Svetlana Egorova

BACKGROUND AND PURPOSE: Enlarged perivascular spaces (EPVSs) have been associated with relapses and brain atrophy in multiple sclerosis (MS). We investigated the association of EPVS with clinical and MRI features of disease worsening in a well‐characterized cohort of relapsing‐remitting MS patients prospectively followed for up to 10 years.METHODS: Baseline EPVSs were scored on 1.5T MRI in 30 converters to moderate‐severe disability, and 30 nonconverters matched for baseline characteristics.RESULTS: EPVS scores were not significantly different between converters and nonconverters, nor associated with accrual of lesions or brain atrophy.CONCLUSIONS: Our preliminary findings from a relatively small study sample argue against a potential use of EPVS as early indicator of risk for disease worsening in relapsing‐remitting MS patients in a clinical setting. Although the small sample size and clinical 1.5T MRI may have limited our ability to detect a significant effect, we provided estimates of the association of EPVS with clinical and MRI indicators of disease worsening in a well‐characterized cohort of MS patients.

BACKGROUND AND PURPOSE: Two common approaches for measuring disease severity in multiple sclerosis (MS) are the clinical exam and brain magnetic resonance imaging (MRI) scan. Although most patients show similar disease severity on both measures, some patients have clinical/MRI dissociation.METHODS: Subjects from a comprehensive care MS center who had a concurrent brain MRI, spinal cord MRI, clinical examination, and patient reported outcomes were classified into three groups based on the Expanded Disability Status Scale (EDSS) and cerebral T2 hyperintense lesion volume (T2LV). The first group was the low lesion load/high disability group (LL/HD) with T2LV < 2 ml and EDSS ≥ 3. The second group was the high lesion load/low disability group (HL/LD) with T2LV > 6 ml and EDSS ≤ 1.5. All remaining subjects were classified as not dissociated. The three groups were compared using regression techniques for unadjusted analyses and to adjust for age, disease duration, and gender.RESULTS: Twenty‐two subjects were classified as LL/HD (4.1%; 95% CI: 2.6%, 6.2%), and 50 subjects were classified as HL/LD (9.4%; 95% CI: 7.0%, 12.2%). Subjects in the LL/HD group were more likely to have a progressive form of MS and had significantly lower physical quality of life in adjusted and unadjusted analysis. Subjects in HL/LD had significantly more gadolinium‐enhancing lesions, and subjects in the LL/HD group had significantly more cervical spinal cord lesions.CONCLUSIONS: Our results indicate that dissociation may occur between physical disability and cerebral lesion volume in either direction in patients with MS. Type of MS, brain atrophy, and spinal cord lesions may help to bridge this dissociation.

It is unclear whether fatigue is a consequence or a predictive trait of disease worsening. To investigate the predictive value of fatigue toward conversion to confirmed moderate–severe disability in patients with relapsing-remitting multiple sclerosis (RRMS). We retrospectively selected from the Comprehensive Longitudinal Investigations in MS at the Brigham and Women’s Hospital (CLIMB) study cohort RRMS patients who converted to confirmed (⩾2 years) Expanded Disability Status Scale (EDSS) score ⩾3 within a follow-up period ⩾3 years. We contrasted the Modified Fatigue Impact Scale (MFIS) score of 33 converters, obtained at least 1 year before conversion to EDSS ⩾3, with that of 33 non-converter RRMS patients matched for baseline characteristics. Total MFIS score was higher in converter versus non-converter MS patients (median 37 vs 13; p < 0.0001). EDSS and Center for Epidemiological Studies Depression scale (CES-D) scores were also higher in the converters (median EDSS 1.5 vs 0, p < 0.0001; median CES-D 30 vs 24, p < 0.0001) and were both associated with MFIS score (EDSS: rho = 0.42, p = 0.0005; CES-D: rho = 0.72, p < 0.0001). After adjusting for EDSS and CES-D in multivariate analysis, MFIS remained a significant predictor of subsequent conversion to confirmed EDSS ⩾3. Fatigue is a promising indicator of risk for conversion to confirmed moderate–severe disability in RRMS patients.

Background: Osteopontin (OPN) is a pleiotropic protein with important roles in inflammation and immunity that has been suggested as a candidate biomarker for disease activity in multiple sclerosis (MS). Objective: We evaluated plasma levels of OPN in an unselected cohort of MS patients, to determine its potential as a biomarker for disease subtype and/or disease activity in a regular clinical setting. Methods: We analyzed OPN plasma levels in 492 consecutive MS patients, using a commercial enzyme-linked immunosorbent assay (ELISA). Results: OPN levels were higher in relapsing–remitting and secondary progressive MS, compared to healthy controls. Treatment with natalizumab or glatiramer acetate was associated with lower OPN levels. There was no significant association between the OPN levels and disease activity, as measured by clinical or radiological criteria. One-third of patients with high OPN levels had concurrent disorders that may also be associated with increased OPN expression, and which may mask a modest effect of MS disease activity on OPN levels. Conclusion: Our data do not support a role for circulating OPN levels as a biomarker for disease activity in a heterogeneous clinical setting, but does not rule out a potential role in the cerebrospinal fluid, in a controlled setting such as a clinical trial, or in concert with other biomarkers.

Objective: MicroRNAs (miRNAs) are single‐stranded, small noncoding RNAs that regulate gene expression. Because they are stable in serum, they are being developed as biomarkers for cancer and other diseases. In multiple sclerosis (MS), miRNAs have been studied in cell populations but not in the circulation. In MS, a major challenge is to develop immune biomarkers to monitor disease. We asked whether circulating miRNAs could be identified in MS and whether they are linked to disease stage and/or disability.Methods: A total of 368 miRNAs were measured in ethylenediaminetetraacetic acid plasma in 10 relapsing–remitting MS (RRMS) patients, 9 secondary progressive MS (SPMS) patients, and 9 healthy controls (HCs) using miRCURY LNA™ Universal RT microRNA polymerase chain reaction panels. Nineteen miRNAs from this discovery set were validated using qPCR on an independent set of 50 RRMS patients, 51 SPMS patients, and 32 HCs.Results: We found that circulating miRNAs are differentially expressed in RRMS and SPMS versus HCs and in RRMS versus SPMS. We also found miRNAs to be linked to Expanded Disability Status Scale (EDSS). hsa‐miR‐92a‐1* was identified in the largest number of comparisons. It was different in RRMS versus SPMS, and RRMS versus HCs, and showed an association with EDSS and disease duration. miR‐92 has target genes involved in cell cycle regulation and cell signaling. The let‐7 family of miRNAs differentiated SPMS from HCs and RRMS from SPMS. let‐7 miRNAs regulate stem cell differentiation and T cell activation, activate Toll‐like receptor 7, and are linked to neurodegeneration. hsa‐miR‐454 differentiated RRMS from SPMS, and hsa‐miR‐145 differentiated RRMS from HCs and RRMS from SPMS. Interestingly, the same circulating miRNAs (let‐7 and miR‐92) that were differentially expressed in RRMS versus SPMS also differentiated amyotrophic lateral sclerosis (ALS) from RRMS subjects, but were not different between SPMS and ALS, suggesting that similar processes may occur in SPMS and ALS.Interpretation: Our results establish circulating miRNAs as a readily accessible blood biomarker to monitor disease in MS. ANN NEUROL 2013;73:729–740