Structural MRI of 47XXY and 47XXX Sex Chromosomal Abnormalities (SCA).

SCA and Imaging Research

The SPNL worked in collaboration with the Department of Pediatrics at the National Jewish Medical and Research Center in Denver, Colorado (Dr. Bruce Bender, PI). The Denver SCA study of individuals with sex chromosome abnormalities began in 1964 as the first study in the world to screen a large number of consecutive newborns for SCA and to follow them prospectively. This study is now concluded.

Although the features of individuals with SCA are highly variable, different forms of SCA may be associated with specific behavioral and cognitive phenotypes. Using MRI, we investigated the neurodevelopmental consequences of SCA and its association with measures of cognitive and behavioral performances assessed in the Denver SCA Study.

The morphometric methods utilized in structural image processing and analysis in the Stanford Psychiatry Neuroimaging Laboratory (SPNL) incorporate semi- or fully automated procedures using our image processing program, BrainImage©. Processing and segmentation of 3D-SPGR datasets is comprised of a set of semi-automated procedures that have been validated in our laboratory.

The neuroanatomic regions of interest generated from this image processing pipeline include those volumes that are of interest in the various forms of SCA, given the phenotypic features of Turner syndrome, Klinefelter Syndrome, and 47,XXX. These include but are not limited to: total brain, parietal lobe, temporal lobe, occipital lobe, cerebellum, ventricular volume, hippocampus, parahippocampal gyrus and superior temporal gyrus. Segmented white matter, gray matter, and CSF image volumes are also measured for these areas.

Structural MRI Research in 47,XXX and 47,XXY

A strucutral MRI study of individuals with Klinefelter syndrome (KS), a condition characterized by an extra X chromosome in males (47,XXY), showed a significant reductions in left temporal lobe gray matter volumes in subjects with KS compared with normal control subjects. Subjects with KS are known to have reduced male hormone (testosterone) levels, and the effects of this on brain morphology was therefore studied. Half of the men in this study received testosterone supplementation (KS+T), and half not (KS-T). Verbal fluency scores were significantly higher in the KS+T compared with the KS-T group. Thus, supernumerary X chromosome material in men is associated with a reduction in left temporal lobe gray matter, a finding that is consistent with the verbal and language deficits associated with KS. Also, relative preservation of gray matter in the left temporal region is associated with exposure to exogenous androgen during development. A history of testosterone supplementation also appears to be associated with increased verbal fluency scores in KS patients.

The excess of 47,XXX and 47,XXY karyotypes found in cytogenetic screening studies of individuals with schizophrenia has given support for an increased risk of psychiatric illness among men and women with SCA. Mesial temporal lobe structures, including the amygdala and hippocampus, are thought to be associated with abnormalities of mood and behavior in humans and in the neurobiology of schizophrenia. We therefore investigated the variations in volumes of mesial temporal lobe structures in men and women with SCA. Regional and total brain volumes were measured in subjects with 47,XXY, subjects with 47,XXX, and normal genetic control individuals. Amygdala volumes were significantly reduced in men with 47,XXY, compared to control men, while the decrease in women with 47,XXX was not as pronounced. Hippocampus volumes were preserved in both groups, compared to same-gender controls. Longitudinal studies of SCA individuals have shown an increased incidence of mild psychopathology and behavioral dysfunction in men with 47,XXY and more overt psychiatric illness in women with 47,XXX, compared to control populations. The alteration in amygdala volumes in individuals with a supernumerary X chromosome may provide a neuroanatomic basis for these findings.

Current research is focused on assessment and imaging of girls with Turner syndrome.