Lars M. Rimol

Sex-dependent association of common variants of microcephaly genes with brain structure

Loss-of-function mutations in the genes associated with primary microcephaly (MCPH) reduce human brain size by about two-thirds, without producing gross abnormalities in brain organization or physiology and leaving other organs largely unaffected [Woods CG, et al. (2005) Am J Hum Genet 76:717–728]. There is also evidence suggesting that MCPH genes have evolved rapidly in primates and humans and have been subjected to selection in recent human evolution [Vallender EJ, et al. (2008) Trends Neurosci 31:637–644]. Here, we show that common variants of MCPH genes account for some of the common variation in brain structure in humans, independently of disease status. We investigated the correlations of SNPs from four MCPH genes with brain morphometry phenotypes obtained with MRI. We found significant, sex-specific associations between common, nonexonic, SNPs of the genes CDK5RAP2, MCPH1, and ASPM, with brain volume or cortical surface area in an ethnically homogenous Norwegian discovery sample (n = 287), including patients with mental illness. The most strongly associated SNP findings were replicated in an independent North American sample (n = 656), which included patients with dementia. These results are consistent with the view that common variation in brain structure is associated with genetic variants located in nonexonic, presumably regulatory, regions.

A common MECP2 haplotype associates with reduced cortical surface area in humans in two independent populations

The gene MECP2 is a well-known determinant of brain structure. Mutations in the MECP2 protein cause microencephalopathy and are associated with several neurodevelopmental disorders that affect both brain morphology and cognition. Although mutations in MECP2 result in severe neurological phenotypes, the effect of common variation in this genetic region is unknown. We find that common sequence variations in a region in and around MECP2 show association with structural brain size measures in 2 independent cohorts, a discovery sample from the Thematic Organized Psychosis research group, and a replication sample from the Alzheimers Disease Neuroimaging Initiative. The most statistically significant replicated association (P < 0.025 in both cohorts) involved the minor allele of SNP rs2239464 with reduced cortical surface area, and the finding was specific to male gender in both populations. Variations in the MECP2 region were associated with cortical surface area but not cortical thickness. Secondary analysis showed that this allele was also associated with reduced surface area in specific cortical regions (cuneus, fusiform gyrus, pars triangularis) in both populations.

Association analysis of ANK3 gene variants in nordic bipolar disorder and schizophrenia case–control samples†

Genetic variants in ankyrin 3 (ANK3) have recently been shown to be associated with bipolar disorder (BD). We genotyped three ANK3 SNPs previously found to be associated with BD (rs10994336, rs1938526, and rs9804190) in a Scandinavian BD case–control sample (N = 854/2,614). Due to evidence of genetic overlap between BD and schizophrenia (SZ), we also genotyped these three SNPs in a Scandinavian SZ case–control sample (N = 1,073/2,919). Combining our Scandinavian samples with an Icelandic sample (N = 435 BD cases, 651 SZ cases, and 11,491 healthy controls), we found rs10994336 and rs9804190 to be nominally significantly associated with BD in this combined Nordic BD sample (N = 1,289/14,105). Nominal P was 0.015/0.018 (fixed/random effect) for rs10994336 (Bonferroni corrected P = 0.044/0.053) and 0.023 for rs9804190 (Bonferroni corrected P = 0.069). None of the SNPs were significantly associated with SZ in the combined Nordic SZ case–control sample (N = 1,724/14,410). These results further support that ANK3 is a susceptibility gene specific to BD and that more than one risk locus is involved.

Visual–motor deficits relate to altered gray and white matter in young adults born preterm with very low birth weight

Individuals born preterm and at very low birth weight (birth weight ≤ 1500 g) are at an increased risk of perinatal brain injury and neurodevelopmental deficits over the long term. This study examined whether this clinical group has more problems with visual-motor integration, motor coordination, and visual perception compared to term-born controls, and related these findings to cortical surface area and thickness and white matter fractional anisotropy. Forty-seven preterm-born very low birth weight individuals and 56 term-born controls were examined at 18-22 years of age with a combined cognitive, morphometric MRI, and diffusion tensor imaging evaluation in Trondheim, Norway. Visual-motor skills were evaluated with the Beery-Buktenica Developmental Test of Visual-Motor Integration-V (VMI) copying test and its supplemental tests of motor coordination and visual perception. 3D T1-weighted MPRAGE images and diffusion tensor imaging were done at 1.5 T. Cortical reconstruction generated in FreeSurfer and voxelwise maps of fractional anisotropy calculated with Tract-Based Spatial Statistics were used to explore the relationship between MRI findings and cognitive results. Very low birth weight individuals had significantly lower scores on the copying and motor coordination tests compared with controls. In the very low birth weight group, VMI scores showed significant positive relationships with cortical surface area in widespread regions, with reductions of the superior temporal gyrus, insula, and medial occipital lobe in conjunction with the posterior ventral temporal lobe. Visual perception scores also showed positive relationships with cortical thickness in the very low birth weight group, primarily in the lateral occipito-temporo-parietal junction, the superior temporal gyrus, insula, and superior parietal regions. In the very low birth weight group, visual-motor performance correlated positively with fractional anisotropy especially in the corpus callosum, inferior fronto-occipital fasciculus bilaterally, and anterior thalamic radiation bilaterally, driven primarily by an increase in radial diffusivity. VMI scores did not demonstrate a significant relationship to cortical surface area, cortical thickness, or diffusion measures in the control group. Our results indicate that visual-motor integration problems persist into adulthood for very low birth weight individuals, which may be due to structural alterations in several specific gray-white matter networks. Visual-motor deficits appear related to reduced surface area of motor and visual cortices and disturbed connectivity in long association tracts containing visual and motor information. We conjecture that these outcomes may be due to perinatal brain injury or aberrant cortical development secondary to injury or due to very preterm birth.

Association of Genetic Variants on 15q12 With Cortical Thickness and Cognition in Schizophrenia

CONTEXT Cortical thickness is a highly heritable structural brain measurement, and reduced thickness has been associated with schizophrenia, bipolar disorder, and decreased cognitive performance among healthy control individuals. Identifying genes that contribute to variation in cortical thickness provides a means to elucidate some of the biological mechanisms underlying these diseases and general cognitive abilities. OBJECTIVES To identify common genetic variants that affect cortical thickness in patients with schizophrenia, patients with bipolar disorder, and controls and to test these variants for association with cognitive performance. DESIGN A total of 597 198 single-nucleotide polymorphisms were tested for association with average cortical thickness in a genome-wide association study. Significantly associated single-nucleotide polymorphisms were tested for their effect on several measures of cognitive performance. SETTING Four major hospitals in Oslo, Norway. PARTICIPANTS A total of 1054 case individuals and controls were analyzed in the genome-wide association study and follow-up cognitive study. The genome-wide association study included controls (n = 181) and individuals with DSM-IV -diagnosed schizophrenia spectrum disorder (n = 94), bipolar spectrum disorder (n = 97), and other psychotic and affective disorders (n = 49). MAIN OUTCOME MEASURES Cortical thickness measured with magnetic resonance imaging and cognitive performance as assessed by several neuropsychological tests. RESULTS Two closely linked genetic variants (rs4906844 and rs11633924) within the Prader-Willi and Angelman syndrome region on chromosome 15q12 showed a genome-wide significant association (P = 1.1 x 10(-8) with average cortical thickness and modest association with cognitive performance (permuted P = .03) specifically among patients diagnosed as having schizophrenia. CONCLUSION This genome-wide association study identifies a common genetic variant that contributes to the heritable reduction of cortical thickness in schizophrenia. These results highlight the usefulness of cortical thickness as an intermediate phenotype for neuropsychiatric diseases. Future independent replication studies are required to confirm these findings.

Executive function relates to surface area of frontal and temporal cortex in very-low-birth-weight late teenagers

BACKGROUND Being born with very low birth weight (VLBW; birth weight (BW) ≤1500 g) is associated with increased risk of maldevelopment of the immature brain which may affect neurological functioning. Deficits in attention and executive function problems have been reported in VLBW survivors compared with healthy subjects. AIMS The aim of this study was to evaluate attention and executive functions and to relate the clinical test results to cortical morphometry findings in VLBW young adults compared with term-born controls. STUDY DESIGN Prospective follow-up study of three year cohorts of VLBW and control children from birth to adulthood. OUTCOME MEASURES A comprehensive neuropsychological test battery was administered to 55 VLBW subjects born preterm (mean BW: 1217 g) and 81 term-born controls (mean BW: 3707 g) at age 19-20. Cerebral MRI was successfully obtained in 46 VLBW subjects and 61 controls. The FreeSurfer software package was applied for the cortical analyses based on T1-weighted MRI images. RESULTS The VLBW group obtained inferior scores on 15 of the 29 neuropsychological measures assessing attention and executive function and on both the attention and executive function domain scores. We found positive correlations between the executive function domain score and cortical surface area, especially in the antero-medial frontal and the temporal lobes of the brain in the VLBW group. CONCLUSION Young adults born with VLBW show deficits in attention and executive function compared with controls. The executive problems were related to smaller cortical surface area in brain regions known to be involved in higher order cognitive functioning.

Limited microstructural and connectivity deficits despite subcortical volume reductions in school-aged children born preterm with very low birth weight

Preterm birth and very low birth weight (VLBW, ≤1500 g) are worldwide problems that burden survivors with lifelong cognitive, psychological, and physical challenges. In this multimodal structural magnetic resonance imaging (MRI) and diffusion MRI (dMRI) study, we investigated differences in subcortical brain volumes and white matter tract properties in children born preterm with VLBW compared to term-born controls (mean age=8 years). Subcortical brain structure volumes and cortical thickness estimates were obtained, and fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were generated for 18 white matter tracts. We also assessed structural relationships between white matter tracts and cortical thickness of the tract endpoints. Compared to controls, the VLBW group had reduced volumes of thalamus, globus pallidus, corpus callosum, cerebral white matter, ventral diencephalon, and brain stem, while the ventricular system was larger in VLBW subjects, after controlling for age, sex, IQ, and estimated total intracranial volume. For the dMRI parameters, group differences were not significant at the whole-tract level, though pointwise analysis found shorter segments affected in forceps minor and left superior longitudinal fasciculus - temporal bundle. IQ did not correlate with subcortical volumes or dMRI measures in the VLBW group. While the deviations in subcortical volumes were substantial, there were few differences in dMRI measures between the two groups, which may reflect the influence of advances in perinatal care on white matter development.

Cortical trajectories during adolescence in preterm born teenagers with very low birthweight.

While cross-sectional neuroimaging studies on cortical development predict reductions in cortical volume (surface area and thickness) during adolescence, this is the first study to undertake a longitudinal assessment of cortical surface area changes across the continuous cortical surface during this period. We studied the developmental dynamics of cortical surface area and thickness in adolescents and young adults (aged 15-20) born with very low birth weight (VLBW; <1500 g) as well as in term-born controls. Previous studies have demonstrated brain structural abnormalities in cortical morphology, as well as long-term motor, cognitive and behavioral impairments, in adolescents and young adults with VLBW, but the developmental dynamics throughout adolescence have not been fully explored. T1-weighted MRI scans from 51 VLBW (27 scanned twice) and 79 term-born adolescents (37 scanned twice) were used to reconstruct the cortical surface and produce longitudinal estimates of cortical surface area and cortical thickness. Linear mixed model analyses were performed, and the main effects of time and group, as well as time × group interaction effects, were investigated. In both groups, cortical surface area decreased up to 5% in some regions, and cortical thickness up to 8%, over the five-year period. The most affected regions were located on the lateral aspect of the hemispheres, in posterior temporal, parietal and to some extent frontal regions. There was no significant interaction between time and group for either morphometry variable. In conclusion, cortical thickness decreases from 15 to 20 years of age, in a similar fashion in the clinical and control groups. Moreover, we show for the first time that developmental trajectories of cortical surface area in preterm and term-born adolescents do not diverge during adolescence.

Brain Morphometry and Cognition in Young Adults Born Small for Gestational Age at Term

OBJECTIVES To examine brain volumes and cortical surface area and thickness and to relate these brain measures to cognitive function in young adults born small for gestational age (SGA) at term compared with non-SGA control patients. STUDY DESIGN This population-based follow-up study at age 20 years included 58 term-born SGA (birth weight <10th percentile, mean: 2915 g) and 81 non-SGA controls (birth weight ≥ 10th percentile, mean: 3707 g). Brain volumes and cortical surface area and thickness were investigated with magnetic resonance imaging, which was successfully obtained in 47 SGA patients and 61 control patients. Cognitive function was assessed using the Wechsler Adult Intelligence Scale, 3rd edition. A subgroup analysis was performed in the SGA group among subjects diagnosed with fetal growth restriction (FGR) based on repeated fetal ultrasound measurements. RESULTS The SGA group showed regional reductions in cortical surface area, particularly in the frontal, parietal, and temporal lobes. Total brain volume, cortical gray matter, cerebral white matter, and putamen volumes were reduced in the SGA group compared with control patients, but there were no differences in specific subcortical brain structure volumes when correcting for intracranial volume. Reductions were most pronounced among SGA subjects with FGR. No associations were found between brain measures and IQ measures in either group. CONCLUSION Young adults born SGA at term show a global reduction in brain volume as well as regional reductions in cortical surface area. We speculate whether these reductions may be confined to those exposed to FGR. None of the brain measures correlated with cognition.

Cortical morphometry and IQ in VLBW children without cerebral palsy born in 2003-2007.

Children born prematurely with very low birth weight (VLBW: bw ≤ 1500 g) have an increased risk of preterm perinatal brain injury, which may subsequently alter the maturation of the brain, including the cerebral cortex. The aim of study was to assess cortical thickness and surface area in VLBW children compared with term-born controls, and to investigate possible relationships between cortical morphology and Full IQ. In this cross-sectional study, 37 VLBW and 104 term children born between the years 2003–2007 were assessed cognitively at 5–10 years of age, using age appropriate Wechsler tests. The FreeSurfer software was used to obtain estimates of cortical thickness and surface area based on T1-weighted MRI images at 1.5 Tesla. The VLBW children had smaller cortical surface area bilaterally in the frontal, temporal, and parietal lobes. A thicker cortex in the frontal and occipital regions and a thinner cortex in posterior parietal areas were observed in the VLBW group. There were significant differences in Full IQ between groups (VLBW M = 98, SD = 9.71; controls M = 108, SD = 13.57; p < 0.001). There was a positive relationship between IQ and surface area in both groups, albeit significant only in the larger control group. In the VLBW group, reduced IQ was associated with frontal cortical thickening and temporo-parietal thinning. We conclude that cortical deviations are evident in childhood even in VLBW children born in 2003–2007 who have received state of the art medical treatment in the perinatal period and who did not present with focal brain injuries on neonatal ultrasonography. The cortical deviations were associated with reduced cognitive functioning.