Shelley C. Heaton

Ubiquitin C-terminal hydrolase is a novel biomarker in humans for severe traumatic brain injury

Objective:Ubiquitin C-terminal hydrolase (UCH-L1), also called neuronal-specific protein gene product (PGP 9.3), is highly abundant in neurons. To assess the reliability of UCH-L1 as a potential biomarker for traumatic brain injury (TBI) this study compared cerebrospinal fluid (CSF) levels of UCH-L1 from adult patients with severe TBI to uninjured controls; and examined the relationship between levels with severity of injury, complications and functional outcome. Design:This study was designed as prospective case control study. Patients:This study enrolled 66 patients, 41 with severe TBI, defined by a Glasgow coma scale (GCS) score of ≤8, who underwent intraventricular intracranial pressure monitoring and 25 controls without TBI requiring CSF drainage for other medical reasons. Setting:Two hospital system level I trauma centers. Measurements and Main Results:Ventricular CSF was sampled from each patient at 6, 12, 24, 48, 72, 96, 120, 144, and 168 hrs following TBI and analyzed for UCH-L1. Injury severity was assessed by the GCS score, Marshall Classification on computed tomography and a complicated postinjury course. Mortality was assessed at 6 wks and long-term outcome was assessed using the Glasgow outcome score 6 months after injury. TBI patients had significantly elevated CSF levels of UCH-L1 at each time point after injury compared to uninjured controls. Overall mean levels of UCH-L1 in TBI patients was 44.2 ng/mL (±7.9) compared with 2.7 ng/mL (±0.7) in controls (p <.001). There were significantly higher levels of UCH-L1 in patients with a lower GCS score at 24 hrs, in those with postinjury complications, in those with 6-wk mortality, and in those with a poor 6-month dichotomized Glasgow outcome score. Conclusions:These data suggest that this novel biomarker has the potential to determine injury severity in TBI patients. Further studies are needed to validate these findings in a larger sample.

αII-Spectrin Breakdown Product Cerebrospinal Fluid Exposure Metrics Suggest Differences in Cellular Injury Mechanisms after Severe Traumatic Brain Injury

Traumatic brain injury (TBI) produces alphaII-spectrin breakdown products (SBDPs) that are potential biomarkers for TBI. To further understand these biomarkers, the present study examined (1) the exposure and kinetic characteristics of SBDPs in cerebrospinal fluid (CSF) of adults with severe TBI, and (2) the relationship between these exposure and kinetic metrics and severity of injury. This clinical database study analyzed CSF concentrations of 150-, 145-, and 120-kDa SBDPs in 38 severe TBI patients. Area under the curve (AUC), mean residence time (MRT), maximum concentration (C(max)), time to maximum concentration (T(max)), and half-life (t(1/2)) were determined for each SBDP. Markers of calpain proteolysis (SBDP150 and SBDP145) had a greater median AUC and C(max) and a shorter MRT than SBDP120, produced by caspase-3 proteolysis in the CSF in TBI patients ( p < 0.001). AUC and MRT for SBDP150 and SBDP15 were significantly greater in patients with worse Glasgow Coma Scale (GCS) scores at 24 h after injury compared to those whose GCS scores improved (AUC p=0.013, MRT p=0.001; AUC p=0.009, MRT p=0.021, respectively). A positive correlation was found between patients with longer elevations in intracranial pressure (ICP) measurements of 25mmHg or higher and those with a greater AUC and MRT for all three biomarkers. This is the first study to show that the biomarkers of proteolysis differentially associated with calpain and caspase-3 activity have distinct CSF exposure profiles following TBI that suggest a prominent role for calpain activity. Further studies are being conducted to determine if exposure and kinetic metrics for biofluid-based biomarkers can predict clinical outcome.

The Test of Everyday Attention for Children (TEA-Ch): patterns of performance in children with ADHD and clinical controls.

The present study explores the utility of the Test of Everyday Attention for Children (TEA-Ch) as a measure of the attentional impairments displayed by children with Attention Deficit Hyperactivity Disorder (ADHD). Sixty-three children with ADHD and 23 non-ADHD Clinical Control children were compared on subtests of the TEA-Ch reflecting three attentional domains: sustained, selective, and attentional control. Results show that children with ADHD performed significantly worse than clinical controls on subtests of sustained attention and attentional control. The groups did not differ, however, on subtests of selective attention. These findings suggest that the TEA-Ch is sensitive to attentional deficits unique to ADHD and holds promise as a useful tool in the assessment of ADHD. Performance patterns and future directions are discussed.

Human Traumatic Brain Injury Induces Autoantibody Response against Glial Fibrillary Acidic Protein and Its Breakdown Products

The role of systemic autoimmunity in human traumatic brain injury (TBI) and other forms of brain injuries is recognized but not well understood. In this study, a systematic investigation was performed to identify serum autoantibody responses to brain-specific proteins after TBI in humans. TBI autoantibodies showed predominant immunoreactivity against a cluster of bands from 38–50 kDa on human brain immunoblots, which were identified as GFAP and GFAP breakdown products. GFAP autoantibody levels increased by 7 days after injury, and were of the IgG subtype predominantly. Results from in vitro tests and rat TBI experiments also indicated that calpain was responsible for removing the amino and carboxyl termini of GFAP to yield a 38 kDa fragment. Additionally, TBI autoantibody staining co-localized with GFAP in injured rat brain and in primary rat astrocytes. These results suggest that GFAP breakdown products persist within degenerating astrocytes in the brain. Anti-GFAP autoantibody also can enter living astroglia cells in culture and its presence appears to compromise glial cell health. TBI patients showed an average 3.77 fold increase in anti-GFAP autoantibody levels from early (0–1 days) to late (7–10 days) times post injury. Changes in autoantibody levels were negatively correlated with outcome as measured by GOS-E score at 6 months, suggesting that TBI patients with greater anti-GFAP immune-responses had worse outcomes. Due to the long lasting nature of IgG, a test to detect anti-GFAP autoantibodies is likely to prolong the temporal window for assessment of brain damage in human patients.

Conceptualizing functional cognition in stroke.

Background. Up to 65% of individuals demonstrate poststroke cognitive impairments, which may increase hospital stay and caregiver burden. Randomized stroke clinical trials have emphasized physical recovery over cognition. Neuropsychological assessments have had limited utility in randomized clinical trials. These issues accentuate the need for a measure of functional cognition (the ability to accomplish everyday activities that rely on cognitive abilities, such as locating keys, conveying information, or planning activities). Objective. The aim of the study was to present the process used to establish domains of functional cognition for development of computer adaptive measure of functional cognition for stroke. Methods. Functional cognitive domains involved in identifying relevant neuropsychological constructs from the literature were conceptualized and finalized after advisory panel feedback from experts in neurology, neuropsychology, aphasiology, clinical trials, and epidemiology. Results. The following 17 domains were proposed: receptive aphasia, expressive aphasia, agraphia, alexia, calculation, visuospatial, visuoperceptual, visuoconstruction, attention, language usage, executive functions, orientation, processing speed, memory, working memory, mood, awareness and abstract reasoning. The advisory panel recommended retaining the first 12 domains. Recommended changes included: to address only encoding and retrieval of recent information in the memory domain; to add domains for limb apraxia and poststroke depression; and to keep orientation as a separate domain or reclassify it under memory or attention. The final 10 domains included: language, reading and writing, numeric/calculation, limb praxis, visuospatial function, social use of language, emotional function, attention, executive function, and memory. Conclusion. Conceptualizing domains of functional cognition is the first step in developing a computer adaptive measure of functional cognition for stroke. Additional steps include developing, refining, and field-testing items, psychometric analysis, and computer adaptive test programming.

The Role of Multidimensional Attentional Abilities in Academic Skills of Children With ADHD

Despite reports of academic difficulties in children with attention-deficit/hyperactivity disorder (ADHD), little is known about the relationship between performance on tests of academic achievement and measures of attention. The current study assessed intellectual ability, parent-reported inattention, academic achievement, and attention in 45 children (ages 7—15) diagnosed with ADHD. Hierarchical regressions were performed with selective, sustained, and attentional control/switching domains of the Test of Everyday Attention for Children as predictor variables and with performance on the Wechsler Individual Achievement Test—Second Edition as dependent variables. It was hypothesized that sustained attention and attentional control/switching would predict performance on achievement tests. Results demonstrate that attentional control/ switching accounted for a significant amount of variance in all academic areas (reading, math, and spelling), even after accounting for verbal IQ and parent-reported inattention. Sustained attention predicted variance only in math, whereas selective attention did not account for variance in any achievement domain. Therefore, attentional control/switching, which involves components of executive functions, plays an important role in academic performance.

The item level psychometrics of the behaviour rating inventory of executive function-adult (BRIEF-A) in a TBI sample

Primary objective: To determine whether the psychometrics of the BRIEF-A are adequate for individuals diagnosed with TBI. Research design: A prospective observational study in which the BRIEF-A was collected as part of a larger study. Methods and procedures: Informant ratings of the 75-item BRIEF-A on 89 individuals diagnosed with TBI were examined to determine items level psychometrics for each of the two BRIEF-A indexes: Behaviour Rating Index (BRI) and Metacognitive Index (MI). Patients were either outpatients or at least 1 year post-injury. Main outcomes and results: Each index measured a latent trait, separating individuals into five-to-six ability levels and demonstrated good reliability (0.94 and 0.96). Four items were identified that did not meet the infit criteria. Conclusions: The results provide support for the use of the BRIEF-A as a supplemental assessment of executive function in TBI populations. However, further validation is needed with other measures of executive function. Recommendations include use of the index scores over the Global Executive Composite score and use of the difficulty hierarchy for setting therapy goals.

UCH-L1 and GFAP Serum Levels in Neonates with Hypoxic–Ischemic Encephalopathy: A Single Center Pilot Study

Objective: We examined two potential biomarkers of brain damage in hypoxic–ischemic encephalopathy (HIE) neonates: glial fibrillary acidic protein (GFAP; a marker of gliosis) and ubiquitin C-terminal hydrolase L1 (UCH-L1; a marker of neuronal injury). We hypothesized that the biomarkers would be measurable in cord blood of healthy neonates and could serve as a normative reference for brain injury in HIE infants. We further hypothesized that higher levels would be detected in serum samples of HIE neonates and would correlate with brain damage on magnetic resonance imaging (MRI) and later developmental outcomes.? Study Design: Serum UCH-L1 and GFAP concentrations from HIE neonates (n = 16) were compared to controls (n = 11). The relationship between biomarker concentrations of HIE neonates and brain damage (MRI) and developmental outcomes (Bayley-III) was examined using Pearson correlation coefficients and a mixed model design. Result: Both biomarkers were detectable in cord blood from control subjects. UCH-L1 concentrations were higher in HIE neonates (p < 0.001), and associated with cortical injury (p < 0.055) and later motor and cognitive developmental outcomes (p < 0.05). The temporal change in GFAP concentrations during (from birth to 96 h of age) predicted motor developmental outcomes (p < 0.05) and injury to the basal ganglia and white matter. Conclusion: Ubiquitin C-terminal hydrolase L1 and GFAP should be explored further as promising serum biomarkers of brain damage and later neurodevelopmental outcomes in neonates with HIE.

Conceptualizing functional cognition in traumatic brain injury rehabilitation

Primary objective: To conceptualize functional cognitive constructs across the continuum of traumatic brain injury (TBI) recovery, to form the foundation for the Computer Adaptive Measure of Functional Cognition for TBI (CAMFC-TBI). Background: TBI often has a profound impact on a survivors ability to return to previous level of functioning and significantly reduces the overall quality of life for survivors and caregivers. Few assessments are designed to evaluate TBIs impact on cognitive functioning in everyday life. Neuropsychological tests are time consuming and may have questionable ecological validity for predicting functional outcomes. Global functional assessments contain few cognitive items and may lack psychometric rigour. Presently there is a lack of efficient, precise, ecologically valid functional cognitive measures. Main outcome and results: Studies that used neuropsychological and global functional assessments were reviewed to direct conceptualization of functional cognitive constructs across TBI recovery stages. An advisory panel reviewed study methodology and functional cognitive constructs development. They validated the need for the CAMFC-TBI and the six functional cognitive constructs: attention, memory, processing speed, executive functioning, social communication and emotional management. Conclusion: Conceptualizing functional cognitive constructs is the first step in CAMFC-TBI development. Future project stages include item pool development, qualitative testing, field-testing, psychometric analysis and computerized adaptive test programming.

Parent–Child Interaction Therapy as a Family-Oriented Approach to Behavioral Management Following Pediatric Traumatic Brain Injury: A Case Report

OBJECTIVE To present a case study illustrating the application of parent-child interaction therapy (PCIT) for management of a childs externalizing behaviors related to a severe traumatic brain injury (TBI). METHODS An 11-year-old boys history and injury are described, followed by a description of PCIT and the course of therapy. RESULTS After 9 sessions of PCIT, the child displayed fewer negative behaviors, and his mothers distress was reduced. CONCLUSIONS This case demonstrates the feasibility of using PCIT with a child older than the recommended age range to address behavior problems associated with TBI.