What mental domains should cognitive tasks target in the development of Alzheimer’s disease &what properties should such tasks possess to ensure they are fit for this purpose? Professor Keith A. Wesnes Practice Leader Bracket, Goring-on-Thames, UK Visiting Professor Division of Psychology, Northumbria University, Newcastle, UK Adjunct Professor Centre for Human Psychopharmacology, Swinburne University, Melbourne, Australia
Does cognitive function decline just when we get old? Not according to data published widely since the 1980son tens of thousands of well educated individuals in very good health Timothy A. Salthouse Brown-Forman Professor of Psychology Director of Cognitive Aging Laboratory Department of Psychology, University of VirginiaSummarized in: WHAT IS NORMAL COGNITIVE AGING? Timothy Salthouse Alzheimer’s Association Research Roundtable Early Risk Assessment for Alzheimer’s Disease November 13, 2007
Research Question How have the neuropsychological tests as used in ADNI performed over the long term?• Data from 249 non-cognitively impaired individuals – Mean age 76 years (range 60-90) – Mean MMSE 29 (range 24-30)• Repeatedly administered a range of widely used neuropsychological tests for up to 6 years• Downloaded from ADNI database 19th September 2012Wesnes KA, Schneider LS (2012) Are neuropsychological tests such as those used in ADNIsuitable for long-term trials of cognition enhancers for preclinical Alzheimer’s disease?Journal of Nutrition, Health & Aging 16: 810
Have practice effects, absence of pre-study training & the need for equivalent forms of cognitive tests been ignored in guidelines? Uniform Criteria/Requirements for Optimal Cognitive Assessment Instruments Sensitivity range • absence of ceiling and floor effects Practice effects • determines the need for practice sessions before the start of the trial Equivalent forms • for repeated testing over the course of the trial Validity • the instrument must measure the intended disease-relevant cognitive functions Longitudinal data • information should be available on expected change over the course of the trial
Major aspects of cognition which decline in normal ageing also decline in a severity related fashion in Alzheimer’s disease Power of Attention Speed of Retrieval of information held in Working Memory Means & 95% Confidence Intervals Means & 95% Confidence Intervals 500 1000 1000 1500 1500 msecMsec 2000 2000 2500 2500 3000 I -24 -34 -4 4 -54 -8 7 MC Mi ld rat e ere 4 4 4 4 7 CI ld te ere 18 25 35 45 55 AD de ev 8 -2 5 -3 5 -4 5-5 5-8 aM Mi era ev ls ls ls ls ls Mo d-S 1 2 3 4 5 AD d ma ma ma ma ma Mo als als als als als Mo d-S No r No r No r No r No r AD D rm rm rm rm rm AD Mo A No No No No No AD Verbal Recognition Sensitivity Index Speed of Retrieval from Episodic Memory Means & 95% Confidence Intervals Means & 95% Confidence Intervals 1000 0.6 2000 0.5 3000 0.4 Msec 4000 SI 0.3 5000 0.2 6000 0.1 7000 I -24 -34 -44 - 54 -87 MC I Mi ld te ere -2 4 -34 -44 -54 -90 MC Mil d rat e ere 18 25 35 45 55 era ev 18 25 35 45 54 AD de ev als als als als als AD od d-S als als als als als Mo d-S rm rm rm rm rm DM Mo orm orm orm orm orm AD Mo No No No No No A N N N N N AD ADWesnes KA, Lenderking W (2012) The transition of cognitive decline from normal ageing to MildCognitive Impairment and Alzheimer’s disease Journal of Nutrition, Health & Aging 16: 863
Preclinical AD: 256 normotensive subjects of the same average age and MMSE scores as the ADNI sample tested over 5 years Power of Attention Quality of Working Memory Means with 95% Confidence Intervals Means with 95% Confidence Intervals 0 0.05 20 0.00 40 60 -0.05 SI Units 80 msec Decline from year 0 -0.10 100 120 -0.15 140 160 -0.20 180 1 2 3 4 5 1 2 3 4 5 Years Years Quality of Episodic Recognition Memory Speed of Memory Means with 95% Confidence Intervals Means with 95% Confidence Intervals 0.00 0 -0.05 100 SI Units msec -0.10 200 -0.15 300 -0.20 1 2 3 4 5 1 2 3 4 5 Years Years Wesnes K et al (2012).The year by year changes in cognitive function in a non-demented population aged 70 to 90 over a five year period. Journal of Frailty & Aging 1: 76.
“This may be a genuine placebo effect, or partlydue to other factors such as learning /familiaritywith the tests themselves, which again given themildly affected state of the patients may havehappened. In future studies, using two baselinescores and parallel versions of tests may overcomethis”. (Page 92)
257 older adults with hypertension (mean age 76 years),were recruited from general practice and treated with 8–16 mg candesartan or placebo once daily over 5 years(mean follow-up period of 44 months). Additionalantihypertensive therapy was permitted in both groups toachieve treatment targets.
Public domain trials with a computerised cognitive test system showing treatment effects in therapeutic trials in MCI & AD
Requirements for Cognitive Tests for Pre-dementia Trials Must Haves Nice To Haves• Approvable by regulatory authorities • Administrable by non-specialists• Relevance to the core cognitive • Established association biomarkers impairments in AD • Brief• Relevance to everyday behaviour • Multiple language versions• As far as possible specific to • Highly sensitive particular domains • Automatic data capture & analysis• Established sensitivity to: • Do not induce stress or anxiety – longitudinal impairment • Sensitive to neurogenesis – improvements with treatment • Precisely assess speed of cognition• Absence of ceiling & floor effects • Capable of being administered• Tests which can be performed by remotely eg via internet unimpaired & impaired patients • Established factor structure• Adequate # of parallel forms • Established databases of various• Absence of training effects after pre- populations and drug effects study familiarisation • 21 CFR Part 11 Compliant