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Background and Objectives: Blood biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have recently been Food and Drug Administration approved as predictors of intracranial lesions on CT after mild traumatic brain injury (mTBI). However, most cases with mTBI are CT negative, and no biomarkers are approved to assist diagnosis in these individuals. In this study, we aimed to determine the optimal combination of blood biomarkers to assist mTBI diagnosis in otherwise healthy adults younger than 50 years presenting to an emergency department within 6 hours of injury. To further understand the utility of biomarkers, we assessed how biological sex, presence or absence of loss of consciousness and/or post-traumatic amnesia (LOC/PTA), and delayed presentation affected classification performance., Methods: Blood samples, symptom questionnaires, and cognitive tests were prospectively conducted for participants with mTBI recruited from The Alfred Hospital Level 1 Emergency & Trauma Center and uninjured controls. Follow-up testing was conducted at 7 days. Simoa quantified plasma GFAP, UCH-L1, tau, neurofilament light chain (NfL), interleukin (IL)-6, and IL-1β. Area under the receiver operating characteristic (AUC) analysis assessed classification accuracy for diagnosed mTBI, and logistic regression models identified optimal biomarker combinations., Results: Plasma IL-6 (AUC 0.91, 95% CI 0.86-0.96), GFAP (AUC 0.85, 95% CI 0.78-0.93), and UCH-L1 (AUC 0.79, 95% CI 0.70-0.88) best differentiated mTBI (n = 74) from controls (n = 44) acutely (<6 hours), with NfL (AUC 0.81, 95% CI 0.72-0.90) the only marker to have such utility subacutely (7 days). Biomarker performance was similar between sexes and for participants with and without LOC/PTA, with the exception at 7 days, where GFAP and IL-6 retained some utility in female participants (GFAP: AUC 0.71, 95% CI 0.55-0.88; IL-6: AUC 0.71, 95% CI 0.55-0.87) and in those with LOC/PTA (GFAP: AUC 0.73, 95% CI 0.59-0.86; IL-6: AUC 0.71, 95% CI 0.57-0.84). Acute IL-6 ( R 2 = 0.50, 95% CI 0.34-0.64) outperformed GFAP and UCH-L1 combined ( R 2 = 0.35, 95% CI 0.17-0.50), with the best acute model featuring GFAP and IL-6 ( R 2 = 0.54, 95% CI 0.34-0.68)., Discussion: These findings indicate that adding IL-6 to a panel of brain-specific proteins such as GFAP and UCH-L1 might assist in the acute diagnosis of mTBI in adults younger than 50 years. Multiple markers had high classification accuracy in participants without LOC/PTA. When compared with the best-performing acute markers, subacute measures of plasma NfL resulted in minimal reduction in classification accuracy. Future studies will investigate the optimal time frame over which plasma IL-6 might assist diagnostic decisions and how extracranial trauma affects utility., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: Enlarged perivascular spaces (ePVS) have been identified as a key signature of glymphatic system dysfunction in neurologic conditions. The incidence and clinical implications of ePVS after traumatic brain injury (TBI) are not yet understood. We investigated whether individuals with chronic moderate-to-severe TBI had an increased burden of ePVS and whether ePVS burden is modulated by the presence of focal lesions, older brain age, and poorer sleep quality. We examined whether an increased burden of ePVS was associated with poorer cognitive and emotional outcomes., Methods: Using a cross-sectional design, participants with a single moderate-to-severe chronic TBI (sustained ≥10 years ago) were recruited from an inpatient rehabilitation program. Control participants were recruited from the community. Participants underwent 3T brain MRI, neuropsychological assessment, and clinical evaluations. ePVS burden in white matter was quantified using automated segmentation. The relationship between the number of ePVS, group membership, focal lesions, brain age, current sleep quality, and outcome was modeled using negative binomial and linear regressions., Results: This study included 100 participants with TBI (70% male; mean age = 56.8 years) and 75 control participants (54.3% male; mean age = 59.8 years). The TBI group had a significantly greater burden of ePVS (prevalence ratio rate [PRR] = 1.29, p = 0.013, 95% CI 1.05-1.57). The presence of bilateral lesions was associated with greater ePVS burden (PRR = 1.41, p = 0.021, 95% CI 1.05-1.90). There was no association between ePVS burden, sleep quality (PRR = 1.01, p = 0.491, 95% CI 0.98-1.048), and sleep duration (PRR = 1.03, p = 0.556, 95% CI 0.92-1.16). ePVS was associated with verbal memory (β = -0.42, p = 0.006, 95% CI -0.72 to -0.12), but not with other cognitive domains. The burden of ePVS was not associated with emotional distress (β = -0.70, p = 0.461, 95% CI -2.57 to 1.17) or brain age (PRR = 1.00, p = 0.665, 95% CI 0.99-1.02)., Discussion: TBI is associated with a greater burden of ePVS, especially when there have been bilateral brain lesions. ePVS was associated with reduced verbal memory performance. ePVS may indicate ongoing impairments in glymphatic system function in the chronic postinjury period., (© 2023 American Academy of Neurology.)

Background and Objectives: Traumatic brain injury (TBI) has been promoted as a risk factor for Alzheimer disease (AD). There is evidence of elevated β-amyloid (Aβ) and tau, the pathologic hallmarks of AD, immediately following TBI. It is not clear whether Aβ and tau remain elevated in the chronic period. To address this issue, we assessed Aβ and tau burden in long-term TBI survivors and healthy controls using PET imaging., Methods: Using a cross-sectional design, we recruited individuals following a single moderate to severe TBI at least 10 years previously from an inpatient rehabilitation program. A demographically similar healthy control group was recruited from the community. PET data were acquired using 18 F-NAV4694 (Aβ) and 18 F-MK6240 (tau) tracers. Aβ deposition was quantified using the Centiloid scale. Tau deposition was quantified using the standardized uptake value ratio (SUVR) in 4 regions of interest (ROIs). As a secondary measure, PET scans were also visually read as positive or negative. We examined PET data in relation to time since injury and age at injury. PET data were analyzed in a series of regression analyses., Results: The sample comprised 87 individuals with TBI (71.3% male; 28.7% female; mean 57.53 years, SD 11.53) and 59 controls (59.3% male; 40.7% female; mean 60.34 years, SD 11.97). Individuals with TBI did not have significantly higher 18 F-NAV4694 Centiloid values ( p = 0.067) or 18 F-MK6240 tau SUVRs in any ROI ( p ≤ 0.001; SUVR greater for controls). Visual assessment was consistent with the quantification; individuals with TBI were not more likely than controls to have a positive Aβ ( p = 0.505) or tau scan ( p = 0.221). No associations were identified for Aβ or tau burden with time since injury ( p = 0.057 to 0.332) or age at injury., Discussion: A single moderate to severe TBI was not associated with higher burden of Aβ or tau pathologies in the chronic period relative to healthy controls. Aβ and tau burden did not show a significant increase with years since injury, and burden did not appear to be greater for those who were older at the time of injury., (© 2022 American Academy of Neurology.)

Purpose of Review: Recent research has provided extensive characterization as to the frequency and nature of sleep disturbances following traumatic brain injury (TBI). This review summarizes the current state of knowledge and proposes future directions for research., Recent Findings: Complaints of sleep disturbance are common following TBI, and objective assessments of sleep largely corroborate these complaints. Sleep is often disturbed in the acute phase postinjury and can persist for decades, with the prevalence of sleep disorders higher in patients with TBI as compared with the general population. The factors causing sleep disturbance appear to involve numerous interrelated primary and secondary factors, including direct damage to vital sleep-regulating regions of the brain, alterations in the circadian system, lowered mood as well as increased anxiety and pain. The complex web of contributing factors implies that combination therapies targeting a number of putative causal mechanisms may yield the greatest success in terms of improving sleep postinjury., Summary: Sleep disturbance is a common consequence of TBI. Research is needed to ascertain the primary drivers of sleep disturbance postinjury to guide the development of targeted interventions. In the absence of a single mechanism, combination therapies may prove most fruitful.

Unlabelled: A variety of methods have been used to quantify aspects of recovery after anesthesia. Most are narrowly focused, are not patient-rated, and have not been validated. We therefore set out to develop a patient-rated quality of recovery score. We constructed a 61-item questionnaire that asked individuals (patients and relatives, medical and nursing staff; total n = 136) to rate various postoperative items describing features a patient may experience postoperatively. The most highly ranked items were included in a final nine-point index score, which we called the "QoR Score." We then studied two cohorts of surgical patients (n = 449). There was good convergent validity between the QoR Score and the visual analog scale score (rho = 0.55, P < 0.0001). Discriminant construct validity was supported by comparing resultant QoR Scores in patients undergoing day-stay, minor, and major surgery (P = 0.008), as well as a negative correlation with duration of hospital stay (rho = -0.20, P < 0.0001), and, using multivariate regression, demonstrating a significant negative relationship between QoR Score and female gender (P = 0.048) and older age (P = 0.041). There was also good interrater agreement (rho = 0.55, P < 0.0001), test-retest reliability (median rho = 0.61, P < 0.0001), and internal consistency (alpha = 0.57 and 0.90, P < 0.0001). There was a significant difference between the groups of patients recovering from major and minor surgery (P < 0.001). This study demonstrates that the QoR Score has good validity, reliability, and clinical acceptability in patients undergoing many types of surgery., Implications: We set out to develop a patient-rated quality of recovery score (QoR) that could be used both as a measure of outcome in perioperative trials and for clinical audit. We first surveyed patients and staff to identify important aspects of recovery, then developed a nine-point QoR Score. This was then compared with other measures of postoperative outcome. We found that the QoR Score is a useful measure of recovery after anesthesia and surgery.