Translational Imaging-Genetics: Making a Clinical Impact

Transcription

1 Translational Imaging-Genetics: Making a Clinical Impact Aristotle Voineskos MD, PhD, FRCP(C) Head, Kimel Family Translational Imaging-Genetics Research Lab Staff Psychiatrist, Geriatric and Schizophrenia Programs, CAMH Assistant Professor, Department of Psychiatry, University of Toronto

2 Autism Schizophrenia Bipolar I Disorder Language Deficits Stereotyped Behaviours Socio-emotional Deficits Mood Instability/Impulsivity Psychosis (Delusions/ Hallucinations) Severe Moderate Mild Cognitive Deficits/Burden

3 Shared Genetic Susceptibility for SCZ and BD: The ZNF804A Gene 1. Evidence from Whole Genome Association Studies:O Donovan et al Nat Gen, 2008; ISC, Nat, 2009, Steinberg Mol Psych, 2010, Riley Mol Psych, Bioinformatic Analysis: Risk SNP likely lies in a myelin/ oligodendrocyte transcription factor binding site Riley, Neurocognitive Phenotypes: Attention, Working Memory, Episodic Memory Balog GBB 2010, Walters JT Arch Gen Psych, Imaging Phenotypes: Altered connectivity (Esslinger, Science 2009); Altered white and gray matter volumes (Lencz, NPP, 2010)

4 ZNF804A: Influencing Connectivity Phenotypes Relevant to the Major Psychoses Fronto-temporal disconnectivity Prefrontal interhemispheric disconnectivity Esslinger et al, Science, 2009

5 ZNF804A variation and DLPFC/hippocampal functional coupling Rasetti R, Arch Gen Psych, 2011

6 ZNF804A s effects on cortical thickness occurred at cortical regions with shared neural vulnerability for SCZ and BD Voineskos, Lerch et al, Neuropsychopharmacology, 2011

7 Working Memory Deficits in Schizophrenia

8 Working Memory Performance Deficits Across the Adult Lifespan in Schizophrenia 235 Schiz, 333 Healthy controls Rajji, Voineskos et al, AJGP, in press

9 γ Oscillations and DLPFC Function Gamma (30-50Hz) Oscillations (γ) in DLPFC Represent important electrophysiological measures which are generated through the execution of higher order cognitive tasks (e.g., working memory) in the DLPFC (Tallon-Baudry, 1999; Lewis, 2005). Cho et al, PNAS, 2006

10 Glutamate decarboxylase 1 (GAD1) gene Encode the GAD67 protein responsible for catalyzing L- glutamic acid to GABA 2q31; 46 kb; 17 exons GAD1 is key to the development of inhibitory interneurons Lewis DA, Nat Med, 2006

11 GAD1, Brain Structure, Function and Cognition Rs and BOLD fmri during NBACK WM Task Marenco et al, NPP, 2011 Straub et al, Mol Psych, 2007

12 GAD1, Hippocampal Volume, and Fronto-Limbic Circuitry rs : F 1,65 =7.658, p=0.007 rs : F 1,65 =5.513, p=0.022 Lett et al

13 Repetitive Transcranial Magnetic Stimulation (rtms): A Therapeutic Tool for Working Memory Deficits rtms involves stimulation of the cortex by train of magnetic pulses at frequencies between 0.5 to 50 Hz. rtms increases : (1) GABA mediated cortical inhibition (2) oscillatory activity during the n-back memory task.

14 A) Sham Active Change in Mean Sum of γ Power Change in Mean Absolute γ Power B) Brain Region Frontal Posterior p < Sham Active Barr et al. Neuropsychopharmacology 2009

15 A pilot rtms treatment trial for working memory deficits in schizophrenia Enrolment rtms (n=16) Received at least one treatment session Assessed for Eligibility (n=42) Randomized (n=33) Excluded (n=9) Did not meet inclusion criteria (n=2) Declined participation (n=7) Sham Control (n=17) Received at least one treatment session Allocation Follow-up Discontinued Prior to Week 1 Completion of Treatment (n=1) Discontinued Prior to Week 2 Completion of Treatment (n=1) Discontinued Prior to Week 3 Completion of Treatment (n=1) Discontinued Prior to Week 4 Completion of Treatment (n=0) Analyzed (n=13) Discontinued Prior to Week 1 Completion of Treatment (n=1) Discontinued Prior to Week 2 Completion of Treatment (n=2) Discontinued Prior to Week 3 Completion of Treatment (n=0) Discontinued Prior to Week 4 Completion of Treatment (n=0) Analyzed (n=14) Barr et al, under review

16 rtms improves WM performance Active Sham Percent change correct response to target Back N-Back Condition 3-Back Barr et al, under review

17 White Matter Tract Structure Modulates Cortical Function Voineskos, Farzan et al, Biological Psychiatry, 2010

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19 Imaging-Genetics Relevant to AD ApoE4 allele modulates brain function decades before any evident clinical process Filipinni, N, PNAS, 2009

20 BDNF Key in Disease and Therapeutics 1. Long-term potentiation and plasticity learning and memory 2. BDNF highly expressed in entorhinal cortex and hippocampus 3. BDNF mediates myelination; provides trophic support for oligodendrocytes 4. A Novel Therapeutic Agent (Blurton-Jones, 2009, PNAS) (Nagahara, AH Nat Med, 2009)

21 Voineskos, Lerch, et al, Arch Gen Psych, 2011

22 Voineskos, Lerch, et al, Arch Gen Psych, 2011

23 BDNF: Treatment Implications Nagahara et al, Nat Med, 2009

24 J Neurosci, 2009 BDNF treatment reduces Abeta production in primary neurons BDNF treatment reduces Abeta levels in wild type but not SORL1 deficient mice

25 The Sortilin Related Receptor SORL1 and Genetic Risk for Late-Onset Alzheimer Disease Rogaeva et al, Nat Gen, 2007

26 Rogaeva et al, Nat Gen, 2007

27 Arch Neurol, 2008

28 SORL1 risk variants, and integrity of WM tracts susceptible in early AD Felsky et al

29 Acknowledgements/Support Kimel Family Translational Imaging-Genetics Research Laboratory Mallar Chakravarty Tris Lett Dan Felsky Arash Nazeri Scott McCain William Razmy Aysah Amath Geriatric Mental Health Program Benoit Mulsant Bruce Pollock Tarek Rajji Dielle Miranda APA/APIRE Schizophrenia Program Jeff Daskalakis George Foussias Gary Remington Neuroscience/Neurogenetics Jim Kennedy Fang Liu Arun Tiwari Natalie Freeman Clement Zai CAMH R.I.C. Nancy Lobaugh HSC Jason Lerch, Stephanie Ameis Kimel Family, Michael and Sonja Koerner, and Paul Garfinkel New Investigator Award