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Methodological improvements in quantifying cognitive change in clinical trials: An example with single-dose administration of donepezil

  • Methodological Improvements in Quantifying Cognitive Change in Clinical Trials
  • Published:
JNHA - The Journal of Nutrition, Health and Aging

Abstract

Objectives

Change in cognitive function in response to a pharmacologic challenge can be observed with greater sensitivity by employing cognitive tests with optimal psychometric properties and a statistical approach that more accurately accounts for individual variability in performance. To demonstrate this approach we examined the cognitive effects of a single acute dose administration of an acetylcholinesterase inhibitor, donepezil, in healthy older adults and in older adults with mild Alzheimer’s disease (AD).

Design

Placebo-controlled crossover study with three separate testing days: baseline, placebo, and donepezil, with assessments at baseline, and 1-, 2-, 3-, 6-, and 8-hrs post-dosing on each day.

Setting

Early phase I clinical trial.

Participants

15 healthy older adults; 14 older adults with mild Alzheimer’s disease. Intervention Single acute dose of 5mg donepezil.

Measurements

Performance on the Groton Maze Learning Test (GMLT), a computerized neuropsychological measure of spatial working memory and error monitoring.

Results

A single acute dose of donepezil improved GMLT performance in healthy older adults (effect size: 0.83 at 6 hrs post-dosing) and older adults with mild AD (effect size: 0.58 at 3 hrs post-dosing).

Conclusion

The GMLT detected cognitive improvement following a single, acute dose administration of donepezil in healthy older adults and older adults with mild AD. The choice of cognitive tests designed for repeated administration, as well as an analytic approach that emphasizes individual-level change in cognitive function, provides a sensitive approach to detecting central nervous system drug penetration and activity of cognitive-enhancing agents.

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References

  1. Hasselmo ME. The role of acetylcholine in learning and memory. Curr Opin Neurobiol. 2006;16:710–715.

    Article  PubMed  CAS  Google Scholar 

  2. Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med 1998;158:1021–1031.

    Article  PubMed  CAS  Google Scholar 

  3. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology 1999;50:136–145.

    Google Scholar 

  4. Yesavage JA, Mumenthaler MS, Taylor JL, Friedman L, O’Hara R, Sheikh J, Tinklenberg J, Whitehouse PJ. Donepezil and flight simulator performance: effects on retention of complex skills. Neurology 2002;59:123–125.

    Article  PubMed  CAS  Google Scholar 

  5. Grön G, Kirstein M, Thielscher A, Riepe MW, Spitzer M. Cholinergic enhancement of episodic memory in healthy young adults. Psychopharmacology 2005;182:170–179.

    Article  PubMed  Google Scholar 

  6. FitzGerald DB, Crucian GP, Mielke JB, Shenal BV, Burks D, Womack KB, Ghacibeh G, Drago V, Foster PS, Valenstein E, Heilman KM. Effects of donepezil on verbal memory after semantic processing in healthy older adults. Cogn Behav Neurol 2008;21:57–64.

    Article  PubMed  Google Scholar 

  7. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 2006;Jan 25;(1):CD005593.

  8. Tariot PN, Cummings JL, Katz IR, Mintzer J, Perdomo CA, Schwam EM, Whalen E. A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer’s disease in the nursing home setting. J Am Geriatr Soc 2001;49:1590–1599.

    Article  PubMed  CAS  Google Scholar 

  9. Beglinger LJ, Tangphao-Daniels O, Kareken DA, Zhang L, Mohs R, Siemers ER. Neuropsychological test performance in healthy elderly volunteers before and after donepezil administration: a randomized, controlled study. J Clin Psychopharmacol 2005;25:159–165.

    Article  PubMed  CAS  Google Scholar 

  10. Beglinger LJ, Gaydos BL, Kareken DA, Tangphao-Daniels O, Siemers ER, Mohs RC. Neuropsychological test performance in healthy volunteers before and after donepezil administration. J Psychopharmacol 2004;18:102–108.

    Article  PubMed  CAS  Google Scholar 

  11. Mollica CM, Maruff P, Vance A. Development of a statistical approach to classifying treatment response in individual children with ADHD. Hum Psychopharmacol 2004;19:445–456.

    Article  PubMed  Google Scholar 

  12. Falleti MG, Maruff P, Collie A, Darby DG. Practice effects associated with the repeated assessment of cognitive function using the CogState battery at 10-minute, one week and one month test-retest intervals. J Clin Exp Neuropsychol 2006;28:1095–1112.

    Article  PubMed  Google Scholar 

  13. Collie A, Maruff P, Snyder PJ, Darekar MA, Huggins JP. Cognitive testing in early phase clinical trials: outcome according to adverse event profile in a Phase I study. Hum Psychopharmacol 2006;21:481–488.

    Article  PubMed  CAS  Google Scholar 

  14. Lewis MS, Maruff P, Silbert BS, Evered LA, Scott DA. The influence of different error estimates in the detection of post-operative cognitive dysfunction using reliable change indices with correction for practice effects. Arch Clin Neuropsychol 2006;21:421–427.

    Article  PubMed  Google Scholar 

  15. Lewis MS, Maruff P, Silbert BS, Evered LA, Scott DA. The sensitivity and specificity of three common statistical rules for the classification of post-operative cognitive dysfunction following coronary artery bypass graft surgery. Acta Anaesthesiol Scand 2006;50:50–57.

    Article  PubMed  CAS  Google Scholar 

  16. Maruff P, Werth J, Giordani B, Caveney AF, Feltner D, Snyder PJ. A statistical approach for classifying change in cognitive function in individuals following pharmacologic challenge: an example with alprazolam. Psychopharmacology 2006;186:7–17.

    Article  PubMed  CAS  Google Scholar 

  17. Snyder PJ, Werth J, Giordani B, Caveney AF, Feltner D, Maruff P. A method for determining the magnitude of change across different cognitive functions in clinical trials: the effects of acute administration of two different doses alprazolam. Hum Psychopharmacol 2005;20:263–273.

    Article  PubMed  CAS  Google Scholar 

  18. Snyder PJ, Bednar MM, Cromer JR, Maruff P. Reveral of scopolamine-induced deficits with a single dose of donepezil, an acetylecholinesterase inhibitor. Alzheimer’s & Dementia 2005;1:126–135.

    Article  CAS  Google Scholar 

  19. Gorus E, De Raedt R, Lambert M, Lemper JC, Mets T. Reaction times and performance variability in normal aging, mild cognitive impairment, and Alzheimer’s disease. J Geriatr Psychiatry Neurol 2008;21:204–218.

    Article  PubMed  Google Scholar 

  20. Stopford CL, Snowden JS, Thompson JC, Neary D. Variability in cognitive presentation of Alzheimer’s disease. Cortex 2008;44:185–195.

    Article  PubMed  Google Scholar 

  21. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939–944.

    PubMed  CAS  Google Scholar 

  22. Barker J. The stepping-stone maze: a directly visible space-problem apparatus. J Gen Psychol 1931;5:280–285.

    Google Scholar 

  23. Milner B. Visually-guided maze learning in man: effects of bilateral hippocampal, bilateral frontal, and unilateral cerebral lesions. Neuropsychologia 1965;3:317–338.

    Article  Google Scholar 

  24. Pietrzak RH, Maruff P, Mayes LC, Roman SA, Sosa JA, Snyder PJ. An examination of the construct validity and factor structure of the Groton Maze Learning Test, a new measure of spatial working memory, learning efficiency, and error monitoring. Arch Clin Neuropsychol 2008;23:433–445.

    Article  PubMed  Google Scholar 

  25. Pietrzak RH, Cohen H, Snyder PJ. Spatial learning efficiency and error monitoring in normal aging: an investigation using a novel hidden maze learning test. Arch Clin Neuropsychol 2007;22:235–245.

    Article  PubMed  Google Scholar 

  26. Pietrzak RH, Maruff P, Snyder PJ. Convergent validity and effect of instruction modification on the Groton Maze Learning Test, a new measure of spatial working memory and error monitoring. Int J Neurosci, in press.

  27. Bland JM, Altman DG. Measurement error. BMJ 1996;313:744.

    PubMed  CAS  Google Scholar 

  28. Rogers SL, Friedhoff LT. Pharmacokinetic and pharmacodynamic profile of donepezil HCl following single oral doses. Br J Clin Pharmacol 1998;46Suppl 1:1–6.

    Article  PubMed  CAS  Google Scholar 

  29. Fredrickson A, Snyder PJ, Cromer J, Thomas E, Lewis M, Maruff P. The use of effect sizes to characterize the nature of cognitive change in psychopharmacological studies: an example with scopolamine. Hum Psychopharmacol 2008;23:425–436.

    Article  PubMed  CAS  Google Scholar 

  30. Collie A, Darekar A, Weissgerber G, Toh MK, Snyder PJ, Maruff P, Huggins JP. Cognitive testing in early-phase clinical trials: development of a rapid computerized test battery and application in a simulated Phase I study. Contemp Clin Trials 2007;28:391–400.

    Article  PubMed  Google Scholar 

  31. Maruff, P., Thomas, E., Cysique, L., Brew, B., Collie, A., Snyder, P. J., & Pietrzak, R. H. Validity of the CogState brief computerized cognitive test battery: Relationship to standardized tests and sensitivity to cognitive impairment in mild traumatic brain injury, schizophrenia and AIDS dementia complex. Arch Clin Neuropsychol, in press.

  32. Pietrzak, R. H., Snyder, P. J., Olver, J., Norman, T., & Maruff, P. A comparison of the CogState Schizophrenia Battery and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery in assessing cognitive impairment in chronic schizophrenia, J Clin Exp Neuropsychol, in press.

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Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    R. H. Pietrzak

  2. Centre for Neuroscience, University of Melbourne, Melbourne, Victoria, Australia

    P. Maruff

  3. Department of Clinical Neurosciences, Warren Alpert Medical School of Brown University, Providence, RI, USA

    Peter J. Snyder

  4. CogState, Ltd., Melbourne, Victoria, Australia

    P. Maruff

  5. Child Study Center, Yale University School of Medicine, New Haven, CT, USA

    Peter J. Snyder

  6. Lifespan Affiliated Hospitals, Aldrich Building, Suite 132, 593 Eddy Street, Providences, RI, 02903, USA

    Peter J. Snyder

Authors
  1. R. H. Pietrzak
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  2. P. Maruff
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  3. Peter J. Snyder
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Correspondence to Peter J. Snyder.

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Pietrzak, R.H., Maruff, P. & Snyder, P.J. Methodological improvements in quantifying cognitive change in clinical trials: An example with single-dose administration of donepezil. J Nutr Health Aging 13, 268–273 (2009). https://doi.org/10.1007/s12603-009-0071-4

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  • DOI: https://doi.org/10.1007/s12603-009-0071-4

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