We described recently a subacute serum autoantibody response toward glial fibrillary acidic protein (GFAP) and its breakdown products 5-10 days after severe traumatic brain injury (TBI). Here, we ...expanded our anti-GFAP autoantibody (AutoAbGFAP) investigation to the multicenter observational study Transforming Research and Clinical Knowledge in TBI Pilot (TRACK-TBI Pilot) to cover the full spectrum of TBI (Glasgow Coma Scale 3-15) by using acute (<24 h) plasma samples from 196 patients with acute TBI admitted to three Level I trauma centers, and a second cohort of 21 participants with chronic TBI admitted to inpatient TBI rehabilitation. We find that acute patients self-reporting previous TBI with loss of consciousness (LOC) (n = 43) had higher day 1 AutoAbGFAP (mean ± standard error: 9.11 ± 1.42; n = 43) than healthy controls (2.90 ± 0.92; n = 16; p = 0.032) and acute patients reporting no previous TBI (2.97 ± 0.37; n = 106; p < 0.001), but not acute patients reporting previous TBI without LOC (8.01 ± 1.80; n = 47; p = 0.906). These data suggest that while exposure to TBI may trigger the AutoAbGFAP response, circulating antibodies are elevated specifically in acute TBI patients with a history of TBI. AutoAbGFAP levels for participants with chronic TBI (average post-TBI time 176 days or 6.21 months) were also significantly higher (15.08 ± 2.82; n = 21) than healthy controls (p < 0.001). These data suggest a persistent upregulation of the autoimmune response to specific brain antigen(s) in the subacute to chronic phase after TBI, as well as after repeated TBI insults. Hence, AutoAbGFAP may be a sensitive assay to study the dynamic interactions between post-injury brain and patient-specific autoimmune responses across acute and chronic settings after TBI.
Background
Although acute neurologic impairment might be transient, other long-term effects can be observed with mild traumatic brain injury. However, when pediatric patients with mild traumatic ...brain injury present for medical care, conventional imaging with CT and MR imaging often does not reveal abnormalities.
Objective
To determine whether edge density imaging can separate pediatric mild traumatic brain injury from typically developing controls.
Materials and methods
Subjects were recruited as part of the “Therapeutic Resources for Attention Improvement using Neuroimaging in Traumatic Brain Injury” (TRAIN-TBI) study. We included 24 adolescents (χ=14.1 years of age, σ=1.6 years, range 10–16 years), 14 with mild traumatic brain injury (TBI) and 10 typically developing controls. Neurocognitive assessments included the pediatric version of the California Verbal Learning Test (CVLT) and the Attention Network Task (ANT). Diffusion MR imaging was acquired on a 3-tesla (T) scanner. Edge density images were computed utilizing fiber tractography. Principal component analysis (PCA) and support vector machines (SVM) were used in an exploratory analysis to separate mild TBI and control groups. The diagnostic accuracy of edge density imaging, neurocognitive tests, and fractional anisotropy (FA) from diffusion tensor imaging (DTI) was computed with two-sample
t
-tests and receiver operating characteristic (ROC) metrics.
Results
Support vector machine–principal component analysis of edge density imaging maps identified three white matter regions distinguishing pediatric mild TBI from controls. The bilateral tapetum, sagittal stratum, and callosal splenium identified mild TBI subjects with sensitivity of 79% and specificity of 100%. Accuracy from the area under the ROC curve (AUC) was 94%. Neurocognitive testing provided an AUC of 61% (CVLT) and 71% (ANT). Fractional anisotropy yielded an AUC of 48%.
Conclusion
In this proof-of-concept study, we show that edge density imaging is a new form of connectome mapping that provides better diagnostic delineation between pediatric mild TBI and healthy controls than DTI or neurocognitive assessments of memory or attention.
The National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH-NINDS) Traumatic Brain Injury (TBI) Imaging Common Data Elements (CDEs) are standardized definitions for ...pathological intracranial lesions based on their appearance on neuroimaging studies. The NIH-NINDS TBI Imaging CDEs were designed to be as consistent as possible with the U.S. Food and Drug Administration (FDA) definition of biomarkers as "an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention." However, the FDA qualification process for biomarkers requires proof of reliable biomarker test measurements. We determined the interrater reliability of TBI Imaging CDEs on subacute brain magnetic resonance imaging (MRI) performed on 517 mild TBI patients presenting to 11 U.S. level 1 trauma centers. Three U.S. board-certified neuroradiologists independently evaluated brain MRI performed 2 weeks post-injury for the following CDEs: traumatic axonal injury (TAI), diffuse axonal injury (DAI), and brain contusion. We found very high interrater agreement for brain contusion, with prevalence- and bias-adjusted kappa (PABAK) values for pairs of readers from 0.92 95% confidence interval, 0.88-0.95 to 0.94 0.90-0.96. We found intermediate agreement for TAI and DAI, with PABAK values of 0.74-0.78 0.70-0.82. The near-perfect agreement for subacute brain contusion is likely attributable to the high conspicuity and distinctive appearance of these lesions on T1-weighted images. Interrater agreement for TAI and DAI was lower, because signal void in small vascular structures, and artifactual foci of signal void, can be difficult to distinguish from the punctate round or linear areas of slight hemorrhage that are a common hallmark of TAI/DAI on MRI.
Introduction: Risk factors for young adults with mTBI are not well understood. Improved understanding of age and sex as risk factors for impaired six-month outcomes in young adults is needed.
...Methods: Young adult mTBI subjects aged 18-39 years (18-29y; 30-39y) with six-month outcomes were extracted from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study. Multivariable regressions were performed for outcomes with age, sex, and the interaction factor age-group*sex as variables of interest, controlling for demographic and injury variables. Mean-differences (B) and 95% CIs are reported.
Results: One hundred mTBI subjects (18-29y, 70%; 30-39y, 30%; male, 71%; female, 29%) met inclusion criteria. On multivariable analysis, age-group*sex was associated with six-month post-traumatic stress disorder (PTSD; PTSD Checklist-Civilian version); compared with female 30-39y, female 18-29y (B= −19.55 −26.54, −4.45), male 18-29y (B= −19.70 −30.07, −9.33), and male 30-39y (B= −15.49 −26.54, −4.45) were associated with decreased PTSD symptomatology. Female sex was associated with decreased six-month functional outcome (Glasgow Outcome Scale-Extended (GOSE): B= −0.6 1.0, −0.1). Comparatively, 30-39y scored higher on six-month nonverbal processing speed (Wechsler Adult Intelligence Scale-Processing Speed Index (WAIS-PSI); B= 11.88, 95% CI 1.66, 22.09).
Conclusions: Following mTBI, young adults aged 18-29y and 30-39y may have different risks for impairment. Sex may interact with age for PTSD symptomatology, with females 30-39y at highest risk. These results may be attributable to cortical maturation, biological response, social modifiers, and/or differential self-report. Confirmation in larger samples is needed; however, prevention and rehabilitation/counseling strategies after mTBI should likely be tailored for age and sex.
Trial registration:
ClinicalTrials.gov identifier: NCT01565551.
Large-scale diffusion MRI tractography remains a significant challenge. Users must orchestrate a complex sequence of instructions that requires many software packages with complex dependencies and ...high computational costs. We developed MaPPeRTrac, an edge-centric tractography pipeline that simplifies and accelerates this process in a wide range of high-performance computing (HPC) environments. It fully automates either probabilistic or deterministic tractography, starting from a subject’s magnetic resonance imaging (MRI) data, including structural and diffusion MRI images, to the edge density image (EDI) of their structural connectomes. Dependencies are containerized with Singularity (now called Apptainer) and decoupled from code to enable rapid prototyping and modification. Data derivatives are organized with the Brain Imaging Data Structure (BIDS) to ensure that they are findable, accessible, interoperable, and reusable following FAIR principles. The pipeline takes full advantage of HPC resources using the Parsl parallel programming framework, resulting in the creation of connectome datasets of unprecedented size. MaPPeRTrac is publicly available and tested on commercial and scientific hardware, so it can accelerate brain connectome research for a broader user community. MaPPeRTrac is available at:
https://github.com/LLNL/mappertrac
.
To quantitatively determine the delivery of systemic liposomal doxorubicin to tumors treated with pulsed high-intensity focused ultrasound and to study the mechanism underlying this delivery in a ...murine model.
All animal work was performed in compliance with guidelines and approval of institutional animal care committee. C3H mice received subcutaneous injections in the flank of a cell suspension of SCC7, a murine squamous cell carcinoma cell line; mice (n = 32) in drug delivery study received unilateral injections, whereas mice (n = 10) in mechanistic study received bilateral injections. Tumors were treated when they reached 1 cm(3) in volume. In the drug delivery study, doxorubicin hydrochloride liposomes were injected into the tail vein: Mice received therapy with doxorubicin injections and high-intensity focused ultrasound, doxorubicin injections alone, or neither form of therapy (controls). Tumors were removed, and the doxorubicin content was assayed with fluorescent spectrophotometry. In the mechanistic study, all mice received an injection of 500-kDa dextran-fluorescein isothyocyanate into the tail vein, and half of them were exposed to high-intensity focused ultrasound prior to injection. Contralateral tumors served as controls for each group. Extravasation of dextran-fluorescein isothyocyanate was observed by using in vivo confocal microscopy.
Mean doxorubicin concentration in tumors treated with pulsed high-intensity focused ultrasound was 9.4 microg . g(-1) +/- 2.1 (standard deviation), and it was significantly higher (124% 9.4 microg . g(-1)/4.2 microg . g(-1)) than in those that were not treated with high-intensity focused ultrasound (4.2 microg . g(-1) +/- 0.95) (P < .001, unpaired two-tailed Student t test). Extravasation of dextran-fluorescein isothyocyanate was observed in the vasculature of tumors treated with high-intensity focused ultrasound but not in that of untreated tumors.
Pulsed high-intensity focused ultrasound is an effective method of targeting systemic drug delivery to tumor tissue. Potential mechanisms for producing the observed enhancement are discussed.
Introduction: Mild traumatic brain injury (MTBI) can cause persistent functional deficits and healthcare burden. Understanding the association between intracranial contusions and outcome may aid in ...MTBI treatment and prognosis.
Methods: MTBI patients with Glasgow Coma Scale 13-15 and 6-month outcomes Glasgow Outcome Scale-Extended (GOSE), without polytrauma from the prospective TRACK-TBI Pilot study were analyzed. Intracranial contusions on computed tomography (CT) were coded by location. Multivariable regression evaluated associations between intracranial injury type (temporal contusion TC, frontal contusion, extraaxial epidural/subdural/subarachnoid, other-intraaxial intracerebral/intraventricular hemorrhage, axonal injury) and GOSE. Odds ratios (OR) are reported.
Results: Overall, 260 MTBI subjects were aged 44.4 ± 18.1-years; 67.7% were male. Ninety-seven subjects were CT-positive and 46 had contusions (41.3%-frontal, 30.4%-temporal, 21.7%-frontal + temporal, 2.2% each-parietal/occipital/brainstem); 95.7% had concurrent extraaxial hemorrhage. Mortality was 0% at discharge and 2.3% by 6-months.
GOSE distribution was 2.3%-death, 1.5%-severe disability, 27.7%-moderate disability, 68.5%-good recovery. Forty-six percent of TC-positive subjects suffered moderate disability or worse (GOSE ≤6) and 41.7% were unable to return to baseline work capacity (RTBWC), compared to 29.1%/20.4% for CT-negative and 26.1%/20.9% for CT-positive subjects without TC. On multivariable regression, TC associated with OR = 3.33 (95% CI 1.16-9.60, p = 0.026) for GOSE ≤6, and OR = 4.48 (1.49-13.51, p = 0.008) for inability to RTBWC.
Conclusions: Parenchymal contusions in MTBI are often accompanied by extraaxial hemorrhage. TCs may be associated with 6-month functional impairment. Their presence on imaging should alert the clinician to the need for heightened surveillance of sequelae complicating RTBWC, with low threshold for referral to services.
Objective: To determine characteristics and concordance of subjective cognitive complaints (SCCs) 6 months following mild-traumatic brain injury (mTBI) as assessed by two different TBI common data ...elements (CDEs).
Research design: The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot Study was a prospective observational study that utilized the NIH TBI CDEs, Version 1.0. We examined variables associated with SCC, performance on objective cognitive tests (Wechsler Adult Intelligence Scale, California Verbal Learning Test, and Trail Making Tests A and B), and agreement on self-report of SCCs as assessed by the acute concussion evaluation (ACE) versus the Rivermead Post Concussion Symptoms Questionnaire (RPQ).
Results: In total, 68% of 227 participants endorsed SCCs at 6 months. Factors associated with SCC included less education, psychiatric history, and being assaulted. Compared to participants without SCC, those with SCC defined by RPQ performed significantly worse on all cognitive tests. There was moderate agreement between the two measures of SCCs (kappa = 0.567 to 0.680).
Conclusion: We show that the symptom questionnaires ACE and RPQ show good, but not excellent, agreement for SCCs in an mTBI study population. Our results support the retention of RPQ as a basic CDE for mTBI research.
Abbreviations: BSI-18: Brief Symptom Inventory; 18CDEs: common data elements; CT: computed tomography; CVLT: California Verbal Learning Test; ED: emergency department; GCS: Glasgow coma scale; LOC: loss of consciousnessm; TBI: mild-traumatic brain injury; PTA: post-traumatic amnesia; SCC: subjective cognitive complaints; TBI: traumatic brain injury; TRACK-TBI: Transforming Research and Clinical Knowledge in Traumatic Brain Injury; TMT: Trail Making Test; WAIS-PSI: Wechsler Adult Intelligence Scale, Fourth Edition, Processing Speed Index
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