Download Progress in endophenotypes in ADHD

Scientific Update
of
ADHD
Russell Schachar
The Hospital for Sick Children
Department of Psychiatry
Brain and Behaviour Programme
University of Toronto
Affiliations
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CIHR
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NINDS
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Barr, Kennedy, Ickowicz, Crosbie, Pakulak, Ornstein
Noseworthy, Chevrier
Robaey, Perusse
Levin, Dennis, Barnes
Lilly
Purdue Frederick
Shire
Outline
Summary and
overview current
understanding
 Neuroscience 101

Genes
Proteins
Brain structure
Cognitive function
Behavior

Caveats
ADHD
hyp-imp
inattention
function
environment
Cell membranes,
transmitters, assemblies…
Proteins
g1
g2
g3
Genetics
What are genes?
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DNA is specific
sequence of
nucleotide bases
that encode
instructions for
proteins
Genome is
complete set of
DNA
How do genes function?
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Many changes evident and
passed on
Most changes cannot be
seen by microscope
Most base pairs are not
involved in genes and are
not functional
Can be used to track
functional changes
May regulate gene
expression or function
Epigenetic factors affect
gene function
Many hereditary effects may
be outside of genes
Neurotransmitter systems
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Dopamine
transporter
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Serotonin
Noradrenalin
Glutamate
GABA
Transporters and
receptors variably
distributed
Dopamine D4 48bp Repeat
Variants: Pharmacologic differences not
linearly correlated with number of repeats
EC50
Asghari et al, 1995
Jovanovic et al, 1999
2R
4R
7R
10R
Implication: the 7R allele has a blunted response to dopamine
Critical
SNAP-25
for controlled release of
neurotransmitters into the synaptic cleft
Loss of expression of a single copy of the gene
results in dysregulation in the controlled release
of glutamate, dopamine, and serotonin in select
brain regions
SNAP-25
Genes, proteins and neural
development
Neural development
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Stem cells differentiate
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Growth factors (sonic hedgehog, notch, BDNF)
Half survive
Development depends of where they end up, activity
there (use it or lose it!)
Rate of division/survival depends on experience,
formation of synapses, integration into networks
Loss of neurons normal (exaggerated in some
diseases)
Neurons likely regenerate and affected by experience
(can teach old dog new tricks)
Environment can affect gene expression
Brain tour
Phineas Gage
Prefrontal cortex
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Not involved in specific tasks
Executive control of behaviour, thought and affect
Organization and planning for future action and social
goals
Balances perceptual, instinctual and motivational
input
Reflective: guided by internal states and intentions
Control subordinate attention and motor processes
Prefrontal subcortical circuits
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Begin and end in frontal cortex
Pass through subcortical structures
Reciprocal and interacting connections
 Excitatory and inhibitory neurotransmitters
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Separate yet overlapping and interacting
Specific and intermingled mixture of deficits
Evident in individuals with massive lesions
Dorsolateral circuit
 Organization,
planning, attention
 Lesions generate concrete thinking,
inability to stop, shift set, filter and
ignore distractions, plan and organize
Orbitofrontal circuit
Mediates socially appropriate behaviour
 Lesions lead to marked personality change,
social disinhibition, explosiveness,
tactlessness, lability, lack of interpersonal
sensitivity
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Anterior cingulate circuit
Motivation, balancing competing demands,
performance monitoring
 Lesions result in akinetic mutism, apathy,
lack of motivation, insensitive to errors
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Frontal/ executive processes
“wave of attention”
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Encoding, maintaining, retrieving in
working memory
Preparing and anticipating
Interference management
Withholding of response tendency
Maintain set
Retract or inhibition
Error detection
Error correction
Summary
Considerable understanding of brain
development and function
 Differentiation in structure and function
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Cognitive
deficits
Genetic risks
Structural and functional
anomalies
ADHD genetics
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Highly genetic
Not simple Mendelian inheritance
Multigenic
 Non-genetic factors contribute separately and
through various combinations
 Disorder occurs when combination of genetic and
non-genetic factors exceeds some threshold
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Nature of risk and mode of inheritance
unknown
Genetics of ADHD
% risk to family
% concordance
100
30
25
75
20
50
15
10
MZ
DZ
25
5
0
0
ADHD families
Control families
Stevenson
(1992)
Gillis et al.
(1992)
Levy et al.
(1997)
Genome Scan
D19S229
D19S247
D19S204
D19S221
D19S179
D19S248
D19S178
D19S246
D19S180
D19S254
Systematically
screen all of the
chromosomes for
linkage using DNA
markers spaced at
regular intervals
Genome scans for ADHD
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Fisher et al., 2002
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Ogdie et al., 2003
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UCLA 126 affected sib pairs
no regions met genome-wide significance levels
suggestive 5p12, 10q26, 12q23, 16p13 (Smalley, 2002)
expansion of Fisher et al., sample + 144 sib pairs
17p11 (LOD 2.98), 16p13
Bakker et al., 2003
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164 Dutch affected sib pairs
regions with LOD scores > 3, 15q15.1, 7p13
LOD score > 2, 9q33.3
Candidate gene study
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Case-control
 Compare
samples
 Ethnicity
 Associated

characteristic or disorder
Family-based
 Compare
siblings
children and their parents or
Dopamine, cognition and
behaviour
Neurotoxin reduces DA in rats
 hyperlocomotion, learning problems
 DA depletion impairs working memory
 Impulsiveness associated with low
extracellular DA
 Blocking DA reuptake makes DA more
available and improves executive control
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Drugs and ADHD
Psychostimulants and ADHD
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54 – 75 % adults and
children with ADHD
responds to methylphenidate
(0.6 mg/kg)
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(Spencer et al 2001)
The behavioural
modifications induced by
stimulants occurs with the
reaching of peak plasma
level
Dopamine Transporter
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Some individuals with ADHD, have higher
expression of the dopamine transporter.
Possible mechanism of genetic susceptibility is over
expression of the DAT protein
Stimulants blockade dopamine transporter and
temporarily correct the levels of dopamine.
DAT Knock Out mouse
 difficulty shifting - perseverative errors
 novelty-driven hyperactivity
 spatial learning deficit
Synaptosomal-Associated Protein
of 25 kDa (SNAP-25)
Rationale: mouse irradiation mutant strain
Coloboma has a single copy of the SNAP-25 gene.
The other copy has been deleted.
1) hyperactive
2) responsive to dextroamphetamine
3) not responsive to methylphenidate
4) delayed in some developmental milestones
A number of Genes Identified as
linked to ADHD
What now?
Confirm linkage in larger samples
 Determine how these genes contribute to
ADHD
 Additional candidates e.g., neurotrophic
factors
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Neuroimaging
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Computed tomography (CT)
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Series of x rays from different angles
Positron emission tomography (PET)
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Inject radioisotope that emits positrons
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Water labelled with oxygen-15 measure changes in blood flow
Deoxyglucose labelled with florine-18 which accumulates in active
cells
Magnetic resonance imaging (MRI)
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Magnets detect magnetic molecules
fMRI detects changes in magnetic properties of
hemoglobin as it carries O2 to active brain cells
Brain structure and ADHD
Inhibitory control
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Withholding and withdrawing of responses if
intention or circumstances change or error is
made
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Failure of inhibition results in errors &
impulsiveness
Inhibition and ADHD
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Activates orbital, DLPF and basal ganglia
Rich in DA
Disruption of DA by knock out or neurotoxins
affects executive control
DA tone associated with executive control
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Impulsiveness associated with low extracellular
DA
Blocking DA (mostly in basal ganglia)
reuptake makes DA more available and
improves executive control
Stop Signal Task
*
fixation point
X/O
go stimulus: choice reaction time
task
500 ms
motor response
1000 ms
Inter-trial interval = 3000 ms
Stop Signal Task
*
X/O
500 ms
stop signal delay (variable)
RED
SCREEN
or
TONE
1000 ms
500 ms
stop signal
Latency of inhibition (SSRT) in
ADHD
and
controls
SSRT (ms)
350
300
250
200
SSRT
150
100
50
0
ADHD
Normal Control
Schachar et al., 2001
Inhibition & psychopathology
SSRT (ms)
500
400
300
200
100
us
An
xi
o
D
HD
+C
AD
du
ct
Co
n
HD
AD
No
rm
al
0
• IQ, age, aggression, speed, reading
Osterlaans et al., 1999
Impulsive Personality
Logan, Schachar & Tannock, 1997
650
Mean RT in MS
550
450
SSRT
Go RT
350
250
150
0
2
4
6
Impulsivity Score
8
Inhibition and Methylphenidate
Response
T-score (Mean = 50, SD = 10)
65
60
55
ssrt
% still
50
45
40
35
placebo
low
medium
high
Tannock, Schachar & Logan, 1995
Inhibition & Family History for ADHD
%
Percent of Family History for ADHD
60
50
48.1
40
30
18.5
20
7.7
10
0
Poor
Inhibition
Good
Inhibition
Normal
Control
Crosbie & Schachar (2001)
Inhibition in concordant and
discordant
siblings
SSRT ms
350
300
250
200
150
100
50
0
Concordant
Disconcordant
Controls
Evidence of performance
monitoring
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Introspection
Slowing following errors
Slowing following correct responses
Self-detected action slips or errors due to
faulty knowledge (external feedback)
Pattern seen in range of tasks
Speeded choice response tasks
 Memory tasks
 Inhibition tasks
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Relevance of performance
monitoring to ADHD
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Poorly regulated behaviour
“often fails to give close attention to details or
makes careless mistakes in schoolwork, work,
or other activities”
Inaccurate and variable task performance
ms
Slowing after non-stopped
responses in ADHD and controls
80
60
40
20
0
ADHD
Normal Control
Executive control summary
New breed of measures of specific
processes
 Cognitively and neurally distinct,
multiple deficits characteristic of
ADHD
 Functional assessment warranted
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What do you mean “Cognitive tests
are not diagnostic”?
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Clinic sample (N = 100)
ADHD
50/25
controls
50/5
Of 30 cases with “diagnostic marker”, 25/30 =83%
will be ADHD
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General population (N = 100)
ADHD
5/2.5
controls
95/19
Therefore, of every 21.5 cases with the “diagnostic
marker”, 19/21.5 = 88% will be controls!
“Environmental” causes of
ADHD/cognitive deficit
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Traumatic
 closed head injury
 prematurity
 radiation
Toxic
 alcohol (FAS)
 smoking
Social / stress (alteration in DA, NA, S release in
PFC)
 in animals & humans disrupts complex
cognitive function
 maternal stress during pregnancy
 disrupted early care–giving
School policy dilemma
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ADHD is a learning
problem associated
with cognitive
deficits and
academic
underachievement
Approach differs from RD
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But is handled
differently than
learning disability
Accommodation in
classroom
Summary
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Heritable
Genetic risks
Structure
Function
Non-genetic factors
Educational system
Opportunities for participation
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Children 6 -16 years
Presumptive diagnosis of ADHD
Two affected children and both parents
 Willing to give blood
 No exclusions
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Teju Pathare
(416) 813-8291
One affect, sibling unaffected
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Tracee Francis
(416) 813-6568