The accepted standard treatment of relapsing multiple sclerosis consists of medications for disease symptoms, including treatment for acute exacerbations. However, currently there is no therapy that alters the progression of physical disability associated with this disease. The purpose of this study was to determine whether interferon beta-1a could slow the progressive, irreversible, neurological disability of relapsing multiple sclerosis. Three hundred one patients with relapsing multiple sclerosis were randomized into a double-blinded, placebo-controlled, multicenter phase III trial of interferon beta-1a. Interferon beta-1a, 6.0 million units (30 micrograms¿, was administered by intramuscular injection weekly. The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Expanded Disability Status Scale (EDSS). Interferon beta-1a treatment produced a significant delay in time to sustained EDSS progression (p = 0.02). The Kaplan-Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9% in the placebo group and 21.9% in the interferon beta-1a-treated group. Patients treated with interferon beta-1a also had significantly fewer exacerbations (p = 0.03) and a significantly lower number and volume of gadolinium-enhanced brain lesions on magnetic resonance images (p-values ranging between 0.02 and 0.05). Over 2 years, the annual exacerbation rate was 0.90 in placebo-treated patients versus 0.61 in interferon beta-1a-treated patients. There were no major adverse events related to treatment. Interferon beta-1a had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity measured by gadolinium-enhanced lesions on brain magnetic resonance images. This treatment may alter the fundamental course of relapsing multiple sclerosis.

Initiating treatment with interferon beta-1a at the time of a first demyelinating event is beneficial for patients with brain lesions on MRI that indicate a high risk of clinically definite multiple sclerosis.

Objective: We used ultra-high field MRI to visualize cortical lesion types described by neuropathology in 16 patients with multiple sclerosis (MS) compared with 8 age-matched controls; to characterize the contrast properties of cortical lesions including T2*, T2, T1, and phase images; and to investigate the relationship between cortical lesion types and clinical data. Methods:We collected, on a 7-T scanner, 2-dimensional fast low-angle shot (FLASH)-T2*-weighted spoiled gradient-echo, T2-weighted turbo spin-echo (TSE) images (0.33 ϫ 033 ϫ 1 mm 3 ), and a 3-dimensional magnetization-prepared rapid gradient echo.Results: Overall, 199 cortical lesions were detected in patients on both FLASH-T2* and T2-TSE scans. Seven-tesla MRI allowed for characterization of cortical plaques into type I (leukocortical), type II (intracortical), and type III/IV (subpial extending partly or completely through the cortical width) lesions as described histopathologically. Types III and IV were the most frequent type of cortical plaques (50.2%), followed by type I (36.2%) and type II (13.6%) lesions. Each lesion type was more frequent in secondary progressive than in relapsing-remitting MS. This difference, however, was significant only for type III/IV lesions. T2*-weighted images showed the highest, while phase images showed the lowest, contrast-to-noise ratio for all cortical lesion types. In patients, the number of type III/IV lesions was associated with greater disability (p Ͻ 0.02 by Spearman test) and older age (p Ͻ 0.04 by Spearman test).Conclusions: Seven-tesla MRI detected different histologic cortical lesion types in our small multiple sclerosis (MS) sample, suggesting, if validated in a larger population, that it may prove a valuable tool to assess the contribution of cortical MS pathology to clinical disability. GLOSSARY ANOVA ϭ analysis of variance; BN ϭ background noise; CNR ϭ contrast-to-noise ratio; DIR ϭ double-inversion recovery; EDSS ϭ Expanded Disability Status Scale; FLAIR ϭ fluid-attenuated inversion recovery; FLASH ϭ fast low-angle shot; GM ϭ gray matter; MPRAGE ϭ magnetization-prepared rapid gradient echo; MR ϭ magnetic resonance; MS ϭ multiple sclerosis; NACGM ϭ normal-appearing cortical gray matter; RF ϭ radiofrequency; ROI ϭ region of interest; RRMS ϭ relapsingremitting multiple sclerosis; SNR ϭ signal-to-noise ratio; SPMS ϭ secondary progressive multiple sclerosis; TA ϭ time of acquisition; TE ϭ echo time; TR ϭ repetition time; TSE ϭ turbo spin-echo; WM ϭ white matter.Although cortical lesions were identified as a common finding in multiple sclerosis (MS) from the earliest pathologic studies, 1-3 their significance was underestimated until recent histopathologic data revealed that they constitute a substantial proportion of the total brain MS lesion load. 4,5 The ability of standard field strength scanners (1.5 T, 3 T) to detect and characterize cortical MS pathology is still significantly lower than neuropathology.6 Ultra-high field systems (7 T to 9.4 T) allow a 2-to 3-fold improvement in image sign...

Objective In multiple sclerosis (MS), using simultaneous magnetic resonance-positron emission tomography (MR-PET) imaging with 11C-PBR28, we quantified expression of the 18kDa translocator protein (TSPO), a marker of activated microglia/macrophages, in cortex, cortical lesions, deep gray matter (GM), white matter (WM) lesions and normal-appearing WM (NAWM) to investigate the in vivo pathological and clinical relevance of neuroinflammation. Methods Fifteen secondary-progressive MS (SPMS) and 12 relapsing-remitting MS (RRMS) cases, and 14 matched healthy controls underwent 11C-PBR28 MR-PET. MS subjects underwent 7 Tesla T2*-weighted imaging for cortical lesions segmentation; neurological and cognitive evaluation. 11C-PBR28 binding was measured using normalized 60-90-minutes standardized uptake values and volume of distribution ratios. Results Relative to controls, MS subjects exhibited abnormally high 11C-PBR28 binding across the brain, the greatest increases being in cortex and cortical lesions, thalamus, hippocampus, and NAWM. MS WM lesions showed relatively modest TSPO increases. With the exception of cortical lesions, where TSPO expression was similar, 11C-PBR28 uptake across the brain was greater in SPMS than in RRMS. In MS, increased 11C-PBR28 binding in cortex, deep GM, and NAWM correlated with neurological disability and impaired cognitive performance; cortical thinning correlated with increased thalamic TSPO levels. Interpretation In MS, neuroinflammation is present in the cortex, cortical lesions, deep GM, and NAWM, and closely linked to poor clinical outcome and, at least partly, to neurodegeneration. Distinct inflammatory-mediated factors may underlie accumulation of cortical and WM lesions. Quantification of TSPO levels in MS could prove a sensitive tool for evaluating in vivo the inflammatory component of GM pathology, particularly in cortical lesions.

We used a surface-based analysis of T2* relaxation rates at 7 T magnetic resonance imaging, which allows sampling quantitative T2* throughout the cortical width, to map in vivo the spatial distribution of intracortical pathology in multiple sclerosis. Ultra-high resolution quantitative T2* maps were obtained in 10 subjects with clinically isolated syndrome/early multiple sclerosis (≤ 3 years disease duration), 18 subjects with relapsing-remitting multiple sclerosis (≥ 4 years disease duration), 13 subjects with secondary progressive multiple sclerosis, and in 17 age-matched healthy controls. Quantitative T2* maps were registered to anatomical cortical surfaces for sampling T2* at 25%, 50% and 75% depth from the pial surface. Differences in laminar quantitative T2* between each patient group and controls were assessed using general linear model (P < 0.05 corrected for multiple comparisons). In all 41 multiple sclerosis cases, we tested for associations between laminar quantitative T2*, neurological disability, Multiple Sclerosis Severity Score, cortical thickness, and white matter lesions. In patients, we measured, T2* in intracortical lesions and in the intracortical portion of leukocortical lesions visually detected on 7 T scans. Cortical lesional T2* was compared with patients' normal-appearing cortical grey matter T2* (paired t-test) and with mean cortical T2* in controls (linear regression using age as nuisance factor). Subjects with multiple sclerosis exhibited relative to controls, independent from cortical thickness, significantly increased T2*, consistent with cortical myelin and iron loss. In early disease, T2* changes were focal and mainly confined at 25% depth, and in cortical sulci. In later disease stages T2* changes involved deeper cortical laminae, multiple cortical areas and gyri. In patients, T2* in intracortical and leukocortical lesions was increased compared with normal-appearing cortical grey matter (P < 10(-10) and P < 10(-7)), and mean cortical T2* in controls (P < 10(-5) and P < 10(-6)). In secondary progressive multiple sclerosis, T2* in normal-appearing cortical grey matter was significantly increased relative to controls (P < 0.001). Laminar T2* changes may, thus, result from cortical pathology within and outside focal cortical lesions. Neurological disability and Multiple Sclerosis Severity Score correlated each with the degree of laminar quantitative T2* changes, independently from white matter lesions, the greatest association being at 25% depth, while they did not correlate with cortical thickness and volume. These findings demonstrate a gradient in the expression of cortical pathology throughout stages of multiple sclerosis, which was associated with worse disability and provides in vivo evidence for the existence of a cortical pathological process driven from the pial surface.