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Alzheimer Disease Biomarkers as Outcome Measures for Clinical Trials in MCI

Caroli, Anna PhD*; Prestia, Annapaola PsyD; Wade, Sara PhD‡§; Chen, Kewei PhD; Ayutyanont, Napatkamon PhD; Landau, Susan M. PhD; Madison, Cindee M. MS; Haense, Cathleen MD#; Herholz, Karl MD**; Reiman, Eric M. MD; Jagust, William J. MD; Frisoni, Giovanni B. MD†,††; for the Alzheimer’s Disease Neuroimaging Initiative

Alzheimer Disease & Associated Disorders: April–June 2015 - Volume 29 - Issue 2 - p 101–109
doi: 10.1097/WAD.0000000000000071
Original Articles

Background: The aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI).

Methods: Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer’s Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer’s Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid Aβ1-42 concentration—ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy—HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms.

Results: Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency.

Conclusion: These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials.

*Medical Imaging Unit, Biomedical Engineering Department, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Bergamo

Laboratory of Epidemiology and Neuroimaging, IRCCS Fatebenefratelli, Brescia

§Department of Decision Science, Bocconi University, Milan, Italy

Department of Engineering, University of Cambridge

**Institute of Brain, Behaviour, and Mental Health University of Cambridge, Cambridge

Banner Alzheimer’s Institute, Phoenix, AZ

Helen Wills Neuroscience Institute, University of California, Berkeley, CA

#Hannover Medical School, Clinic for Nuclear Medicine, Hannover, Germany

††Departments of Internal Medicine and Psychiatry, University Hospitals and University of Geneva, Geneva, Switzerland

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Data collection and sharing of ADNI data for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; BioClinica Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd., and its affiliated company Genentech Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace Inc.; Merck & Co. Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. This research was also supported by NIH Grants P30 AG010129 and K01 AG030514.

Supported in part by the National Institute of Mental Health (R01MH57899), the National Institute on Aging (R01AG031581 and P30AG19610), and the state of Arizona.

The authors declare no conflicts of interest.

Reprints: Giovanni B. Frisoni, MD, Laboratory of Epidemiology and Neuroimaging, IRCCS Fatebenefratelli, IRCCS Centro San Giovanni di Dio-Fatebenefratelli, via Pilastroni 4, Brescia 25125, Italy (e-mail: gfrisoni@fatebenefratelli.it).

Received May 13, 2014

Accepted October 17, 2014

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