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Cortical gray matter structure in boys with Klinefelter syndrome.

ABSTRACT: Klinefelter syndrome (KS, 47,XXY) is a common sex chromosome aneuploidy in males that is associated with a wide range of cognitive, social and emotional characteristics. The neural bases of these symptoms, however, are unclear. Brain structure in 19 pre- or early-pubertal boys with KS (11.5 ± 1.8 years) and 22 typically developing (control) boys (8.1 ± 2.3 years) was examined using surface-based analyses of cortical gray matter volume, thickness and surface area. Boys in the KS group were treatment-naïve with respect to testosterone replacement therapy. Reduced volume in the insula and dorsomedial prefrontal cortex was observed in the KS relative to the TD group, as well as increased volume in the parietal, occipital and motor regions. Further inspection of surface-based metrics indicated that whereas KS-associated increases in volume were driven by differences in thickness, KS-associated reductions in volume were associated with decreases in surface area. Exploratory analyses additionally indicated several correlations between brain structure and behavior, providing initial support for a neural basis of cognitive and emotional symptoms of this condition. Taken together, these data add support for a neuroanatomical phenotype of KS and extend previous studies through clarifying the precise neuroanatomical structural characteristics of that give rise to volumetric alterations.

SUBMITTER: Foland-Ross LC

PROVIDER: S-EPMC8321133 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Cortical gray matter structure in boys with Klinefelter syndrome.

Foland-Ross Lara C LC Gil Maureen M Shrestha Sharon Bade SB Chromik Lindsay C LC Hong David D Reiss Allan L AL

Psychiatry research. Neuroimaging 20210504

Klinefelter syndrome (KS, 47,XXY) is a common sex chromosome aneuploidy in males that is associated with a wide range of cognitive, social and emotional characteristics. The neural bases of these symptoms, however, are unclear. Brain structure in 19 pre- or early-pubertal boys with KS (11.5 ± 1.8 years) and 22 typically developing (control) boys (8.1 ± 2.3 years) was examined using surface-based analyses of cortical gray matter volume, thickness and surface area. Boys in the KS group were treatm ...[more]

PMID: 34038819

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Project description:Klinefelter syndrome (KS, 47,XXY) is the most common sex chromosome aneuploidy in males. A variety of complex clinical needs is associated with KS, including physical, cognitive and psychosocial impairments. Standard treatment for KS consists of androgen replacement therapy in adolescence to offset testosterone deficiency. Such treatment has a beneficial effect on the physical and behavioral manifestations of this syndrome. Whether androgen supplementation has a significant influence on the brain, however, is unknown. In the current study, we examined regional gray matter volume in boys with KS to assess whether treatment with oxandrolone, a synthetic hormone analog of testosterone, was associated with structural changes in the brain. Specifically, we focused our investigation on the hippocampus, given (1) its involvement in KS, and (2) the high concentration of androgen receptors found in this region. Structural magnetic resonance imaging data was acquired from a subsample of boys who completed a 2-year double-blind clinical trial in which patients were randomized to treatment with oxandrolone or to placebo, as well as from a sample of typically developing (TD) boys. Group differences in hippocampal volume were examined. A significant main effect of group was observed. Pairwise comparisons indicated smaller hippocampal volume in the placebo group relative to the oxandrolone group, as well as smaller volume in the placebo group relative to the TD control group. No difference in volume was observed between the treatment and TD groups. Moreover, across KS subgroups, a significant positive association was observed between hippocampus volume and performance on a spatial memory task, indicating treatment-based changes in brain structure may underlie cognitive change. These findings confirm prior reports implicating a role of the hippocampus in KS and are important in extending previous research by demonstrating a significant effect of androgens on brain structure.

Project description:IntroductionWe performed a whole-transcriptome correlation analysis, followed by the pathway enrichment and testing of innate immune response pathway analyses to evaluate the hypothesis that transcriptional activity can predict cortical gray matter thickness (GMT) variability during normal cerebral aging.MethodsTranscriptome and GMT data were available for 379 individuals (age range=28-85) community-dwelling members of large extended Mexican American families. Collection of transcriptome data preceded that of neuroimaging data by 17 years. Genome-wide gene transcriptome data consisted of 20,413 heritable lymphocytes-based transcripts. GMT measurements were performed from high-resolution (isotropic 800 ?m) T1-weighted MRI. Transcriptome-wide and pathway enrichment analysis was used to classify genes correlated with GMT. Transcripts for sixty genes from seven innate immune pathways were tested as specific predictors of GMT variability.ResultsTranscripts for eight genes (IGFBP3, LRRN3, CRIP2, SCD, IDS, TCF4, GATA3, and HN1) passed the transcriptome-wide significance threshold. Four orthogonal factors extracted from this set predicted 31.9% of the variability in the whole-brain and between 23.4 and 35% of regional GMT measurements. Pathway enrichment analysis identified six functional categories including cellular proliferation, aggregation, differentiation, viral infection, and metabolism. The integrin signaling pathway was significantly (p<10(-6)) enriched with GMT. Finally, three innate immune pathways (complement signaling, toll-receptors and scavenger and immunoglobulins) were significantly associated with GMT.ConclusionExpression activity for the genes that regulate cellular proliferation, adhesion, differentiation and inflammation can explain a significant proportion of individual variability in cortical GMT. Our findings suggest that normal cerebral aging is the product of a progressive decline in regenerative capacity and increased neuroinflammation.

Dataset Information

Cortical gray matter structure in boys with Klinefelter syndrome.

Publications

Cortical gray matter structure in boys with Klinefelter syndrome.

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