Christine Till

MRI correlates of cognitive impairment in childhood-onset multiple sclerosis.

OBJECTIVE Brain MRI measures were correlated with neuropsychological function in 35 pediatric-onset multiple sclerosis (MS) patients and 33 age- and sex-matched healthy controls. METHOD Mean age of MS patients was 16.3 ± 2.3 years with average disease duration of 4.3 ± 3.1 years. Cortical gray matter, thalamic, and global brain volumes were calculated for all participants using a scaling factor computed using normalization of atrophy method to normalize total and regional brain volumes for head size. T1- and T2-weighted lesion volumes were calculated for MS patients. RESULTS Cognitive impairment (CI) was identified in 29% of the MS cohort. Cognitive deficits predominantly involved attention and processing speed, expressive language, and visuomotor integration. Relative to controls, the MS group showed significantly lower thalamic volume (p < .001), total brain volume (p < .008), and gray matter volume (p < .015). Corpus callosum area and thalamic volume differentiated patients identified as having CI from those without CI (p < .05). Regression models controlling for disease duration and age indicated that thalamic volume accounted for significant incremental variance in predicting global IQ, processing speed, and expressive vocabulary (ΔR2 ranging from .43 to .60) and was the most robust MRI predictor of cognition relative to other MRI metrics. CONCLUSIONS The robust association between cognitive function and reduced size of thalamus and global brain volume in pediatric-onset MS patients implicate neurodegenerative processes early in the disease course, and suggest that plasticity of an immature central nervous system is not sufficient to protect patients from the deleterious consequences of MS on cognitive neural networks. (PsycINFO Database Record (c) 2011 APA, all rights reserved).

Prediction of Return to Productivity After Severe Traumatic Brain Injury: Investigations of Optimal Neuropsychological Tests and Timing of Assessment

OBJECTIVES (1) To examine predictive validity of global neuropsychological performance, and performance on timed tests (controlling for manual motor function) and untimed tests, including attention, memory, executive function, on return to productivity at 1 year after traumatic brain injury (TBI). (2) To compare predictive validity at 8 weeks versus 5 months postinjury. (3) To examine predictive validity of early degree of recovery (8wk-5mo postinjury) for return to productivity. DESIGN Longitudinal, within subjects. SETTING Inpatient neurorehabilitation and community. PARTICIPANTS Patients (N=63) with moderate to severe TBI. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES PRIMARY OUTCOME return to productivity at 1 year postinjury. Primary predictors: neuropsychological composite scores. Control variables: posttraumatic amnesia, acute care length of stay (LOS), Glasgow Coma Scale score, age, and estimated premorbid intelligence quotient. RESULTS Return to productivity was significantly correlated with global neuropsychological performance at 5 months postinjury (P<.05) and showed a trend toward significance at 8 weeks. Performance on the untimed composite score, and more specifically executive and memory functions, mirrored this pattern. Logical Memory performance significantly predicted return to productivity, but not other memory tests. Timed tests showed no significance or trend at either time point. Early degree of recovery did not predict return to productivity. Among control variables, only acute care LOS was predictive of return to productivity. CONCLUSIONS Findings validate utility of early neuropsychological assessment for predicting later return to productivity. They also provide more precise information regarding the optimal timing and test type: results support testing at 5 months postinjury on untimed tests (memory and executive function), but not simple attention or speed of mental processing. Findings are discussed with reference to previous literature.

Prenatal exposure to organic solvents and child neurobehavioral performance.

The present study compared the cognitive and behavioral functioning of 3- to 7-year-old children (n=33) whose mothers worked with organic solvents during pregnancy with a group of unexposed children (n=28) matched on age, gender, parental socioeconomic status (SES), and ethnicity. Participants were recruited prospectively by the Motherisk Program, an antenatal counseling service in Canada. An exposure index was estimated using questionnaire data obtained at the time of initial contact. Groups were compared on a variety of tasks, including subtests from the NEPSY, a visual CPT, as well as on parent-rated measures of childrens behavior. Regression analyses indicated lower composite scores in children with increased exposure on Receptive language (P<.01), Expressive language (P<.01), and Graphomotor ability (P=.001), adjusted for demographics. No group differences were observed on measures of Attention (P=.97), Visuo-spatial ability (P=.33), and Fine-motor ability (P=.33). On the Child Behavior Checklist (CBCL), overall mean differences on broad- and narrow-band scales were not significant, but significantly more exposed children were rated as having mild or severe problem behaviors. The findings suggest that maternal occupational exposure to organic solvents during pregnancy is associated with poorer outcome in selective aspects of cognitive and neuromotor functioning in offspring.

Onset of multiple sclerosis before adulthood leads to failure of age-expected brain growth

Objective: To determine the impact of pediatric-onset multiple sclerosis (MS) on age-expected brain growth. Methods: Whole brain and regional volumes of 36 patients with relapsing-remitting MS onset prior to 18 years of age were segmented in 185 longitudinal MRI scans (2–11 scans per participant, 3-month to 2-year scan intervals). MRI scans of 25 age- and sex-matched healthy normal controls (NC) were also acquired at baseline and 2 years later on the same scanner as the MS group. A total of 874 scans from 339 participants from the NIH-funded MRI study of normal brain development acquired at 2-year intervals were used as an age-expected healthy growth reference. All data were analyzed with an automatic image processing pipeline to estimate the volume of brain and brain substructures. Mixed-effect models were built using age, sex, and group as fixed effects. Results: Significant group and age interactions were found with the adjusted models fitting brain volumes and normalized thalamus volumes (p < 10−4). These findings indicate a failure of age-normative brain growth for the MS group, and an even greater failure of thalamic growth. In patients with MS, T2 lesion volume correlated with a greater reduction in age-expected thalamic volume. To exclude any scanner-related influence on our data, we confirmed no significant interaction of group in the adjusted models between the NC and NIH MRI Study of Normal Brain Development groups. Conclusions: Our results provide evidence that the onset of MS during childhood and adolescence limits age-expected primary brain growth and leads to subsequent brain atrophy, implicating an early onset of the neurodegenerative aspect of MS.

White matter integrity and math performance in pediatric multiple sclerosis: a diffusion tensor imaging study.

Multiple sclerosis is associated with reduced white matter integrity and deficits in key cognitive processes important for arithmetic. This study examined the relationship between white matter microstructure and academic ability in 31 youths with multiple sclerosis (aged 11–19 years) and 34 demographically matched controls. Using diffusion tensor imaging, fractional anisotropy was calculated in corpus callosum and in lateralized hemispheric lobes. Difficulties with written arithmetic ability were observed in 26% of patients. Arithmetic ability correlated with fractional anisotropy values across all segments of the corpus callosum and in right frontal and parietal regions, controlling for age (r values >0.5, P<0.005). Findings highlight the functional impact of compromised white matter microstructure across diffuse regions of the brain on mathematical ability.

Diffusion tensor imaging and cognitive speed in children with multiple sclerosis

OBJECTIVES To compare white matter (WM) integrity in children with MS and healthy children using diffusion tensor imaging (DTI), and correlate DTI findings with disease activity, lesion burden, and cognitive processing speed. METHODS Fractional anisotropy (FA) and mean diffusivity (MD) in normal-appearing white matter (NAWM) were measured in four corpus callosum (CC), eight hemispheric regions, and the normal-appearing thalamus of 33 children and adolescents with MS and 30 age-matched healthy controls. Images were acquired on a GE LX 1.5T scanner. DTI parameters used were 25 directions, b = 1000 s/mm(2), and 5mm slice thickness. MS patients had T2 lesion volumes and Expanded Disability Status Scale (EDSS) scores were measured; all participants underwent two speeded cognitive tasks (Visual Matching and Symbol Digit Modalities Test (SDMT)). RESULTS MS participants displayed lower FA values in the genu (p<0.005), splenium (p<0.001) and in NAWM of bilateral parietal, temporal, and occipital lobes (p<0.001) versus controls. FA and MD in the thalamus did not differ between groups. Higher lesion volumes correlated with reduced FA in CC and hemispheric NAWM. DTI metrics did not correlate with EDSS. FA values in CC regions correlated with Visual Matching (p<0.001) and SDMT (p<0.005) in MS participants only. INTERPRETATION DTI analyses indicate widespread NAWM disruption in children with MS-with the degree of abnormality correlating with impaired cognitive processing speed. These findings support an early onset tissue pathology in MS and illustrate its functional consequence.

Factors associated with emotional and behavioral outcomes in adolescents with multiple sclerosis

Background: Multiple sclerosis (MS) onset during adolescence has the potential to disrupt a key period of psychosocial maturation. Objective: We aimed to examine the prevalence and risk factors associated with emotional and behavioral outcomes in adolescents with MS. Methods: The Behavioral Assessment System for Children-2nd Edition (BASC-2) was completed by 31 adolescents with MS (mean age = 16.1 years), 31 age-matched controls, and parents of all participants. BASC-2 outcomes were compared between groups. Base rates were examined for scores falling at least one or two standard deviations below norm. Associations between BASC-2 outcomes and features of disease severity and IQ were examined. Results: Youth with MS were reported by their parents to have more symptoms of depression and somatization and lower adaptive skills compared with reports by parents of controls. On the self-report, patients endorsed more problems of inattention/hyperactivity and lower self-reliance relative to controls. Behavioral concerns and reduced adaptive functioning in the MS group were associated with fatigue, poor relations with parents, and perceived social stress. Psychosocial outcomes did not associate with number of relapses, Expanded Disability Status Scale score, disease duration, brain lesion volume or IQ. Conclusion: Youth with MS are at risk of difficulties in behavioral and emotional health. Relations with parents emerged as a key factor influencing the emotional well-being of youth with MS, suggesting an important role for family-centered care in this population.

Meeting Report: Measuring Endocrine-Sensitive Endpoints within the First Years of Life

An international workshop titled “Assessing Endocrine-Related Endpoints within the First Years of Life” was held 30 April–1 May 2007, in Ottawa, Ontario, Canada. Representatives from a number of pregnancy cohort studies in North America and Europe presented options for measuring various endocrine-sensitive endpoints in early life and discussed issues related to performing and using those measures. The workshop focused on measuring reproductive tract developmental endpoints [e.g., anogenital distance (AGD)], endocrine status, and infant anthropometry. To the extent possible, workshop participants strove to develop or recommend standardized measurements that would allow comparisons and pooling of data across studies. The recommended outcomes include thigh fat fold, breast size, vaginal cytology, AGD, location of the testis, testicular size, and growth of the penis, with most of the discussion focusing on the genital exam. Although a number of outcome measures recommended during the genital exam have been associated with exposure to endocrine-disrupting chemicals, little is known about how predictive these effects are of later reproductive health or other chronic health conditions.

Contribution of the cerebellum to cognitive performance in children and adolescents with multiple sclerosis

Background: Posterior fossa lesions are common in pediatric-onset multiple sclerosis (MS), which is of concern, given the known role of the cerebellum in cognition. Objectives: To investigate the relationship between cerebellar pathology and cognitive function in youth with pediatric-onset MS. Methods: Twenty-eight pediatric-onset relapsing–remitting MS patients (21 girls; mean age 16.2 years; mean disease duration 4.3 years, median Expanded Disability Status Scale 1.25) were compared to 33 age- and sex-matched healthy controls. Participants underwent structural magnetic resonance imaging (MRI) and neuropsychological evaluation to assess intelligence, attention, processing speed, language, visuo-motor integration, and fine-motor dexterity. Associations between cognitive outcomes and cerebellar volume independent of cerebral volume were examined. Results: Cognitive and motor performance of the MS group was reduced relative to controls (all p<0.003). While cerebellar volumes did not differ between groups, cerebellar posterior lobe volume and infratentorial lesion volume accounted for extra variance on measures of information processing (R2=0.43; p=0.02) and vocabulary (R2=0.56; p=0.04) in patients (controlling for cerebral volume and sex), but not in controls. Conclusion: Smaller cerebellar posterior lobe volume, a known region for cognitive processing, and increased lesion burden in the posterior fossa adversely impact cognitive function, an important functional consequence of MS onset during childhood.

Magnetic Resonance Imaging Predictors of Executive Functioning in Patients with Pediatric-Onset Multiple Sclerosis

Executive functions (EFs) are vulnerable to disruption in pediatric-onset multiple sclerosis (MS) patients. We describe the pattern and correlates of executive dysfunction in 34 adolescents with MS on neuropsychological tests and the parent version of the Behavior Rating Inventory of Executive Function (BRIEF). The adolescents with MS performed lower than age-matched controls in several areas of executive functioning, with 44% of patients being impaired on the Trail Making Test-Part B. On the BRIEF, problems in working memory and planning/organization were identified in the patient group compared with controls, particularly in patients with a younger age at disease onset. Task performance and parent-ratings of EF skills were strongly related to whole brain and regional brain volume metrics and, to a lesser extent, T(2)-weighted lesion volume. Working memory and attention switching are at greatest risk of impairment. Results support the inclusion of neuropsychological assessment alongside parent-report measures of EF skills in childhood-onset MS.