title: MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD.
abstract: OBJECTIVE
  To assess the feasibility of using MRI measurements as a surrogate endpoint for disease progression in a therapeutic trial for AD.
  
  
  METHODS
  A total of 362 patients with probable AD from 38 different centers participated in the MRI portion of a 52-week randomized placebo-controlled trial of milameline, a muscarinic receptor agonist. The therapeutic trial itself was not completed due to projected lack of efficacy on interim analysis; however, the MRI arm of the study was continued. Of the 362 subjects who underwent a baseline MRI study, 192 subjects underwent a second MRI 1 year later. Hippocampal volume and temporal horn volume were measured from the MRI scans.
  
  
  RESULTS
  The annualized percent changes in hippocampal volume (-4.9%) and temporal horn volume (16.1%) in the study patients were consistent with data from prior single-site studies. Correlations between the rate of MRI volumetric change and change in behavioral/cognitive measures were greater for the temporal horn than for the hippocampus. Decline over time was more consistently seen with imaging measures, 99% of the time for the hippocampus, than behavioral/cognitive measures (p < 0.001). Greater consistency in MRI than behavioral/clinical measures resulted in markedly lower estimated sample size requirements for clinical trials. The estimated number of subjects per arm required to detect a 50% reduction in the rate of decline over 1 year are: AD Assessment Scale-cognitive subscale 320; Mini-Mental Status Examination 241; hippocampal volume 21; temporal horn volume 54.
  
  
  CONCLUSIONS
  The consistency of MRI measurements obtained across sites, and the consistency between the multisite milameline data and that obtained in prior single-site studies, demonstrate the technical feasibility of using structural MRI measures as a surrogate endpoint of disease progression in therapeutic trials. However, validation of imaging as a biomarker of therapeutic efficacy in AD awaits a positive trial.
authors.affiliation: Department of Diagnostic Radiology, Mayo Clinic and Foundation, Rochester, MN, USA. jack.clifford@mayo.edu
authors.forename: C R
authors.initials: CR
authors.lastname: Jack
authors.forename: M
authors.initials: M
authors.lastname: Slomkowski
authors.forename: S
authors.initials: S
authors.lastname: Gracon
authors.forename: T M
authors.initials: TM
authors.lastname: Hoover
authors.forename: J P
authors.initials: JP
authors.lastname: Felmlee
authors.forename: K
authors.initials: K
authors.lastname: Stewart
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: M
authors.initials: M
authors.lastname: Shiung
authors.forename: P C
authors.initials: PC
authors.lastname: O'Brien
authors.forename: R
authors.initials: R
authors.lastname: Cha
authors.forename: D
authors.initials: D
authors.lastname: Knopman
authors.forename: R C
authors.initials: RC
authors.lastname: Petersen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology*; D015415:Biomarkers; D001921:Brain / Q000473:pathology*; D004095:Dihydropyridines / Q000627:therapeutic use*; D018450:Disease Progression; D005240:Feasibility Studies; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000627:therapeutic use; D009483:Neuropsychological Tests; D010091:Oximes / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D012016:Reference Values; D018401:Sample Size; D017678:Sex Distribution; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D004095:Dihydropyridines; D018721:Muscarinic Agonists; D018696:Neuroprotective Agents; D010091:Oximes; C084978:milameline