of abnormal CVR and CBF voxels show a concomitant abnormal FA value. These data indicate that DAI and DVI represent two distinct TBI endophenotypes that are spatially independent.