Annually in the United States, at least 3.5 million people seek medical attention for traumatic brain injury (TBI). The development of therapies for TBI is limited by the absence of diagnostic and ...prognostic biomarkers. Microtubule-associated protein tau is an axonal phosphoprotein. To date, the presence of the hypophosphorylated tau protein (P-tau) in plasma from patients with acute TBI and chronic TBI has not been investigated.
To examine the associations between plasma P-tau and total-tau (T-tau) levels and injury presence, severity, type of pathoanatomic lesion (neuroimaging), and patient outcomes in acute and chronic TBI.
In the TRACK-TBI Pilot study, plasma was collected at a single time point from 196 patients with acute TBI admitted to 3 level I trauma centers (<24 hours after injury) and 21 patients with TBI admitted to inpatient rehabilitation units (mean SD, 176.4 44.5 days after injury). Control samples were purchased from a commercial vendor. The TRACK-TBI Pilot study was conducted from April 1, 2010, to June 30, 2012. Data analysis for the current investigation was performed from August 1, 2015, to March 13, 2017.
Plasma samples were assayed for P-tau (using an antibody that specifically recognizes phosphothreonine-231) and T-tau using ultra-high sensitivity laser-based immunoassay multi-arrayed fiberoptics conjugated with rolling circle amplification.
In the 217 patients with TBI, 161 (74.2%) were men; mean (SD) age was 42.5 (18.1) years. The P-tau and T-tau levels and P-tau-T-tau ratio in patients with acute TBI were higher than those in healthy controls. Receiver operating characteristic analysis for the 3 tau indices demonstrated accuracy with area under the curve (AUC) of 1.000, 0.916, and 1.000, respectively, for discriminating mild TBI (Glasgow Coma Scale GCS score, 13-15, n = 162) from healthy controls. The P-tau level and P-tau-T-tau ratio were higher in individuals with more severe TBI (GCS, ≤12 vs 13-15). The P-tau level and P-tau-T-tau ratio outperformed the T-tau level in distinguishing cranial computed tomography-positive from -negative cases (AUC = 0.921, 0.923, and 0.646, respectively). Acute P-tau levels and P-tau-T-tau ratio weakly distinguished patients with TBI who had good outcomes (Glasgow Outcome Scale-Extended GOS-E, 7-8) (AUC = 0.663 and 0.658, respectively) and identified those with poor outcomes (GOS-E, ≤4 vs >4) (AUC = 0.771 and 0.777, respectively). Plasma samples from patients with chronic TBI also showed elevated P-tau levels and a P-tau-T-tau ratio significantly higher than that of healthy controls, with both P-tau indices strongly discriminating patients with chronic TBI from healthy controls (AUC = 1.000 and 0.963, respectively).
Plasma P-tau levels and P-tau-T-tau ratio outperformed T-tau level as diagnostic and prognostic biomarkers for acute TBI. Compared with T-tau levels alone, P-tau levels and P-tau-T-tau ratios show more robust and sustained elevations among patients with chronic TBI.
Objective
To determine the clinical relevance, if any, of traumatic intracranial findings on early head computed tomography (CT) and brain magnetic resonance imaging (MRI) to 3‐month outcome in mild ...traumatic brain injury (MTBI).
Methods
One hundred thirty‐five MTBI patients evaluated for acute head injury in emergency departments of 3 LEVEL I trauma centers were enrolled prospectively. In addition to admission head CT, early brain MRI was performed 12 ± 3.9 days after injury. Univariate and multivariate logistic regression were used to assess for demographic, clinical, socioeconomic, CT, and MRI features that were predictive of Extended Glasgow Outcome Scale (GOS‐E) at 3 months postinjury.
Results
Twenty‐seven percent of MTBI patients with normal admission head CT had abnormal early brain MRI. CT evidence of subarachnoid hemorrhage was associated with a multivariate odds ratio of 3.5 (p = 0.01) for poorer 3‐month outcome, after adjusting for demographic, clinical, and socioeconomic factors. One or more brain contusions on MRI, and ≥4 foci of hemorrhagic axonal injury on MRI, were each independently associated with poorer 3‐month outcome, with multivariate odds ratios of 4.5 (p = 0.01) and 3.2 (p = 0.03), respectively, after adjusting for head CT findings and demographic, clinical, and socioeconomic factors.
Interpretation
In this prospective multicenter observational study, the clinical relevance of abnormal findings on early brain imaging after MTBI is demonstrated. The addition of early CT and MRI markers to a prognostic model based on previously known demographic, clinical, and socioeconomic predictors resulted in a >2‐fold increase in the explained variance in 3‐month GOS‐E. ANN NEUROL 2013;73:224–235
Priming is a nonconscious form of memory that involves a change in a person's ability to identify, produce or classify an item as a result of a previous encounter with that item or a related item. ...One important question relates to the specificity of priming - the extent to which priming reflects the influence of abstract representations or the retention of specific features of a previous episode. Cognitive neuroscience analyses provide evidence for three types of specificity: stimulus, associative and response. We consider empirical, methodological and conceptual issues that relate to each type of specificity, and suggest a theoretical perspective to help in guiding future research.
The Indoor Air Quality (IAQ) of the bedroom environment has recently garnered attention since air pollution can affect sleep. Previous studies investigated IAQ and sleep quality in controlled ...environments which impacts both self-reported and measured sleep quality. Studies within a participant’s home environment are ecologically valid and reduce participant bias. Here, we study 20 participants over 77 days in Austin, TX. We monitored five components of IAQ using the BEVO Beacon, a calibrated purpose-built environmental monitor, and measured participant sleep quality through wearable activity trackers and 4-question surveys sent four times a week. We found significant decreases in sleep quality during nights with elevated CO, CO2, and temperature. Elevated CO was associated with a mean increase in 0.9 self-reported awakenings and decreases in device-measured sleep time of 21.6 min and sleep efficiency of 0.6%. Increased CO2 and temperature were associated with decreases in device-measured sleep time of 17.5 and 15.2 min, respectively. Elevated PM2.5 and TVOCs concentrations were associated with overall improvements in sleep quality. Participants reported a mean of 4.4 fewer awakenings and had a 1.1% increased in measured sleep efficiency for nights with elevated PM2.5. Elevated TVOCs were associated with an increase in sleep time of 14.5 min. These findings indicate a need to study the relationship between these aggregate IAQ measures and sleep quality more closely. Our results also indicate that pollutants can independently affect sleep quality regardless of the CO2 measurements. Compared to literature, our study is the longest and includes the most IAQ parameters.
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•Low-cost sensors allow the study of a variety of variables across many individuals.•Elevated CO, CO2, and temperature were associated with worse sleep quality.•Elevated PM and TVOCs were associated with improvements in some sleep metrics.•Only TST was correlated between self-reported and device-measured sleep quality.
Physical activity has been found to alter sleep architecture, but these effects have been studied predominantly in the laboratory and the generalizability of these findings to naturalistic ...environments and longer time intervals, as well as their psychological effects, have not been evaluated. Recent technological advancements in wearable devices have made it possible to capture detailed measures of sleep outside the lab, including timing of specific sleep stages. In the current study, we utilized photoplethysmography coupled with accelerometers and smartphone ambulatory assessment to collect daily measurements of sleep, physical activity and mood in a sample of N = 82 over multi-month data collection intervals. We found a robust inverse relationship between sedentary behavior and physical activity and sleep architecture: both low-intensity and moderate-to-vigorous physical activity were associated with increased NREM sleep and decreased REM sleep, as well as a longer REM latency, while higher levels of sedentary behavior showed the opposite pattern. A decreased REM/NREM ratio and increased REM latency were in turn associated with improved wellbeing, including increased energy, reduced stress and enhanced perceived restfulness of sleep. Our results suggest that physical activity and sleep account for unique variance in a person's mood, suggesting that these effects are at least partially independent.
Reliable diagnosis of traumatic brain injury (TBI) is a major public health need. Glial fibrillary acidic protein (GFAP) is expressed in the central nervous system, and breakdown products (GFAP-BDP) ...are released following parenchymal brain injury. Here, we evaluate the diagnostic accuracy of elevated levels of plasma GFAP-BDP in TBI. Participants were identified as part of the prospective Transforming Research And Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study. Acute plasma samples (<24 h post-injury) were collected from patients presenting with brain injury who had CT imaging. The ability of GFAP-BDP level to discriminate patients with demonstrable traumatic lesions on CT, and with failure to return to pre-injury baseline at 6 months, was evaluated by the area under the receiver operating characteristic curve (AUC). Of the 215 patients included for analysis, 83% had mild, 4% had moderate, and 13% had severe TBI; 54% had acute traumatic lesions on CT. The ability of GFAP-BDP level to discriminate patients with traumatic lesions on CT as evaluated by AUC was 0.88 (95% confidence interval CI, 0.84-0.93). The optimal cutoff of 0.68 ng/mL for plasma GFAP-BDP level was associated with a 21.61 odds ratio for traumatic findings on head CT. Discriminatory ability of unfavorable 6 month outcome was lower, AUC 0.65 (95% CI, 0.55-0.74), with a 2.07 odds ratio. GFAP-BDP levels reliably distinguish the presence and severity of CT scan findings in TBI patients. Although these findings confirm and extend prior studies, a larger prospective trial is still needed to validate the use of GFAP-BDP as a routine diagnostic biomarker for patient care and clinical research. The term "mild" continues to be a misnomer for this patient population, and underscores the need for evolving classification strategies for TBI targeted therapy. (ClinicalTrials.gov number NCT01565551; NIH Grant 1RC2 NS069409).
We evaluated 3T diffusion tensor imaging (DTI) for white matter injury in 76 adult mild traumatic brain injury (mTBI) patients at the semiacute stage (11.2±3.3 days), employing both whole-brain ...voxel-wise and region-of-interest (ROI) approaches. The subgroup of 32 patients with any traumatic intracranial lesion on either day-of-injury computed tomography (CT) or semiacute magnetic resonance imaging (MRI) demonstrated reduced fractional anisotropy (FA) in numerous white matter tracts, compared to 50 control subjects. In contrast, 44 CT/MRI-negative mTBI patients demonstrated no significant difference in any DTI parameter, compared to controls. To determine the clinical relevance of DTI, we evaluated correlations between 3- and 6-month outcome and imaging, demographic/socioeconomic, and clinical predictors. Statistically significant univariable predictors of 3-month Glasgow Outcome Scale-Extended (GOS-E) included MRI evidence for contusion (odds ratio OR 4.9 per unit decrease in GOS-E; p=0.01), ≥1 ROI with severely reduced FA (OR, 3.9; p=0.005), neuropsychiatric history (OR, 3.3; p=0.02), age (OR, 1.07/year; p=0.002), and years of education (OR, 0.79/year; p=0.01). Significant predictors of 6-month GOS-E included ≥1 ROI with severely reduced FA (OR, 2.7; p=0.048), neuropsychiatric history (OR, 3.7; p=0.01), and years of education (OR, 0.82/year; p=0.03). For the subset of 37 patients lacking neuropsychiatric and substance abuse history, MRI surpassed all other predictors for both 3- and 6-month outcome prediction. This is the first study to compare DTI in individual mTBI patients to conventional imaging, clinical, and demographic/socioeconomic characteristics for outcome prediction. DTI demonstrated utility in an inclusive group of patients with heterogeneous backgrounds, as well as in a subset of patients without neuropsychiatric or substance abuse history.
Brain-derived neurotrophic factor (BDNF) is important for neuronal survival and regeneration. We investigated the diagnostic and prognostic values of serum BDNF in traumatic brain injury (TBI). We ...examined serum BDNF in two independent cohorts of TBI cases presenting to the emergency departments (EDs) of the Johns Hopkins Hospital (JHH; n = 76) and San Francisco General Hospital (SFGH, n = 80), and a control group of JHH ED patients without TBI (n = 150). Findings were subsequently validated in the prospective, multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot study (n = 159). We investigated the association between BDNF, glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) and recovery from TBI at 6 months in the TRACK-TBI Pilot cohort. Incomplete recovery was defined as having either post-concussive syndrome or a Glasgow Outcome Scale Extended score <8 at 6 months. Median day-of-injury BDNF concentrations (ng/mL) were lower among TBI cases (JHH TBI, 17.5 and SFGH TBI, 13.8) than in JHH controls (60.3; p = 0.0001). Among TRACK-TBI Pilot subjects, median BDNF concentrations (ng/mL) were higher in mild (8.3) than in moderate (4.3) or severe TBI (4.0; p = 0.004. In the TRACK-TBI cohort, the 75 (71.4%) subjects with very low BDNF values (i.e., <the 1st percentile for non-TBI controls, <14.2 ng/mL) had higher odds of incomplete recovery than those who did not have very low values (odds ratio, 4.0; 95% confidence interval CI: 1.5-11.0). The area under the receiver operator curve for discriminating complete and incomplete recovery was 0.65 (95% CI: 0.52-0.78) for BDNF, 0.61 (95% CI: 0.49-0.73) for GFAP, and 0.55 (95% CI: 0.43-0.66) for UCH-L1. The addition of GFAP/UCH-L1 to BDNF did not improve outcome prediction significantly. Day-of-injury serum BDNF is associated with TBI diagnosis and also provides 6-month prognostic information regarding recovery from TBI. Thus, day-of-injury BDNF values may aid in TBI risk stratification.
Recent observation of objects speeds up their subsequent identification and classification. This common form of learning, known as repetition priming, can operate in the absence of explicit memory ...for earlier experiences, and functional neuroimaging has shown that object classification improved in this way is accompanied by 'neural priming' (reduced neural activity) in prefrontal, fusiform and other cortical regions. These observations have led to suggestions that cortical representations of items undergo 'tuning', whereby neurons encoding irrelevant information respond less as a given object is observed repeatedly, thereby facilitating future availability of pertinent object knowledge. Here we provide experimental support for an alternative hypothesis, in which reduced cortical activity occurs because subjects rapidly learn their previous responses. After a primed object classification (such as 'bigger than a shoebox'), cue reversal ('smaller than a shoebox') greatly slowed performance and completely eliminated neural priming in fusiform cortex, which suggests that these cortical item representations were no more available for primed objects than they were for new objects. In contrast, prefrontal cortex activity tracked behavioural priming and predicted the degree to which cue reversal would slow down object classification-highlighting the role of the prefrontal cortex in executive control.
Abstract Using MRI to diagnose mental disorders has been a long-term goal. Despite this, the vast majority of prior neuroimaging work has been descriptive rather than predictive. The current study ...applies support vector machine (SVM) learning to MRI measures of brain white matter to classify adults with Major Depressive Disorder (MDD) and healthy controls. In a precisely matched group of individuals with MDD ( n =25) and healthy controls ( n =25), SVM learning accurately (74%) classified patients and controls across a brain map of white matter fractional anisotropy values (FA). The study revealed three main findings: 1) SVM applied to DTI derived FA maps can accurately classify MDD vs. healthy controls; 2) prediction is strongest when only right hemisphere white matter is examined; and 3) removing FA values from a region identified by univariate contrast as significantly different between MDD and healthy controls does not change the SVM accuracy. These results indicate that SVM learning applied to neuroimaging data can classify the presence versus absence of MDD and that predictive information is distributed across brain networks rather than being highly localized. Finally, MDD group differences revealed through typical univariate contrasts do not necessarily reveal patterns that provide accurate predictive information.
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