Dataset Information

Comprehensive Evaluation of Healthy Volunteers Using Multi-Modality Brain Injury Assessments: An Exploratory, Observational Study.

ABSTRACT: Introduction: Even though mild traumatic brain injury is common and can result in persistent symptoms, traditional measurement tools can be insensitive in detecting functional deficits after injury. Some newer assessments do not have well-established norms, and little is known about how these measures perform over time or how cross-domain assessments correlate with one another. We conducted an exploratory study to measure the distribution, stability, and correlation of results from assessments used in mild traumatic brain injury in healthy, community-dwelling adults. Materials and Methods: In this prospective cohort study, healthy adult men and women without a history of brain injury underwent a comprehensive brain injury evaluation that included self-report questionnaires and neurological, electroencephalography, sleep, audiology/vestibular, autonomic, visual, neuroimaging, and laboratory testing. Most testing was performed at 3 intervals over 6 months. Results: The study enrolled 83 participants, and 75 were included in the primary analysis. Mean age was 38 years, 58 were male, and 53 were civilians. Participants did not endorse symptoms of post-concussive syndrome, PTSD, or depression. Abnormal neurological examination findings were rare, and 6 had generalized slowing on electroencephalography. Actigraphy and sleep diary showed good sleep maintenance efficiency, but 21 reported poor sleep quality. Heart rate variability was most stable over time in the sleep segment. Dynavision performance was normal, but 41 participants had abnormal ocular torsion. On eye tracking, circular, horizontal ramp, and reading tasks were more likely to be abnormal than other tasks. Most participants had normal hearing, videonystagmography, and rotational chair testing, but computerized dynamic posturography was abnormal in up to 21% of participants. Twenty-two participants had greater than expected white matter changes for age by MRI. Most abnormal findings were dispersed across the population, though a few participants had clusters of abnormalities. Conclusions: Despite our efforts to enroll normal, healthy volunteers, abnormalities on some measures were surprisingly common. Trial Registration: This study was registered at www.clinicaltrials.gov, trial identifier NCT01925963.

SUBMITTER: Weaver LK

PROVIDER: S-EPMC6315163 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Comprehensive Evaluation of Healthy Volunteers Using Multi-Modality Brain Injury Assessments: An Exploratory, Observational Study.

Weaver Lindell K LK Wilson Steffanie H SH Lindblad Anne S AS Churchill Susan S Deru Kayla K Price Robert R Williams Christopher S CS Orrison William W WW Patel Jigar B JB Walker James M JM Meehan Anna A Mirow Susan S

Frontiers in neurology 20181217

<b>Introduction:</b> Even though mild traumatic brain injury is common and can result in persistent symptoms, traditional measurement tools can be insensitive in detecting functional deficits after injury. Some newer assessments do not have well-established norms, and little is known about how these measures perform over time or how cross-domain assessments correlate with one another. We conducted an exploratory study to measure the distribution, stability, and correlation of results from assess ...[more]

PMID: 30631299

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Project description:OBJECTIVES:To employ metabolomics-based pathway and network analyses to evaluate the cerebrospinal fluid metabolome after severe traumatic brain injury in children and the capacity of combination therapy with probenecid and N-acetylcysteine to impact glutathione-related and other pathways and networks, relative to placebo treatment. DESIGN:Analysis of cerebrospinal fluid obtained from children enrolled in an Institutional Review Board-approved, randomized, placebo-controlled trial of a combination of probenecid and N-acetylcysteine after severe traumatic brain injury (Trial Registration NCT01322009). SETTING:Thirty-six-bed PICU in a university-affiliated children's hospital. PATIENTS AND SUBJECTS:Twelve children 2-18 years old after severe traumatic brain injury and five age-matched control subjects. INTERVENTION:Probenecid (25?mg/kg) and N-acetylcysteine (140?mg/kg) or placebo administered via naso/orogastric tube. MEASUREMENTS AND MAIN RESULTS:The cerebrospinal fluid metabolome was analyzed in samples from traumatic brain injury patients 24 hours after the first dose of drugs or placebo and control subjects. Feature detection, retention time, alignment, annotation, and principal component analysis and statistical analysis were conducted using XCMS-online. The software "mummichog" was used for pathway and network analyses. A two-component principal component analysis revealed clustering of each of the groups, with distinct metabolomics signatures. Several novel pathways with plausible mechanistic involvement in traumatic brain injury were identified. A combination of metabolomics and pathway/network analyses showed that seven glutathione-centered pathways and two networks were enriched in the cerebrospinal fluid of traumatic brain injury patients treated with probenecid and N-acetylcysteine versus placebo-treated patients. Several additional pathways/networks consisting of components that are known substrates of probenecid-inhibitable transporters were also identified, providing additional mechanistic validation. CONCLUSIONS:This proof-of-concept neuropharmacometabolomics assessment reveals alterations in known and previously unidentified metabolic pathways and supports therapeutic target engagement of the combination of probenecid and N-acetylcysteine treatment after severe traumatic brain injury in children.

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Project description:BACKGROUND:Previous studies found that [18F]LSN3316612 was a promising positron emission tomography (PET) radioligand for imaging O-GlcNAcase in nonhuman primates and human volunteers. This study sought to further evaluate the suitability of [18F]LSN3316612 for human clinical research. METHODS:Kinetic evaluation of [18F]LSN3316612 was conducted in a combined set of baseline brain scans from 17 healthy human volunteers and test-retest imaging was conducted in 10 of these volunteers; another 6 volunteers had whole-body scans to measure radiation exposure to body organs. Total distribution volume (VT) estimates were compared for the one- and two-tissue compartment models with the arterial input function. Test-retest variability and reliability were evaluated via mean difference and intraclass correlation coefficient (ICC). The time stability of VT was assessed down to a 30-min scan time. An alternative quantification method for [18F]LSN3316612 binding without blood was also investigated to assess the possibility of eliminating arterial sampling. RESULTS:Brain uptake was generally high and could be quantified as VT with excellent identifiability using the two-tissue compartment model. [18F]LSN3316612 exhibited good absolute test-retest variability (12.5%), but the arithmetic test-retest variability was far from 0 (11.3%), reflecting a near-uniform increase of VT on the retest scan in nine of 10 volunteers. VT values were stable after 110 min in all brain regions, suggesting that no radiometabolites accumulated in the brain. Measurements obtained using only brain activity (i.e., area under the curve (AUC) from 150-180 min) correlated strongly with regional VT values during test-retest conditions (R2 = 0.84), exhibiting similar reliability to VT (ICC = 0.68 vs. 0.64). Estimated radiation exposure for [18F]LSN3316612 PET was 20.5 ± 2.1 ?Sv/MBq, comparable to other 18F-labeled radioligands for brain imaging. CONCLUSIONS:[18F]LSN3316612 is an excellent PET radioligand for imaging O-GlcNAcase in the human brain. Alternative quantification without blood is possible, at least for within-subject repeat studies. However, the unexplained increase of VT under retest conditions requires further investigation.

Dataset Information

Comprehensive Evaluation of Healthy Volunteers Using Multi-Modality Brain Injury Assessments: An Exploratory, Observational Study.

Publications

Comprehensive Evaluation of Healthy Volunteers Using Multi-Modality Brain Injury Assessments: An Exploratory, Observational Study.

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