National Alliance for Medical Image Computing AHM, SLC, January 2007 Velo-Cardio-Facial Syndrome PRINCIPAL INVESTIGATOR: Marek Kubicki,

National Alliance for Medical Image Computing http://na-mic.org

AHM, SLC, January 2007

Velo-Cardio-Facial Syndrome

PRINCIPAL INVESTIGATOR: Marek Kubicki, MD, PhD

INVESTIGATORS:Zora Kikinis, PhDSylvain Bouix, PhDMarc Niethammer, PhDMartha Shenton, PhDChristine Finn, MDRaju Kucherlapati, MDRESEARCH ASSISTANT:Doug Markant, BA



Velo-Cardio-Facial Syndrome (VCFS)

• Condition defined by Sphrintzen in 1978

• Chromosome 22 q11.2 deletion. Deletion of 1.5 to 3 Mb (single copies of 30 to 45 genes missing)

• Prevalence 1 in every 4000 newborns



VCFS Symptoms

• "velum" latin meaning soft palate

Cleft palate, small or aplastic tonsils,

hypernasal speech• “kardia" greek meaning heart

VSD , right sided aortic arch, tetralogy

of Fallot, aberrant subclavian artery• "facial" latin having to do with the face

maxillary excess, malar flatness, facial asymmetry, thin upper lip, prominent nasal root, large nasal tip, pinched, hypoplastic base



Common Cognitive Deficits in VCFS

• Psychomotor and perceptual deficits• Learning and memory disabilities• Emotional abnormalities (flat affect and poor

social interaction). • High incidence for schizophrenia and/or

bipolar disorder in adult (30% VCFS patients develop schizophrenia)



Neuroimaging Findings in VCFS

• MRI case reports (most)

- high frequency of nonspecific white matter hyperintensities (30% of cases)

- cavum septi pellucidi (in 45% of cases)

• MRI quantitative reports (few)

- Reduced volumes of regions related to language and verbal memory (superior temporal gyrus, hippocampus, amygdala and parietal lobe).

- Increased volume and posterior displacement of the corpus callosum

• DTI (two studies)

- Reduced anisotropy in frontal, parietal, and temporal white matter

- Reduced anisotropy in white matter tracts connecting frontal and temporal lobes

- Reduced anisotropy in inferior parietal lobule which is correlated with scores from the arithmetic subscale of the WISC/WAIS, after co-varying for IQ and age of subjects.



Neuroimaging Findings in VCFS Cases with Schizophrenia

• MRI (3 studies, only one with IQ matched populations)

- Decreased total gray and white matter volumes

- Increased total and sulcal CSF volumes.

- Decreased frontal, temporal and parietal gray matter volumes

- Increased corpus callosum volume

Based on scarce findings, VCFS investigators proposed a model, in which a deficiency in frontal maturation leads to a vulnerability for schizophrenia among individuals with VCFS

• DTI

- None



VCFS Schizophrenia Candidate Genes

• COMT (controls dopamine degradation in prefrontal cortex, related to attention and memory)

• RTN4R (also known as Nogo-66 Receptor, related to axonal regeneration and plasticity as well as myelin)

• PRODH (one of the enzymes to convert proline to glutamate)

• ZDH8

• SNAP29

• TBX1



Project

• Subject recruitment

• Psychological interview

• DNA analysis, genotyping of the 22q11.2 region

• Brain imaging (MRI and DTI on 3T)

• Analysis of imaging data, and genetic correlations



Aims

• Etiology of schizophrenia and

related diseases

• Prognosis of mental health diseases in VCFS

• Early intervention



Hypotheses Regions that we want to study with MRI

- DLPC (COMT)

- Orbital Frontal Gyrus (emotion)

- Cingulate Gyrus (attention, emotion)

- Hippocampus (memory, learning)

Tracts that we want to study with DTI

- Fornix (memory)

- Arcuate Fasciculus (language)

- Cingulum Bundle (attention)

- Uncinate Fasciculus (emotion, affective flattening)



Potential Challenges for Atlas Based Scripts

• Brain atrophy

• Congenital abnormalities

• Brain asymmetry

• White matter lesions



Velo-Cardio-Facial Syndrome (VCFS) as a Genetic Model for Schizophrenia.

PRINCIPAL INVESTIGATOR: Marek Kubicki, MD, PhDINVESTIGATORS:Zora Kikinis, PhDSylvain Bouix, PhDMarc Niethammer, PhDChristine Finn, MDRaju Kucherlapati, MD Martha Shenton, PhDRESEARCH ASSISTANT:Doug Markant, BA

BACKGROUND:

• VCFS is a rare genetic syndrome (single copies of 30-45 genes on 22 chromosome are missing)

• 30% of patients with VCFS develop schizophrenia

AIMS:

• To characterize anatomical similarities and dissimilarities between VCFS and Schizophrenia

• To find “schizophrenia” genes

DATA:

• DTI, MRI, haplotypes, neuropsychology

Documents

National Alliance for Medical Image Computing AHM, SLC, January 2007 Velo-Cardio-Facial Syndrome PRINCIPAL INVESTIGATOR: Marek Kubicki,