Reduced fractional anisotropy and axial diffusivity in white matter in 22q11.2 deletion syndrome: A pilot study
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.
Section snippets
Subjects
Nine subjects with 22q11.2DS and nine healthy subjects, group matched for age, gender and PSES, were included in this study (Table 1). Deletion of the chromosomal region 22q11.2 was reconfirmed by Fluorescent-In-Situ-Hybridization (FISH) in the patient group. Patients were recruited from a multidisciplinary 22q11.2DS treatment program at Brigham and Women's Hospital, Children's Hospital, and Massachusetts General Hospital, Boston, MA, and through advertisements placed on 22q11.2DS related
Results
FA was compared between 22q11.2DS and controls using a whole brain voxel-by-voxel approach, TBSS, to evaluate localized WM abnormalities. Only one region of the cerebrum showed statistically significant reductions of FA (t ≥ 3, p < 0.05corrected), and this was localized to left parietal lobe WM (Fig. 1), where the inferior fronto-occipital fasciculus (IFOF), the inferior longitudinal fasciculus (ILF), the superior longitudinal fasciculus (SLF), cingulum and anterior thalamic radiation intersect.
Discussion
Changes in major WM tracts were investigated in 22q11.2DS using whole brain TBSS, a method that has not previously been applied to this population. Findings revealed FA reductions in left parietal lobe WM, where several WM tracts, including IFOF, ILF, SLF, cingulum and thalamic radiation intersect. Reduced AD values, but not RD changes were observed. These findings suggests axonal, rather than myelin disruption.
Four other studies have used DT-MRI to analyze WM in 22q11.2DS (Barnea-Goraly et
Role of funding source
This work was supported, in part, by a NARSAD Young Investigator Award (ZK), by the Department of Veterans Affairs Merit Awards (MES), by a VA Schizophrenia Center grant (MES), by grants from the National Institute of Mental Health, including a Career Reentry Supplement (ZK) on R01 MH 50740 (MES), a K05 MH 070047 (MES), R01MH082918 (SB), and a NIH Mental Health Centers for Interventional Development and Applied Research-CIDAR-P50 MH 080272 (MES, MK), and, finally, by the National Alliance for
Contributors
Z. Kikinis, S. Bouix, R. Kikinis, M.E. Shenton and M. Kubicki designed the imaging study and wrote the protocol. T. Asami and T. Ballinger advised and performed image analysis. C.T. Finn, E. Tworog-Dube and R. Kucherlapati recruited the patients and provided feedback on the study patients as well as providing their expertise in 22q11.2DS. Z. Kikinis wrote the manuscript. All authors contributed to, and have approved, the manuscript.
Conflict of interest
None of the authors have a financial conflict of interest regarding this report.
Acknowledgment
We thank Dr. Ferenc Jolesz and the Department of Radiology at BWH for providing some of the funding for images for this pilot study.
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