Reduced fractional anisotropy and axial diffusivity in white matter in 22q11.2 deletion syndrome: A pilot study

Abstract

Individuals with 22q11.2 deletion syndrome (22q11.2DS) evince a 30% incidence of schizophrenia. We compared the white matter (WM) of 22q11.2DS patients without schizophrenia to a group of matched healthy controls using Tract-Based-Spatial-Statistics (TBSS). We found localized reduction of Fractional Anisotropy (FA) and Axial Diffusivity (AD; measure of axonal integrity) in WM underlying the left parietal lobe. No changes in Radial Diffusivity (RD; measure of myelin integrity) were observed. Of note, studies in chronic schizophrenia patients report reduced FA, no changes in AD, and increases in RD in WM. Our findings suggest different WM microstructural pathology in 22q11.2DS than in patients with schizophrenia.

Introduction

22q11 deletion syndrome (22q11.2DS), also known as Velo-cardio-facial syndrome (VCFS) (Shprintzen, 2008), is a rare disease caused by a deletion in chromosome 22. Up to 30% of patients with this diagnosis suffer from schizophrenia, thus making the syndrome a target for the exploration of factors that lead to psychosis (van Amelsvoort et al., 2004, Gothelf et al., 2007b, Chow et al., 2011, da Silva Alves et al., 2011, Kates et al., 2011).

Effects in humans include schizophrenia (Murphy et al., 1999, Bassett et al., 2005), learning disabilities (Murphy et al., 1998), autism (Niklasson et al., 2009), depression (Green et al., 2009), and bipolar disorder (Papolos et al., 1996). The exact cause of this high comorbidity is not known, but the frequently occurring dysmorphology of heart, limbs (short statue), face and brain suggests a developmental disorder involving cells of the neural crest (Kirby et al., 1983). 22q11.2DS is characterized by a microdeletion of 30–45 genes on chromosome 22. Studies in a 22q11.2DS mouse model (LgDel mouse) demonstrate that reduced expression of several of these genes results in abnormalities in the number, location and connectivity of neurons in the developing brain (Meechan et al., 2010).

One of the most influential hypotheses in schizophrenia suggests abnormalities in brain connectivity (Konrad and Winterer, 2008). Abnormal brain connectivity in schizophrenia is now supported by changes in white matter (WM) fiber tracts (Kubicki et al., 2007, Ellison-Wright and Bullmore, 2009), as well as by abnormalities in neural circuitry, which are based on fMRI studies (Deserno et al., 2012). Additionally, altered oligodendroglial cells, decreased myelination of fibers, and changes in the expression of myelin-related genes have all been associated with schizophrenia (e.g., Hakak et al., 2001, Uranova et al., 2001, Davis et al., 2003, Tkachev et al., 2003), suggesting abnormalities in myelin in this disorder. Interestingly, while DT-MRI studies in 22q11.2DS patients also report abnormalities in WM integrity (Barnea-Goraly et al., 2003, Simon et al., 2008, Sundram et al., 2010, da Silva Alves et al., 2011), animal studies point to neurons and their axons, rather than myelin, as the possible source of observed WM abnormalities in 22q11.2DS (Meechan et al., 2010).

The method used in general today to explore WM, in vivo, is Diffusion Tensor Magnetic Resonance Imaging (DT-MRI). The majority of DT-MRI studies use Fractional Anisotropy (FA) for quantification. FA is a measure that describes the directionality of water diffusion. Its value ranges from 0 to 1, with a value of 0 corresponding to a perfectly isotropic environment, where water is unrestricted as for example in cerebrospinal fluid, and with a value of 1 corresponding to a perfect anisotropic environment, where water is most restricted in all but one direction, as for example in WM fiber bundles (Basser et al., 1994). More specifically, FA has higher values in WM, where myelinated axons are highly organized. Here, water diffusion is believed to be hindered by barriers (i.e., anisotropic), such as the membranes, myelin and cytoskeleton (Beaulieu, 2002). Nevertheless, while FA is sensitive to all changes in WM micro and macro structure, it is very nonspecific when it comes to tissue pathology. Other DT-MRI indices, however, such as parallel diffusivity (also known as axial diffusivity or AD) and perpendicular diffusivity (also known as radial diffusivity or RD), are believed to be more specific to underlying micropathology. These measures have, in fact, been shown to be markers of axonal (AD) and myelin (RD) integrity in a series of mouse experiments (Song et al., 2003, Song et al., 2005). AD and RD measures have also subsequently been applied to clinical populations in order to study adolescent development (e.g.,(Giorgio et al., 2010), aging (Van Hecke et al., 2008), cerebral tumors (Nagesh et al., 2008), multiple sclerosis (Roosendaal et al., 2009, Klawiter et al., 2011), autism (Barnea-Goraly et al., 2010), schizophrenia (Ashtari et al., 2007, Seal et al., 2008, Whitford et al., 2010), and 22q11.2DS (Simon et al., 2008)).

In this study we investigate differences in WM pathology between adult 22q11.2DS patients without schizophrenia and matched healthy controls using DT-MRI. Group comparisons are performed using Tract-Based Spatial Statistics (TBSS) (Smith et al., 2006), a method that allows for hypothesis-free voxel-based whole brain WM group comparisons. TBSS is a new generation of voxel-based methods that instead of performing statistical group analysis for each voxel of the WM, compares only voxels that belong to large fiber bundles. This requires that only correspondence between major tracts across all subjects needs to be established, which minimizes registration errors, and reduces partial volume effects.

Based on the high risk of schizophrenia in 22q11.2DS patients, we hypothesize that our patients with 22q11.2DS will be characterized by reduced FA, which is similar to WM changes observed in schizophrenia patients and in subjects at ultra high risk for schizophrenia (Carletti et al., 2012). We further hypothesize that either increases in RD (indicative of abnormalities in myelin as suggested by imaging and nonimaging schizophrenia studies), or decreases in AD (indicative of axonal changes as suggested by 22q11.2DS mouse model) will account for FA abnormalities.