MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD.
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.
Jack
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CR
Department of Diagnostic Radiology, Mayo Clinic and Foundation, Rochester, MN, USA. jack.clifford@mayo.edu
Slomkowski
M
M
Gracon
S
S
Hoover
T M
TM
Felmlee
J P
JP
Stewart
K
K
Xu
Y
Y
Shiung
M
M
O'Brien
P C
PC
Cha
R
R
Knopman
D
D
Petersen
R C
RC
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
D015415:Biomarkers; D004095:Dihydropyridines; D018721:Muscarinic Agonists; D018696:Neuroprotective Agents; D010091:Oximes; C084978:milameline