Developmental trajectories of brain structure in adolescents with 22q11.2 deletion syndrome: A longitudinal study
Introduction
The 22q11.2 deletion syndrome (22q11.2DS), also known as velocardiofacial and DiGeorge syndromes, is caused by a microdeletion in the long arm of chromosome 22 (Carlson et al., 1997). The exact incidence of the syndrome is not yet certain but is estimated to be at least 1 in 5000 live births (Botto et al., 2003). Thus, 22q11.2DS is the most common microdeletion syndrome known in humans. The phenotypic expression of 22q11.2DS is extremely broad and includes physical anomalies, cognitive deficits, and psychiatric manifestations (Shprintzen, 2000).
Most subjects with 22q11.2DS have learning disabilities with full-scale IQ (FSIQ) scores ranging from normal range to moderate mental retardation with a mean FSIQ in the borderline range (mid-seventies) (Swillen et al., 1997). In addition to physical and cognitive deficits, individuals with 22q11.2DS have high rates of psychiatric disorders (Feinstein et al., 2002, Murphy et al., 1999). Most striking, up to one third of subjects with 22q11.2DS develop schizophrenia-like psychotic disorders by early adulthood. This makes 22q11.2DS the most common identifiable genetic risk factor for schizophrenia (Gothelf et al., 2005, Murphy et al., 1999).
Cross-sectional quantitative imaging studies indicate diffuse alterations in the brain structure of children with 22q11.2DS. Total brain volume is decreased by 8.5%–11% and there are extensive regional abnormalities in both gray matter (GM) and white matter (WM) volumes (Eliez et al., 2000, Kates et al., 2001, Simon et al., 2005). Frontal lobe grey and white matter volumes are relatively increased while posterior cortical regions including parietal and occipital grey and white matter volumes are reduced (Campbell et al., 2006, Eliez et al., 2000, Kates et al., 2001). In addition, there are aberrations of posterior fossa anatomy, most notably cerebellar grey and white matter volume reductions (Bish et al., 2006, Eliez et al., 2001a, Eliez et al., 2001b). Abnormal volumes have also been reported for other brain regions, including enlarged volumes of ventricular cerebrospinal fluid (CSF), caudate nucleus, and amygdala (Campbell et al., 2006, Eliez et al., 2002, Eliez et al., 2001a, Eliez et al., 2001b, Kates et al., 2006, Simon et al., 2005).
There are relatively fewer imaging studies of adults with 22q11.2DS (Chow et al., 2002, van Amelsvoort et al., 2004). These studies have compared brain anatomy of psychotic versus nonpsychotic 22q11.2DS individuals. In general, subjects with 22q11.2DS and psychosis demonstrate morphological abnormalities similar to those detected in schizophrenia. These abnormalities include reduced whole brain volume — particularly WM, smaller GM volume in frontal and temporal lobes, and increase in ventricular volume (Chow et al., 2002, van Amelsvoort et al., 2004).
The goal of the present study was to assess longitudinal neurodevelopment in individuals with 22q11.2DS during the critical period of adolescence. However, since this is the first comparative longitudinal study of brain development in 22q11.2DS, we could not test hypotheses based on prior information about neurodevelopmental trajectories in this disorder. Accordingly, we chose to focus on the development of candidate brain regions that were previously reported to be abnormal in cross-sectional studies of both 22q11.2DS (Campbell et al., 2006, Chow et al., 2002, Eliez et al., 2002, Eliez et al., 2001a, Eliez et al., 2001b, Kates et al., 2006, Simon et al., 2005, van Amelsvoort et al., 2004) and schizophrenia (reviewed in DeLisi et al., 2006, Shenton et al., 2001). Thus we analyzed change in volume of the cerebral lobes, superior temporal gyrus (STG), ventricular CSF, cerebellum, amygdala, hippocampus, and caudate nucleus.
In addition, we focused on identifying neuroanatomical markers for the evolution of psychotic disorders and for the decline in VIQ scores that were identified in a previous study of this cohort (Gothelf et al., 2005). We hypothesized that changes in the above mentioned candidate brain regions would be more robust in those 22q11.2DS individuals who developed psychotic disorders compared to those who remained nonpsychotic. Since language functions are predominantly related to the left hemisphere (Capozzoli, 1999, Gernsbacher and Kaschak, 2003), we also hypothesized that the decline in VIQ scores in subjects with 22q11.2DS would be associated with a more robust decline in left cerebral GM volume.
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Participants
The time 1 (T1) sample, collected between 1998 and 2000, included 29 children with 22q11.2DS and 29 typically developing (TD) controls [nineteen 22q11.2DS subjects and no controls participated in a previous study by our group that reported on prefrontal imaging data (Gothelf et al., 2005)]. Prospective recruitment was performed through the Northern California Velocardiofacial Association and by advertising on our web site (cibsr.stanford.edu). The presence of the 22q11.2 microdeletion was
Results
The summary of baseline (T1) and follow-up (T2) brain tissue volumes in 22q11.2DS and typically developing controls are presented in Table 2.
Discussion
This is the first longitudinal study to investigate brain development trajectories in children with 22q11.2DS as compared to a matched age and gender control group. Compared to controls, subjects with 22q11.2DS showed abnormal developmental trajectories in several brain regions during transition into late adolescence–youngadulthood. Compared to controls, children with 22q11.2DS demonstrated a greater increase in total cranial and cerebellar WM, STG GM, and caudate nucleus volumes. They also
Role of funding source
The funding for this study was provided by NIH grants HD31715, MH50047, MH19908 to Allan L. Reiss and by NARSAD grant to Doron Gothelf; the NIMH and NARSAD had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors
Drs. Gothelf, Eliez, and Reiss designed the study protocol; Drs. Gothelf and Eliez, Mr. Gu, and Ms. Penniman collected data and evaluated subjects; Drs. Gothelf and Reiss and Mr. Gu, and Ms. Penniman analyzed the data and wrote the manuscript.
Conflict of interest
All authors declare that they have no conflicts of interest.
Acknowledgments
DG was supported by NARSAD Young Investigator Award and ALR was supported by NIH grants HD31715, MH50047 and MH19908. The authors would like to thank the subjects and their families for participating in the study.
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