camh - translational imaging-genetics
TRANSCRIPT
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
Translational Imaging-Genetics: Making a Clinical Impact
Language Deficits
Autism Schizophrenia Bipolar I Disorder
Psychosis (Delusions/Hallucinations)
Socio-emotional Deficits
Stereotyped Behaviours
Mood Instability/Impulsivity
Cognitive Deficits/Burden
Severe Moderate Mild
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)
Fronto-temporal disconnectivityPrefrontal interhemispheric disconnectivity
ZNF804A: Influencing Connectivity Phenotypes Relevant to the Major Psychoses
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: F1,65=7.658, p=0.007
• rs3749034: F1,65=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.
Sham ActiveC
hang
e in
Mea
n A
bsol
ute γ
Pow
er
Cha
nge
in M
ean
Sum
of γ
Pow
er
A)
B)
FrontalPosterior
Brain Region
-0.5
0.5
1.5
2.5
3.5
Sham Active
p < 0.001
Barr et al. Neuropsychopharmacology 2009
A pilot rTMS treatment trial for working memory deficits in schizophrenia
Assessed for Eligibility(n=42)
Randomized(n=33)
Excluded (n=9)Did not meet inclusion
criteria (n=2)Declined participation (n=7)
rTMS (n=16)
Received at least one treatment session
Sham Control(n=17)
Received at least one treatment session
Enr
olm
ent
Allo
catio
nFo
llow
-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)
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=13)
Analyzed(n=14)
Barr et al, under review
-8
-4
0
4
8
12
16
N-Back Condition
Active
Sham
1-Back 3-Back
Percent change correct response to
target
rTMS improves WM performance
Barr et al, under review
White Matter Tract Structure Modulates Cortical Function
Voineskos, Farzan et al, Biological Psychiatry, 2010
Imaging-Genetics Relevant to AD
Filipinni, N, PNAS, 2009
ApoE4 allele modulates brain function decades before any evident clinical process
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
BDNF treatment reduces Abeta production in primary neurons
BDNF treatment reduces Abeta levels in wild type but not SORL1 deficient mice
J Neurosci, 2009
Rogaeva et al, Nat Gen, 2007
The Sortilin Related Receptor SORL1 and Genetic Risk for Late-Onset Alzheimer Disease
Rogaeva et al, Nat Gen, 2007
Arch Neurol, 2008
SORL1 risk variants, and integrity of WM tracts susceptible in early AD
Felsky et al
Kimel Family Translational Imaging-Genetics Research LaboratoryMallar Chakravarty Tris LettDan FelskyArash NazeriScott McCainWilliam RazmyAysah Amath
Geriatric Mental Health ProgramBenoit MulsantBruce PollockTarek RajjiDielle Miranda
Schizophrenia ProgramJeff DaskalakisGeorge FoussiasGary Remington
Neuroscience/NeurogeneticsJim KennedyFang LiuArun TiwariNatalie FreemanClement Zai
Kimel Family, Michael and Sonja Koerner, and Paul Garfinkel New Investigator Award
Acknowledgements/Support
HSC – Jason Lerch, Stephanie Ameis
APA/APIRE
CAMH R.I.C. – Nancy Lobaugh