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Cognitive Impairment
7 th October 2014, v1.0
Aims of this resource
This presentation provides an overview of cognitive impairment, and is designed for PhD
students and post-graduates
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Summary of contents
• What do we mean by cognitive ‘impairment’?
• Re-introduce computerized cognitive assessment and its advantages
• Consider cognitive deficits across the lifespan
• Highlight the importance of cognitive impairment: why does it matter?
• Brain circuitry involved in cognition, in health and disease
• Scientific model – fronto-striatal circuitry with relatively functionally
segregated ‘loops’
• Neuromodulation: different ‘chemical messengers’ playing key roles in
cognition
• Use of behavioural tests and neuroimaging techniques
• Key examples of CNS disorders with overview of diagnostic criteria, common cognitive
deficits, and cognitive treatment mechanisms
• Focus on attention deficit hyperactivity disorder (ADHD), depression, and
Alzheimer’s Disease (AD)
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What do we mean by cognitive impairment?
The term cognitive ‘impairment’ (or ‘deficit’) is commonly used, but precision is
needed in its definition
Impairment is always relative to some comparator
e.g. Cognitive impairment as *compared* to a healthy control group (or normative
data); or against a pre-determined threshold
When reporting results of cognitive assessments, it is important to specify whether this
is a ‘statistically significant’ impairment and to also consider reporting effect size
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What do we mean by cognitive impairment?
Example
Response inhibition refers to the suppression of motor responses when environmental
circumstances change. An example of this cognitive function in life would be stopping
the car accelerator if a traffic light suddenly changed to amber/red
Stop-signal reaction
time (msec)
Using a laboratory based test of response inhibition, one study examined performance in
people with damage to the left brain hemisphere, right brain hemisphere, and healthy
controls (three groups)1
*
270
worse response
inhibition
*
250
230
210
* indicates p<0.05 statistically significant
difference between groups
190
170
150
Right
Left
Control
1Aron
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et al., Nat Neurosci, 2003
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What do we mean by cognitive impairment?
Example
Another way of expressing cognitive impairment is in terms of effect size
In this example, effect sizes are shown for the impairment in response inhibition in
patients with obsessive-compulsive disorder (OCD), and relatives of patients with OCD,
versus controls1
OCD patients
greater impairment
Relatives of OCD patients
0
0.2
0.4
0.6
0.8
1
Effect Size (Cohen’s D)
1Chamberlain
2007
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et al., Am J Psych
Impaired inhibitory control
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Assessment of cognition: a refresher
What might make an ‘ideal’ set of cognitive tests?
• Capture the spectrum of different cognitive functions and separate them
• Good psychometric properties
• Reliability (consistency, test-retest)
• Validity (face, content, discriminant)
• Sensitive: able to maximize detection of cognitive impairments in
disorders/syndromes; and effects of interventions
• Translational: can be directly related to neural circuitry and neurochemical systems
• Respected by scientific community
• Availability of a large normative database
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Assessment of cognition: a refresher
Computerized assessment as the gold standard
Cognitive assessment initially relied on pen/paper tests, before the advent of computer
technology
Computerized assessment is now the gold standard, with potential
advantages:
- Objectively tease apart distinct cognitive abilities
- Automated data collection and processing; quality control
- Accuracy (such as in measurement of response latencies)
- Can be made less reliant on complex motor skill; special interface technology
- Translational: neuroimaging, animal models
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Cognitive impairment across the lifespan
Drug and alcohol
abuse
Down’s
syndrome
ADHD
Autism
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reserved
Diabetes
Mood disorders
Schizophrenia
Alzheimer’s
disease
Parkinson’s
disease
Pain
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Why is cognitive impairment important?
Key considerations
• Central to the definition and/or diagnosis of some conditions (core pathology); e.g.
Alzheimer’s Disease
• Can contribute to the onset of a disorder (predisposing/precipitating factor)
• Can contribute to the persistence of a disorder and prognosis (long-term outcome)
• Interferes with treatment (e.g. may struggle to complete psychotherapy homework
due to executive dysfunction) and everyday function
• Identification of deficits informs neurobiology and treatment (including identification
of novel treatment targets)
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Brain circuitry underpinning cognition
The brain is a highly complex organ (>100 billion neurones, each
with up to 15,000 connections, in humans)
Simplified scientific models are used to understand the basis of
cognition and its impairment
Can analogise the brain to an information processing device:
circuits forming relatively segregated ‘loops’ that have different
functions
The cortex, especially frontal cortex (red), is heavily involved in
high level cognitive functions such as working memory, response
inhibition, sustained attention, and cognitive flexibility (setshifting)
1Arnsten
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et al., Bio Psych, 2011
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Brain circuitry underpinning cognition
Cortex
neuromodulators
Affective Loop
Orbitofrontal
cortex,
amygdala,
hippocampus
Globus pallidus, thalamus,
and other sub-cortical relay
stations
Executive Loop
Motor loop
Prefrontal cortex,
associative
cortex, parietal
lobe, temporal
lobe
Premotor, motor,
and
somatosensory
cortices
Striatum
Nucleus
accumbens
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Caudate
Putamen
After Arnsten et al., Bio Psych,
2011
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Exploring the neural basis of cognitive impairment
Functional brain imaging: fMRI
Brain activity can be mapped using various techniques.
The BOLD technique (Blood Oxygen Level Dependent): functional
magnetic resonance imaging (fMRI)
Participants lie in a brain scanner and undertake one or more cognitive
tasks during functional brain scanning. In addition, structural brain scans
are recorded.
Signal change in different brain regions during a cognitive process can be
identified (as compared to the resting state, or to another aspect of the
task such as a control condition)
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Exploring the neural basis of drug effects
Functional brain imaging: pharmaco-fMRI
Pharmaco-fMRI refers to a type of study design in which fMRI is combined
with one or more drug manipulations
For example, a single dose of the ADHD medication atomoxetine improved
response inhibition1
Pharmaco-fMRI revealed that this cognitive enhancement was associated
with increased activation in the right inferior frontal gyrus, a key node in
the brain’s inhibitory control network
Enhanced brain
activation in the right
inferior frontal gyrus
following atomoxetine
treatment, detected
using CANTAB2
1Chamberlain
2009
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et al., Bio Psych,
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Exploring the neural basis of drug effects
Functional brain imaging: radioligand-PET
In radioligand-PET, participants are injected with a radioactive tracer, which binds to brain
components (such as dopamine transporters)
This allows indirect measurement of neuromodulator systems and effects of drug
manipulations
Striatum drug binding
/ subjective ‘high’
For example, administration of cocaine (highly addictive substance) led to rapid binding of
cocaine in the brain’s reward centre (striatum) and this effect was strongly related to
subjective ratings of feeling ‘high’1
cocaine binding
subjective ‘high’
Time
1Adapted
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from Volkow et al., Arch Gen Psych, 1995
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Cognitive impairment in selected disorders
Overview
The next section will consider these disorders in turn:
• Attention deficit hyperactivity disorder (ADHD)
• Depression
• Alzheimer’s Disease
For each, we will survey:
•
•
•
•
Symptoms
Epidemiology
Common cognitive deficits
Effects of treatments on cognition
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Computerized assessment: CANTAB
Comprehensively captures all important cognitive domains
Established validation including excellent psychometric properties
Proven sensitivity to drug and disease effects where cognition is a factor
Comprehensively validated by >30 years of global translational research, and >1300
peer-reviewed papers
Used in over 700 academic research institutions worldwide
Extensive normative and clinical data
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CANTAB
Tailored packages
Core Cognitive Battery
Research key aspects of cognitive performance using computerized tests that
have proven sensitivity to pharmacological manipulation
ADHD Battery
Reliably study the cognitive effects in conditions characterized by excessive
impulsivity and the inability to control behaviors
Depression Battery
For research into cognitive impairment associated with depression (including
treatment resistant depression) and related mood disorders during acute
mood episodes and periods of remission
Schizophrenia Battery
Accurately research cognitive effects in schizophrenia and related syndromes
Dementia Battery
For measuring the severity of impairment in patients with prodromal
Alzheimer’s disease and those functioning within the dementia range
Or create your own test combination
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Cognitive impairment in selected disorders
ADHD: symptoms
ADHD is characterized by symptoms of hyperactivity-impulsivity, and/or inattention
≥ 5 symptoms per domain
Symptoms persist for ≥ 6 months
Some symptoms must have occurred ≤ 12 years of age
Problems in two or more settings (e.g. home and school)
Clinically significant distress and/or impairment
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Cognitive impairment in selected disorders
ADHD: epidemiology
Global prevalence of ADHD in children is ~7%, and in adults ~3%1
There is some geographical variation in prevalence – higher rates in South America, lower
rates in the Middle East. The reasons are unclear
ADHD is more common in males than in females (ratio 3:1  9:1)
ADHD associated with total excess cost of >$31.6 billion/year in the USA in 2000 (only 5%
of this was due to direct cost of treatment)2
Healthcare costs akin to asthma per child
Associated with negative long-term outcomes, especially when left untreated
e.g. unemployment, criminality, substance misuse, road traffic accidents, childhood
pregnancies, knock on depression and anxiety, suicide/self-harm3
1Polanczyk
et al., Am J Psychiatry 2007; 2Birnbaum et al.,
Curr Med Res Opin, 2005; Chan et al., Arch Pediatr Adolesc
Med., 2002; 3Biederman & Faraone, Lancet, 2005
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Cognitive impairment in selected disorders
ADHD: common cognitive deficits
The CANTAB ADHD Battery allows accurate quantification of cognitive problems in ADHD,
and effects of interventions
Attention /
reaction time
Executive
Function
Rapid Visual Information
Processing (RVP)
Spatial Working
Memory (SWM)
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Response
Control
Stop Signal Task
(SST)
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Cognitive impairment in selected disorders
ADHD: common cognitive deficits
Patients with ADHD often show impaired attention, working memory, and response
inhibition1
significant clinical
impairment
Sustained Attention (RVP)
greater
impairment
Executive Function (SWM)
CANTAB discriminates the
cognitive profile of ADHD
from other conditions
including2
Response Control (SST)
-Anxiety/Depression
-Personality Disorder
-Conduct Disorder
0
0.5
1
Impairment (Cohen’s D) in ADHD v Controls
1From
Chamberlain et al., Bio Psych, 2011; and Gau & Huang, Psych Med, 2014; see also Fried et al., Journ Atten Disorders, 2012; 2Dowson et al.,
Acta Psych Scand, 2010; Lipszyc & Schachar, J Int Neuropsych Soc, 2010
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Cognitive impairment in selected disorders
ADHD: effects of treatment on cognition
* p < 0.05 significant linear
reduction in errors with increasing
methylphenidate dose
Errors (SWM)
55
50
45
40
better
working
memory
35
30
Placebo
Low
Medium
High
CANTAB SST detected cognitive benefits of
atomoxetine (selective norepinephrine
reuptake inhibitor) following just a singledose in patients with ADHD2
Stop Signal Reaction Time
(SST)
CANTAB SWM showed dose-dependent
improvement from single-dose
methylphenidate treatment in patients with
ADHD1
* p < 0.05
250
230
better inhibitory
control
210
190
170
150
Placebo
Atomoxetine
higher dose
1Bedard
et al., J Am Child Adolesc Psych, 2004
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2Chamberlain
et al., Bio Psych, 2007
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Cognitive impairment in selected disorders
Depression: symptoms
Depression is characterized by at least five of the following symptoms over a two week
period:
•
•
•
•
•
•
•
•
•
Depressed mood (e.g. feeling sad, empty, hopeless) *
Loss of interest in pleasurable activities *
Weight loss or gain; or appetite loss or gain
Insomnia
Psychomotor agitation or retardation
Fatigue / loss of energy
Excessive feelings of worthlessness or guilt
Poor concentration or indecisiveness
Recurrent thoughts of death / suicide
(* at least one of these two must be present for the diagnosis)
Significant functional impairment
Not due to effects of another disorder (e.g. schizophrenia, or a medical condition), or to
physiological effects of substances
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Cognitive impairment in selected disorders
Depression: epidemiology
Depression is the leading cause of disability across the world, and a major contributor to
global burden of disease1
Point prevalence globally is around 5% (some geographical variation: lower in East Asia,
higher in Africa & Middle East)2
More common in females than in males (ratio 2:1)
Economic cost is massive: tens of billions of dollars in the USA per year alone 3
Long-term outcomes, especially when untreated, include increased risk of cardiovascular
disease (including diabetes), unemployment, social isolation, premature death, and suicide
1World
Health Organisation Factsheet on Depression, 2012;
et al., Psych Med, 2013; 3Wang et al., Int J Meth Psych
Res, 2003
2Ferrai
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Cognitive impairment in selected disorders
Depression: common cognitive deficits
The CANTAB Depression Battery allows accurate quantification of cognitive effects when
testing investigational drugs for mood disorders.
Attention /
reaction time
Planning
Executive
function
Mnemonic
Executive
function
Emotional
processing
Forced choice
recognition
memory
Rapid Visual
Information
Processing (RVP)
One Touch
Stockings of
Cambridge (OTS)
Spatial Working
Memory (SWM)
Affective Go/No-Go
(AGN)
Delayed Matching to
Sample (DMS)
also includes Visual Analogue Scales (VAS) to measure subjective mood ratings
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Cognitive impairment in selected disorders
Depression: common cognitive deficits
Depressed patients are particularly sensitive
to being told they are wrong (‘negative
feedback) across different tests2
Significant clinical
impairment
Recognition Memory
(DMS)
Attention / Reaction
Times (RVP)
Probability of error after
making a mistake
Depressed patients often show deficits on
aspects of recognition memory, sustained
attention, and executive planning1
abnormal
sensitivity to
negative
feedback
30
20
10
0
greater
impairment
Executive Function
(OTS)
0
1
Depressed patients were
impaired compared to all
other groups (p<0.01)
2
Impairment (Z-score) in depression versus controls
1Egerhazi
et al., Neuropsych Hungar, 2013; see also Rock et al., Psych Med, 2013
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2Elliott
et al., J Neurol Neurosurg Psych, 1997
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Cognitive impairment in selected disorders
Depression: effects of treatment on cognition
Similar beneficial effects on CANTAB working memory following 24-week treatment with
duloxetine or escitalopram, in patients with depression1
50
45
Pre-treatment
40
Post-treatment
Total errors (SWM)
35
30
25
20
15
10
Both treatments were
associated with similar
improvements (main
effect of treatment
p<0.01 across multiple
CANTAB domains, but no
significant group x
treatment interactions)
improvement
5
0
Duloxetine
Escitalopram
1Herrera-Guzman
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et al., Psych Res, 2010
Page 28
Cognitive impairment in selected disorders
Alzheimer’s Disease: symptoms
Alzheimer’s Disease (AD) is usually diagnosed based on the ‘NINCDS-ADRDA’ criteria1
Definite Alzheimer's disease: The patient meets the criteria for probable Alzheimer's
disease and has histopathologic evidence of AD via autopsy or biopsy
Probable Alzheimer's disease: Dementia confirmed by clinical and neuropsychological
examination. Cognitive impairments must be progressive and present in two or more
domains (memory, language, perceptual skills, attention, constructive abilities, orientation,
problem solving and functional abilities)
Onset of cognitive deficits between ages of 40 and 90 years
Not due to other disorders
1National
Institute of Neurological and Communicative Disorders and Stroke and the
Alzheimer's Disease and Related Disorders Association, 1984 as amended
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Cognitive impairment in selected disorders
Alzheimer’s Disease: epidemiology
Gender ratio depends on type of
dementia: in AD more women than
men affected (ratio ~ 2:1)
Economic cost is vast: estimated
cost of Alzheimer’s Disease
estimated at 214 billion dollars per
year in the USA alone2
150
Millions of people
with dementia
~50 million people have dementia
worldwide, Alzheimer’s Disease (AD)
being the most common form1
Negative outcomes include early
death (AD leads to 500,000 deaths
globally per year)1
100
low/middle income
countries
50
high income countries
2013
Year
2050
1www.alz.co.uk/research/statistics;
2alz.org/facts
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Cognitive impairment in selected disorders
Alzheimer’s Disease: common cognitive deficits
The CANTAB Dementia battery allows rapid and highly sensitive, touchscreen assessment
measuring cognitive effects of investigational drugs for Alzheimer’s Disease, and related
syndromes
Rapid Visual
Information
Processing
(RVP)
Paired
Associates
Learning (PAL)
Spatial
Working
Memory (SWM)
Attention /
reaction time
Visual learning
and memory
Executive
function /
working memory
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Reaction Time
(RTI)
Delayed
Matching to
Sample (DMS)
Motor and mental
response speed
Forced choice
recognition memory
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Cognitive impairment in selected disorders
Alzheimer’s Disease: common cognitive deficits
Patients with AD, and Mild Cognitive Impairment
(the early form of AD) show impaired episodic
memory, attention, and working memory1
Episodic memory deteriorates
progressively over time in AD and its
prodrome2
Significant clinical impairment
greater
impairment
Attention / Reaction
Times (RVP)
Alzheimer's
Disease
MCI
Executive Function
(SWM)
PAL: total errors
Episodic Memory
(PAL)
worse performance
120
100
80
60
Alzheimer’s Disease
40
Progressing Questionable
Dementia (QD)
Controls
20
0
0
6
12
18
24
Time of assessment (months)
0 1 2 3 4 5 6 7 8
Impairment
(Z-Score)
vs Controls
Cognitive Impairment
© Cambridge
Cognition 2015.
All rights
reserved
1Egerhazi
et al., Prog Neuropsych Bio Psych, 2007; 2Fowler et
al., J Int Neuropsych Soc, 2002
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Cognitive impairment in selected disorders
Alzheimer’s Disease: effects of treatment on cognition
Cognitive improvement following 12-week Phenserine
treatment (cholinesterase inhibition) in Alzheimer’s
Disease. The ADAS-cog composite measure was
insensitive1
Selective cognitive improvement following 4-week
SAM-531 treatment (5-HT6 antagonism) at
3mg/day in Alzheimer’s Disease2
* p < 0.05
10
20
Phenserine (Axonyx)
Placebo
8
6
Improvement
4
2
0
-2
Change in PAL
total errors
adjusted
Change from baseline
* p < 0.05
12
15
10
5
0
Placebo 0.5mg 1.5mg
3mg
5mg
-5
-4
Deterioration
-6
-8
-10
CANTAB-PAL
-10
CANTAB-PAL
ADAS-Cog
1Greig
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reserved
et al., Curr Alz Res, 2005; 2Brisard et al., ICAD conference, 2010
Page 33
Cognitive impairment in other settings
Cognitive assessment is invaluable for understanding the role of brain dysfunction
across a multitude of disorders/syndromes, only some of which we have considered.
Examples of conditions in which cognitive impairment can occur:
ADHD
Depression
Alzheimer's disease
Schizophrenia
Pain
Sleep disorders
Down's syndrome
Parkinson's disease
Diabetes
Traumatic brain injury
Substance abuse
Cancer
Huntington's disease
Epilepsy
Autism
Fragile X
Bipolar disorder
Multiple sclerosis
Impulse-control disorders
Allergic diseases
Genetic disorders
Cardiovascular disease
Eating disorders
Obesity
Respiratory disorders
Anxiety disorders/stress
Stroke
These impairments inform biological models of brain disease, and represent key
treatment targets1
1e.g.
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Chamberlain et al., Bio Psych, 2011
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