Predicting Clinical Outcomes 7-10 Years after Severe Traumatic Brain Injury: Exploring the Prognostic Utility of the IMPACT Lab Model and Cerebrospinal Fluid UCH-L1 and MAP-2.

BACKGROUND: Severe traumatic brain injury (TBI) is a major contributor to disability and mortality in the industrialized world. Outcomes of severe TBI are profoundly heterogeneous, complicating outcome prognostication. Several prognostic models have been validated for acute prediction of 6-month global outcomes following TBI (e.g., morbidity/mortality). In this preliminary observational prognostic study, we assess the utility of the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) Lab model in predicting longer term global and cognitive outcomes (7-10 years post injury) and the extent to which cerebrospinal fluid (CSF) biomarkers enhance outcome prediction. METHODS: Very long-term global outcome was assessed in a total of 59 participants (41 of whom did not survive their injuries) using the Glasgow Outcome Scale-Extended and Disability Rating Scale. More detailed outcome information regarding cognitive functioning in daily life was collected from 18 participants surviving to 7-10 years post injury using the Cognitive Subscale of the Functional Independence Measure. A subset (n = 10) of these participants also completed performance-based cognitive testing (Digit Span Test) by telephone. The IMPACT lab model was applied to determine its prognostic value in relation to very long-term outcomes as well as the additive effects of acute CSF ubiquitin C-terminal hydrolase-L1 (UCH-L1) and microtubule associated protein 2 (MAP-2) concentrations. RESULTS: The IMPACT lab model discriminated favorable versus unfavorable 7- to 10-year outcome with an area under the receiver operating characteristic curve of 0.80. Higher IMPACT lab model risk scores predicted greater extent of very long-term morbidity (ß = 0.488 p = 0.000) as well as reduced cognitive independence (ß = - 0.515, p = 0.034). Acute elevations in UCH-L1 levels were also predictive of lesser independence in cognitive activities in daily life at very long-term follow-up (ß = 0.286, p = 0.048). Addition of two CSF biomarkers significantly improved prediction of very long-term neuropsychological performance among survivors, with the overall model (including IMPACT lab score, UCH-L1, and MAP-2) explaining 89.6% of variance in cognitive performance 7-10 years post injury (p = 0.008). Higher acute UCH-L1 concentrations were predictive of poorer cognitive performance (ß = - 0.496, p = 0.029), whereas higher acute MAP-2 concentrations demonstrated a strong cognitive protective effect (ß = 0.679, p = 0.010). CONCLUSIONS: Although preliminary, results suggest that existing prognostic models, including models with incorporation of CSF markers, may be applied to predict outcome of severe TBI years after injury. Continued research is needed examining early predictors of longer-term outcomes following TBI to identify potential targets for clinical trials that could impact long-ranging functional and cognitive outcomes.

The Role of Sleep-Disordered Breathing Symptoms in Neurocognitive Function Among Youth With Sickle Cell Disease.

OBJECTIVE: To examine associations between sleep-disordered breathing (SDB) and executive/attentional function in pediatric sickle cell disease (SCD). METHODS: Sixty youth with SCD ages 8-18 years and caregivers completed the Pediatric Sleep Questionnaire (PSQ), Delis Kaplan Executive Function System Trail Making Test (DKEFS TMT), Psychomotor Vigilance Test (PVT), and the Behavior Rating Inventory Of Executive Function, Second Edition (BRIEF-2) Parent Report. RESULTS: The PSQ significantly predicted the BRIEF-2 Parent Report, F(1, 58) = 44.64, p < .001, R2 = 0.44, f2 = 0.77. CONCLUSIONS: Sleep-disordered breathing symptoms may predict informant-rated executive dysfunction in pediatric SCD, but not performance-based executive function.

Examining the Item-Level Factor Structure of the Behavior Rating Inventory of Executive Function-Adult Version Within a Traumatic Brain Injury Sample.

OBJECTIVE: To conduct the first item-level exploration of scale and index structure of the self-report Behavior Rating Inventory of Executive Function-Adult version (BRIEF-A) in traumatic brain injury (TBI). DESIGN: This was an observational cross-sectional study design using secondary data. We conducted exploratory factor analyses (EFA) to explore the index structure and scale structure of the BRIEF-A. We conducted EFA with all 70 items of the BRIEF-A to examine the index structure. Based on the finding of index structure, we conducted EFA on the 30 items of the Behavioral Regulation Index (BRI) and the 40 items of the Metacognitive Index (MI). SETTING: Data were collected through 5 studies in outpatient and community settings in the southeast United States. PARTICIPANTS: Individuals (N=338) aged 18-89 years with a history of mild to severe TBI who were able to speak English fluently. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The BRIEF-A. RESULTS: The 2-factor structure aligned with the BRIEF-A manual at the index level. Scale structure for the MI (40 items) resulted in 1 factor, whereas the BRI (30 items) could be represented by either a 2- or 3-factor structure. The 2-factor structure of the BRI is more parsimonious and matched other factor analyses derived from the sum of scale items. CONCLUSIONS: We confirmed the manual designated index structure (BRI and MI) of the BRIEF-A but took precautions against using the 9 scales. Instead, we recommend using the 2 designated index scores and 2 newly identified composite scores representing Behavioral Control Trait and Emotional Control Trait.

Association of Serum Bilirubin with the Severity and Outcomes of Intracerebral Hemorrhages.

Intracerebral hemorrhage (ICH) is the second most common subtype of stroke, and it is often associated with a high mortality rate and significant morbidity among survivors. Recent studies have shown that bilirubin, a product of heme metabolism, can exhibit cytoprotective, antioxidant and, anti-inflammatory properties. However, little is known about the role of bilirubin in combating several pathophysiological pathways caused by intracerebral bleeding in patients with ICH. In this study, data were collected retrospectively on 276 patients with ICH who were admitted to a university hospital between 5 January 2014 and 31 December 2017. We assessed the relationship between levels of total, direct, and indirect serum bilirubin and assessments of initial stroke severity and clinical outcomes by using Spearman's rank correlation and Kruskal-Wallis H tests. A secondary examination of the carrier protein albumin was also undertaken. Our study found that higher levels of direct bilirubin were correlated with worse admission Glasgow Coma Scales (GCS) (rs = -0.17, p = 0.011), worse admission ICH Scores (rs = 0.19, p = 0.008), and worse discharge modified Rankin Scales (mRS) (rs = 0.15, p = 0.045). Direct bilirubin was still significantly correlated with discharge mRS after adjusting for temperature at admission (rs = 0.16, p = 0.047), oxygen saturation at admission (rs = 0.15, p = 0.048), white blood cell count (rs = 0.18, p = 0.023), or Troponin T (rs = 0.25, p = 0.001) using partial Spearman's correlation. No statistical significance was found between levels of total or indirect bilirubin and assessments of stroke severity and outcomes. In contrast, higher levels of albumin were correlated with better admission GCS (rs = 0.13, p = 0.027), discharge GCS (rs = 0.15, p = 0.013), and discharge mRS (rs = -0.16, p = 0.023). We found that levels of total bilirubin, direct bilirubin, and albumin were all significantly related to discharge outcomes classified by discharge destinations (p = 0.036, p = 0.014, p = 0.016, respectively; Kruskal-Wallis H tests). In conclusion, higher direct bilirubin levels were associated with greater stroke severity at presentation and worse outcomes at discharge among patients with ICH. Higher levels of albumin were associated with lower stroke severity and better clinical outcomes. Future prospective studies on the free bioactive bilirubin are needed to better understand the intricate relationships between bilirubin and ICH.

Making a Difference: Affective Distress Explains Discrepancy Between Objective and Subjective Cognitive Functioning After Mild Traumatic Brain Injury.

OBJECTIVE: To assess the relationship between subjective cognitive symptoms and objective cognitive test scores in patients after concussion. We additionally examined factors associated with subjective and objective cognitive dysfunction, as well as their discrepancy. PARTICIPANTS: Eighty-six individuals (65.1% female; 74.4% adult) from an interdisciplinary concussion clinic. METHODS: Subjective and objective cognitive functioning was measured via the SCAT-Symptom Evaluation and the CNS Vital Signs Neurocognition Index (NCI), respectively. Cognitive discrepancy scores were derived by calculating standardized residuals (via linear regression) using subjective symptoms as the outcome and NCI score as the predictor. Hierarchical regression assessed predictors (age, education, time postinjury, attention-deficit/hyperactivity disorder, affective distress, and sleep disturbance) of cognitive discrepancy scores. Nonparametric analyses evaluated relationships between predictor variables, subjective symptoms, and NCI. RESULTS: More severe affective and sleep symptoms (large and medium effects), less time postinjury (small effect), and older age (small effect) were associated with higher subjective cognitive symptoms. Higher levels of affective distress and less time since injury were associated with higher cognitive discrepancy scores (ß = .723, P < .001; ß = -.204, P < .05, respectively). CONCLUSION: Clinical interpretation of subjective cognitive dysfunction should consider these additional variables. Evaluation of affective distress is warranted in the context of higher subjective cognitive complaints than objective test performance.

Predicting long-term cognitive and neuropathological consequences of moderate to severe traumatic brain injury: Review and theoretical framework.

Prognostic modeling in moderate to severe traumatic brain injury (TBI) has historically focused primarily on the projection of crude outcomes such as the risk of mortality and disability. Initial work in this area has perpetuated the notion that prognosis after moderate to severe TBI can be measured as a single, static, and dichotomous outcome. However, more recent conceptualizations describe moderate to severe TBI as the initiation of a chronic disease state with high levels of inter-individual variability in terms of symptom manifestation and disease progression. Unfortunately, existing prognostic models provide limited insight into the extent of chronic cognitive and neurodegenerative changes experienced by moderate to severe TBI survivors. Though prior research has identified a variety of acute factors that appear to influence post-injury cognitive and neuropathological outcomes, an empirically supported framework for prognostic modeling of these injury-distal outcomes does not exist. The current review considers the literature on an expanded array of empirically supported predictors (both premorbid and injury-related) in association with long-term sequelae of moderate to severe TBI. We also provide a theoretical framework and statistical approach for prognostic modeling in moderate to severe TBI in order to unify efforts across research groups and facilitate important progress in this research area.

The Role of Executive Functioning and Academic Achievement in the Academic Self-Concept of Children and Adolescents Referred for Neuropsychological Assessment.

The current study evaluated a model of youth academic self-concept which incorporates practical executive functioning behaviors and academic achievement. Though greater academic achievement has been linked to both positive self-concept and better executive functioning, these constructs have not been examined simultaneously. It was hypothesized that academic achievement would mediate the association between problems with executive functioning and academic self-concept such that youth with more problems with executive functioning would have lower academic achievement and, in turn, lower academic self-concept. Clinical data was analyzed from a diagnostically heterogeneous sample of youth (n = 122) who underwent neuropsychological evaluation. Problems with executive functioning were assessed using the Behavior Rating Inventory of Executive Function. Academic achievement was assessed using the Woodcock⁻Johnson Tests of Achievement or Wechsler Individual Achievement Test. Academic self-concept was assessed using the youth-report version of the Behavioral Assessment System for Children. Surprisingly, findings indicate that academic achievement is not significantly associated with problems with executive functioning or academic self-concept. However, greater problems with executive functioning are associated with decreased academic self-concept. The overall model included several covariates and accounted for 10% of the variance in academic self-concept. Findings suggest that executive skills may be essential for aligning academic achievement with classroom performance. Though various child characteristic covariates were included, the model accounted for a small amount of variance suggesting that future studies should examine contributing contextual factors.

Factor structure and item level psychometrics of the Social Problem Solving Inventory-Revised: Short Form in traumatic brain injury.

Social problem-solving deficits characterise individuals with traumatic brain injury (TBI), and poor social problem solving interferes with daily functioning and productive lifestyles. Therefore, it is of vital importance to use the appropriate instrument to identify deficits in social problem solving for individuals with TBI. This study investigates factor structure and item-level psychometrics of the Social Problem Solving Inventory-Revised: Short Form (SPSI-R:S), for adults with moderate and severe TBI. Secondary analysis of 90 adults with moderate and severe TBI who completed the SPSI-R:S was performed. An exploratory factor analysis (EFA), principal components analysis (PCA) and Rasch analysis examined the factor structure and item-level psychometrics of the SPSI-R:S. The EFA showed three dominant factors, with positively worded items represented as the most definite factor. The other two factors are negative problem-solving orientation and skills; and negative problem-solving emotion. Rasch analyses confirmed the three factors are each unidimensional constructs. It was concluded that the total score interpretability of the SPSI-R:S may be challenging due to the multidimensional structure of the total measure. Instead, we propose using three separate SPSI-R:S subscores to measure social problem solving for the TBI population.

Lateral Ventricle Volume Asymmetry Predicts Midline Shift in Severe Traumatic Brain Injury.

Midline shift following severe traumatic brain injury (sTBI) detected on computed tomography (CT) scans is an established predictor of poor outcome. We hypothesized that lateral ventricular volume (LVV) asymmetry is an earlier sign of developing asymmetric intracranial pathology than midline shift. This retrospective analysis was performed on data from 84 adults with blunt sTBI requiring a ventriculostomy who presented to a Level I trauma center. Seventy-six patients underwent serial CTs within 3 h and an average of three scans within the first 10 d of sTBI. Left and right LVVs were quantified by computer-assisted manual volumetric measurements. LVV ratios (LVR) were determined on the admission CT to evaluate ventricular asymmetry. The relationship between the admission LVR value and subsequent midline shift development was tested using receiver operating characteristic (ROC) analysis, and odds ratio (OR) and relative risk tests. Sixty patients had no >5 mm midline shift on the initial admission scan. Of these, 15 patients developed it subsequently (16 patients already had >5 mm midline shift on admission scans). For >5 mm midline shift development, admission LVR of >1.67 was shown to have a sensitivity of 73.3% and a specificity of 73.3% (area under the curve=0.782; p<0.0001). LVR of >1.67 as exposure yielded an OR of 7.56 (p<0.01), and a risk ratio of 4.42 (p<0.01) for midline shift development as unfavorable outcome. We propose that LVR captures LVV asymmetry and is not only related to, but also predicts the development of midline shift already at admission CT examination. Lateral ventricles may have a higher "compliance" than midline structures to developing asymmetric brain pathology. LVR analysis is simple, rapidly accomplished and may allow earlier interventions to attenuate midline shift and potentially improve ultimate outcomes.

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.

Cognitive predictors of verbal memory in a mixed clinical pediatric sample.

Verbal memory problems, along with other cognitive difficulties, are common in children diagnosed with neurological and/or psychological disorders. Historically, these "memory problems" have been poorly characterized and often present with a heterogeneous pattern of performance across memory processes, even within a specific diagnostic group. The current study examined archival neuropsychological data from a large mixed clinical pediatric sample in order to understand whether functioning in other cognitive areas (i.e., verbal knowledge, attention, working memory, executive functioning) may explain some of the performance variability seen across verbal memory tasks of the Children's Memory Scale (CMS). Multivariate analyses revealed that among the cognitive functions examined, only verbal knowledge explained a significant amount of variance in overall verbal memory performance. Further univariate analyses examining the component processes of verbal memory indicated that verbal knowledge is specifically related to encoding, but not the retention or retrieval stages. Future research is needed to replicate these findings in other clinical samples, to examine whether verbal knowledge predicts performance on other verbal memory tasks and to explore whether these findings also hold true for visual memory tasks. Successful replication of the current study findings would indicate that interventions targeting verbal encoding deficits should include efforts to improve verbal knowledge.

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.

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 child's externalizing behaviors related to a severe traumatic brain injury (TBI). METHODS: An 11-year-old boy's 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 mother's 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.

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 survivor's 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 TBI's 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.

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 < or =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.

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.

alphaII-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.

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.

Clinical significance of alphaII-spectrin breakdown products in cerebrospinal fluid after severe traumatic brain injury.

Following traumatic brain injury (TBI), the cytoskeletal protein alpha-II-spectrin is proteolyzed by calpain and caspase-3 to signature breakdown products. To determine whether alpha -II-spectrin proteolysis is a potentially reliable biomarker for TBI in humans, the present study (1) examined levels of spectrin breakdown products (SBDPs) in cerebrospinal fluid (CSF) from adults with severe TBI and (2) examined the relationship between these levels, severity of injury, and clinical outcome. This prospective case control study enrolled 41 patients with severe TBI, defined by a Glasgow Coma Scale (GCS) score of < or =8, who underwent intraventricular intracranial pressure monitoring. Patients without TBI requiring CSF drainage for other medical reasons served as controls. Ventricular CSF was sampled from each patient at 6, 12, 24, 48, 72, 96, and 120 h following TBI and analyzed for SBDPs. Outcome was assessed using the Glasgow Outcome Score (GOS) 6 months after injury. Calpain and caspase-3 mediated SBDP levels in CSF were significantly increased in TBI patients at several time points after injury, compared to control subjects. The time course of calpain mediated SBDP150 and SBDP145 differed from that of caspase-3 mediated SBDP120 during the post-injury period examined. Mean SBDP densitometry values measured early after injury correlated with severity of injury, computed tomography (CT) scan findings, and outcome at 6 months post-injury. Taken together, these results support that alpha -II-spectrin breakdown products are potentially useful biomarker of severe TBI in humans. Our data further suggests that both necrotic/oncotic and apoptotic cell death mechanisms are activated in humans following severe TBI, but with a different time course after injury.