Objective
Thalamic volume is a candidate magnetic resonance imaging (MRI)‐based marker associated with neurodegeneration to hasten development of neuroprotective treatments. Our objective is to ...describe the longitudinal evolution of thalamic atrophy in MS and normal aging, and to estimate sample sizes for study design.
Methods
Six hundred one subjects (2,632 MRI scans) were analyzed. Five hundred twenty subjects with relapse‐onset MS (clinically isolated syndrome, n = 90; relapsing–remitting MS, n = 392; secondary progressive MS, n = 38) underwent annual standardized 3T MRI scans for an average of 4.1 years, including a 1mm3 3‐dimensional T1‐weighted sequence (3DT1; 2,485 MRI scans). Eighty‐one healthy controls (HC) were scanned longitudinally on the same scanner using the same protocol (147 MRI scans). 3DT1s were processed using FreeSurfer's longitudinal pipeline after lesion inpainting. Rates of normalized thalamic volume loss in MS and HC were compared in linear mixed effects models. Simulation‐based sample size calculations were performed incorporating the rate of atrophy in HC.
Results
Thalamic volume declined significantly faster in MS subjects compared to HC, with an estimated decline of −0.71% per year (95% confidence interval CI = −0.77% to −0.64%) in MS subjects and −0.28% per year (95% CI = −0.58% to 0.02%) in HC (p for difference = 0.007). The rate of decline was consistent throughout the MS disease duration and across MS clinical subtypes. Eighty or 100 subjects per arm (α = 0.1 or 0.05, respectively) would be needed to detect the maximal effect size with 80% power in a 24‐month study.
Interpretation
Thalamic atrophy occurs early and consistently throughout MS. Preliminary sample size calculations appear feasible, adding to its appeal as an MRI marker associated with neurodegeneration. Ann Neurol 2018;83:223–234
Alemtuzumab is a monoclonal antibody that targets CD52, a protein expressed at high levels on T and B lymphocytes, and at lower levels on other components of the innate immune system.1 Alemtuzumab 12 ...mg per day is administered intravenously over five consecutive days, followed by a second course on three consecutive days 12 months later.1 Alemtuzumab is a potent disease-modifying therapy for the treatment of relapsing-remitting multiple sclerosis,2–4 with efficacy sustained over several years, even in the absence of continued treatment.5,6 However, despite its efficacy, use of alemtuzumab has been restricted by serious and potentially fatal risks,1–4,7 and intense monitoring is required during alemtuzumab administration. All five patients were women (aged 38–49 years), had relapsing-remitting multiple sclerosis with long disease durations (8–21 years), had been exposed to two or more treatments before alemtuzumab, and met 2010 McDonald Criteria.10 We collected detailed information on medical history, concomitant medications, infusion courses and protocols, blood pressure, and intracranial haemorrhage characteristics (appendix). CJA has received consulting fees from Novartis, Sanofi-Genzyme, Biogen Idec, Guerbet LLC, and Genentech; CK has received speaking or consulting fees from Novartis, Sanofi-Genzyme, Teva, Amgen, Biogen Idec, Accorda, and Mallinckrodt, and grants from Sanofi-Genzyme; AD has received personal fees from Biogen, Genzyme, Mallinckrodt, Novartis, Amgen, and Promius; AB has served on advisory boards or served on the speakers' bureau for Biogen Idec, Sanofi-Genzyme, Genentech, Novartis, Medtronic, Neuromodulation, Multiple Sclerosis Association of America, and Peer View; NS has received speaking fees from Genentech and consulting fees from Medtronic; and JK has received speaking fees from Amgen, Allergan, Teva, and Lilly.
Digital Twin (DT) is a novel concept that may bring a paradigm shift for precision medicine. In this study we demonstrate a DT application for estimating the age of onset of disease-specific brain ...atrophy in individuals with multiple sclerosis (MS) using brain MRI. We first augmented longitudinal data from a well-fitted spline model derived from a large cross-sectional normal aging data. Then we compared different mixed spline models through both simulated and real-life data and identified the mixed spline model with the best fit. Using the appropriate covariate structure selected from 52 different candidate structures, we augmented the thalamic atrophy trajectory over the lifespan for each individual MS patient and a corresponding hypothetical twin with normal aging. Theoretically, the age at which the brain atrophy trajectory of an MS patient deviates from the trajectory of their hypothetical healthy twin can be considered as the onset of progressive brain tissue loss. With a tenfold cross validation procedure through 1000 bootstrapping samples, we found the onset age of progressive brain tissue loss was, on average, 5-6 years prior to clinical symptom onset. Our novel approach also discovered two clear patterns of patient clusters: earlier onset versus simultaneous onset of brain atrophy.
Objective
The aim of this work was to evaluate the preprogressive phase in subjects with radiologically isolated syndrome (RIS) who evolve to primary progressive multiple sclerosis (PPMS).
Methods
A ...multicenter RIS cohort was previously established. Demographic, clinical, and radiological characteristics of subjects with RIS that evolved directly to PPMS were compared to those that developed a relapsing disease course from onset (clinically isolated syndrome CIS or relapsing‐remitting MS) and were also compared to two other population‐ and clinic‐based PPMS cohorts.
Results
Of the 453 subjects with RIS, 128 evolved to symptomatic MS during the follow‐up (113 developed a first acute clinical event consistent with CIS/MS, 15 evolved to PPMS). PPMS prevalence (11.7%) and onset age (mean ± standard deviation; 49.1 ± 12.1) in the RIS group were comparable to other PPMS populations (p > 0.05). Median time to PPMS was 3.5 years (range, 1.6–5.4). RIS evolved to PPMS more commonly in men (p = 0.005) and at an older age (p < 0.001) when compared to CIS/MS, independent of follow‐up duration. Subjects who evolved to PPMS had more spinal cord lesions (100%) before symptomatic evolution than those that developed CIS/MS (64%) and those that remained asymptomatic (23%) within the follow‐up period (P = 0.005). Other MRI characteristics in the preprogressive phase of PPMS were indistinguishable from CIS/MS.
Interpretation
Subjects with RIS evolve to PPMS at the same frequency as expected from general MS populations in an age‐dependent manner. Besides age, unequivocal presence of spinal cord lesions and being male predicted evolution to PPMS. Our findings further suggest that RIS is biologically part of the MS spectrum. Ann Neurol 2016;79:288–294
The article provides an overview of the importance of whole-brain atrophy in multiple sclerosis (MS) and proposes steps that would be necessary prior to incorporating whole-brain volume measurements ...into routine clinical practice.
Whole-brain atrophy is clinically relevant, present early in the disease, and measureable in a reproducible manner using MRI. Several of the currently available approved disease-modifying therapies can slow the rate of whole-brain atrophy at the group level. As such, clinicians may want to use whole-brain volume measurements for clinical decision-making.
Despite its relevance and face validity, several steps must be taken before whole-brain volume measurements are ready to be incorporated into clinical practice, including the adoption of a standardized MRI protocol for MS, the establishment of a gold-standard image postprocessing software to measure whole-brain volume, and the development of specific statistical methods to translate whole-brain volume measurements into clinically relevant metrics at the individual level. As neurodegeneration becomes the focus of MS research worldwide and the likely target of the next generation of disease-modifying therapies, MRI metrics associated with neurodegeneration will be critically important to monitor disease progression and treatment response at the group and individual levels.
To determine whether body mass index (BMI) or vitamin D status is associated with MRI measures of neurodegeneration in a cohort of individuals with relapsing-remitting multiple sclerosis (RRMS) or ...clinically isolated syndrome (CIS).
Expression, Proteomics, Imaging, Clinical (EPIC) is a longitudinal multiple sclerosis (MS) cohort study at the University of California, San Francisco. Participants had clinical evaluations, brain MRI, and blood draws annually. We evaluated patients with CIS or RRMS at baseline. In multivariate repeated-measures analyses adjusted for age, sex, ethnicity, smoking status, and use of MS treatments, annual 25-hydroxyvitamin D levels and BMI were evaluated for their association with subsequent brain volumes (normalized gray matter nGMV, brain parenchymal nBPV, and white matter volumes, as determined by Structural Image Evaluation using Normalization of Atrophy-X).
Among 469 participants, each 1-kg/m
higher BMI was independently associated with reduced nGMV in multivariate models (-1.1 mL, 95% confidence interval CI -1.8 to -0.5,
= 0.001). BMI was likewise independently associated with nBPV (nBPV per 1-kg/m
greater BMI: -1.1 mL, 95% CI -2.1 to -0.05,
= 0.039). Vitamin D levels did not appear to be meaningfully associated with brain volumes.
Higher BMI appears to be associated with greater reductions in nGMV and nBPV, which is relevant because, in particular, nGMV loss portends greater longer-term disability. Because obesity is modifiable, further studies should explore these relationships in detail, and evaluating the effect of reducing BMI on imaging and clinical outcomes in MS may be warranted.
Radiologically isolated syndrome (RIS), in which asymptomatic demyelinating-appearing lesions are detected incidentally on MRI, can be a pre-clinical form of multiple sclerosis (MS). In this study, ...we measured cerebellar volumes on 3D T1-weighted 3T MR images in 21 individuals with RIS and 38 age- and sex-matched healthy controls (HC). Normalized cerebellar white matter volume and the anterior cerebellar gray matter volume were significantly decreased in RIS compared to HC (p = 0.003 and p = 0.005, respectively). Our findings support reports of regional brain atrophy in RIS prior to the development of a seminal attack related to inflammatory demyelination.
Individuals can be deemed to have radiologically isolated syndrome (RIS) if they have incidental demyelinating-appearing lesions in their brain or spinal cord that are highly suggestive of multiple ...sclerosis but their clinical history does not include symptoms consistent with multiple sclerosis. Data from international longitudinal cohorts indicate that around half of people with RIS will develop relapsing or progressive symptoms of multiple sclerosis within 10 years, suggesting that in some individuals, RIS is a presymptomatic stage of multiple sclerosis. Risk factors for progression from RIS to clinical multiple sclerosis include younger age (ie, <35 years), male sex, CSF-restricted oligoclonal bands, spinal cord or infratentorial lesions, and gadolinium-enhancing lesions. Other imaging, biological, genetic, and digital biomarkers that might be of value in identifying individuals who are at the highest risk of developing multiple sclerosis need further investigation. Two 2-year randomised clinical trials showed the efficacy of approved multiple sclerosis immunomodulatory medications in preventing the clinical conversion to multiple sclerosis in some individuals with RIS. If substantiated in longer-term studies, these data have the potential to transform our approach to care for the people with RIS who are at the greatest risk of diagnosis with multiple sclerosis.
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