Safety and Efficacy of Erythropoietin in Traumatic Brain Injury Patients: A Pilot Randomized Trial

Background. Erythropoietin (EPO) is a neuroprotective agent utilized in stroke patients. This pilot study represents the first randomized trial of EPO in traumatic brain injury (TBI) patients. Methods. Adult, blunt trauma patients with evidence of TBI were randomized to EPO or placebo within 6 hours of injury. Baseline and daily serum S-100B and Neuron Specific Enolase (NSE) levels were measured. Results. TBI was worse in the EPO (n = 11) group compared to placebo patients (n = 5). The use of EPO did not impact NSE (P = .89) or S100 B (P = .53) levels compared to placebo. Conclusions. At the dose used, EPO did not reduce neuronal cell death compared to placebo; however, TBI severity was worse in the EPO group while levels of NSE and S100-B were similar to the less injured placebo group making it difficult to rule out a treatment effect. A larger, balanced study is necessary to confirm a potential treatment effect

White matter integrity in physically fit older adults

Background: White matter (WM) integrity declines with normal aging. Physical activity may attenuate age-related WM integrity changes and improve cognitive function. This study examined brain WM integrity in Masters athletes who have engaged in life-long aerobic exercise training. We tested the hypothesis that life-long aerobic training is associated with improved brain WM integrity in older adults. Methods: Ten Masters athletes (3 females, age = 72.2 ± 5.3 years, endurance training \u3e15 years) and 10 sedentary older adults similar in age and educational level (2 females, age = 74.5 ± 4.3 years) participated. MRI fluid-attenuated-inversion-recovery (FLAIR) images were acquired to assess white matter hyperintensities (WMH) volume. Diffusion tensor imaging (DTI) was performed to evaluate the WM microstructural integrity with a DTI-derived metric, fractional anisotropy (FA) and mean diffusivity (MD). Results: After normalization to whole-brain volume, Masters athletes showed an 83% reduction in deep WMH volume relative to their sedentary counterparts (0.05 ± 0.05% vs. 0.29 ± 0.29%, p b 0.05). In addition, we found an inverse relationship between aerobic fitness (VO2max) and deep WMH volume (r = −0.78, p \u3c 0.001). Using TBSS, Masters athletes showed higher FA values in the right superior corona radiata (SCR), both sides of superior longitudinal fasciculus (SLF), right inferior fronto-occipital fasciculus (IFO), and left inferior longitudinal fasciculus (ILF). In addition, Masters athletes also showed lower MD values in the left posterior thalamic radiation (PTR) and left cingulum hippocampus. Conclusions: These findings suggest that life-long exercise is associated with reducedWMH and may preserveWM fiber microstructural integrity related to motor control and coordination in older adults

White matter integrity in physically fit older adults

Background: White matter (WM) integrity declines with normal aging. Physical activity may attenuate age-related WM integrity changes and improve cognitive function. This study examined brain WM integrity in Masters athletes who have engaged in life-long aerobic exercise training. We tested the hypothesis that life-long aerobic training is associated with improved brain WM integrity in older adults. Methods: Ten Masters athletes (3 females, age = 72.2 ± 5.3 years, endurance training \u3e15 years) and 10 sedentary older adults similar in age and educational level (2 females, age = 74.5 ± 4.3 years) participated. MRI fluid-attenuated-inversion-recovery (FLAIR) images were acquired to assess white matter hyperintensities (WMH) volume. Diffusion tensor imaging (DTI) was performed to evaluate the WM microstructural integrity with a DTI-derived metric, fractional anisotropy (FA) and mean diffusivity (MD). Results: After normalization to whole-brain volume, Masters athletes showed an 83% reduction in deep WMH volume relative to their sedentary counterparts (0.05 ± 0.05% vs. 0.29 ± 0.29%, p b 0.05). In addition, we found an inverse relationship between aerobic fitness (VO2max) and deep WMH volume (r = −0.78, p \u3c 0.001). Using TBSS, Masters athletes showed higher FA values in the right superior corona radiata (SCR), both sides of superior longitudinal fasciculus (SLF), right inferior fronto-occipital fasciculus (IFO), and left inferior longitudinal fasciculus (ILF). In addition, Masters athletes also showed lower MD values in the left posterior thalamic radiation (PTR) and left cingulum hippocampus. Conclusions: These findings suggest that life-long exercise is associated with reducedWMH and may preserveWM fiber microstructural integrity related to motor control and coordination in older adults

The Effect of Tamoxifen and Raloxifene on Estrogen Metabolism and Endometrial Cancer Risk

Selective estrogen receptor modulators (SERMs) demonstrate differential endometrial cancer (EC) risk. While tamoxifen (TAM) use increases the risk of endometrial hyperplasia and malignancy, raloxifene (RAL) has neutral effects on the uterus. How TAM increases the risk of EC and why TAM and RAL differentially modulate the risk for EC, however, remain elusive. Here, we tested the hypothesis that TAM increases the risk for EC, at least in part, by enhancing the local estrogen biosynthesis and directing estrogen metabolism towards the formation of genotoxic and hormonally active estrogen metabolites. In addition, the differential effects of TAM and RAL in EC risk are attributed to their differential effect on estrogen metabolism/metabolites. The endometrial cancer cell line (Ishikawa cells) and the nonmalignant immortalized human endometrial glandular cell line (EM1) were used for the study. The profile of estrogen/estrogen metabolites (EM), depurinating estrogen-DNA adducts, and the expression of estrogen-metabolizing enzymes in cells treated with 17β-estradiol (E2) alone or in combination with TAM or RAL were investigated using high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS(2)), ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS), and Western blot analysis, respectively. TAM significantly increased the total EM and enhanced the formation of hormonally active and carcinogenic estrogen metabolites, 4-hydroxestrone (4-OHE1) and 16α-hydroxyestrone, with concomitant reduction in the formation of antiestrogenic and anticarcinogenic 2-hydroxyestradiol and 2-methoxyestradiol. Furthermore, TAM increased the formation of depurinating estrogen-DNA adducts 4-OHE1 [2]-1-N7Guanine and 4-OHE1 [2]-1-N3 Adenine. TAM-induced alteration in EM and depurinating DNA adduct formation is associated with altered expression of estrogen metabolizing enzymes CYP1A1, CYP1B1, COMT, NQO1, and SF-1 as revealed by Western blot analysis. In contrast to TAM, RAL has minimal effect on EM, estrogen-DNA adduct formation, or estrogen-metabolizing enzymes expression. These data show that TAM perturbs the balance of estrogen-metabolizing enzymes and alters the disposition of estrogen metabolites, which can explain, at least in part, the mechanism for TAM-induced EC. These results also implicate the differential effect of TAM and RAL on estrogen metabolism/metabolites as a potential mechanism for their disparate effects on the endometrium

Association of Head Injury with Late-Onset Epilepsy: Results from the Atherosclerosis Risk in Communities Cohort

Background and Objectives Late-onset epilepsy (LOE; i.e., epilepsy starting in later adulthood) affects a significant number of individuals. Head injury is also a risk factor for acquired epilepsy, but the degree to which prior head injury may contribute to LOE is less well understood. Our objective was to determine the association between head injury and subsequent development of LOE. Methods Included were 8,872 participants enrolled in the Atherosclerosis Risk in Communities (ARIC) study with continuous Centers for Medicare Services fee-for-service (FFS) coverage (55.1% women, 21.6% Black). We identified head injuries through 2018 from linked Medicare fee for service claims for inpatient/emergency department care, active surveillance of hospitalizations, and participant self-report. LOE cases through 2018 were identified from linked Medicare FFS claims. We used Cox proportional hazards models to evaluate associations of head injury with LOE, adjusting for demographic, cardiovascular, and lifestyle factors. Results The adjusted hazard ratio (HR) for developing LOE after a history of head injury was 1.88 (95% confidence interval [CI] 1.44-2.43). There was evidence for dose-response associations with greater risk for LOE with increasing number of prior head injuries (HR 1.37, 95% CI 1.01-1.88 for 1 prior head injury and HR 3.55, 95% CI 2.51-5.02 for 2+ prior head injuries, compared to no head injuries) and with more severe head injury (HR 2.53, 95% CI 1.83-3.49 for mild injury and HR 4.90, 95% CI 3.15-7.64 for moderate/severe injury, compared to no head injuries). Associations with LOE were significant for head injuries sustained at older age (age ≥67 years: HR 4.01, 95% CI 2.91-5.54), but not for head injuries sustained at younger age (age < 67 years: HR 0.98, 95% CI 0.68-1.41). Discussion Head injury was associated with increased risk of developing LOE, particularly when head injuries were sustained at an older age, and there was evidence for higher risk for LOE after a greater number of prior head injuries and after more severe head injuries. Classification of Evidence This study provides Class I evidence that an increased risk of late-onset epilepsy is associated with head injury and that this risk increases further with multiple and more severe head injuries

Changes in Plasma von Willebrand Factor and Cellular Fibronectin in MRI-Defined Traumatic Microvascular Injury

The neuropathology of traumatic brain injury (TB) is diverse, including primary injury to neurons, axons, glial cells, vascular structures, and secondary processes, such as edema and inflammation that vary between individual patients. Traumatic microvascular injury is an important endophenotype of TBI-related injury. We studied patients who sustained a TBI requiring ER evaluation and had an MRI performed within 48 h of injury. We classified patients into 3 groups based on their MRI findings: (1) those that had evidence of traumatic microvascular injury on susceptibility or diffusion weighted MRI sequences without frank hemorrhage [Traumatic Vascular Injury (TVI) group; 20 subjects]. (2) those who had evidence of intraparenchymal, subdural, epidural, or subarachnoid hemorrhage [Traumatic Hemorrhage (TH) group; 26 subjects], and (3) those who had no traumatic injuries detected by MRI [MRI-negative group; 30 subjects]. We then measured plasma protein biomarkers of vascular injury [von Willebrand Factor (vWF) or cellular fibronectin (cFn)] and axonal injury (phosphorylated neurofilament heavy chain; pNF-H). We found that the TVI group was characterized by decreased expression of plasma vWF (p < 0.05 compared to MRI-negative group; p < 0.00001 compared to TH group) <= 48 h after injury. cFN was no different between groups <= 48 h after injury, but was increased in the TVI group compared to the MRI-negative (p < 0.00001) and TH (p < 0.00001) groups when measured <= 48 h from injury. pNF-H was increased in both the TH and TVI groups compared to the MRI-negative group <= 48 h from injury. When we used the MRI grouping and molecular biomarkers in a model to predict Glasgow Outcome Scale-Extended (GOS-E) score at 30-90 days, we found that inclusion of the imaging data and biomarkers substantially improved the ability to predict a good outcome over clinical information alone. These data indicate that there is a distinct, vascular-predominant endophenotype in a subset of patients who sustain a TBI and that these injuries are characterized by a specific biomarker profile. Further work to will be needed to determine whether these biomarkers can be useful as predictive and pharmacodynamic biomarkers for vascular-directed therapies after TBI

Frontal traumatic brain injury in rats causes long-lasting impairments in impulse control that are differentially sensitive to pharmacotherapeutics and associated with chronic neuroinflammation.

Traumatic brain injury (TBI) affects millions yearly, and is increasingly associated with chronic neuropsychiatric symptoms. We assessed the long-term effects of different bilateral frontal controlled cortical impact injury severities (mild, moderate, severe) on the five-choice serial reaction time task, a paradigm with relatively independent measurements of attention, motor impulsivity and motivation. Moderately- and severely-injured animals exhibited impairments across all cognitive domains that were still evident 14 weeks post-injury, while mild-injured animals only demonstrated persistent deficits in impulse control. However, recovery of function varied considerably between subjects such that some showed no impairment (“TBI-resilient”), some demonstrated initial deficits that recovered (“TBI-vulnerable”) and some never recovered (“chronically-impaired”). Three clinically-relevant treatments for impulsecontrol or TBI, amphetamine, atomoxetine, and amantadine, were assessed for efficacy in treating injury-induced deficits. Susceptibility to TBI affected the response to pharmacological challenge with amphetamine. Whereas sham and TBI-resilient animals showed characteristic impairments in impulse control at higher doses, amphetamine had the opposite effect in chronically-impaired rats, improving task performance. In contrast, atomoxetine and amantadine reduced premature responding but increased omissions, suggesting psychomotor slowing. Analysis of brain tissue revealed that generalized neuroinflammation was associated with impulsivity even when accounting for the degree of brain damage. This is one of the first studies to characterize psychiatric-like symptoms in experimental TBI. Our data highlight the importance of testing pharmacotherapies in TBI models in order to predict efficacy, and suggest that neuroinflammation may represent a treatment target for impulse control problems following injury

Pathological Computed Tomography Features Associated with Adverse Outcomes after Mild Traumatic Brain Injury:A TRACK-TBI Study with External Validation in CENTER-TBI

Importance: A head computed tomography (CT) with positive results for acute intracranial hemorrhage is the gold-standard diagnostic biomarker for acute traumatic brain injury (TBI). In moderate to severe TBI (Glasgow Coma Scale [GCS] scores 3-12), some CT features have been shown to be associated with outcomes. In mild TBI (mTBI; GCS scores 13-15), distribution and co-occurrence of pathological CT features and their prognostic importance are not well understood. Objective: To identify pathological CT features associated with adverse outcomes after mTBI. Design, Setting, and Participants: The longitudinal, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled patients with TBI, including those 17 years and older with GCS scores of 13 to 15 who presented to emergency departments at 18 US level 1 trauma centers between February 26, 2014, and August 8, 2018, and underwent head CT imaging within 24 hours of TBI. Evaluations of CT imaging used TBI Common Data Elements. Glasgow Outcome Scale-Extended (GOSE) scores were assessed at 2 weeks and 3, 6, and 12 months postinjury. External validation of results was performed via the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Data analyses were completed from February 2020 to February 2021. Exposures: Acute nonpenetrating head trauma. Main Outcomes and Measures: Frequency, co-occurrence, and clustering of CT features; incomplete recovery (GOSE scores <8 vs 8); and an unfavorable outcome (GOSE scores <5 vs ≥5) at 2 weeks and 3, 6, and 12 months. Results: In 1935 patients with mTBI (mean [SD] age, 41.5 [17.6] years; 1286 men [66.5%]) in the TRACK-TBI cohort and 2594 patients with mTBI (mean [SD] age, 51.8 [20.3] years; 1658 men [63.9%]) in an external validation cohort, hierarchical cluster analysis identified 3 major clusters of CT features: contusion, subarachnoid hemorrhage, and/or subdural hematoma; intraventricular and/or petechial hemorrhage; and epidural hematoma. Contusion, subarachnoid hemorrhage, and/or subdural hematoma features were associated with incomplete recovery (odds ratios [ORs] for GOSE scores <8 at 1 year: TRACK-TBI, 1.80 [95% CI, 1.39-2.33]; CENTER-TBI, 2.73 [95% CI, 2.18-3.41]) and greater degrees of unfavorable outcomes (ORs for GOSE scores <5 at 1 year: TRACK-TBI, 3.23 [95% CI, 1.59-6.58]; CENTER-TBI, 1.68 [95% CI, 1.13-2.49]) out to 12 months after injury, but epidural hematoma was not. Intraventricular and/or petechial hemorrhage was associated with greater degrees of unfavorable outcomes up to 12 months after injury (eg, OR for GOSE scores <5 at 1 year in TRACK-TBI: 3.47 [95% CI, 1.66-7.26]). Some CT features were more strongly associated with outcomes than previously validated variables (eg, ORs for GOSE scores <5 at 1 year in TRACK-TBI: neuropsychiatric history, 1.43 [95% CI.98-2.10] vs contusion, subarachnoid hemorrhage, and/or subdural hematoma, 3.23 [95% CI 1.59-6.58]). Findings were externally validated in 2594 patients with mTBI enrolled in the CENTER-TBI study. Conclusions and Relevance: In this study, pathological CT features carried different prognostic implications after mTBI to 1 year postinjury. Some patterns of injury were associated with worse outcomes than others. These results support that patients with mTBI and these CT features need TBI-specific education and systematic follow-up