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Cognitive Impairment

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. Summary of contents. What do we mean by cognitive ‘impairment’?

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Cognitive Impairment

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  1. Cognitive Impairment 7th October 2014, v1.0

  2. Aims of this resource This presentation provides an overview of cognitive impairment, and is designed for PhD students and post-graduates

  3. 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)

  4. 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

  5. * 270 250 230 Stop-signal reaction time (msec) 210 190 170 150 Right Left Control 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 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 worse response inhibition * * indicates p<0.05 statistically significant difference between groups 1Aron et al., Nat Neurosci, 2003

  6. 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 greater impairment Effect Size (Cohen’s D) 1Chamberlain et al., Am J Psych2007 Impaired inhibitory control

  7. Assessment of cognition: a refresher 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 What might make an ‘ideal’ set of cognitive tests?

  8. Assessment of cognition: a refresher 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 Computerized assessment as the gold standard

  9. Cognitive impairment across the lifespan Parkinson’s disease Drug and alcohol abuse Down’s syndrome Alzheimer’s disease Schizophrenia Autism ADHD Diabetes Pain Mood disorders

  10. 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)

  11. 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 (set-shifting) 1Arnsten et al., Bio Psych, 2011

  12. Brain circuitry underpinning cognition Cortex neuromodulators Affective Loop Orbitofrontal cortex, amygdala, hippocampus Executive Loop Prefrontal cortex, associative cortex, parietal lobe, temporal lobe Motor loop Premotor, motor, and somatosensory cortices Globus pallidus, thalamus, and other sub-cortical relay stations Striatum Nucleus accumbens Caudate Putamen After Arnsten et al., Bio Psych, 2011

  13. Exploring the neural basis of cognitive impairment Functional brain imaging: fMRI Brain activity can be mapped using various techniques. The BOLDtechnique (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)

  14. 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 et al., Bio Psych, 2009

  15. 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 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 Striatum drug binding / subjective ‘high’ cocaine binding subjective ‘high’ Time 1Adapted from Volkow et al., Arch Gen Psych, 1995

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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 PediatrAdolesc Med., 2002; 3Biederman & Faraone, Lancet, 2005

  21. 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 Executive Function Attention / reaction time Response Control Rapid Visual Information Processing (RVP) Spatial Working Memory (SWM) Stop Signal Task (SST)

  22. Cognitive impairment in selected disorders ADHD: common cognitive deficits • Patients with ADHD often show impaired attention, working memory, and response inhibition1 significant clinical impairment greater impairment CANTAB discriminates the cognitive profile of ADHD from other conditions including2 -Anxiety/Depression -Personality Disorder -Conduct Disorder 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., JournAtten Disorders, 2012; 2Dowson et al., Acta Psych Scand, 2010; Lipszyc & Schachar, J IntNeuropsychSoc, 2010

  23. Cognitive impairment in selected disorders ADHD: effects of treatment on cognition CANTAB SWM showed dose-dependent improvement from single-dose methylphenidate treatment in patients with ADHD1 CANTAB SST detected cognitive benefits of atomoxetine (selective norepinephrine reuptake inhibitor) following just a single-dose in patients with ADHD2 * p < 0.05 significant linear reduction in errors with increasing methylphenidate dose * p < 0.05 better inhibitory control Stop Signal Reaction Time (SST) Errors (SWM) better working memory higher dose 1Bedard et al., J Am Child Adolesc Psych, 2004 2Chamberlain et al., Bio Psych, 2007

  24. 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

  25. 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 alone3 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; 2Ferrai et al., Psych Med, 2013; 3Wang et al., Int J Meth Psych Res, 2003

  26. 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. Forced choice recognition memory Attention / reaction time Planning Executive function Mnemonic Executive function Emotional processing 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

  27. Cognitive impairment in selected disorders Depression: common cognitive deficits • Depressed patients often show deficits on aspects of recognition memory, sustained attention, and executive planning1 • Depressed patients are particularly sensitive to being told they are wrong (‘negative feedback) across different tests2 abnormal sensitivity to negative feedback Significant clinical impairment greater impairment Depressed patients were impaired compared to all other groups (p<0.01) Impairment (Z-score) in depression versus controls 1Egerhazi et al., NeuropsychHungar, 2013; see also Rock et al., Psych Med, 2013 2Elliott et al., J NeurolNeurosurg Psych, 1997

  28. 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 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) Total errors (SWM) improvement 1Herrera-Guzman et al., Psych Res, 2010

  29. 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

  30. Cognitive impairment in selected disorders Alzheimer’s Disease: epidemiology ~50 million people have dementia worldwide, Alzheimer’s Disease (AD) being the most common form1 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 Negative outcomes include early death (AD leads to 500,000 deaths globally per year)1 150 100 Millions of people with dementia low/middle income countries 50 high income countries 2050 2013 Year 1www.alz.co.uk/research/statistics; 2alz.org/facts

  31. 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) Delayed Matching to Sample (DMS) Paired Associates Learning (PAL) Spatial Working Memory (SWM) Reaction Time (RTI) Attention / reaction time Visual learning and memory Executive function / working memory Motor and mental response speed Forced choice recognition memory

  32. 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 120 Significant clinical impairment worse performance 100 80 greater impairment PAL: total errors 60 Alzheimer’s Disease Progressing Questionable Dementia (QD) 40 Controls 20 0 0 6 12 18 24 Time of assessment (months) 1Egerhazi et al., ProgNeuropsych Bio Psych, 2007; 2Fowler et al., J IntNeuropsychSoc, 2002 Impairment (Z-Score) vs Controls

  33. 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 * p < 0.05 12 Phenserine (Axonyx) 10 Placebo 8 6 Improvement 4 2 Change from baseline 0 -2 -4 Deterioration -6 CANTAB-PAL -8 -10 CANTAB-PAL ADAS-Cog 1Greig et al., CurrAlz Res, 2005; 2Brisard et al., ICAD conference, 2010

  34. 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: These impairments inform biological models of brain disease, and represent key treatment targets1 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 1e.g. Chamberlain et al., Bio Psych, 2011

  35. UK Headquarters Cambridge Cognition  Tunbridge Court, Tunbridge Lane Bottisham, Cambridge CB25 9TU  UK Tel+44 (0)1223 810700 Emailinfo@camcog.com US Office 2750 Rasmussen RoadPark CityUtah 84098USA Tel +1 (801) 891-6155Emailinfo@camcog.com

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