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

Duration of Posttraumatic Amnesia Predicts Neuropsychological and Global Outcome in Complicated Mild Traumatic Brain Injury.

OBJECTIVES: Examine the effects of posttraumatic amnesia (PTA) duration on neuropsychological and global recovery from 1 to 6 months after complicated mild traumatic brain injury (cmTBI). PARTICIPANTS: A total of 330 persons with cmTBI defined as Glasgow Coma Scale score of 13 to 15 in emergency department, with well-defined abnormalities on neuroimaging. METHODS: Enrollment within 24 hours of injury with follow-up at 1, 3, and 6 months. MEASURES: Glasgow Outcome Scale-Extended, California Verbal Learning Test II, and Controlled Oral Word Association Test. Duration of PTA was retrospectively measured with structured interview at 30 days postinjury. RESULTS: Despite all having a Glasgow Coma Scale Score of 13 to 15, a quarter of the sample had a PTA duration of greater than 7 days; half had PTA duration of 1 of 7 days. Both cognitive performance and Extended Glasgow Outcome Scale outcomes were strongly associated with time since injury and PTA duration, with those with PTA duration of greater than 1 week showing residual moderate disability at 6-month assessment. CONCLUSIONS: Findings reinforce importance of careful measurement of duration of PTA to refine outcome prediction and allocation of resources to those with cmTBI. Future research would benefit from standardization in computed tomographic criteria and use of severity indices beyond Glasgow Coma Scale to characterize cmTBI

The chronic and evolving neurological consequences of traumatic brain injury.

Traumatic brain injury (TBI) can have lifelong and dynamic effects on health and wellbeing. Research on the long-term consequences emphasises that, for many patients, TBI should be conceptualised as a chronic health condition. Evidence suggests that functional outcomes after TBI can show improvement or deterioration up to two decades after injury, and rates of all-cause mortality remain elevated for many years. Furthermore, TBI represents a risk factor for a variety of neurological illnesses, including epilepsy, stroke, and neurodegenerative disease. With respect to neurodegeneration after TBI, post-mortem studies on the long-term neuropathology after injury have identified complex persisting and evolving abnormalities best described as polypathology, which includes chronic traumatic encephalopathy. Despite growing awareness of the lifelong consequences of TBI, substantial gaps in research exist. Improvements are therefore needed in understanding chronic pathologies and their implications for survivors of TBI, which could inform long-term health management in this sizeable patient population

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

APOE ɛ4 is associated with postictal confusion in patients with medically refractory temporal lobe epilepsy

This study examined the relationship between the APOE ɛ4 allele and postictal confusion in patients with medically intractable temporal lobe epilepsy (TLE). Patients with at least one ɛ4 allele (n = 22) were three times more likely to exhibit postictal confusion (68%) than the 63 patients without ɛ4 (43%). These preliminary results demonstrate that APOE ɛ4 is associated with an increased risk of postictal confusion in patients with medically intractable TLE, suggesting possible dysfunction in neuronal recovery mechanisms

Long-term Multidomain Patterns of Change After Traumatic Brain Injury: A TRACK-TBI LONG Study.

BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) may be a chronic condition carrying risk of future sequelae; few prospective studies examine long-term postinjury outcomes. We examined the prevalence of functional, cognitive, and psychiatric change outcomes from 1 to 7 years postinjury. METHODS: Transforming Research and Clinical Knowledge in TBI LONG (TRACK-TBI LONG) participants were prospectively enrolled within 24 hours of injury and followed up to 1 year postinjury; a subset participated in long-term follow-up from 2 to 7 years postinjury. Reliable change thresholds for the Brief Test of Adult Cognition by Telephone General Composite (cognition) and Brief Symptom Inventory (BSI)-18 (psychiatric) were derived from orthopedic trauma controls (OTCs). Multiple assessments were completed (postinjury baseline assessment and 2 or 3 visits 2-7 years postinjury) within a sample subset. Change was assessed for functional outcome (Glasgow Outcome Scale-Extended [GOSE]) and self-report/informant report of decline. Prevalence ratios for outcomes classified as stable, improved, and declined were reported individually and collectively. The Fisher exact test and log-binomial regression models examined factors associated with decline and improvement. RESULTS: Of the sample (N = 1,264; mild TBI [mTBI], Glasgow Coma Scale [GCS] 13-15, n = 917; moderate-to-severe TBI [msTBI], GCS 3-12, n = 193; or OTC n = 154), stable was the most prevalent outcome. Functional outcome showed the highest rates of decline, regardless of TBI severity (mild = 29%; moderate/severe = 23%). When measures were collectively considered, rates of decline included mTBI (21%), msTBI (26%), and OTC (15%). Age and preinjury employment status were associated with functional decline (per 10 years; relative risk [RR] 1.16, 95% CI 1.07-1.25, p < 0.001; higher in retired/disabled/not working vs full-time/part-time; RR 1.81, 95% CI 1.33-2.45, respectively) in the mTBI group. Improvement in functional recovery 2-7 years postinjury was associated with higher BSI scores (per 5 points; RR 1.11, 95% CI 1.04-1.18, p = 0.002) and GOSE score of 5-7 (GOSE = 8 as reference; RR 2.64, 95% CI 1.75-3.97, p < 0.001). Higher BSI scores and identifying as Black (RR 2.28, 95% CI 1.59-3.25, p < 0.001) were associated with a greater likelihood of improved psychiatric symptoms in mTBI (RR 1.21, 95% CI 1.14-1.29, p < 0.001). A greater likelihood of cognitive improvement was observed among those with higher educational attainment in msTBI (per 4 years; RR 2.61, 95% CI 1.43-4.79, p = 0.002). DISCUSSION: Function across domains at 1-year postinjury, a common recovery benchmark, undergoes change across the subsequent 6 years. Results support consideration of TBI as a chronic evolving condition and suggest continued monitoring, rehabilitation, and support is required to optimize long-term independence and quality of life

Common Data Elements for Traumatic Brain Injury: Recommendations From the Biospecimens and Biomarkers Working Group

Recent advances in genomics, proteomics, and biotechnology have provided unprecedented opportunities for translational research and personalized medicine. Human biospecimens and biofluids represent an important resource from which molecular data can be generated to detect and classify injury and to identify molecular mechanisms and therapeutic targets. To date, there has been considerable variability in biospecimen and biofluid collection, storage, and processing in traumatic brain injury (TBI) studies. To realize the full potential of this important resource, standardization and adoption of best practice guidelines are required to insure the quality and consistency of these specimens. The aim of the Biospecimens and Biomarkers Working Group was to provide recommendations for core data elements for TBI research and develop best practice guidelines to standardize the quality and accessibility of these specimens. Consensus recommendations were developed through interactions with focus groups and input from stakeholders participating in the interagency workshop on Standardization of Data Collection in TBI and Psychological Health held in Washington, DC, in March 2009. With the adoption of these standards and best practices, future investigators will be able to obtain data across multiple studies with reduced costs and effort and accelerate the progress of genomic, proteomic, and metabolomic research in TBI

Genome-wide association of familial late-onset alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE

Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10-81), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10-8). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies. © 2011 Wijsman et al