title: MRI-based brain atrophy rates in ADNI phase 2: acceleration and enrichment considerations for clinical trials.
abstract: The goal of this work was to assess statistical power to detect treatment effects in Alzheimer's disease (AD) clinical trials using magnetic resonance imaging (MRI)-derived brain biomarkers. We used unbiased tensor-based morphometry (TBM) to analyze n = 5,738 scans, from Alzheimer's Disease Neuroimaging Initiative 2 participants scanned with both accelerated and nonaccelerated T1-weighted MRI at 3T. The study cohort included 198 healthy controls, 111 participants with significant memory complaint, 182 with early mild cognitive impairment (EMCI) and 177 late mild cognitive impairment (LMCI), and 155 AD patients, scanned at screening and 3, 6, 12, and 24 months. The statistical power to track brain change in TBM-based imaging biomarkers depends on the interscan interval, disease stage, and methods used to extract numerical summaries. To achieve reasonable sample size estimates for potential clinical trials, the minimal scan interval was 6 months for LMCI and AD and 12 months for EMCI. TBM-based imaging biomarkers were not sensitive to MRI scan acceleration, which gave results comparable with nonaccelerated sequences. ApoE status and baseline amyloid-beta positron emission tomography data improved statistical power. Among healthy, EMCI, and LMCI participants, sample size requirements were significantly lower in the amyloid+/ApoE4+ group than for the amyloid-/ApoE4- group. ApoE4 strongly predicted atrophy rates across brain regions most affected by AD, but the remaining 9 of the top 10 AD risk genes offered no added predictive value in this cohort.
authors.affiliation: Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Marina del Rey, CA, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Hua
authors.affiliation: Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Marina del Rey, CA, USA; Interdepartmental Neuroscience Graduate Program, University of California, Los Angeles, School of Medicine, Los Angeles, CA, USA.
authors.forename: Christopher R K
authors.initials: CRK
authors.lastname: Ching
authors.affiliation: Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Marina del Rey, CA, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Mezher
authors.affiliation: Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Marina del Rey, CA, USA.
authors.forename: Boris A
authors.initials: BA
authors.lastname: Gutman
authors.affiliation: Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Marina del Rey, CA, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Derrek P
authors.initials: DP
authors.lastname: Hibar
authors.affiliation: Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Marina del Rey, CA, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Bhatt
authors.affiliation: Department of Psychiatry, University of Illinois at Chicago, College of Medicine, Chicago, IL, USA; Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Alex D
authors.initials: AD
authors.lastname: Leow
authors.affiliation: Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.affiliation: Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Matt A
authors.initials: MA
authors.lastname: Bernstein
authors.affiliation: Department of Radiology, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine and Psychiatry, University of California, San Francisco, San Francisco, CA, USA; Department Veterans Affairs Medical Center, San Francisco, CA, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.affiliation: Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Marina del Rey, CA, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Psychiatry, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Engineering, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: pthomp@usc.edu.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D058227:Amyloidogenic Proteins; D001057:Apolipoproteins E; D001284:Atrophy; D001921:Brain / Q000473:pathology*; D002986:Clinical Trials as Topic; D003072:Cognition Disorders / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging / Q000379:methods*; D012306:Risk
chemical_list: D058227:Amyloidogenic Proteins; D001057:Apolipoproteins E
keywords: Alzheimer's disease; Amyloid; ApoE; Enrichment; Imaging biomarker; Longitudinal; Mild cognitive impairment