10.1177/1051228404266264 Journal of Neuroimaging Vol 14 No 3(Supplement) July 2004 Pelletier et al: Brain Atrophy in MS Measurement of Whole-Brain Atrophy in Multiple Sclerosis Daniel Pelletier, MD Kathleen Garrison, MSc Roland Henry, PhD ABSTRACT Brain atrophy reflects the net result of irreversible and destruc- tive pathological processes in multiple sclerosis (MS). The gross morphological changes can be accurately quantified using standard magnetic resonance imaging (MRI) acquisitions and various image analysis tools. The current methods used to assess whole-brain atrophy in patients with MS can be classi- fied into 2 groups based on their reliance on segmentation and registration. Segmentation-based methods employed to mea- sure whole-brain atrophy in MS include the brain parenchymal fraction, the index of brain atrophy, the whole-brain ratio, the brain to intracranial capacity ratio, fuzzy connectedness/ Udupa’s method, 3DVIEWNIX, the Alfano method, and SIENAX. Current registration-based methods used to measure whole- brain atrophy in MS include the brain boundary shift integral, SIENA, statistical parametric mapping, template-driven seg- mentation, and voxel-based morphometry. Most of the meth- ods presented here are sensitive to subtle changes in brain structures and have been successfully applied to MS as mea- sures of whole-brain atrophy. Yet comparative studies of these methods are limited and are complicated by the lack of a gold standard for image acquisition, a segmentation algorithm, an image analysis method, or a reproducibility measure. Overall, the measure of whole-brain atrophy from MRI contributes to an appreciation of the dynamics of MS pathology and its relation- ship to the clinical course of MS. Determination of the relative reproducibility, precision, sensitivity, and validity of these meth- ods will promote the use of whole-brain atrophy measures as components of comprehensive MRI-based outcome assessment in MS clinical trials. Key words: Multiple sclerosis, brain atrophy, magnetic reso- nance imaging (MRI) techniques. Pelletier D, Garrison K, Henry R. Measurement of whole-brain atrophy in multiple sclerosis. J Neuroimaging 2004;14:11S-19S. DOI: 10.1177/1051228404266264 Brain atrophy reflects the net result of irreversible and destructive pathological processes in multiple sclerosis (MS). Axonal damage and loss, chronic demyelination, and gliosis all contribute to a reduction in brain parenchymal tissue volume and a corresponding expan- sion of cerebrospinal fluid (CSF) spaces. These gross changes in morphology can be accurately quantified using standard magnetic resonance imaging (MRI) acqui- sitions and various image analysis tools. Because brain volume changes over time are small, accurate calculation of whole-brain atrophy requires a highly reproducible measurement, and MRI can detect subtle changes in brain structure. Conventional MRI sequences can be used to estimate brain tissue volumes and areas, which are then used to quantify whole-brain atrophy in cross- sectional or longitudinal value comparisons. Measure- ment of whole-brain atrophy using MRI has emerged as an objective and reliable marker of disease progression in patients with MS and as a potential outcome measure in clinical trials of treatments for MS. Although the optimal method for quantifying whole-brain atrophy in MS has not yet been established, this article reviews the current approaches and considerations in the measurement of whole-brain atrophy. A summary of the specific methods discussed in this article is provided in Table 1. Methodological Concepts The quantification of brain tissue volume is the basic con- cept underlying all methods for the measurement of brain atrophy from MRI. Although several different methods are available, a few fundamental concepts and techniques serve as the defining characteristics of atrophy assessment methods. These concepts are described below and in- clude normalization, automation, and registration. Normalization An important distinction among volumetric measure- ments of whole-brain atrophy is whether brain size is re- ported as actual volume or as normalized volume. In Copyright © 2004 by the American Society of Neuroimaging 11S Received March 1, 2004. Accepted for publication March 30, 2004. From the Multiple Sclerosis Center, University of Califor- nia San Francisco. Address correspondence to Dr Daniel Pelletier, UCSF Multiple Sclerosis Center, 350 Parnassus Avenue, Suite 908, San Francisco, CA 94117. E-mail: danp@ itsa.ucsf.edu.