Whole-brain atrophy in multiple sclerosis measured by two segmentation processes from various MRI sequences
Introduction
Cerebral atrophy (CA) occurs at a rate between 0.1% and 0.3% per year as part of the normal ageing process beyond the fourth decade, but is accelerated in several neurological conditions such as multiple sclerosis (MS) and Alzheimer's disease [1]. The loss of tissue within the brain and spinal cord is thought to result from myelin damage and axonal loss, followed by Wallerian degeneration and the loss of extracellular space and vascular compartments. Since CA can be measured serially on MRI scans of the brain, it has been proposed as a means of monitoring the progression of MS [2] and Alzheimer's disease [3].
Numerous MRI studies [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15] have investigated the magnitude of the correlation between brain volume decrease and clinical findings in MS, both cross-sectionally and longitudinally. CA can develop in the early, relapsing–remitting (RR) phase of MS [4], [5], [8], [13], [15]. The degree of tissue loss is, however, greater in patients with more disabling, chronic progressive disease courses [6], [7], [8], [13]. Where putative disease-modifying treatments for MS are available, conventional MRI measures of lesion load have shown limited sensitivity and specificity for monitoring treatment effects. CA assessed from serial brain MRI scans is, therefore, being studied as an additional outcome measure in clinical trials of these treatments.
Atrophy is usually measured from T1-weighted MRI scans, since this gives good contrast between the CSF and the brain parenchyma. However, several MRI pulse sequence types have been proposed or used to measure atrophy, including conventional T1-weighted spin echo (SE) [7], [14], [15], fluid-attenuated inversion recovery (FLAIR) [16], 3D gradient echo (3D) [6], [11] and a method that uses double-echo proton-density/T2-weighted images in a subtraction technique that produces an image with T1-like contrast [17]. The FLAIR sequence has potential benefits since the cerebrospinal fluid (CSF) is greatly suppressed, resulting in a very clear definition of the brain parenchyma. On the other hand, the amount of intracranial CSF is an important indicator of the degree of atrophy, so it may be beneficial to retain some signal from CSF. Whatever the pulse sequence employed, the resulting image must have good contrast between the parenchyma and CSF.
CA can be assessed as a change in the absolute volume of brain parenchyma, or as a change in a normalized index of brain volume such as the brain parenchymal fraction (BPF) [18]. The advantages of the BPF as a measure of atrophy are twofold. First, an assessment of the degree of atrophy of the brain can be obtained in cross-sectional studies by a single measurement, since the normalization procedure takes account of absolute brain size. Secondly, any variation in the calibration of the MRI scanner gradient strengths should have little effect on the BPF; variations in magnetic field gradient strength have confounded previous atrophy studies and should be corrected by normalizing to some other constant dimension, such as those of the skull [19].
The measurement of atrophy can be time consuming when the technique is applied to studies involving many patients. Ideally, any technique should be as automated as possible, so as to minimize the possibility of introducing operator-dependent errors in the measure. A fully automated (FA) technique would remove this source of error altogether and allow scans to be evaluated quickly and inexpensively. However, it is also important to assess the reproducibility of the whole of the data collection and image analysis method, since the pulse sequence used and the analysis procedure are often strongly coupled. This study examines the scan–rescan reproducibility achievable using different T1-weighted pulse sequences with both a fully automated, and a semi-automated (SA) method of analysis. Since this work was commenced, a similar study has recently been published [20]; however, the current work extends this by comparing scan–rescan reproducibility, fully automated vs. semi-automated processing, and a wide range of pulse sequences acquired on two MRI scanners. This latter aspect is especially interesting, since in the context of multi-center clinical trials, it is important to show that finding of reproducibility will generalize to different types of scanner. In order to test the validity and general applicability of the fully automated method, we also applied this technique to a larger cohort of patients whose MRI scans were collected longitudinally as part of a placebo-controlled clinical trial of a disease-modifying agent for MS. The data were collected at baseline and 9 months at 18 centers, using eight different models of MRI scanner and a conventional T1-weighted spin-echo sequence.
Section snippets
MRI scanning
A total of 15 subjects participated into the main part of the study, which was carried out with the approval of the local ethical committees; written informed consent was obtained from all subjects. In order to ensure generalizability of the results, scanning was carried out at two centers: either Neuroimaging Research Unit, University Hospital S. Raffaele (Milan, Italy) (nine subjects, Siemens Vision 1.5T) or Department of Neurology, University at Buffalo, State University of New York (USA)
Results
Table 1 shows the demographic and disease characteristic of the 13 MS patients and 2 healthy controls. For the MS patients, the median age was 38 (range: 27–60) years, median disease duration was 7 (range: 2–13) years and median Expanded Disability Status Scale (EDSS) was 4.5 (range: 2–8).
Fig. 1 shows one slice from the most severely atrophied patient for each of the four sequences. After fully automated processing, visual inspection confirmed successful brain segmentation in all except some of
Discussion
This study examines this issue of reproducibility of measures of cerebral atrophy, how that is influenced by both the type of MRI scan used to measure it, and the type of analysis of those scans. For use in clinical studies and clinical trials of agents designed to reduce CA, a method of estimating CA must be both reproducible and capable of being implemented across multiple MRI scanning centers. In the present study, we studied the influences of the pulse sequence used to collect the image
Conclusions
The aim of this study was to compare the performance of different MRI acquisition pulse sequences when used to acquire data for assessing cerebral atrophy. We compared 2D spin echo, FLAIR, 3D gradient echo and a dual-echo sequence (with echo subtraction). All sequences are capable of yielding good reproducibility, with the differences in test–retest reliability being small. However, the images produced by subtracting early and late echoes in a double-echo T2-weighted sequence are of variable
Acknowledgments
This study was supported in part by research grants to R. Bakshi from the National Institutes of Health (NIH-NINDS 1 K23 NS42379-01) and the National Multiple Sclerosis Society (RG 3258A2/1). The authors thank Teva Pharmaceutical Industries, for allowing us to use the data from the placebo arm of the European–Canadian MRI-monitored Glatiramer Acetate trial. Technical support was provided by Jin Kuwata and Joe Filippini.
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