Gray matter atrophy rate as a marker of disease progression in AD

Abstract

Global gray matter (GM) atrophy rates were quantified from magnetic resonance imaging (MRI) over 6- and 12-month intervals in 37 patients with Alzheimer's disease (AD) and 19 controls using: (1) nonlinear registration and integration of Jacobian values, and (2) segmentation and subtraction of serial GM volumes. Sample sizes required to power treatment trials using global GM atrophy rate as an outcome measure were estimated and compared between the 2 techniques, and to global brain atrophy measures quantified using the boundary shift integral (brain boundary shift integral; BBSI) and structural image evaluation, using normalization, of atrophy (SIENA). Increased GM atrophy rates (approximately 2% per year) were observed in patients compared with controls. Although mean atrophy rates provided by Jacobian integration were smaller than those from segmentation and subtraction of GM volumes, measurement variance was reduced. The number of patients required per treatment arm to detect a 20% reduction in GM atrophy rate over a 12-month follow-up (90% power) was 202 (95% confidence interval [CI], 118-423) using Jacobian integration and 2047 (95% CI 271 to > 10,000) using segmentation and subtraction. Comparable sample sizes for whole brain atrophy were 240 (95% CI, 142-469) using the BBSI and 196 (95% CI, 110-425) using SIENA. Jacobian integration could be useful for measuring GM atrophy rate in Alzheimer's disease as a marker of disease progression and treatment efficacy.

Fig. 1

Example binary gray matter segmentation provided by SPM5 (http://www.fil.ion.ucl.ac.uk/spm/; Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, London, UK), which includes subcortical gray matter structures.

Fig. 2

Gray matter (GM) atrophy rates in Alzheimer's disease (AD) and control subjects. Gray matter atrophy rates (% per year) in patients with Alzheimer's disease and control subjects calculated over intervals of 6 and 12 months using: (1) SPM5 segmentation and subtraction of GM volumes, and (2) nonlinear registration and Jacobian integration over GM regions. Arrows indicate the measurements from 2 subjects (1 control, 1 ad) for whom the segmentation and subtraction estimates of atrophy are markedly outside of the expected range.