Decreased axial diffusivity within language connections: a possible biomarker of schizophrenia risk.

Siblings of patients diagnosed with schizophrenia are at elevated risk for developing this disorder. The nature of such risk associated with brain abnormalities, and whether such abnormalities are similar to those observed in schizophrenia, remain unclear. Deficits in language processing are frequently reported in increased risk populations. Interestingly, white matter pathology involving fronto-temporal language pathways, including arcuate fasciculus (AF), uncinate fasciculus (UF), and inferior occipitofrontal fasciculus (IOFF), are frequently reported in schizophrenia. In this study, high spatial and directional resolution diffusion MRI data was obtained on a 3T magnet from 33 subjects with increased familial risk for developing schizophrenia, and 28 control subjects. Diffusion tractography was performed to measure white matter integrity within AF, UF, and IOFF. To understand these abnormalities, Fractional Anisotropy (FA, a measure of tract integrity) and Trace (a measure of overall diffusion), were combined with more specific measures of axial diffusivity (AX, a putative measure of axonal integrity) and radial diffusivity (RD, a putative measure of myelin integrity). Results revealed a significant decrease in Trace within IOFF, and a significant decrease in AX in all tracts. FA and RD anomalies, frequently reported in schizophrenia, were not observed. Moreover, AX group effect was modulated by age, with increased risk subjects demonstrating a deviation from normal maturation trajectory. Findings suggest that familial risk for schizophrenia may be associated with abnormalities in axonal rather than myelin integrity, and possibly associated with disruptions in normal brain maturation. AX should be considered a possible biomarker of risk for developing schizophrenia.

Pituitary volume in schizophrenia spectrum disorders.

INTRODUCTION: There is converging evidence supporting hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in schizophrenia spectrum disorders (SSD), such as schizotypal personality disorder (SPD), first-episode schizophrenia (FESZ) and chronic schizophrenia (CHSZ). Such an aberrant HPA activity might have volumetric consequences on the pituitary gland. However, previous magnetic resonance imaging (MRI) studies assessing pituitary volume (PV) in SSD are conflicting. The main objective of this study was to examine further PV in SSD. METHODS: PV were manually traced on structural MRIs in 137 subjects, including subjects with SPD (n = 40), FESZ (n = 15), CHSZ (n = 15), and HC (n = 67). We used an ANCOVA to test PV between groups and gender while controlling for inter-subject variability in age, years of education, socioeconomic status, and whole brain volume. RESULTS: Overall, women had larger PV than men, and within the male sample all SSD subjects had smaller PV than HC, statistically significant only for the SPD group. In addition, dose of medication, illness duration and age of onset were not associated with PV. CONCLUSION: Chronic untreated HPA hyperactivity might account for smaller PV in SPD subjects, whereas the absence of PV changes in FESZ and CHSZ patients might be related to the normalizing effects of antipsychotics on PV. SPD studies offer a way to examine HPA related alterations in SSD without the potential confounds of medication effects.

Human middle longitudinal fascicle: variations in patterns of anatomical connections.

Based on high-resolution diffusion tensor magnetic resonance imaging (DTI) tractographic analyses in 39 healthy adult subjects, we derived patterns of connections and measures of volume and biophysical parameters, such as fractional anisotropy (FA) for the human middle longitudinal fascicle (MdLF). Compared to previous studies, we found that the cortical connections of the MdLF in humans appear to go beyond the superior temporal (STG) and angular (AG) gyri, extending to the temporal pole (TP), superior parietal lobule (SPL), supramarginal gyrus, precuneus and the occipital lobe (including the cuneus and lateral occipital areas). Importantly, the MdLF showed a striking lateralized pattern with predominant connections between the TP, STG and AG on the left and TP, STG and SPL on the right hemisphere. In light of the results of the present study, and of the known functional role of the cortical areas interconnected by the MdLF, we suggested that this fiber pathway might be related to language, high order auditory association, visuospatial and attention functions.

Gray matter volume reduction in rostral middle frontal gyrus in patients with chronic schizophrenia.

The dorsolateral prefrontal cortex (DLPFC) is a brain region that has figured prominently in studies of schizophrenia and working memory, yet the exact neuroanatomical localization of this brain region remains to be defined. DLPFC primarily involves the superior frontal gyrus and middle frontal gyrus (MFG). The latter, however is not a single neuroanatomical entity but instead is comprised of rostral (anterior, middle, and posterior) and caudal regions. In this study we used structural MRI to develop a method for parcellating MFG into its component parts. We focused on this region of DLPFC because it includes BA46, a region involved in working memory. We evaluated volume differences in MFG in 20 patients with chronic schizophrenia and 20 healthy controls. Mid-rostral MFG (MR-MFG) was delineated within the rostral MFG using anterior and posterior neuroanatomical landmarks derived from cytoarchitectonic definitions of BA46. Gray matter volumes of MR-MFG were then compared between groups, and a significant reduction in gray matter volume was observed (p<0.008), but not in other areas of MFG (i.e., anterior or posterior rostral MFG, or caudal regions of MFG). Our results demonstrate that volumetric alterations in MFG gray matter are localized exclusively to MR-MFG. 3D reconstructions of the cortical surface made it possible to follow MFG into its anterior part, where other approaches have failed. This method of parcellation offers a more precise way of measuring MR-MFG that will likely be important in further documentation of DLPFC anomalies in schizophrenia.

Angiopoietin-1 and -2 coiled coil domains mediate distinct homo-oligomerization patterns, but fibrinogen-like domains mediate ligand activity.

Activity of endothelial Tie2 receptor tyrosine kinase is modulated by two naturally occurring, secreted ligands, angiopoietin-1 and -2, which have opposing effects on its phosphorylation. Receptor tyrosine kinase activation requires receptor dimerization/multimerization, which, for many receptors, is mediated by homo-oligomeric ligands binding to and bridging receptor molecules. We show here that angiopoietin-1 and -2 form distinct arrays of disulfide-linked homo-oligomeric complexes. Their mobilities on nonreducing gels suggest that angiopoietin-2 exists predominantly as a homodimer but also forms higher order multimers. In contrast, angiopoietin-1 forms some homotrimers, but predominantly exists in higher order multimers. These two structurally related, 60% homologous ligands are predominantly composed of an amino-terminal coiled coil domain and a carboxyl-terminal fibrinogen-like domain. We show that their distinct oligomerization patterns are determined by their coiled coil domains and, furthermore, that their coiled coil domains, but not their fibrinogen-like domains, are sufficient to mediate formation of disulfide-linked homo-oligomers. In contrast, the differential effects of these ligands on endothelial Tie2 phosphorylation is mediated by their fibrinogen-like domains. We conclude from these studies that the coiled coil and fibrinogen-like domains of the angiopoietins have distinct functions with the coiled coil domain mediating ligand homo-oligomerization and the fibrinogen-like domain mediating ligand activity.