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Core 3.2 Activities University of California, Irvine—Brain Imaging Center Steven Potkin, Padhraic Smyth, James Fallon University of Toronto—Neurogenetics Section, Center for Addiction and Mental Health James Kennedy & Aristotle Voineskos. http://www.bic.uci.edu. Overview –.

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  1. Core 3.2 Activities University of California, Irvine—Brain Imaging CenterSteven Potkin, Padhraic Smyth, James FallonUniversity of Toronto—Neurogenetics Section, Center for Addiction and Mental Health James Kennedy & Aristotle Voineskos http://www.bic.uci.edu

  2. Overview – • Genetics Activities • Circuitry and other statistical analyses • Anatomical Accuracy for shape analysis and cortical and subcortical segmentation • DTI Activities

  3. Datasets Available • (1) Toronto genetic data on 300 schizophrenic patient and matched controls; • (2) Vancouver, 47 first episode schizophrenia patients with structural MRI scans, cognitive testing, and genetic; and • (3) Irvine 25 schizophrenic patients with fMRI, PET, EEG and 100k SNP genetic data. • Issues with the NAMIC Toolkit

  4. Genetics and Neuroimaging in Schizophrenia Update James L Kennedy MD, FRCPC I’Anson Professor of Psychiatry and Medical Science Head, Neurogenetics Section, Clarke Division, Director, Department of Neuroscience Research Centre for Addiction and Mental Health (CAMH), University of Toronto & SG Potkin, A Voineskos, D Mueller, M Masellis, N Potapova, F Macciardi

  5. Genetics Summary • SNAP25 gene associated with schizophrenia in Potkin sample, and Toronto sample • BDNF gene candidate for grey matter vol and fxn • Serotonin transporter gene for amygdala function • DISC1 gene for cortical thickness • NMDA, GRIN1 and 2B genes for grey matter • Newest data: MOG gene associated with total brain white matter (as hypothesized in grant app) • Relational database developed for organizing genetic + clinical + imaging data • Training available in genetics National Alliance for Medical Imaging and Computing NAMIC www.na-mic.org

  6. Gene Variants Molecular Genetic Approach Pharmacogenetics Gene Expression Pharmacology Neurobiology Phenotype (Neuroimaging) Endophenotype -Psychophysiology Sub-pheno

  7. EXTRACTING DATA FOR ANALYSIS Data are returned in a format suitable for association-type studies (m-link or case-control). Additional formats may be designed as needed (such as vertical haplotypes {} ). Data may be transcribed and converted to document formats supported by the analysis program (tab de-limited text, etc…). 1 2 2 1 1 2 2 2 2 1 1 1 2 2 1 1 With access to source codes, or by invoking special features in downstream applications, the database can include automated running of analyses or transfer of data to other spreadsheets/databases.

  8. Cytoarchitectural abnormalities Control Comparison of hippocampal pyramids at the CA1 and CA2 interface between control and schizophrenic. Cresyl violet stain, original magnification X250 Conrad et al. (1991) Arch Gen Psychiatry Schizophrenia

  9. DISC-1 Gene Knock-Down (mouse) DISC1 gene knock down with inhibitory RNA in mouse cortex: Result: migration of neurons from ventricular zone during fetal development is impaired by DISC1 knockdown. Morphology resembles schizophrenia pathology Marginal Zone Cortical Plate Intermediate and SubVentricular Zone Strongest inhibition Ventricular side Kamiya et al, Nature Cell Biol 2005

  10. DISC1(Leu607Phe) Genotype in Schizophrenia vs Controls Chi-sq = 0.61; df=2; p=0.74 Potkin sample

  11. Will the Brain Derived Neurotrophic Factor (BDNF) Gene Predict Grey Matter Volume? BDNF-1 SNP BDNF-2 BDNF-3 BDNF-4 Exon 11 Val-66-met (GT)n repeat(function? mRNA stability)

  12. BDNF val66met: MRI functional brain imaging (Egan et al, Cell 2003) The red/yellow areas indicate brain regions (primarily hippocampus) that function differently between val/val (n=8) and val/met (n=5) subjects while performing a working memory task. Subjects with the met allele had more abnormal function.

  13. Haplotype TDT: BDNF (GT)n repeat & val66met in schizophrenia * * HTDT for 170-val66 c2 = 7.11; 1 df; p = 0.007 Muglia et al, (2002)

  14. BDNF(val66met) Genotype in Schizophrenia vs Controls Chi-sq = 0.59; df=2; p=0.74 Potkin sample

  15. HTTLPR (ins/del) in Schizophrenia (following: Hariri et al 2002 => predicts 25% of amygdala fxn) Note: L= LA, and LG functions as S so grouped together under S Chi-sq = 3.3; df=2; p=0.19 Potkin sample

  16. Mochida, 2000

  17. SNAP25 Genotype in Schizophrenia vs Controls Not for distribution Chi-sq = 9.4; df=2; p=0.009 Potkin sample

  18. Myelin Oligodendrocyte Glycoprotein (MOG) • may function as: • a cellular adhesion molecule • a regulator of oligodendrocyte microtubule stability • a mediator of interactions between myelin and the immune system, particularly as an activator of the classical complement cascade via activation of C1q (Johns and Bernard, 1997). • The 2 polymorphisms examined are: • a dinucleotide repeat “MOG-(CA)n” located upstream from the MOG transcription start site (Roth et al., 1995; Barr et al., 2001). • a tetranucleotide repeat “MOG-(TAAA)n” located in the 3’ untranslated region (Roth et al., 1995; Malfroy et al., 1995).

  19. Location of MOG Gene in 6p21.3 Region (MHC Region) Class I Class III Class II C4A, C4B, C2, factor B, 21-OHase GABABR1 LMP/TAP Histone Family NOTCH4 DTNBP1 HLA-F HLA-G HLA-A HLA-C HLA-B MOG SCA1 TNF DM DN DR DQ DO DP   telomere centromere (CA)n (TAAA)n ~ 2.6 Mb Figure 2. Human MHC region and genes within the region.

  20. Hypothesized Autoimmune Mechanism in Schizophrenia Antibodies B-Lymphocyte Inflammation Mast Cell Chemokines Illustration taken from www.phototakeusa.com. Autoantibodies cross-react with neuronal proteins (eg myelin?) during fetal brain development, causing subtle damage to the CNS, leading to SCZ in early adulthood (Swedo, 1994).

  21. Prefrontal fMRI activity & myelin reduced in schizophrenia: Core 3.1 Figure 3:1-4: Statistical parametric maps of the fractional anisotropy (FA) (left) and Magnetic Transfer Ratio (MTR) (myelin) (right) group comparison. Similar areas in yellow on both maps correspond to the location of both the internal capsule and prefrontal white matter, and indicate smaller values of FA and myelin in schizophrenia patients (n=14) compared with controls (n=15).

  22. Will MOG gene variants predict white matter abnormalities? (CA) repeat C1334T C10991T (TAAA) repeat Promoter region Start codon Coding region (diagram not to scale)

  23. MOG in Toronto Schiz sample TDT and Haplotype Samples: • 113 schiz proband small nuclear families from Toronto => MOG-(CA)n & MOG-(TAAA)n • Statistics: • TDT/S-TDT and haplotype analysis using TRANSMIT • Results negative for diagnosis of schizophrenia

  24. Haplotype Analysis of MOG polymorphisms in SCZ Haplotype analysis between MOG-(CA)n and MOG-(TAAA)n.

  25. MOG vs Total Brain White Matter • Sample: Dr. Honer UBC – 47 schiz, 24 cont • Phenotype: automated output from standard structural MRI – total grey and white matter • MRI=> 3D SPGR: FOV 26cm TE 11.2ms TR 2.1ms Matrix 256 x 256 Thickness 1.5 mm Angle - perpendicular to AC-PC line Acquisition time - 6 minutes • C1334T marker genotype associated with white matter volume (P=0.003) • Other MOG markers negative • All MOG markers negative for total grey matter volume Not for distribution

  26. Dopamine System GenesPresented by Aristotle Voineskos MD • COMT – Catechol-O-methyl transferase • DRD3 – Dopamine receptor (D3) • DRD2 – Dopamine receptor (D2)

  27. COMT Gene • Principal metabolizer of dopamine in frontal cortex • Functional genetic variant: val vs. met • Val reduces dopamine levels • Val associated with poorer working memory (Wienberger group) • Ultimate hypothesis: cortical efficiency (fMRI) impaired in val carriers

  28. COMT (val158met) Genotype in Schizophrenia vs Controls Chi-sq = 2.6; df=2; p=0.27 Potkin sample

  29. DRD3 Gene • Upregulation of D3 receptors and D3 mRNA following antipsychotic in rat brain • Gly vs Ser variant reveal differences in affinity for dopamine • Gly variant leads to increased striatal activity following haldol administration (Potkin et al ’03) • Preliminary: gly variant incr in schizophrenia

  30. Brain Metabolism Following Haloperidol Treatment by D3 Genotype (FDG, n=14) Gly-Ser & Ser-Ser (n=9) Haloperidol (5wks) Baseline Baseline Gly-Gly (n=5) (UCI Brain Imaging Centre; Potkin, Kennedy & Basile, 2003)

  31. Dopamine D3 Receptor GenePotkin sample N=25

  32. Intro to Dopamine D2 Receptor • D2 gene is the most established candidate gene • All antipsychotic meds bind to D2 receptor; these meds treat positive sx successfully (hallucinations, delusions) • D2 receptor should be involved at some level in pathophysiology of disease

  33. 5) TaqIB 8) rs2242591 1) -241 A/G 10) rs2242593 7) NcoI 3) rs4648317 6) Taq1D 8 6 1 2 3 4 5 7 11) TaqIA 4) rs1125394 2) –141 Ins/Del 9) rs2242592 D2 Linkage Disequilibrium in Caucasians (Haploview)

  34. DRD2 (-141C ins/del) Genotype in Schizophrenia vs Controls Chi-sq = 0.61; df=2; p=0.74 Potkin sample

  35. Genetics Summary • SNAP25 gene associated with schizophrenia in Potkin sample, and Toronto sample • BDNF gene candidate for grey matter vol and fxn • Serotonin transporter gene for amygdala function • DISC1 gene for cortical thickness • Dopamine genes predict cortical & striatal fxn? • Newest data: MOG gene associated with total brain white matter (as hypothesized in grant app) • Relational database developed for organizing genetic + clinical + imaging data • Training available in genetics National Alliance for Medical Imaging and Computing NAMIC www.na-mic.org

  36. Can Alleles Predict Circuitry? • Need for anatomical accuracy • D1 alleles predictions in schizophrenia • Clinical response to clozapine • Circuitry used in working memory task

  37. Sternberg task: Five Two 5 6 2 8 1 0 9 8 3 6 9 + + + + Core 3.2 and Core 1: Anatomical Accuracy Five items compared to Two

  38. COMT Genotype and Cortical Efficiency During fMRI Working Memory Task Val-val>val-met>met-met use more DLPFC to do same task, SPM 99, p<.005 Egan et al PNAS 2001

  39. ?? ?? ?? Statistical Parametric Map - GE-2048 Resolution Mai et al Human Atlas, 2001 ??

  40. Improved Circuit Specification Motor Circuit (BA6) Orbital Cortex Amygdala

  41. Potkin et al ,2003

  42. Circuitry via Path Analysis: PLS Circuitry in a Working Memory task (5-2 load) by DRD1 genotype in schizophrenia

  43. Spatial fMRI Activation Patterns • Padhraic Smyth, UC Irvine

  44. fMRI Activation Surface Modeling • Model activation response surface (beta-maps,…) • Analyze variability of the features A 2-dimensional slice of right precentral gyrus at z=53

  45. Subject 3 • Estimated parameters for activation centers + : 4 runs within visit 1 O : 4 runs within visit 2

  46. Detecting Spatial fMRI Activation Patterns Activation patterns estimated by mixture model (Kim, et al, 2005) Thresholded voxels (p<0.05) beta map fBIRN phantom sensorimotor task z=30 slice Not for distribution

  47. Core 1, 2, and Core 3.2 Activities • Anatomical Accuracy and Flexibility for Integration of Imaging Modalities (e.g. MRI, DTI, fMRI, PET and EEG) and statistical analyses • Slicer development in tractography: Alpha and Beta testing. • Development of new visualization techniques and visual analytics. • Bug reporting and tracking. • Prototype testing. • Feature requests. • Participants: Core 1: Allan Tannenbaum lab (GT), Guido Gerig lab (UNC) Core 2: Ron Kikinis and Steve Pieper labs UCI: Jim Fallon, Martina Panzenboeck, Vid Petrovic, Falko Kuester

  48. Cytoarchitectonics- Brodmann areas Blumenfeld Fig 2-15 pg 32

  49. Classical Approaches to Cytoarchitectonic Mapping of Human Prefrontal Cortex All pictures/drawings are from Rajkowska, G. & Goldman-Rakic, P.S. (1995). Cerebral Cortex5:323-337.

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