Novel Statistically-Derived Composite Measures for Assessing the Efficacy of Disease-Modifying Therapies in Prodromal Alzheimer’s Disease Trials: An AIBL Study

Article type: Research Article

Authors: Burnham, Samantha C.^{a; a} | Raghavan, Nandini^b | Wilson, William^c | Baker, David^d | Ropacki, Michael T.^e | Novak, Gerald^b | Ames, David^{f; g} | Ellis, Kathryn^f | Martins, Ralph N.^{h; i} | Maruff, Paul^j | Masters, Colin L.^k | Romano, Gary^b | Rowe, Christopher C.^{l; m} | Savage, Gregⁿ | Macaulay, S. Lance^o | Narayan, Vaibhav A.^b | for the Alzheimer’s Disease Neuroimaging Initiative | the AIBL Research Group

Affiliations: [a] CSIRO Digital Productivity Flagship, Floreat, WA, Australia | [b] Janssen Research and Development, Raritan, NJ, USA | [c] CSIRO Digital Productivity Flagship, North Ryde, NSW, Australia | [d] Janssen Research and Development, Titusville, NJ, USA | [e] Janssen Research and Development, Fremont, CA, USA | [f] Academic Unit for Psychiatry of Old Age, Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia | [g] National Ageing Research Institute, Parkville, VIC, Australia | [h] Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical Sciences, Edith Cowan University, Joondalup, WA, Australia | [i] Sir James McCusker Alzheimer’s Disease Research Unit (Hollywood Private Hospital), Perth, WA, Australia | [j] Cogstate, Melbourne, VIC, Australia | [k] Mental Health Research Institute (MHRI), The University of Melbourne, Parkville, VIC, Australia | [l] Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, Australia | [m] Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia | [n] ARC Centre of Excellence in Cognition and its Disorders, and Department of Psychology, Macquarie University, Sydney, NSW, Australia | [o] CSIRO Food and Nutrition Flagship, Melbourne, VIC, Australia

Correspondence: [*] Correspondence to: Samantha Burnham, DPF, CSIRO, Private Bag 5, Wembley, WA 6913, Australia. Tel.: +61 0 8 9333 6706; Fax: +61 0 8 9333 6121; [email protected]

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Note: [2] http://www.aibl.csiro.au/about/aibl-research-team

Abstract: Background: There is a growing consensus that disease-modifying therapies must be given at the prodromal or preclinical stages of Alzheimer’s disease (AD) to be effective. A major unmet need is to develop and validate sensitive measures to track disease progression in these populations. Objective: To generate novel statistically-derived composites from standard scores, which have increased sensitivity in the assessment of change from baseline in prodromal AD. Methods: An empirically based method was employed to generate domain specific, global, and cognitive-functional novel composites. The novel composites were compared and contrasted with each other, as well as standard scores for their ability to track change from baseline. The longitudinal characteristics and power to detect decline of the measures were evaluated. Data from participants in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study characterized as mild cognitively impaired with high neocortical amyloid-β burden were utilized for the study. Results: The best performing standard scores were CDR Sum-of-Boxes and MMSE. The statistically-derived novel composites performed better than the standard scores from which they were derived. The domain-specific composites generally did not perform as well as the global composites or the cognitive-functional composites. Conclusion: A systematic method was employed to generate novel statistically-derived composite measures from standard scores. Composites comprised of measures including function and multiple cognitive domains appeared to best capture change from baseline. These composites may be useful to assess progression or lack thereof in prodromal AD. However, the results should be replicated and validated using an independent clinical sample before implementation in a clinical trial.

Keywords: Alzheimer’s disease, clinical marker, clinical trial, mild cognitive impairment, prodromal stage

DOI: 10.3233/JAD-143015

Journal: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 1079-1089, 2015