Upload
marin
View
25
Download
2
Tags:
Embed Size (px)
DESCRIPTION
Imaging Gene Effects: in Search of Neurogenetic Mechanisms in Schizophrenia. Karen Faith Berman, M.D. Section on Integrative Neuroimaging Clinical Brain Disorders Branch Genes, Cognition, & Psychosis Program National Institute of Mental Health Intramural Research Program, NIH, DHHS - PowerPoint PPT Presentation
Citation preview
Imaging Gene Effects:in Search of Neurogenetic Mechanisms
in Schizophrenia
Karen Faith Berman, M.D.Section on Integrative Neuroimaging
Clinical Brain Disorders BranchGenes, Cognition, & Psychosis Program
National Institute of Mental HealthIntramural Research Program, NIH, DHHS
Genes:
multiple susceptibility
alleles each of small effect
Cells:
subtle molecular
abnormalities
Systems:
abnormal information processing
psychiatric illness
Behavior:
complex functional interactions and
emergent phenomena
The Wisconsin Card Sorting Task
temperament
cognition
Brain dysfunction occurs at multiple levels of neuronal organization
Genes and Neuropsychiatric Illness:Why are they important?
• Majority of risk for psychiatric illness is related to inheritance
• Genes clarify effects of the environment• Genes may identify at-risk individuals• Genes transcend phenomenological
diagnosis & represent mechanisms of disease
• Genes are entry points to molecular pathways that may lead to development of new treatments
The Human Genome Sequence is Now Known (ca.2003)
Genes: 30,000
Proteins: 600,000
Variations in theGenome: > 6 million• copy number vaiations: CVNs) • single nucleotide polymorphisms: SNPs
Nucleotides: 3 billion
Single Nucleotide Polymorphisms: SNPs
single nucleotide polymorphism
AATCC → AAGCC
}
Functional SNP (truncates protein)
Complex (i.e.multifactorial) disorders like neuropsychiatric illness are polygenic and
genetically heterogeneous
affected person
unaffected
“nonpenetrant”
From: Goldman et al Nat Rev Gen 2005
Genes:
multiple susceptibility
alleles each of small effect
Cells:
subtle molecular
abnormalities
Systems:
abnormal information processing
psychiatric illness
Behavior:
complex functional interactions and
emergent phenomena
The path from here to there…
The Wisconsin Card Sorting Task
temperament
cognition
Genes:
multiple susceptibility
alleles each of small effect
Cells:
subtle molecular
abnormalities
Systems:
abnormal information processing
psychiatric illness
Behavior:
complex functional interactions and
emergent phenomena
The Wisconsin Card Sorting Task
temperament
cognition
Neuroimaging
Genes:
multiple susceptibility
alleles each of small effect
Cells:
subtle molecular
abnormalities
Systems:
abnormal information processing
psychiatric illness
Behavior:
complex functional interactions and
emergent phenomena
The Wisconsin Card Sorting Task
temperament
cognition
Clinical Phenomena Related to DLPFC Dysfunction: negative symptoms, executive function, working memory
DLPFC Physiological Dysfunction: local & system-level
Cellular Manifestations:DLPFC Pathophysio-logy & Subcortical Dopamine Dysregulation
Prefrontal Function and Striatal DA Activity Are Inversely Related
Pycock et al. 1980Luillot et al. 1987Jaskiw et al. 1988Deutch et al. 1989Kolachana et al. 1997Saunders et al. 1998Roberts et al. 1999
brainstem
striatum
prefrontal cortexGLU
GABA
DOPAMINE
DA
DA
GABA
DLPFC Pathophysiology and Striatal Dopamine Dysregulation
(Controls > Patients)
DLPFC Hypofunction in Patients
Increased Striatal F-DOPA Ki in Patients
0.008
0.009
0.010
0.011
Str
iata
l Up
take
(O
ccip
ital
Ref
eren
ce R
egio
n)
CONTROLS PATIENTS
P = 0.007, t-testP = 0.016, U test
rCBFOxygen-15 water
Presynaptic Dopamine: 6-18F-DOPA
Meyer-Lindenberg et al. Nature Neuroscience 2002
.008 .010 .012 .008 .010 .012
50
55
60
50
55
60
CONTROLS PATIENTS
No
rmal
ized
R. D
LP
FC
rC
BF
- W
CS
T
Rs = .37 p = .47
Rs = -.83p = 0.04
Striatal Ki Striatal Ki
No
rmal
ized
R. D
LP
FC
rC
BF
- W
CS
TMeyer-Lindenberg et al. Nature Neuroscience 2002
DLPFC Pathophysiology Predicts Striatal Dopamine Dysregulation
Meyer-Lindenberg et al. Nature Neuroscience 2002
Genes:
multiple susceptibility
alleles each of small effect
Cells:
subtle molecular
abnormalities
Systems:
abnormal information processing
psychiatric illness
Behavior:
complex functional interactions and
emergent phenomena
The Wisconsin Card Sorting Task
temperament
cognition
Clinical Phenomena Related to DLPFC Dysfunction: negative symptoms, executive function, working memory
DLPFC Physiological Dysfunction: local & system-level
Cellular Manifestations:DLPFC Pathophysio-logy & Subcortical Dopamine Dysregulation
Genetic MechanismsCOMT, Sub-cortical DA, & DLPFC Patho-physiology
presynaptic
postsynapticCOMT
DopamineTransporter(reuptake)
Two Mechanisms for Intrasynaptic Trafficking of Excess Dopamine
Catechol-O-methyl transferase (COMT) and dopamine trafficking in the synapse
• COMT accounts for more than 60% of DA degradation in PFC, but <15% in striatum (Karoum et al 1994)
• dopamine transporter has a minimal role in prefrontal synapses, but is abundant in striatum (Sesack et al 1998, Lewis et al 2001, Moron et al 2002, Mazei et al 2002)
• COMT has primacy for dopamine trafficking in PFC.
DLPFC Striatum
COMT mRNA expression in COMT mRNA expression in human brain: human brain: in situ hybridizationin situ hybridization
Matsumoto et al Neuroscience 2003
Allelic variability in COMT
1 27kb
COMT-S START CODON
COMT-MB START CODONTRANSMEMBRANE SEGMENT
STOP CODON
PROMOTER
5´
22q11.2222q11.23CHROMOSOME 22
…CGTG…
..AGVKD..
…CATG…
..AGMKD...
G1947 A1947
COMT-MB/S:
Val158/108 Met158/108
SOURCE: NCBI, GEN-BANK, ACCESSION # Z26491
PROMOTER
The The COMTCOMT val val158/108158/108met met PolymorphismPolymorphism
VALINE ALLELE“high-activity”thermo-stableancestral allele
METHIONINE ALLELE
“low-activity”thermo-labilehuman allele
- Of interest in schizophrenia- Poorer executive cognition & working memory- Less efficient prefrontal physiology
Adapted from Seamans et al. J Neurosci 2001
Dopamine Signaling in Prefrontal Cortex
Optimal D1-receptor activity stateSuboptimal D1-receptor activity state
Dopamine biases pyramidal neurons to respond to sustained/consistent and not to transient excitatory inputs
(i.e. DA focuses and stabilizes the response network)
“Inverted U Dose-Response” Curve
PD
Supported by findings from several studiesArnsten and Goldman-Rakic, 1986, 1990Arnsten et al., 1994Murphy et al., 1994, 1996 a,b, 1997Williams and Goldman-Rakic, 1995Verma and Moghaddam, 1996
From Goldman-Rakic 2000
PD
Predicted effects of COMT genotype on prefrontal cortical function
‘vm’ – intermediate
‘vv’ - high COMT activitylow synaptic dopamine
“mm’ – low COMT activityhigh synaptic dopamine
PD
with amphetamine
“mm’ – low COMT activityhigh synaptic dopamine
‘vv’ - high COMT activitylow synaptic dopamine
Predicted effects of COMT genotype on prefrontal cortical function
Prefrontal Function and Striatal DA Activity Are Inversely Related
Pycock et al. 1980Luillot et al. 1987Jaskiw et al. 1988Deutch et al. 1989Kolachana et al. 1997Saunders et al. 1998Roberts et al. 1999Bertolino et al. 2000, 2001Meyer-Lindenberg et al. 2002brainstem
striatum
prefrontal cortexGLU
GABA
DOPAMINE
DA
DA
GABA
COMT val
COMT Genotype Affects Midbrain Dopamine in Postmortem Brain
Val / Met Val / Val0.0
1.2
0.8
0.4
1.6
2.0
COMT GENOTYPEAkil et al., J. Neurosci, 2003
TH
mR
NA
Opt
ical
Den
sity
TH mRNA, Post-Mortem
51 yr old male, VAL/VAL
49 yr old male, VAL/MET
Categ. Box & Whisker Plot: Midbrain Ki
COMT GENOTYPE
Met / Met Val / Met
0.00250.0000
0.0030
0.0035
Mid
brai
n K
i
18F FluoroDOPA, in vivo
Val / Met Val / Val0.0
1.2
0.8
0.4
1.6
2.0
COMT GENOTYPEAkil et al., J. Neurosci, 2003
TH
mR
NA
Opt
ical
Den
sity
TH mRNA, Post-Mortem
Meyer et. al., Nature Neuroscience, 2005
COMT Genotype Affects MidbrainDopamine in vivo
Prefrontal Cortical Activity
Midbrain FDOPA and PFC rCBFby COMT Genotype
Relationship between midbrainFDOPA and PFC rCBF
by COMT genotype
Meyer Lindenberg et al. Nature Neuroscience, 2005
Adjusted data fit the “Inverted U Dose-Response” curve directly
From Goldman-Rakic 2000 Supported by findings from:Arnsten and Goldman-Rakic, 1986, 1990Arnsten et al., 1994Murphy et al., 1994, 1996 a,b, 1997Williams and Goldman-Rakic, 1995Verma and Moghaddam, 1996
Slifstein et al. Mol Psych, 2008
[11C]NNC 112 binding map Effect size for Val/Val compared with Met carriers.
COMT Genotype Also Affects D1 Dopamine Receptors
Abi-Dargham et al. J. Neurosci. 2002
The plot thickens genetically:The plot thickens genetically:multiple functional loci in multiple functional loci in COMTCOMT
5’
P2 P1
TXNRD2
5’ 3’
Exons 1 2 3 4 5 6
rs165599“Shifman et al”
val/metrs4680
- 287rs2097603
rs737865“Shifman et al”
rs 6269 rs 4633
hCV2539283* hCV11804654*
1917bp
hCV2538753*
6218bp 8821bp 4706bp
M3rs2020917
M2Rs4646310
Rel
ativ
e C
OM
T a
ctiv
ity
N=29
ANOVA p=0.0002
N=17
Rel
ativ
e C
OM
T a
ctiv
ity
N=29
ANOVA p=0.0002
N=17val/met effect on
COMTactivity
val/val met/met
Chen et al AJHG (2004)
200000
400000
600000
800000
1000000
1200000
1400000
genotype
Rel
ativ
e C
OM
T a
ctiv
ity
*
1/1 1/2 2/2
p<.05
200000
400000
600000
800000
1000000
1200000
1400000
genotype
Rel
ativ
e C
OM
T a
ctiv
ity
*
1/1 1/2 2/2
p<.05
200000
400000
600000
800000
1000000
1200000
1400000
genotype
Rel
ativ
e C
OM
T a
ctiv
ity
*
1/1 1/2 2/2
p<.05
-287 effect on COMT activity in
met/met background
Bray et al AJHG 2003
Lessons & Current Hot Topics
• Haplotype effects• Gene-gene interactions• Gene-environment interactions
Genes related to psychopathology are not about psychiatric diagnoses, per se. They are about the development and abnormal function of brain circuits related to the processing of cognitive and emotional information.
Imaging Genetics and the Future of Neuropsychiatry
Where will imaging gene effects take us?
Greater appreciation of modifiable environmental triggers?
• Primary prevention?
Outcome prediction?
New therapeutic targets?
NOVEL TREATMENTSTolcapone enhances DLPFC efficiency during
working memory in schizophreniaTHEN: COMT inhibitor previously used to augment Parkinson’s disease treamentNOW: ?Cognitive/neurophysiological enhancement for schizophrenia?
(Apud et al. Neuropsychopharmacol 2007; Apud & Weinberger NeuroRx 2006)
Genes:
multiple susceptibility
alleles each of small effect
Cells:
subtle molecular
abnormalities
Systems:
abnormal information processing
psychiatric illness
Behavior:
complex functional interactions and
emergent phenomena
The Wisconsin Card Sorting Task
temperament
cognition
Clinical Phenomena Related to DLPFC Dysfunction: negative symptoms, executive function, working memory
DLPFC Physiological Dysfunction: local & system-level
Cellular Manifestations:DLPFC Pathophysio-logy & Subcortical Dopamine Dysregulation
Genetic MechanismsCOMT, Sub-cortical DA, & DLPFC Patho-physiology
THANKS TO:NIMH INTRAMURAL RESEARCH PROGRAM
Section on Integrative Neuroimaging Zentralinstitut, MannheimPhilip Kohn Andreas Meyer-Lindenberg MD,PhDShane Kippenhan, Ph.D.
Mbemba Jabbi, Ph.D Clinical Brain Disorders BranchKatherine Roe, Ph.D. Daniel Weinberger, M.D. Tiffany Nash Bhaskar Kolachana, Ph.DJoel Bronstein Joel Kleinman, M.D., Ph.D. Deepak Sarpal Venkata Mattay, M.D. Dylan Wint, M.D. Joseph Callicott, M.D.Angela IanniJasmin Salloum, Ph.D. Joseph Masdeu, M.D. Daniel Eisenberg, M.D.
NIH PET DEPARTMENT Peter Herscovitch, M.D.
Richard Carson, Ph.D.