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
Autism Schizophrenia Bipolar I Disorder Language Deficits Stereotyped Behaviours Socio-emotional Deficits Mood Instability/Impulsivity Psychosis (Delusions/ Hallucinations) Severe Moderate Mild Cognitive Deficits/Burden
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, 2010 2. Bioinformatic Analysis: Risk SNP likely lies in a myelin/ oligodendrocyte transcription factor binding site Riley, 2010 3. Neurocognitive Phenotypes: Attention, Working Memory, Episodic Memory Balog GBB 2010, Walters JT Arch Gen Psych, 2010 3. Imaging Phenotypes: Altered connectivity (Esslinger, Science 2009); Altered white and gray matter volumes (Lencz, NPP, 2010)
ZNF804A: Influencing Connectivity Phenotypes Relevant to the Major Psychoses Fronto-temporal disconnectivity Prefrontal interhemispheric disconnectivity Esslinger et al, Science, 2009
ZNF804A variation and DLPFC/hippocampal functional coupling Rasetti R, Arch Gen Psych, 2011
ZNF804A s effects on cortical thickness occurred at cortical regions with shared neural vulnerability for SCZ and BD Voineskos, Lerch et al, Neuropsychopharmacology, 2011
Working Memory Deficits in Schizophrenia
Working Memory Performance Deficits Across the Adult Lifespan in Schizophrenia 235 Schiz, 333 Healthy controls Rajji, Voineskos et al, AJGP, in press
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
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
GAD1, Brain Structure, Function and Cognition Rs7557793 and BOLD fmri during NBACK WM Task Marenco et al, NPP, 2011 Straub et al, Mol Psych, 2007
GAD1, Hippocampal Volume, and Fronto-Limbic Circuitry rs1978340: F 1,65 =7.658, p=0.007 rs3749034: F 1,65 =5.513, p=0.022 Lett et al
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.
A) Sham Active Change in Mean Sum of γ Power Change in Mean Absolute γ Power B) 3.5 2.5 1.5 0.5-0.5 Brain Region Frontal Posterior p < 0.001 Sham Active Barr et al. Neuropsychopharmacology 2009
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
rtms improves WM performance 16 12 Active Sham Percent change correct response to target 8 4 0-4 -8 1-Back N-Back Condition 3-Back Barr et al, under review
White Matter Tract Structure Modulates Cortical Function Voineskos, Farzan et al, Biological Psychiatry, 2010
Imaging-Genetics Relevant to AD ApoE4 allele modulates brain function decades before any evident clinical process Filipinni, N, PNAS, 2009
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)
Voineskos, Lerch, et al, Arch Gen Psych, 2011
Voineskos, Lerch, et al, Arch Gen Psych, 2011
BDNF: Treatment Implications Nagahara et al, Nat Med, 2009
J Neurosci, 2009 BDNF treatment reduces Abeta production in primary neurons BDNF treatment reduces Abeta levels in wild type but not SORL1 deficient mice
The Sortilin Related Receptor SORL1 and Genetic Risk for Late-Onset Alzheimer Disease Rogaeva et al, Nat Gen, 2007
Rogaeva et al, Nat Gen, 2007
Arch Neurol, 2008
SORL1 risk variants, and integrity of WM tracts susceptible in early AD Felsky et al
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