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 randomizedplacebo-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. CONCLUSION: 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.
RCT Entities:
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. CONCLUSION: 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: R C Petersen; C R Jack; Y C Xu; S C Waring; P C O'Brien; G E Smith; R J Ivnik; E G Tangalos; B F Boeve; E Kokmen Journal: Neurology Date: 2000-02-08 Impact factor: 9.910
Authors: C R Jack; R C Petersen; Y Xu; P C O'Brien; G E Smith; R J Ivnik; B F Boeve; E G Tangalos; E Kokmen Journal: Neurology Date: 2000-08-22 Impact factor: 9.910
Authors: C R Jack; F W Sharbrough; C K Twomey; G D Cascino; K A Hirschorn; W R Marsh; A R Zinsmeister; B Scheithauer Journal: Radiology Date: 1990-05 Impact factor: 11.105
Authors: Sandhitsu R Das; Brian B Avants; John Pluta; Hongzhi Wang; Jung W Suh; Michael W Weiner; Susanne G Mueller; Paul A Yushkevich Journal: Neuroimage Date: 2012-01-28 Impact factor: 6.556
Authors: Jonathan H Morra; Zhuowen Tu; Liana G Apostolova; Amity E Green; Christina Avedissian; Sarah K Madsen; Neelroop Parikshak; Xue Hua; Arthur W Toga; Clifford R Jack; Norbert Schuff; Michael W Weiner; Paul M Thompson Journal: Hum Brain Mapp Date: 2009-09 Impact factor: 5.038
Authors: Jorge Jovicich; Silvester Czanner; Xiao Han; David Salat; Andre van der Kouwe; Brian Quinn; Jenni Pacheco; Marilyn Albert; Ronald Killiany; Deborah Blacker; Paul Maguire; Diana Rosas; Nikos Makris; Randy Gollub; Anders Dale; Bradford C Dickerson; Bruce Fischl Journal: Neuroimage Date: 2009-02-20 Impact factor: 6.556
Authors: Ronald C Petersen; Rosebud O Roberts; David S Knopman; Bradley F Boeve; Yonas E Geda; Robert J Ivnik; Glenn E Smith; Clifford R Jack Journal: Arch Neurol Date: 2009-12