This presentation was made at the AD/PD meeting in Florence on 8th March 2013. In the presentation I discuss early patterns of cognitive dysfunction in patients with Parkinson's disease and Alzheimer's disease. I describe the tests traditionally used to measure cognitive impairment and propose the use of an assessment with the potential to be used successfully in both indications. I propose also that the same collection of measures can profitably be used in other CNS indications. I stress that selection is best made on the basis not of specific tests, but instead on the use of good tests that meet current best practice guidance for measuring cognitive change.

1. Metis Cognition Ltd
Cognitive dysfunction in Parkinson’s and
Alzheimer’s disease: Can we use the same tests for
exploratory and confirmatory trials?
John Harrison BSc (Hons), PhD, CSci, CPsychol
Honorary Senior Lecturer, Imperial College, London, UK.
Consultant Psychologist, Metis Cognition Ltd., Kilmington, UK.
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2. Financial disclosures
• In the past 12 months I have received consultancy
payments and/or honoraria from the following
organisations:
– Astra-Zeneca, Boehringer Ingelheim, Bracket (Clinical)
– CRF Health, EnVivo Pharma, ePharmaSolutions
– Eisai, Eli Lilly, Janssen AI, Lundbeck, MedAvante
– Merck, MyCog, Novartis, Nutricia, Orion Pharma
– Pharmanet/i3, Pfizer, Prana Biotech, Reviva
– Servier, Shire, TCG, TransTech Pharma and Velacor.
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3. Issues for consideration
• Issues relating to cognition test selection in early AD
• Issues relating to cognition test selection in early PD
• Options for test selection
– Traditional test selection
– Proposed test selection
• Conclusions and recommendations
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4. Issues and examples
TRADITIONAL MEASURES AND PATTERNS OF
COGNITIVE DECLINE IN ALZHEIMER’S
DISEASE
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5. Patterns of impairment in AD
Worst possible score = 10
Worst possible score = 12
• Most patients score at ceiling
• No difference between controls and MCI
Grundman MPH et al. (2004). Mild cognitive impairment can be distinguished from
Alzheimer’s disease and normal aging for clinical trials. Archives of Neurology;61: 59-66. metis

6. New options in early AD
EVP-6124 0.3 mg
Cognition Composite Score: EVP-6124 1 mg
ADAS-cog Word Recall, Word Recognition, and Orientation, and EVP-6124 2 mg
COWAT and CFT Placebo
(Increase Indicates Improvement)
0.2
0.15
LSMEAN Change From
0.1
Baseline (± S.E.M.)
0.05
0
EVP-2 mg vs. Placebo
-0.05 Week 23: P-value = 0.0037
Effect Size = 0.42
-0.1
-0.15
0 4 8 12 16 20 24
Study Visit (Week)
Presented at AAIC, July 2012. For a fuller account visit: http://www.alzforum.org/new/detail.asp?id=3214.
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7. Issues and examples
PATTERNS OF COGNITIVE DECLINE
IN PARKINSON’S DISEASE
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8. Early PD - Patterns of Impairment
• Early PD – evidence of cognitive dysfunction in 33-
50%1 of patients, largely in:
– Tests of executive function2
– Tests of attention3
– Timed motor tasks3
• Above tasks have been shown to be drug sensitive3,4
1) Emre M. (2003) Dementia associated with Parkinson’s disease. Lancet Neurology, 2:229-37; Robottom BJ & Weiner WJ (2009)
Parkinson’s disease dementia. Current Psychiatry Reviews, 5: 218-225.
2) Henry J & Crawford J (2004) Verbal fluency deficits in Parkinson's disease: A meta-analysis, Journal of the International
Neuropsychological Society, 10: 608-622.
3) Harrison J et al. (1995) Abnormal refractoriness in patients with Parkinson's disease after brief withdrawal of levodopa treatment.
Journal of Neurology, Neurosurgery, and Psychiatry;59:499-506; Harrison J, Edgar, C, Wesnes, K. (2005) Reaction time tasks: Sensitive
measures of drug efficacy in Parkinson’s disease clinical drug trials. 7th AD/PD meeting. Sorrento, Italy.
4) Emre M et al. (2004). Rivastigmine for the dementia associated with Parkinson’s disease. New England Jnl of Medicine 351:29-38.
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9. EMA Guidance Notes
• ‘PDD and Dementia with Lewy Bodies (DLB) are subsumed
under the umbrella Lewy Body Dementia’ (p.8)
• ‘PDD cognitive deficits are characterised by impairment in
executive function, attention and working memory’(p.8)
• ‘7.1 Pharmacodynamics: ‘As pharmacological effects on
cognition and/or memory and/or psychological function
and/or reaction time are expected, these should be studied.’
(p.11)
CHMP (2008) Guideline on clinical investigation of medicinal products in the treatment of Parkinson’s
disease. Doc.Ref.CPMP/EWP/563/95 Rev. 1. London, EMEA.
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10. Traditional Approach
TRADITIONAL PARKINSON’S
DISEASE TEST SELECTION
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11. AAV2-GAD gene therapy study
• Cognition tests selected to investigate safety
• Cognition assessment composed of:
– Mattis dementia rating scale
– Symbol digit modality test
– Stroop color and word test
– Hopkins verbal learning test
– Controlled oral word association test
• Also employed:
– Neuropsychiatric Inventory
– Beck Depression Inventory
LeWitt PA et al. (2011) AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind,
sham-surgery controlled, randomised trial. Lancet Neurology:10:309-19.
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12. Suggested Approach
ONE SIZE FITS ALL?
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13. Recommended Tests
• Psychomotor speed (Simple Reaction Time )
• Attention (Choice Reaction Time)
• Episodic visual memory (e.g. PAL tasks, One Card Learning)
• Working memory (e.g. N-back tasks, Digit Span)
• Episodic verbal memory task (e.g. ADAS-cog Word Recall,
Hopkins Verbal Learning Test, Rey Auditory Verbal Learning
Test)
• Planning and strategy (e.g. COWAT & CNT)
• Executive function (e.g. DSST, COWAT & CNT)
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14. Conclusions and recommendations
• Patterns of cognitive impairment in early PD & AD can be
quite different
• However, our concerns in exploratory development extend to
considerations of both safety and efficacy
• Consequently a broad assessment of cognition is
recommended
• Employ brief, reliable and stable cognitive measures
• Maximise reliability through continuity
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15. Questions?
Email: john@metiscog.com
Email: john.harrison@imperial.ac.uk
http://www.linkedin.com/in/drjohnharrison
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