Head Injury and Risk of Incident Ischemic Stroke in Community-Dwelling Adults.

BACKGROUND: While stroke is a recognized short-term sequela of traumatic brain injury, evidence about long-term ischemic stroke risk after traumatic brain injury remains limited. METHODS: The Atherosclerosis Risk in Communities Study is an ongoing prospective cohort comprised of US community-dwelling adults enrolled in 1987 to 1989 followed through 2019. Head injury was defined using self-report and hospital-based diagnostic codes and was analyzed as a time-varying exposure. Incident ischemic stroke events were physician-adjudicated. We used Cox regression adjusted for sociodemographic and cardiovascular risk factors to estimate the hazard of ischemic stroke as a function of head injury. Secondary analyses explored the number and severity of head injuries; the mechanism and severity of incident ischemic stroke; and heterogeneity within subgroups defined by race, sex, and age. RESULTS: Our analysis included 12 813 participants with no prior head injury or stroke. The median follow-up age was 27.1 years (25th-75th percentile=21.1-30.5). Participants were of median age 54 years (25th-75th percentile=49-59) at baseline; 57.7% were female and 27.8% were Black. There were 2158 (16.8%) participants with at least 1 head injury and 1141 (8.9%) participants with an incident ischemic stroke during follow-up. For those with head injuries, the median age to ischemic stroke was 7.5 years (25th-75th percentile=2.2-14.0). In adjusted models, head injury was associated with an increased hazard of incident ischemic stroke (hazard ratio [HR], 1.34 [95% CI, 1.12-1.60]). We observed evidence of dose-response for the number of head injuries (1: HR, 1.16 [95% CI, 0.97-1.40]; ≥2: HR, 1.94 [95% CI, 1.39-2.71]) but not for injury severity. We observed evidence of stronger associations between head injury and more severe stroke (National Institutes of Health Stroke Scale score ≤5: HR, 1.31 [95% CI, 1.04-1.64]; National Institutes of Health Stroke Scale score 6-10: HR, 1.64 [95% CI, 1.06-2.52]; National Institutes of Health Stroke Scale score ≥11: HR, 1.80 [95% CI, 1.18-2.76]). Results were similar across stroke mechanism and within strata of race, sex, and age. CONCLUSIONS: In this community-based cohort, head injury was associated with subsequent ischemic stroke. These results suggest the importance of public health interventions aimed at preventing head injuries and primary stroke prevention among individuals with prior traumatic brain injuries.

Effects of Low-Level Light Therapy on Resting-State Connectivity Following Moderate Traumatic Brain Injury: Secondary Analyses of a Double-blinded Placebo-controlled Study.

Background Low-level light therapy (LLLT) has been shown to modulate recovery in patients with traumatic brain injury (TBI). However, the impact of LLLT on the functional connectivity of the brain when at rest has not been well studied. Purpose To use functional MRI to assess the effect of LLLT on whole-brain resting-state functional connectivity (RSFC) in patients with moderate TBI at acute (within 1 week), subacute (2-3 weeks), and late-subacute (3 months) recovery phases. Materials and Methods This is a secondary analysis of a prospective single-site double-blinded sham-controlled study conducted in patients presenting to the emergency department with moderate TBI from November 2015 to July 2019. Participants were randomized for LLLT and sham treatment. The primary outcome of the study was to assess structural connectivity, and RSFC was collected as the secondary outcome. MRI was used to measure RSFC in 82 brain regions in participants during the three recovery phases. Healthy individuals who did not receive treatment were imaged at a single time point to provide control values. The Pearson correlation coefficient was estimated to assess the connectivity strength for each brain region pair, and estimates of the differences in Fisher z-transformed correlation coefficients (hereafter, z differences) were compared between recovery phases and treatment groups using a linear mixed-effects regression model. These analyses were repeated for all brain region pairs. False discovery rate (FDR)-adjusted P values were computed to account for multiple comparisons. Quantile mixed-effects models were constructed to quantify the association between the Rivermead Postconcussion Symptoms Questionnaire (RPQ) score, recovery phase, and treatment group. Results RSFC was evaluated in 17 LLLT-treated participants (median age, 50 years [IQR, 25-67 years]; nine female), 21 sham-treated participants (median age, 50 years [IQR, 43-59 years]; 11 female), and 23 healthy control participants (median age, 42 years [IQR, 32-54 years]; 13 male). Seven brain region pairs exhibited a greater change in connectivity in LLLT-treated participants than in sham-treated participants between the acute and subacute phases (range of z differences, 0.37 [95% CI: 0.20, 0.53] to 0.45 [95% CI: 0.24, 0.67]; FDR-adjusted P value range, .010-.047). Thirteen different brain region pairs showed an increase in connectivity in sham-treated participants between the subacute and late-subacute phases (range of z differences, 0.17 [95% CI: 0.09, 0.25] to 0.26 [95% CI: 0.14, 0.39]; FDR-adjusted P value range, .020-.047). There was no evidence of a difference in clinical outcomes between LLLT-treated and sham-treated participants (range of differences in medians, -3.54 [95% CI: -12.65, 5.57] to -0.59 [95% CI: -7.31, 8.49]; P value range, .44-.99), as measured according to RPQ scores. Conclusion Despite the small sample size, the change in RSFC from the acute to subacute phases of recovery was greater in LLLT-treated than sham-treated participants, suggesting that acute-phase LLLT may have an impact on resting-state neuronal circuits in the early recovery phase of moderate TBI. ClinicalTrials.gov Identifier: NCT02233413 © RSNA, 2024 Supplemental material is available for this article.

Traumatic brain injury and cognitive change over 30 years among community-dwelling older adults.

INTRODUCTION: There is limited evidence regarding the rate of long-term cognitive decline after traumatic brain injury (TBI) among older adults. METHODS: In this prospective cohort study, time-varying TBI was defined by self-report and International Classification of Disease diagnostic codes. Cognitive testing was performed at five visits over 30 years and scores were combined into a global cognition factor score. Adjusted linear mixed-effects models estimated the association of TBI with cognitive change. RESULTS: A total of 11,701 Atherosclerosis Risk in Communities (ARIC) Study participants (mean baseline age 58 years, 58% female, 25% Black) without TBI at baseline were included. Over follow-up, 18% experienced TBI. The adjusted average decline in cognition per decade (standard deviation units) was more than twice as fast among individuals with ≥ 2 incident TBIs (𝛽 = -0.158, 95% confidence interval [CI] = -0.253,-0.063), but not among individuals with 1 TBI (𝛽 = -0.052, 95% CI = -0.107, 0.002), compared to without TBI (𝛽 = -0.057, 95% CI = -0.095, -0.020). DISCUSSION: This study provides robust evidence that TBIs fundamentally alter the trajectories of cognitive decline. HIGHLIGHTS: The adjusted average decline in cognition per decade (standard deviation units) was more than twice as fast among individuals with ≥ 2 incident traumatic brain injuries (TBIs; 𝛽 = -0.158, 95% confidence interval [CI] = -0.253, -0.063), but not with 1 TBI (𝛽 = -0.052, 95% CI = -0.107, 0.002), compared to without TBI (𝛽 = -0.057, 95% CI = -0.095, -0.020). Over a period of 30 years, this difference in cognitive decline is equivalent to individuals with ≥ 2 TBIs being 9.7 years older at baseline. Associations of TBI were stronger among individuals with one or two apolipoprotein E (APOE) ε4 alleles than among individuals with zero APOE ε4 alleles (P interaction = 0.007).

Serum NfL and GFAP as biomarkers of progressive neurodegeneration in TBI.

BACKGROUND: We examined spatial patterns of brain atrophy after mild, moderate, and severe traumatic brain injury (TBI), the relationship between progression of brain atrophy with initial traumatic axonal injury (TAI), cognitive outcome, and with serum biomarkers of brain injury. METHODS: A total of 143 patients with TBI and 43 controls were studied cross-sectionally and longitudinally up to 5 years with multiple assessments, which included brain magnetic resonance imaging, cognitive testing, and serum biomarkers. RESULTS: TBI patients showed progressive volume loss regardless of injury severity over several years, and TAI was independently associated with accelerated brain atrophy. Cognitive performance improved over time. Higher baseline serum neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) were associated with greater rate of brain atrophy over 5 years. DISCUSSSION: Spatial patterns of atrophy differ by injury severity and TAI is associated with the progression of brain atrophy. Serum NfL and GFAP show promise as non-invasive prognostic biomarkers of progressive neurodegeneration in TBI. HIGHLIGHTS: In this longitudinal study of patient with mild, moderate, and severe traumatic brain injury (TBI) who were assessed with paired magnetic resonance imaging (MRI), blood biomarkers, and cognitive assessments, we found that brain atrophy after TBI is progressive and continues for many years even after a mild head trauma without signs of brain injury on conventional MRI. We found that spatial pattern of brain atrophy differs between mild, moderate, and severe TBI, where in patients with mild TBI , atrophy is mainly seen in the gray matter, while in those with moderate to severe brain injury atrophy is predominantly seen in the subcortical gray matter and whiter matter. Cognitive performance improves over time after a TBI. Serum measures of neurofilament light or glial fibrillary acidic protein are associated with progression of brain atrophy after TBI.

Association Between Soluble Intercellular Adhesion Molecule-1 and Intracerebral Hemorrhage Outcomes in the FAST Trial.

BACKGROUND: Neutrophil-mediated inflammation in the acute phase of intracerebral hemorrhage (ICH) worsens outcome in preclinical studies. sICAM-1 (soluble intercellular adhesion molecule-1), an inducible ligand for integrins and cell-cell adhesion molecules, is critical for neutrophil extravasation. We aimed to determine whether serum levels of sICAM-1 are associated with worse outcomes after ICH. METHODS: We conducted a post hoc secondary analysis of an observational cohort using data from the FAST trial (Factor-VII for Acute Hemorrhagic Stroke Treatment). The study exposure was the admission serum level of sICAM-1. The coprimary outcomes were mortality and poor outcome (modified Rankin Scale score 4-6) at 90 days. Secondary radiological outcomes were hematoma expansion at 24 hours and perihematomal edema expansion at 72 hours. We used multiple linear and logistic regression analyses to test for associations between sICAM-1 and outcomes, after adjustment for demographics, ICH severity characteristics, change in the systolic blood pressure in the first 24 hours, treatment randomization arm, and the time from symptom onset to study drug administration. RESULTS: Of 841 patients, we included 507 (60%) with complete data. Hematoma expansion occurred in 169 (33%), while 242 (48%) had a poor outcome. In multivariable analyses, sICAM-1 was associated with mortality (odds ratio, 1.53 per SD increase [95% CI, 1.15-2.03]) and poor outcome (odds ratio, 1.34 per SD increase [CI, 1.06-1.69]). In multivariable analyses of secondary outcomes, sICAM-1 was associated with hematoma expansion (odds ratio, 1.35 per SD increase [CI, 1.11-1.66]), but was not associated with log-transformed perihematomal edema expansion at 72 hours. In additional analyses stratified by treatment assignment, similar results were noted in the recombinant activated factor-VII arm, but not in the placebo arm. CONCLUSIONS: Admission serum levels of sICAM-1 were associated with mortality, poor outcome, and hematoma expansion. Given the possibility of a biological interaction between recombinant activated factor-VII and sICAM-1, these findings highlight the need to further explore the role of sICAM-1 as a potential marker of poor ICH outcomes.

Spatiotemporal profile of atrophy in the first year following moderate-severe traumatic brain injury.

Traumatic brain injury (TBI) triggers progressive neurodegeneration resulting in brain atrophy that continues months-to-years following injury. However, a comprehensive characterization of the spatial and temporal evolution of TBI-related brain atrophy remains incomplete. Utilizing a sensitive and unbiased morphometry analysis pipeline optimized for detecting longitudinal changes, we analyzed a sample consisting of 37 individuals with moderate-severe TBI who had primarily high-velocity and high-impact injury mechanisms. They were scanned up to three times during the first year after injury (3 months, 6 months, and 12 months post-injury) and compared with 33 demographically matched controls who were scanned once. Individuals with TBI already showed cortical thinning in frontal and temporal regions and reduced volume in the bilateral thalami at 3 months post-injury. Longitudinally, only a subset of cortical regions in the parietal and occipital lobes showed continued atrophy from 3 to 12 months post-injury. Additionally, cortical white matter volume and nearly all deep gray matter structures exhibited progressive atrophy over this period. Finally, we found that disproportionate atrophy of cortex along sulci relative to gyri, an emerging morphometric marker of chronic TBI, was present as early as 3 month post-injury. In parallel, neurocognitive functioning largely recovered during this period despite this pervasive atrophy. Our findings demonstrate msTBI results in characteristic progressive neurodegeneration patterns that are divergent across regions and scale with the severity of injury. Future clinical research using atrophy during the first year of TBI as a biomarker of neurodegeneration should consider the spatiotemporal profile of atrophy described in this study.

Association of obesity with mild traumatic brain injury symptoms, inflammatory profile, quality of life and functional outcomes: a TRACK-TBI Study.

OBJECTIVES: Obesity is associated with chronic inflammation, which may impact recovery from mild traumatic brain injury (mTBI). The objective was to assess the role of obesity in recovery of symptoms, functional outcome and inflammatory blood biomarkers after mTBI. METHODS: TRACK-TBI is a prospective study of patients with acute mTBI (Glasgow Coma Scale=13-15) who were enrolled ≤24 hours of injury at an emergency department of level 1 trauma centres and followed for 12 months. A total of 770 hospitalised patients who were either obese (body mass index (BMI) >30.0) or healthy mass (BMI=18.5-24.9) were enrolled. Blood concentrations of high-sensitivity C reactive protein (hsCRP), interleukin (IL) 6, IL-10, tumour necrosis factor alpha; Rivermead Post-Concussion Symptoms Questionnaire (RPQ), Quality of Life After Brain Injury and Glasgow Outcome Score-Extended reflecting injury-related functional limitations at 6 and 12 months were collected. RESULTS: After adjusting for age and gender, obese participants had higher concentrations of hsCRP 1 day after injury (mean difference (MD)=0.65; 95% CI: 0.44 to 0.87, p<0.001), at 2 weeks (MD=0.99; 95% CI: 0.74 to 1.25, p<0.001) and at 6 months (MD=1.08; 95% CI: 0.79 to 1.37, p<0.001) compared with healthy mass participants. Obese participants had higher concentrations of IL-6 at 2 weeks (MD=0.37; 95% CI: 0.11 to 0.64, p=0.006) and 6 months (MD=0.42; 95% CI: 0.12 to 0.72, p=0.006). Obese participants had higher RPQ total score at 6 months (MD=2.79; p=0.02) and 12 months (MD=2.37; p=0.049). CONCLUSIONS: Obesity is associated with higher symptomatology at 6 and 12 months and higher concentrations of blood inflammatory markers throughout recovery following mTBI.

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.

Detection of visuomotor dysfunction in mild traumatic brain injury using binocular retinal polarization scanning.

OBJECTIVE: The head and intraocular trauma tool (HITT) is a portable, binocular retinal polarization scanner (RPS) that detects ocular fixation with high precision to assess visuomotor function. We conducted a pilot evaluation of a prototype binocular RPS device to evaluate alterations in fixation stability, binocularity (convergence), and saccadic latency after mild traumatic brain injury (mTBI). METHODS: Two groups were studied prospectively: (1) single observation study of mTBI patients in a hospital ER (n = 7) and age-matched controls (n = 43); (2) high-school athletes preseason (n = 28), after sports-related mTBI (n = 3), and at season end (n = 5). Subjects were asked to fixate on an internal target and track randomly presented peripheral and central targets as fixation was assessed using binocular RPS. RESULTS: There were clinically and statistically significant alterations in the hospital ER group after mTBI, including a decrease in fixation stability (54.6% in patents vs 90.2% in controls, p = 0.014) and binocularity (28.7% in patients vs 86.6% in controls; p = 0.004). Similar trends, not statistically significant, were observed in saccadic latency in the hospital ER group as well as in the injured high school athletes. CONCLUSION: The HITT device shows promise as an objective, noninvasive method for assessment of the impact of mTBI on visuomotor function. Additional studies with larger patient populations are required to evaluate efficacy for clinical use.

Impact of Therapeutic Interventions on Cerebral Autoregulatory Function Following Severe Traumatic Brain Injury: A Secondary Analysis of the BOOST-II Study.

BACKGROUND: The Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II randomized controlled trial used a tier-based management protocol based on brain tissue oxygen (PbtO2) and intracranial pressure (ICP) monitoring to reduce brain tissue hypoxia after severe traumatic brain injury. We performed a secondary analysis to explore the relationship between brain tissue hypoxia, blood pressure (BP), and interventions to improve cerebral perfusion pressure (CPP). We hypothesized that BP management below the lower limit of autoregulation would lead to cerebral hypoperfusion and brain tissue hypoxia that could be improved with hemodynamic augmentation. METHODS: Of the 119 patients enrolled in the Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II trial, 55 patients had simultaneous recordings of arterial BP, ICP, and PbtO2. Autoregulatory function was measured by interrogating changes in ICP and PbtO2 in response to fluctuations in CPP using time-correlation analysis. The resulting autoregulatory indices (pressure reactivity index and oxygen reactivity index) were used to identify the "optimal" CPP and limits of autoregulation for each patient. Autoregulatory function and percent time with CPP outside personalized limits of autoregulation were calculated before, during, and after all interventions directed to optimize CPP. RESULTS: Individualized limits of autoregulation were computed in 55 patients (mean age 38 years, mean monitoring time 92 h). We identified 35 episodes of brain tissue hypoxia (PbtO2 < 20 mm Hg) treated with CPP augmentation. Following each intervention, mean CPP increased from 73 ± 14 mm Hg to 79 ± 17 mm Hg (p = 0.15), and mean PbtO2 improved from 18.4 ± 5.6 mm Hg to 21.9 ± 5.6 mm Hg (p = 0.01), whereas autoregulatory function trended toward improvement (oxygen reactivity index 0.42 vs. 0.37, p = 0.14; pressure reactivity index 0.25 vs. 0.21, p = 0.2). Although optimal CPP and limits remained relatively unchanged, there was a significant decrease in the percent time with CPP below the lower limit of autoregulation in the 60 min after compared with before an intervention (11% vs. 23%, p = 0.05). CONCLUSIONS: Our analysis suggests that brain tissue hypoxia is associated with cerebral hypoperfusion characterized by increased time with CPP below the lower limit of autoregulation. Interventions to increase CPP appear to improve autoregulation. Further studies are needed to validate the importance of autoregulation as a modifiable variable with the potential to improve outcomes.

Connectomic assessment of injury burden and longitudinal structural network alterations in moderate-to-severe traumatic brain injury.

Traumatic brain injury (TBI) is a major public health problem. Caused by external mechanical forces, a major characteristic of TBI is the shearing of axons across the white matter, which causes structural connectivity disruptions between brain regions. This diffuse injury leads to cognitive deficits, frequently requiring rehabilitation. Heterogeneity is another characteristic of TBI as severity and cognitive sequelae of the disease have a wide variation across patients, posing a big challenge for treatment. Thus, measures assessing network-wide structural connectivity disruptions in TBI are necessary to quantify injury burden of individuals, which would help in achieving personalized treatment, patient monitoring, and rehabilitation planning. Despite TBI being a disconnectivity syndrome, connectomic assessment of structural disconnectivity has been relatively limited. In this study, we propose a novel connectomic measure that we call network normality score (NNS) to capture the integrity of structural connectivity in TBI patients by leveraging two major characteristics of the disease: diffuseness of axonal injury and heterogeneity of the disease. Over a longitudinal cohort of moderate-to-severe TBI patients, we demonstrate that structural network topology of patients is more heterogeneous and significantly different than that of healthy controls at 3 months postinjury, where dissimilarity further increases up to 12 months. We also show that NNS captures injury burden as quantified by posttraumatic amnesia and that alterations in the structural brain network is not related to cognitive recovery. Finally, we compare NNS to major graph theory measures used in TBI literature and demonstrate the superiority of NNS in characterizing the disease.

Traumatic Brain Injury and Early Onset Dementia in Post 9-11 Veterans.

OBJECTIVES: To assess traumatic brain injury (TBI)-related risks factors for early-onset dementia (EOD). BACKGROUND: Younger Post-9/11 Veterans may be at elevated risk for EOD due to high rates of TBI in early/mid adulthood. Few studies have explored the longitudinal relationship between traumatic brain injury (TBI) and the emergence of EOD subtypes. METHODS: This matched case-control study used data from the Veterans Health Administration (VHA) to identify Veterans with EOD. To address the low positive predictive value (PPV = 0.27) of dementia algorithms in VHA records, primary outcomes were Alzheimer's disease (AD) and frontotemporal dementia (FTD). Logistic regression identified conditions associated with dementia subtypes. RESULTS: The EOD cohort included Veterans with AD (n = 689) and FTD (n = 284). There were no significant demographic differences between the EOD cohort and their matched controls. After adjustment, EOD was significantly associated with history of TBI (OR: 3.05, 2.42-3.83), epilepsy (OR: 4.8, 3.3-6.97), other neurological conditions (OR: 2.0, 1.35-2.97), depression (OR: 1.35, 1.12-1.63) and cardiac disease (OR: 1.36, 1.1-1.67). CONCLUSION: Post-9/11 Veterans have higher odds of EOD following TBI. A sensitivity analysis across TBI severity confirmed this trend, indicating that the odds for both AD and FTD increased after more severe TBIs.

Remote blast-related mild traumatic brain injury is associated with differential expression of exosomal microRNAs identified in neurodegenerative and immunological processes.

BACKGROUND: Blast traumatic brain injury (TBI) and subconcussive blast exposure have been associated, pathologically, with chronic traumatic encephalopathy (CTE) and, clinically, with cognitive and affective symptoms, but the underlying pathomechanisms of these associations are not well understood. We hypothesized that exosomal microRNA (miRNA) expression, and their relation to neurobehavioral outcomes among Veterans with blunt or blast mild TBI (mTBI) may provide insight into possible mechanisms for these associations and therapeutic targets. METHODS: This is a subanalysis of a larger Chronic Effects of Neurotrauma Consortium Biomarker Discovery Project. Participants (n = 152) were divided into three groups: Controls (n = 35); Blunt mTBI only (n = 54); and Blast/blast+blunt mTBI (n = 63). Postconcussive and post-traumatic stress symptoms were evaluated using the NSI and PCL-5, respectively. Exosomal levels of 798 miRNA expression were measured. RESULTS: In the blast mTBI group, 23 differentially regulated miRNAs were observed compared to the blunt mTBI group and 23 compared to controls. From the pathway analysis, significantly dysregulated miRNAs in the blast exposure group correlated with inflammatory, neurodegenerative, and androgen receptor pathways. DISCUSSION: Our findings suggest that chronic neurobehavioral symptoms after blast TBI may pathomechanistically relate to dysregulated cellular pathways involved with neurodegeneration, inflammation, and central hormonal regulation.

Molecular biomarkers in the neurological ICU: is there a role?

PURPOSE OF REVIEW: The aim of the article is to summarize recent advances in the field of molecular biomarkers in neurocritical care. RECENT FINDINGS: Advances in ultrasensitive immunoassay technology have made it possible to measure brain-derived proteins that are present at subfemtomolar concentrations in blood. These assays have made it possible to measure neurofilament light chain (NfL) in serum or plasma, and early studies indicate that NfL is a promising prognostic and pharmacodynamic biomarker across a broad range of neurologic disorders, including cardiac arrest and traumatic brain injury. However, as acquired brain injury is a complex and heterogeneous disorder, it is likely that assays of panels of biomarkers will ultimately be needed to maximally impact practice. Micro-RNAs are a novel but exciting class of molecules that also show potential to provide clinically actionable information. SUMMARY: Although not yet ready for adoption into routine clinical practice, several molecular biomarkers are on the cusp of clinical validation. The availability of such tests likely will revolutionize the practice of neurocritical care.

Recent Advances in Blood-Based Biomarkers of Remote Combat-Related Traumatic Brain Injury.

PURPOSE OF REVIEW: Traumatic brain injury (TBI) is highly prevalent among service members and Veterans (SMVs) and associated with changes in blood-based biomarkers. This manuscript reviews candidate biomarkers months/years following military-associated TBI. RECENT FINDINGS: Several blood-based biomarkers have been investigated for diagnostic or prognostic use to inform care years after military-associated TBI. The most promising include increased levels of plasma/serum and exosomal proteins reflecting neuronal, axonal and/or vascular injury, and inflammation, as well as altered microRNA expression and auto-antibodies of central nervous system markers. Diagnostic and prognostic biomarkers of remote TBI outcomes remain in the discovery phase. Current evidence does not yet support single or combination biomarkers for clinical diagnostic use remotely after injury, but there are promising candidates that require validation in larger, longitudinal studies. The use of prognostic biomarkers of future neurodegeneration, however, holds much promise and could improve treatments and/or preventive measures for serious TBI outcomes.

Circulating Neurofilament Light Chain Is Associated With Survival After Pediatric Cardiac Arrest.

OBJECTIVES: To characterize neurofilament light levels in children who achieved return of spontaneous circulation following cardiac arrest compared with healthy controls and determine an association between neurofilament light levels and clinical outcomes. DESIGN: Retrospective cohort study. SETTING: Academic quaternary PICU. PATIENTS: Children with banked plasma samples from an acute respiratory distress syndrome biomarker study who achieved return of spontaneous circulation after a cardiac arrest and healthy controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Neurofilament light levels were determined with a highly sensitive single molecule array digital immunoassay. Patients were categorized into survivors and nonsurvivors and into favorable (Pediatric Cerebral Performance Category score of 1-2 or unchanged from baseline) or unfavorable (Pediatric Cerebral Performance Category score of 3-6 or Pediatric Cerebral Performance Category score change ≥1 from baseline). Associations between neurofilament light level and outcomes were determined using Wilcoxon rank-sum test. We enrolled 32 patients with cardiac arrest and 18 healthy controls. Demographics, severity of illness, and baseline Pediatric Cerebral Performance Category scores were similar between survivors and nonsurvivors. Healthy controls had lower median neurofilament light levels than patients after cardiac arrest (5.5 [interquartile range 5.0-8.2] vs 31.0 [12.0-338.6]; p < 0.001). Neurofilament light levels were higher in nonsurvivors than survivors (78.5 [26.2-509.1] vs 12.4 [10.3-28.2]; p = 0.012) and higher in survivors than healthy controls (p = 0.009). The four patients who survived with a favorable outcome had neurofilament light levels that were not different from patients with unfavorable outcomes (21.9 [8.5--35.7] vs 37.2 [15.4-419.1]; p = 0.60) although two of the four patients who survived with favorable outcomes had progressive encephalopathies with both baseline and postcardiac arrest Pediatric Cerebral Performance Category scores of 4. CONCLUSIONS: Neurofilament light is a blood biomarker of hypoxic-ischemic brain injury and may help predict survival and neurologic outcome after pediatric cardiac arrest. Further study in a larger, dedicated cardiac arrest cohort with serial longitudinal measurements is warranted.

Early seizures and temporal lobe trauma predict post-traumatic epilepsy: A longitudinal study.

OBJECTIVE: Injury severity after traumatic brain injury (TBI) is a well-established risk factor for the development of post-traumatic epilepsy (PTE). However, whether lesion location influences the susceptibility of seizures and development of PTE longitudinally has yet to be defined. We hypothesized that lesion location, specifically in the temporal lobe, would be associated with an increased incidence of both early seizures and PTE. As secondary analysis measures, we assessed the degree of brain atrophy and functional recovery, and performed a between-group analysis, comparing patients who developed PTE with those who did not develop PTE. METHODS: We assessed early seizure incidence (n = 90) and longitudinal development of PTE (n = 46) in a prospective convenience sample of patients with moderate-severe TBI. Acutely, patients were monitored with prospective cEEG and a high-resolution Magnetic Resonance Imaging (MRI) scan for lesion location classification. Chronically, patients underwent a high-resolution MRI, clinical assessment, and were longitudinally monitored for development of epilepsy for a minimum of 2 years post-injury. RESULTS: Early seizures, occurring within the first week post-injury, occurred in 26.7% of the patients (n = 90). Within the cohort of subjects who had evidence of early seizures (n = 24), 75% had a hemorrhagic temporal lobe injury on admission. For longitudinal analyses (n = 46), 45.7% of patients developed PTE within a minimum of 2 years post-injury. Within the cohort of subjects who developed PTE (n = 21), 85.7% had a hemorrhagic temporal lobe injury on admission and 38.1% had early (convulsive or non-convulsive) seizures on cEEG monitoring during their acute ICU stay. In a between-group analysis, patients with PTE (n = 21) were more likely than patients who did not develop PTE (n = 25) to have a hemorrhagic temporal lobe injury (p < 0.001), worse functional recovery (p = 0.003), and greater temporal lobe atrophy (p = 0.029). CONCLUSION: Our results indicate that in a cohort of patients with a moderate-severe TBI, 1) lesion location specificity (e.g. the temporal lobe) is related to both a high incidence of early seizures and longitudinal development of PTE, 2) early seizures, whether convulsive or non-convulsive in nature, are associated with an increased risk for PTE development, and 3) patients who develop PTE have greater chronic temporal lobe atrophy and worse functional outcomes, compared to those who do not develop PTE, despite matched injury severity characteristics. This study provides the foundation for a future prospective study focused on elucidating the mechanisms and risk factors for epileptogenesis.

The epilepsy bioinformatics study for anti-epileptogenic therapy (EpiBioS4Rx) clinical biomarker: Study design and protocol.

The Epilepsy Bioinformatics Study for Anti-epileptogenic Therapy (EpiBioS4Rx) is a longitudinal prospective observational study funded by the National Institute of Health (NIH) to discover and validate observational biomarkers of epileptogenesis after traumatic brain injury (TBI). A multidisciplinary approach has been incorporated to investigate acute electrical, neuroanatomical, and blood biomarkers after TBI that may predict the development of post-traumatic epilepsy (PTE). We plan to enroll 300 moderate-severe TBI patients with a frontal and/or temporal lobe hemorrhagic contusion. Acute evaluation with blood, imaging and electroencephalographic monitoring will be performed and then patients will be tracked for 2 years to determine the incidence of PTE. Validation of selected biomarkers that are discovered in planned animal models will be a principal feature of this work. Specific hypotheses regarding the discovery of biomarkers have been set forth in this study. An international cohort of 13 centers spanning 2 continents will be developed to facilitate this study, and for future interventional studies.

Neuroimaging Findings in US Government Personnel With Possible Exposure to Directional Phenomena in Havana, Cuba.

IMPORTANCE: United States government personnel experienced potential exposures to uncharacterized directional phenomena while serving in Havana, Cuba, from late 2016 through May 2018. The underlying neuroanatomical findings have not been described. OBJECTIVE: To examine potential differences in brain tissue volume, microstructure, and functional connectivity in government personnel compared with individuals not exposed to directional phenomena. DESIGN, SETTING, AND PARTICIPANTS: Forty government personnel (patients) who were potentially exposed and experienced neurological symptoms underwent evaluation at a US academic medical center from August 21, 2017, to June 8, 2018, including advanced structural and functional magnetic resonance imaging analytics. Findings were compared with imaging findings of 48 demographically similar healthy controls. EXPOSURES: Potential exposure to uncharacterized directional phenomena of unknown etiology, manifesting as pressure, vibration, or sound. MAIN OUTCOMES AND MEASURES: Potential imaging-based differences between patients and controls with regard to (1) white matter and gray matter total and regional brain volumes, (2) cerebellar tissue microstructure metrics (eg, mean diffusivity), and (3) functional connectivity in the visuospatial, auditory, and executive control subnetworks. RESULTS: Imaging studies were completed for 40 patients (mean age, 40.4 years; 23 [57.5%] men; imaging performed a median of 188 [range, 4-403] days after initial exposure) and 48 controls (mean age, 37.6 years; 33 [68.8%] men). Mean whole brain white matter volume was significantly smaller in patients compared with controls (patients: 542.22 cm3; controls: 569.61 cm3; difference, -27.39 [95% CI, -37.93 to -16.84] cm3; P < .001), with no significant difference in the whole brain gray matter volume (patients: 698.55 cm3; controls: 691.83 cm3; difference, 6.72 [95% CI, -4.83 to 18.27] cm3; P = .25). Among patients compared with controls, there were significantly greater ventral diencephalon and cerebellar gray matter volumes and significantly smaller frontal, occipital, and parietal lobe white matter volumes; significantly lower mean diffusivity in the inferior vermis of the cerebellum (patients: 7.71 × 10-4 mm2/s; controls: 8.98 × 10-4 mm2/s; difference, -1.27 × 10-4 [95% CI, -1.93 × 10-4 to -6.17 × 10-5] mm2/s; P < .001); and significantly lower mean functional connectivity in the auditory subnetwork (patients: 0.45; controls: 0.61; difference, -0.16 [95% CI, -0.26 to -0.05]; P = .003) and visuospatial subnetwork (patients: 0.30; controls: 0.40; difference, -0.10 [95% CI, -0.16 to -0.04]; P = .002) but not in the executive control subnetwork (patients: 0.24; controls: 0.25; difference: -0.016 [95% CI, -0.04 to 0.01]; P = .23). CONCLUSIONS AND RELEVANCE: Among US government personnel in Havana, Cuba, with potential exposure to directional phenomena, compared with healthy controls, advanced brain magnetic resonance imaging revealed significant differences in whole brain white matter volume, regional gray and white matter volumes, cerebellar tissue microstructural integrity, and functional connectivity in the auditory and visuospatial subnetworks but not in the executive control subnetwork. The clinical importance of these differences is uncertain and may require further study.

Epilepsy as a Network Disorder (2): What can we learn from other network disorders such as dementia and schizophrenia, and what are the implications for translational research?

There is common agreement that many disorders of the central nervous system are 'complex', that is, there are many potential factors that influence the development of the disease, underlying mechanisms, and successful treatment. Most of these disorders, unfortunately, have no cure at the present time, and therapeutic strategies often have debilitating side effects. Interestingly, some of the 'complexities' of one disorder are found in another, and the similarities are often network defects. It seems likely that more discussions of these commonalities could advance our understanding and, therefore, have clinical implications or translational impact. With this in mind, the Fourth International Halifax Epilepsy Conference and Retreat was held as described in the prior paper, and this companion paper focuses on the second half of the meeting. Leaders in various subspecialties of epilepsy research were asked to address aging and dementia or psychosis in people with epilepsy (PWE). Commonalities between autism, depression, aging and dementia, psychosis, and epilepsy were the focus of the presentations and discussion. In the last session, additional experts commented on new conceptualization of translational epilepsy research efforts. Here, the presentations are reviewed, and salient points are highlighted.