DBP2:Harvard

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• Title: Velocardiofacial Syndrome (VCFS) as a genetic model for schizophrenia

Team and Institute

• PI: Marek Kubicki, MD, PhD, Contact: kubicki at bwh.harvard.edu
• NA-MIC Engineering Contact: Brad Davis, Kitware
• NA-MIC Algorithms Contact: Polina Golland, MIT

• Affiliation/Institution: Harvard Medical School, Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital

• Science: VCFS is a genetic disorder characterized by a deletion of a small piece of chromosome-22. The features of this syndrome include deficits in neurological psychomotor and perceptual skills, as well as in cognitive domains such as learning and memory. Most importantly, up to 30% of VCFS patients develop schizophrenia, making it the most commonly known single risk factor for the development of psychosis and a unique model for studying neurodevelopmental changes leading to psychotic deficits. We plan to collect new, high resolution DTI, structural and fMRI data, and apply existing NAMIC tools, as well as help to develop new tools to investigate the contribution of genetic variation to brain and behavioral/cognitive abnormalities, thus bridging the gap between neuroimaging studies and genetics.

• Benefits to NA-MIC: The NAMIC community will gain access to new, high resolution diffusion and fMRI data acquired on the 3T magnet at Brigham and Women’s Hospital. Unlike in schizophrenia, subjects with VCFS have concrete cognitive abnormalities, in addition to a well defined chromosomal abnormality, which, taken together, will make it easier to establish scientific protocols that reveal associated anatomical and functional brain abnormalities in this disorder. Interestingly, some anatomical abnormalities will be shared between VCFS and schizophrenia (e.g., connections within working memory circuits), and some will be not (e.g., sensory and motor paths). Genetic data will also be collected for each individual and will also be available for further analyses with the imaging and neurocognitive data. This NAMIC collaboration with thus enable the PI to apply NAMIC tools to VCFS, a genetic disorder that is viewed as a genetically mediated subtype of schizophrenia. To date, there have only been a small number of neuroimaging studies of this disorder and no studies have combined neurocognitive, neuroimaging, and genetic investigations in the same study. Importantly, this research will also increase our understanding of schizophrenia, and will help establish a multimodal research project involving an important collaboration between computer scientists, cognitive neuroscientists, radiologists, psychiatrists, and geneticists. The focus on imaging and genes also affords a new window of opportunity for defining further the new area of “imaging genomics”.

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Velocardiofacial Syndrome (VCFS) as a genetic model for schizophrenia

Research Goals

Clinical and Scientific Relevance: The main goal of this application is to characterize “intermediate phenotypes”, such as anatomic and functional abnormalities in the brain of patients with velocardiofacial syndrome (VCFS), and to link this information with cognitive/behavioral deficits in schizophrenia and with genetic variations. This area of research represents a new frontier for making schizophrenia more tractable, as well as for shedding new light on the etiology of this devastating disorder.

We propose to study patients with VCFS, a genetic disorder characterized by a deletion of a small piece of chromosome-22, in order to understand this disorder further as well as to evaluate VCFS as a genetic model for schizophrenia. The features of this syndrome include, among other things, deficits in neurological psychomotor and perceptual skills, as well as cognitive deficits in learning and memory. Importantly, up to 30% of VCFS patients develop schizophrenia, making it the most commonly known single risk factor for the development of psychosis and a unique model for studying neurodevelopmental changes leading to psychotic deficits. The deletion region contains about 30 to 40 genes, but only 3- PRODH, RTN4R and COMT have thus far been related to schizophrenia. COMT (catecholamine-O-methyl transferease) is a gene that is important for the catabolism of dopamine and maintaining appropriate levels of dopamine in the human brain, and several studies have associated this gene, or rather different COMT genotypes, with dorso-lateral prefrontal cortex and working memory, which are known to be disrupted in schizophrenia. RTN4R (known also as No-Go-66 receptor) gene, on the other hand, is much less studied than the COMT gene, but might be equally important in studies investigating schizophrenia. This gene mediates axonal growth inhibition and may play a role in regulating axonal regeneration and plasticity in the adult central nervous system. Since dopamine regulation, as well as neuronal plasticity, are both investigated in schizophrenia, VCFS seems to be the perfect genetic model for schizophrenia.

We propose to combine genetic data and sophisticated neuroimaging data analysis. Gray matter regions previously implicated in both VCFS and schizophrenia research (frontal and temporal regions), as well as regions more commonly observed in schizophrenia (medial temporal and subcortical structures), will be delineated and analyzed including shape analysis. In addition, fiber tracts that show abnormalities in schizophrenia, such as the fornix, the cingulum bundle, the uncinate fasciculus, the corpus callosum (also implicated in VCFS studies), and the internal capsule, will be investigated using Diffusion Tensor Imaging, a technique sensitive to white matter fiber integrity. In addition, statistical as well as anatomical relationships between gray and white matter pathology, including anatomical connections between gray matter areas affected in VCFS and schizophrenia and cognitive and clinical symptoms will also be evaluated.

We will scan 15 VCFS patients per year for a total of 45 subjects over the three-year grant period. Half of these subjects will have severe psychiatric symptoms, with a diagnosis of schizophrenia or schizophrenia-like symptoms, and half will have either no psychiatric symptoms or minimal symptoms and no Axis I disorder determined by standardized diagnostic interview. While not part of this project, we will have access to patients with schizophrenia and controls from a larger study of schizophrenia. We thus plan to evaluate N=45 control group, which will consist of healthy controls and schizophrenia subjects without VCFS, matched for age, gender, handedness, parental socio-economic status and IQ. The later control group is important, since most schizophrenia studies exclude low IQ participants, thus results of majority of schizophrenia studies might not be comparable with our VCFS population, which is characterized by IQ below normal.

The specific aims of this project are:

• To detect and localize possible gray and white matter disruptions common to VCFS and schizophrenia.
• To investigate the relationship among anatomical and between anatomical and functional abnormalities (later measured by clinical symptoms and neuropsychological tests).
• To determine the extent to which anatomical as well as functional abnormalities observed in schizophrenia and anatomical and functional differences between VCFS patients with and without schizophrenia can be explained by VCFS genotype. (latter involving genetic haplotype analysis)

Data description

What kind of image data is associated with these goals (modality, resolution, quantity)?

To date, we have collected DTI and Structural Data on the 1.5Tesla magnet on 6 VCFS patients. We are waiting for IRB approval to rescan these subjects, and to start collecting further prospective data on 3Tesla magnet, where we plan to use the following scan parameters:

• Diffusion Tensor MRI: DTI scans will be acquired from a 3 Tesla GE system (General Electric Medical Systems, Milwaukee, WI) using an echo planar imaging (EPI) DTI Tensor sequence. We will use a double echo option in order to reduce eddy-current related distortions (Heid 2000; Alexander 1997). To reduce the impact of EPI spatial distortion, we will use an 8 Channel coil that will allow us to perform parallel imaging using ASSET (Array Spatial Sensitivity Encoding Techniques, GE) with a SENSE-factor (speed-up) of 2. We will acquire 51 directions with b=700, 8 baseline scans with b=0. The original GE sequence has been modified, in order to increase spatial resolution, and to further minimize image artifacts. The following scan parameters will be used: TR 17000 ms, TE 78 ms, FOV 24 cm, 144 x 144 encoding steps, 1.7-mm slice thickness. We will acquire 81 axial-oblique slices parallel to the AC-PC line and perpendicular to the interhemispheric fissure covering the whole brain. The total scan time for the sequence will be 17 minutes. After reconstruction, the diffusion-weighted images will be transferred to Linux workstations, where eigenvalues, eigenvectors and anisotropy indices of the diffusion tensor will be calculated.

• Structural MRI: For the Structural MRI volume and shape measurements, images will be acquired also using a 3T GE scanner (GE Medical Systems, Milwaukee). The acquisition protocol will include two MRI pulse sequences. The first sequence results in contiguous spoiled gradient-recalled acquisition (FastSPGR) with the following parameters; TR=7.5ms, TE=3ms, 15 degree flip angle, 25.6cm2 field of view, NEX=1.0, matrix=256x256. Similar to DTI, we will use an 8 Channel coil that will allow us to perform parallel imaging using ASSET (Array Spatial Sensitivity Encoding Techniques, GE) with a SENSE-factor (speed-up) of 2. The voxel dimensions are 1x1x1 mm. Data will be formatted in the axial plane and analyzed as 186 axial slices, and a total scan time is 4 minutes. The second acquisition sequence (Fast Spin Echo- FSE) produces an axial series of contiguous T2-weighted images (TR=6200ms, TE=103ms, Echo Train Length=16; 25.6cm2 field of view, interleaved acquisitions with 2.0mm slice thickness). The voxel dimensions are 1x1x2.0 mm. This latter pulse sequence is used to measure the volume of the total intracranial contents, used then as an independent factor in a regression procedure to account for the effect of head/brain size.

What other kinds of data are involved (non-image)?

For all the subjects, we are also currently collecting:

• Neuropsychological and Cognitive Data: VCFS patients will be administered a standard battery of cognitive measures in major domains thought to be affected in VCFS and schizophrenic populations, including: general intellectual functioning, verbal intelligence and language functioning, working memory, visuo-spatial and perceptual functioning, executive functioning, and attention among others. In addition, psychiatric diagnostic evaluations will be carried out on all VCFS subjects, and include standardized assessment of general psychiatric symptoms with the Structured Clinical Interview for DSM-IV Axis I (SCID-I) as well as specific measures of positive and negative symptoms of psychosis and measures of schizotypy. It is expected that structural brain abnormalities will correlate with the presence or absence of psychiatric diagnoses in VCFS subjects (e.g., midline defects like cavum septum pellicidum/vergae or enlarged lateral ventricles in psychotic VCFS subjects) and various cognitive measures (e.g., impairment in executive functioning and attention correlated with prefrontal lobe cortex anomalies; arithmetic ability correlated with inferior parietal lobe anomalies; and verbal memory correlated with left superior temporal gyrus, and left amygdale-hippocampal complex).

• Genetic Measures: As testing every putative genetic variant in every candidate gene that may contribute to the VCFS/DGS phenotype would be prohibitive in terms of time and money, haplotype based approaches offer an alternative. These approaches have contributed to the identification of Mendelian disease genes and are now beginning to help identify susceptibility genes for common, complex diseases. The International HapMap Consortium is constructing genome-wide maps of sequence variation that may facilitate large association studies (The International HapMap Consortium:http://www.hapmap.org/). It is predicted that these approaches will be a powerful tool for common diseases like schizophrenia that are thought to result from a small number of common variants (“common disease-common variant” hypothesis). We propose a pilot investigation of the role of genetic variation found in the 22q11-deleted region using “tag” SNPs that define the haplotype map of this region. Using around two tag SNPs per haplotype block we expect that we will genotype around 160 SNPs for subsequent association studies. Although genes outside 22q11 may have a modifying effect on the phenotypic spectrum, our current focus is on genes within the 22q11 region because we feel it is important to first assess the role of the genes within the 3Mb region of deletion. Once genotyping data are assembled, we will use a case-control study design to determine if any of the genes in the commonly deleted 3Mb region are associated with neuropsychiatric phenotypes. Specifically, we will use the identified tag SNPs to genotype a set of cases (VCFS patients with psychiatric symptoms) and a set of controls (VCFS patients without psychiatric symptoms). Neurocognitive measures, or anatomical abnormalities will also be considered as phenotypes of interest. Both single SNP and haplotype analyses will be undertaken.