A longitudinal study of magnetic resonance spectroscopy Huntington's disease biomarkers.

Putaminal metabolites examined using cross-sectional magnetic resonance spectroscopy (MRS) can distinguish pre-manifest and early Huntington's Disease (HD) individuals from controls. An ideal biomarker, however, will demonstrate longitudinal change over short durations. The objective here was to evaluate longitudinal in vivo brain metabolite profiles in HD over 24 months. Eighty-four participants (30 controls, 25 pre-manifest HD, 29 early HD) recruited as part of TRACK-HD were imaged at baseline, 12 months, and 24 months using 3T MRS of left putamen. Automated putaminal volume measurement was performed simultaneously. To quantify partial volume effects, spectroscopy was performed in a second, white matter voxel adjacent to putamen in six subjects. Subjects underwent TRACK-HD motor assessment. Statistical analyses included linear regression and one-way analysis of variance (ANOVA). At all time-points N-acetyl aspartate and total N-acetyl aspartate (NAA), neuronal integrity markers, were lower in early HD than in controls. Total NAA was lower in pre-manifest HD than in controls, whereas the gliosis marker myo-inositol (MI) was robustly elevated in early HD. Metabolites were stable over 24 months with no longitudinal change. Total NAA was not markedly different in adjacent white matter than putamen, arguing against partial volume confounding effects in cross-sectional group differences. Total NAA correlations with disease burden score suggest that this metabolite may be useful in identifying neurochemical responses to therapeutic agents. We demonstrate almost consistent group differences in putaminal metabolites in HD-affected individuals compared with controls over 24 months. Future work establishing spectroscopy as an HD biomarker should include multi-site assessments in large, pathologically diverse cohorts.

The effectiveness of a community-based intervention program for women at-risk for giving birth to a child with Fetal Alcohol Spectrum Disorder (FASD).

The goal of this study was to determine whether the First Steps program (modeled after the Parent-Child Assistance Program) resulted in improved outcomes among women at-risk for giving birth to a child with FASD. We conducted a retrospective analysis of data on 70 participants in the First Steps program. Clients were high risk and faced many life challenges, including: being on welfare, substance abuse, physical and sexual abuse as children, mental health issues, criminal activity, and unplanned pregnancies. We found a significant increase in birth control use and decrease in welfare rates from pre- to post-program. At program exit, many participants were abstinent from alcohol and/or drugs and the majority did not experience a subsequent pregnancy. Clients also showed significant increases in goals and decreases in needs from pre-to post-program. The First Steps program demonstrated promising outcomes for women at-risk for giving birth to a child with FASD.

Developmental cortical thinning in fetal alcohol spectrum disorders.

Regional cortical thickness was evaluated using CIVET processing of 3D T1-weighted images (i) to compare the variation in cortical thickness between 33 participants with fetal alcohol spectrum disorders (FASD) aged 6-30 years (mean age 12.3 years) versus 33 age/sex/hand-matched controls, and (ii) to examine developmental changes in cortical thickness with age from children to young adults in both groups. Significant cortical thinning was found in the participants with FASD in large areas of the bilateral middle frontal lobe, pre- and post- central areas, lateral and inferior temporal and occipital lobes compared to controls. No significant cortical thickness increases were observed for the FASD group. Cortical thinning with age in a linear model was observed in both groups, but the locations were different for each group. FASD participants showed thinning with age in the left middle frontal, bilateral precentral, bilateral precuneus and paracingulate, left inferior occipital and bilateral fusiform gyri; while controls showed decreases with age in the bilateral middle frontal gyrus, right inferior frontal gyrus, bilateral precuneus gyrus, and bilateral occipital gyrus. A battery of cognitive assessments of memory, attention, motor, and verbal abilities was conducted with many of the FASD participants, but no significant correlations were found between these cognitive scores and regional cortical thickness. Non-invasive measurements of cortical thickness in children to young adults with FASD have identified both key regions of cortex that may be more deleteriously affected by prenatal alcohol exposure as well as cortical changes with age that differ from normal developmental thinning.

Brain microstructure is related to math ability in children with fetal alcohol spectrum disorder.

BACKGROUND: Children with fetal alcohol spectrum disorder (FASD) often demonstrate a variety of cognitive deficits, but mathematical ability seems to be particularly affected by prenatal alcohol exposure. Parietal brain regions have been implicated in both functional and structural studies of mathematical ability in healthy individuals, but little is known about the brain structure underlying mathematical deficits in children with FASD. The goal of this study was to use diffusion tensor imaging (DTI) to investigate the relationship between mathematical skill and brain white matter structure in children with FASD. METHODS: Twenty-one children aged 5 to 13 years diagnosed with FASD underwent DTI on a 1.5-T MRI scanner and cognitive assessments including the Woodcock-Johnson Quantitative Concepts test. Voxel-based analysis was conducted by normalizing subject images to a template and correlating fractional anisotropy (FA) values across the brain white matter with age-standardized math scores. RESULTS: Voxel-based analysis revealed 4 clusters with significant correlations between FA and math scores: 2 positively-correlated clusters in the left parietal region, 1 positively-correlated cluster in the left cerebellum, and 1 negatively-correlated cluster in the bilateral brainstem. Diffusion tractography identified the specific white matter tracts passing through these clusters, namely the left superior longitudinal fasciculus, left corticospinal tract and body of the corpus callosum, middle cerebellar peduncle, and bilateral projection fibers including the anterior and posterior limbs of the internal capsule. CONCLUSIONS: These results identify 4 key regions related to mathematical ability and provide a link between brain microstructure and cognitive skills in children with FASD. Given previous findings in typically developing children and those with other abnormal conditions, our results highlight the consistent importance of the left parietal area for mathematical tasks across various populations, and also demonstrate other regions that may be specific to mathematical processing in children with FASD.

The relation between theory of mind and executive functions in children with fetal alcohol spectrum disorders.

BACKGROUND: Children with Fetal Alcohol Spectrum Disorders (FASD) are faced with a range of physical, cognitive, behavioral, and/or learning deficits, as well as poor executive functioning and social skills. Theory of mind (ToM) is the ability to understand that one's own perspective may differ from the perspective of another individual. ToM develops around age 4 and is correlated with performance on executive functioning tasks. OBJECTIVE: The goals of this study were to examine ToM performance in young children with FASD, how age was related to ToM performance, and whether ToM abilities were related to underlying executive function difficulties. METHOD: Fifty-three children (aged 4 to 8 years) participated: 25 children with FASD and 28 control children. All children were tested on measures of ToM, executive functioning, and receptive vocabulary. RESULTS: More children in the FASD group (44%) failed one or both ToM measures than in the control group (25%). Older children with FASD performed worse on ToM than younger children, but this was not the case for the control group. For the FASD group, ToM performance was correlated with a measure of inhibition, but for the control group, ToM was correlated with visual-spatial working memory. CONCLUSIONS: Children with FASD have difficulty on ToM tasks, and this difficulty may be related to underlying deficits in inhibition.

Brain diffusion abnormalities in children with fetal alcohol spectrum disorder.

BACKGROUND: Children with fetal alcohol spectrum disorder (FASD) have a variety of cognitive, behavioral, and neurological impairments, including structural brain damage. Despite the importance of white matter connections for proper brain function, little is known about how these connections, and the deep gray matter structures that act as relay stations, are affected in children with FASD. The purpose of this study was to use diffusion tensor imaging, an advanced magnetic resonance imaging technique, to examine microstructural differences of white and deep gray matter in children with FASD. METHODS: Subjects were 24 children aged 5-13 years previously diagnosed with FASD and 95 healthy children over the same age range. Diffusion tractography was used to delineate 10 major white matter tracts in each individual, and region-of-interest analysis was used to assess 4 deep gray matter structures. Fractional anisotropy, an indicator of white matter integrity, and mean diffusivity, a measure of the average water diffusion, were assessed in all 14 brain structures. RESULTS: Diffusion tensor imaging revealed significant differences of diffusion parameters in several areas of the brain, including the genu and splenium of the corpus callosum, cingulum, corticospinal tracts, inferior fronto-occipital fasciculus, inferior and superior longitudinal fasciculi, globus pallidus, putamen, and thalamus. Reduced white and gray matter volumes, as well as total brain volume, were observed in the FASD group. CONCLUSIONS: These results demonstrate diffusion abnormalities in FASD beyond the corpus callosum and suggest that several specific white matter regions, particularly commissural and temporal connections, and deep gray matter areas of the brain are sensitive to prenatal alcohol exposure.