Assessing Biological and Methodological Aspects of Brain Volume Loss in Multiple Sclerosis

Abstract

IMPORTANCE Before using brain volume loss (BVL) as a marker of therapeutic response in multiple sclerosis (MS), certain biological and methodological issues must be clarified. OBJECTIVES To assess the dynamics of BVL as MS progresses and to evaluate the repeatability and exchangeability of BVL estimates with Jacobian Integration (JI) and Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) (specifically, the Structural Image Evaluation, Using Normalisation, of Atrophy-Cross-Sectional [SIENA-X] tool or FMRIB's Integrated Registration and Segmentation Tool [FIRST]). DESIGN, SETTING, AND PARTICIPANTS A cohort of patients who had either clinically isolated syndrome or MS was enrolled from February 2011 through October 2015. All underwent a series of annual magnetic resonance imaging (MRI) scans. Images from 2 cohorts of healthy volunteers were used to evaluate short-term repeatability of the MRI measurements (n = 34) and annual BVL (n = 20). Data analysis occurred from January to May 2017. MAIN OUTCOMES AND MEASURES The goodness of fit of different models to the dynamics of BVL throughout the MS disease course was assessed. The short-term test-retest error was used as a measure of JI and FSL repeatability. The correlations (R 2) of the changes quantified in the brain using JI and FSL, together with the accuracy of the annual BVL cutoffs to discriminate patients with MS from healthy volunteers, were used to measure compatibility of imaging methods. RESULTS A total of 140 patients with clinically isolated syndrome or MS were enrolled, including 95 women (67.9%); the group had a median (interquartile range) age of 40.7 (33.6-48.1) years. Patients underwent 4 MRI scans with a median (interquartile range) interscan period of 364 (351-379) days. The 34 healthy volunteers (of whom 18 [53%] were women; median [IQR] age, 33.5 [26.2-42.5] years) and 20 healthy volunteers (of whom 10 [50%] were women; median [IQR] age, 33.0 [28.7-39.2] years) underwent 2 MRI scans within a median (IQR) of 24.5 (0.0-74.5) days and 384.5 (366.3-407.8) days for the short-term and long-term MRI follow-up, respectively. The BVL rates were higher in the first 5 years after MS onset (R 2 = 0.65 for whole-brain volume change and R 2 = 0.52 for gray matter volume change) with a direct association with steroids (β = 0.280; P = .02) and an inverse association with age at MS onset, particularly in the first 5 years (β = 0.015; P = .047). The reproducibility of FSL (SIENA) and JI was similar for whole-brain volume loss, while JI gave more precise, less biased estimates for specific brain regions than FSL (SIENA-X and FIRST). The correlation between whole-brain volume loss using JI and FSL was high (R 2 = 0.92), but the same correlations were poor for specific brain regions. The area under curve of the whole-brain volume change to discriminate between patients with MS and healthy volunteers was similar, although the thresholds and accuracy index were distinct for JI and FSL. CONCLUSIONS AND RELEVANCE The proposed BVL threshold of...

MAGNIMS consensus recommendations on the use of brain and spinal cord atrophy measures in clinical practice

“…A change of -0.4% per year has been proposed as the cut off for pathological brain atrophy in MS 24 ( Fig. 1), although care must be taken before applying this threshold as a marker of ther apeutic efficacy owing to the phenomenon of pseudo atrophy (see Brain volume as an outcome measure in randomized clinical trials) 25,26 . Multiple studies have shown that short term changes (over as little as 1 year) in brain volume are predictive of clinical status (diagnosis of MS or disability status) at various follow up times in clinically isolated syndromes 27,28 , relapsing-remitting MS (RRMS) 29 and primary progressive MS [30][31][32] , either in isolation or together with lesion related parameters 33,34 .…”

Retinal and brain damage during multiple sclerosis course: inflammatory activity is a key factor in the first 5 years

“…To quantify brain volumes, we registered T2-fluid-attenuated inversion recovery (FLAIR) images to T1-magnetisation prepared rapid acquisition gradient echo (MPRAGE) scans to ease manual segmentation of the lesions by a trained neurologist (IPV). After lesion in-painting of the T1-MPRAGE scan, we applied a registration-based Jacobian integration algorithm to quantify annual changes in whole brain, grey matter (this metric included cortical and deep gray matter) and thalamic volumes relative to the baseline, according to the methodology described elsewhere 5,17 . In addition, a trained neuro-radiologist quantified the number of gadolinium-enhancing T1 lesions (Gad+) and new/enlarging T2-FLAIR lesions.…”

Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial

“…Chronic T2 lesions with evolving T1 hypointensity may also be considered as a readout for permanent tissue damage accumulation, as well as whole-brain volume loss, where more research is needed to discriminate pathological atrophy from normal aging or noise of the measurement, and determine personalized thresholds of annualized rates of brain volume change. [28][29][30] FIGURE 5: Kaplan-Meier analysis of time to evidence of progression or active disease in the ITT population during the doubleblind controlled period in ORATORIO. Patients are considered as failing NEPAD if one of the following events occurred: protocol-defined relapse, 12-week CDP, 12-week confirmed progression on T25FW or 9HPT, or MRI activity.…”