A DTI study of white matter microstructure in individuals at high genetic risk for schizophrenia

Abstract

Structural brain developmental anomalies, particularly those in frontotemporal white matter pathways, may have a genetic component and place people at increased risk for schizophrenia. The current study employed Diffusion Tensor Imaging (DTI) to measure fractional anisotropy (FA) as a quantitative indicator of white matter integrity. We examined twenty-two participants at high genetic risk for schizophrenia (HR), 23 people with schizophrenia (most of whom were family members of those at HR) and 37 non-psychiatric controls for comparison. In those at HR, reduced FA was observed in the cingulate and angular gyri bilaterally. In a few regions, FA was higher in HR participants than in comparison participants. These regional variations in FA might reflect differences in white matter development from comparison participants. Our data provide some evidence that abnormal white matter integrity may be detectable before the onset of a psychotic illness, although longitudinal studies are necessary to determine whether these individuals at genetic risk with abnormal FA will develop illness and whether these changes are associated with the genetic risk for the disorder.

Introduction

Structural brain abnormalities have consistently been shown to be present in people with schizophrenia (reviewed in (Shenton et al., 2001, Glahn et al., in press)) and the illness has also been shown to be highly heritable (reviewed in McGue and Gottesman, 1991, DeLisi, 1997). The illness rarely is detected prior to late adolescence or early adulthood when the incidence peaks. Several theories have been proposed for this delayed onset, but one intriguing possibility is that of Feinberg (Feinberg, 1982), who suggested that the programmed axonal pruning process and the normal formation of new synaptic connections that normally takes place during adolescence has been disturbed.

Feinberg based his hypothesis on EEG studies of adolescents, but until recently, there has not been anatomical support for this theory. Recently it has been possible to study white matter abnormalities in schizophrenia with MRI using Diffusion Tensor Imaging (DTI). DTI measures the Brownian motion or free diffusion of water through tissue. When applied to neural tissue, DTI assesses the degree to which water diffusion is constrained by barriers such as myelin sheaths, membranes or neuronal fiber tracts. Diffusion in white matter is anisotropic meaning that, in a given white matter voxel, axial diffusion (parallel to the principal fiber direction) is much greater than radial diffusion (perpendicular to the principal fiber direction). Fractional anisotropy (FA) is the most frequently used measure obtained from DTI and is a normalized variable derived from the 3 eigenvalues of the diffusion tensor. FA is a measure of the degree of diffusion anisotropy within a voxel and varies from 0 (corresponding to completely isotropic diffusion) to 1 (corresponding to free diffusion in one direction only). Thus, FA is a measure of white matter microstructure that may reflect fiber organization, fiber directional coherence, and/or fiber integrity (Beaulieu, 2002). White matter abnormalities with axonal disorganization might therefore be expected to decrease FA.

Abnormalities in white matter integrity in schizophrenia, particularly in the frontal lobe and its connections (e.g., the uncinate fasciculus (Kubicki et al., 2002)) have been reported in several diffusion tensor imaging studies (reviewed in Kubicki et al., 2007, Kanaan et al., 2005). Some of these abnormalities appear to be present in patients experiencing a first episode of schizophrenia (Szeszko et al., 2005, Szeszko et al., 2008), as well as in patients with early onset schizophrenia (Kumra et al., 2005). These data suggest that at least some of the DTI findings in schizophrenia are not likely to be medication effects, and that they are present at an early stage in the illness.

If the abnormal white matter integrity seen in schizophrenia is due to deviations in brain development, people who are at high risk for schizophrenia might be expected to have reduced FA or overall reduced white matter integrity that may be detectable before any symptoms of illness are present, and this might represent a biologic vulnerability for later illness. Although it is clear that schizophrenia may arise from environmental or gene–environment interactions, having a first-degree relative with schizophrenia is the strongest known risk factor for schizophrenia (reviewed in Gottesman, 1991). For this reason, in the present study we evaluated a group of genetically at high risk young adults. Individuals in the age range of highest risk for schizophrenia (DeLisi, 1992) from families in which at least one other first-degree relative was previously diagnosed with schizophrenia were scanned using DTI in parallel with adults with schizophrenia from these families, as well as age-appropriate low-risk comparison participants. Because little is known about the regional distribution of FA abnormalities in those at high risk, we performed exploratory voxelwise analyses.