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.

Highlights

  • Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline

  • We compared these measurements both to each other and to 2 whole brain atrophy measures that are currently utilized in clinical trials in AD, namely the BBSI and SIENA

  • We found evidence that gray matter (GM) atrophy is greater in patients with AD compared with controls (ϳ4 times greater) over intervals as short as 6 months

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Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline. Gray matter (GM) may lose volume earlier in AD than white matter (WM) (Serra, et al, 2010; Tanabe et al, 1997), and GM loss has been shown to be associated with ongoing pathological and clinical progression of the disease (Whitwell et al, 2008; de Jong et al, 2008; Mouton et al, 1998; Serra et al, 2010), and may be a more sensitive marker of AD pathology than whole brain atrophy. Optimizing the power of outcome measures for clinical trials is important, as the number of subjects required to show a therapeutic effect on progression may be reduced, thereby leading to more efficient trials and exposing fewer

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