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James L Kennedy MD, FRCPC

Genetics and Neuroimaging: Current Findings and Future Strategies. 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),

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James L Kennedy MD, FRCPC

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  1. Genetics and Neuroimaging: Current Findings and Future Strategies 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, D Mueller, M Masellis, N Potapova, F Macciardi

  2. How do genes determine brain characteristics?

  3. Gene Variants Molecular Genetic Approach Pharmacogenetics Gene Expression Pharmacology Neurobiology Phenotype Endophenotype -Psychophysiology; Neuroimaging Sub-pheno

  4. Candidate gene selection for schizophrenia • Neurotransmitter system genes • e.g. dopamine receptors, transporter • Neurodevelopmental genes • Cortical development, patterning • Neuronal differentiation, migration • Synaptic protein genes • Human post-mortem expression studies (Mirnics et al, 2000; Vawter et al, 2001) • Animal model expression studies (Wong et al, 2002; Barrett et al, 2003) Dissect the neurotransmitter, synaptic machinery, myelin system, etc, with molecular genetics… Neuroimaging will help both hypothesis generation and validation of new genetic findings

  5. 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

  6. TARDIVE DYSKINESIA

  7. Symptoms of TD TD is characterized by abnormal involuntary movements of the lip, jaw and tongue. Choreoathetoid movements of the extremities and/or trunk may occur as well. - Symptoms are measured using scales such as : the Abnormal Involuntary Movement Scale (AIMS) and the Rockland Simpson Scale (RSS). - The AIMS scale ranges from 0 - 40 and patients with higher AIMS scores have more severe symptoms.

  8. Motor effects Cognitive effects

  9. Why DRD3 ? • D3 mRNA and protein have been localized to the ventral side of the striatum and the ventral putamen (motor control) (Joyce & MeadorWoodruff, 1997) • D3 receptors have been shown to have an inhibitory effect on locomotor activity in rats. (Kling-Peterson et al, 1995) • Evidence that the Msc I polymorphism of DRD3 is functional: allelic differences display different affinities for dopamine in vitro. (Lundstrom & Turpin, 1996)

  10. Mean AIMS Scores for DRD3 Msc I Polymorphism after Typical Neuroleptic Treatment Mean 14.20 Corrected Mean AIMS score Mean 3.920 Mean 3.470 n=34 n=53 n=25 DRD3 Genotype F[2,95] = 8.25, p < 0.0005 ( n = 112 ), Power = 0.568, r-square=0.297 (Bonferroni p < 0.0015) (Basile et al, 1999)

  11. Ethnically Stratified Means 9 16 43 33 9 F[2,83]=3.85, p = 0.026 (Bonferroni p = 0.078) F[1,23]=8.10, p = 0.0091 (Bonferroni p = 0.009)

  12. 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)

  13. CYP2D6 vs 1A2 (12.7%) - Metabolism is determined by both affinity and abundance relative to the total liver P450 content. - 2D6 has a higher affinity for most typicals, but it accounts for only 2% of total liver content.  2D6 is “high affinity-low capacity” -2D6 is not inducible; 1A2 is (Shimoda et al, 1994) (1.5%) Note: CYP2D6 also expressed in brain – neuroimaging may capture some of this variance

  14. Mean AIMS Scale Scores for DRD3 by CYP1A2 Genotype Mean AIMS Score CYP1A2 Genotype DRD3 Genotype Additive recessive model strongly supported compared to alternative models

  15. Tardive Dyskinesia Summary : - Given the numerous replications of the DRD3-TD finding, and the PET neuroimaging validation, it appears that the dopamine D3 receptor is involved in TD susceptibility. - The interaction between DRD3 and CYP1A2 genes fits a recessive - recessive model with each gene interacting additively. - The DRD3 and CYP1A2 results account for ~55% of the variance in TD; other genes and environment may account for the rest. ??Clinical genetic test for TD risk in the future??

  16. DOPAMINE D1 RECEPTOR

  17. Dopamine D1 Receptor D1 concentration in PFC 10X greater than D2 (Lidow 1991)… Important for antipsychotic action? (Missale 1998)

  18. Antipsychotic Binding Profiles (Kerwin 1996, in vitro tissue analyses)

  19. Tauscher et al., 2004

  20. D1 Receptor Blockade: • D1 blockade by antipsychotics may potentiate activity in the PFC by disinhibiting NMDA receptor (Williams 1995) D1 NMDA Cognition? Improvement of Symptoms

  21. +1 +1341 Dopamine D1 Gene (DRD1) (5q35.1) Markers in 5’ upstream region may be implicated in the regulation of D1 gene expression. (-1251) (-800) (-48) (+1403) P2 P1 ERE Coding Region

  22. DRD1, PET FDG, & Clozapine Response Genotype 2/2 BPRS = 30% Improvement Genotype 1/2 BPRS = 7% Worsening Genotype 1/2 (Potkin et al, 2002)

  23. Clozapine Response Prediction Algorithm? • Arranz et al (2000) have reported a multi-gene (n = 10+ markers) model for clozapine response in one sample. Includes: D2, D4; 5HT1A, 2A, 2C, 4, 6; H1, H3,… • Model must be replicated in a new sample to be meaningful • Neuroimaging as a augmenting phenotype in each patient may provide valuable intermediary information from the brain, allowing more biologically meaningful subtyping.

  24. Serotonin Transporter

  25. 5HTT specific ligand in PET • 5HTT specific ligand for PET [11C]DASB optimized in Toronto by radiochemist Alan Wilson • N = 20 medication-free depressed patients, 20 anxiety disorder, and 20 normal controls underwent PET imaging with [11C]DASB ligand; blood for genetics • 5HTT gene typed for ins/del in promoter and the VNTR in intron II

  26. [11C] DASB Binding to 5HTT in Depressives vs Normals by Genotype: Frontal Region nM

  27. PET Ligand (DASB) 5HTT Binding Potential correlates with Dysfunctional Attitude [Meyer et al, Toronto PET Group, Arch Gen Psych, 2004] 5HTTLPR genetic marker does not predict 5HTT Binding (Kennedy et al, in prep) Serotonin Transporter Ligand Binding Potential N=20 Major Depressives P < .001 Dysfunctional Attitude Scale Score

  28. 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)

  29. 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.

  30. 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)

  31. Neurotrophic Mechanisms in Depression Nestler et al, 2002

  32. Bipolar Disorder: TDT studies show robust effect of BDNF gene • Combined Toronto sample (Neves-Pereira et al, 2002; N=300) plus MIT (Sklar et al, 2003) (N=200 + 150 NIMH) for val66met yields p = .0000001 • Phenotype dissection of our Toronto bipolar sample shows association with rapid cycling, non-suicidal, non-psychotic, earlier age at onset subjects (Mueller et al, in preparation)

  33. BDNF polymorphisms in Childhood Onset Depression: Pittsburgh Sample N=104 pairs; 2=4.7;df=1; p=0.03 Haplotypep = 0.001 N=104 pairs; 2= 17.8; df=5; p= 0.0032 172 bp allele: OR = 0.55 168 bp allele: OR = 3.94 GT repeat alleles

  34. Hippocampal shape as a phenotype for genetic studies Figure 1d: Principal deformation for the right hippocampus for normal controls (top) and schizophrenia patients (bottom). Four views (front, lateral, back, medial) of each shape are shown. The color indicates the direction and the magnitude of the deformation, changing from blue (inwards) to green (no deformation) to red (outwards).

  35. Will MOG gene variants predict white matter abnormalities?

  36. Prefrontal fMRI activity and myelin reduced in schizophrenia 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).

  37. clustering Bundle selection Measurement along tract UNC Fractional Anisotropy Hypothesis: MOG, MAG, MBP genes will predict quantity or distribution of myelinated tracts

  38. DTI New MRI Imaging Technique Reveals Brain Circuits Cingulum Corpuscallosum Dorsal stream Frontal striatial projections Fornix Actual white matter tracks in schizophrenic patient revealed by DTI (colors and location by J. Fallon)

  39. Complexities in Genetics & Neuroimaging • Genetic variants express themselves in many ways – singularly, or combined (haplotypes, epistasis, partial penetrance…) • What are the appropriate phenotypes to use from brain imaging data? • How to control massive multiple testing of genome scan x brain voxels (millions x millions)?

  40. Summary • D3 gene link to tardive dyskinesia validated by PET imaging • D1 role in schizophrenia and clozapine response supported by genetic variants and PET activity pre/post clozapine • BDNF gene candidate for grey matter measures? • MOG gene candidate for white matter? • Vast expanses of quality data await us: we only need to develop our informatics sophistication… National Alliance for Medical Imaging and Computing: NAMIC www.na-mic.org

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