Treatment reduces the incidence of newly appearing multiple sclerosis lesions evolving into chronic active, slowly expanding lesions: A retrospective analysis.

BACKGROUND AND PURPOSE: Newly appearing lesions in multiple sclerosis (MS) may evolve into chronically active, slowly expanding lesions (SELs), leading to sustained disability progression. The aim of this study was to evaluate the incidence of newly appearing lesions developing into SELs, and their correlation to clinical evolution and treatment. METHODS: A retrospective analysis of a fingolimod trial in primary progressive MS (PPMS; INFORMS, NCT00731692) was undertaken. Data were available from 324 patients with magnetic resonance imaging scans up to 3 years after screening. New lesions at year 1 were identified with convolutional neural networks, and SELs obtained through a deformation-based method. Clinical disability was assessed annually by Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test, Timed 25-Foot Walk, and Paced Auditory Serial Addition Test. Linear, logistic, and mixed-effect models were used to assess the relationship between the Jacobian expansion in new lesions and SELs, disability scores, and treatment status. RESULTS: One hundred seventy patients had ≥1 new lesions at year 1 and had a higher lesion count at screening compared to patients with no new lesions (median = 27 vs. 22, p = 0.007). Among the new lesions (median = 2 per patient), 37% evolved into definite or possible SELs. Higher SEL volume and count were associated with EDSS worsening and confirmed disability progression. Treated patients had lower volume and count of definite SELs (ß = -0.04, 95% confidence interval [CI] = -0.07 to -0.01, p = 0.015; ß = -0.36, 95% CI = -0.67 to -0.06, p = 0.019, respectively). CONCLUSIONS: Incident chronic active lesions are common in PPMS, and fingolimod treatment can reduce their number.

Cardiovascular risk factors in secondary progressive multiple sclerosis: A cross-sectional analysis from the MS-STAT2 randomized controlled trial.

BACKGROUND AND PURPOSE: There is increasing evidence that cardiovascular risk (CVR) contributes to disability progression in multiple sclerosis (MS). CVR is particularly prevalent in secondary progressive MS (SPMS) and can be quantified through validated composite CVR scores. The aim was to examine the cross-sectional relationships between excess modifiable CVR, whole and regional brain atrophy on magnetic resonance imaging, and disability in patients with SPMS. METHODS: Participants had SPMS, and data were collected at enrolment into the MS-STAT2 trial. Composite CVR scores were calculated using the QRISK3 software. Prematurely achieved CVR due to modifiable risk factors was expressed as QRISK3 premature CVR, derived through reference to the normative QRISK3 dataset and expressed in years. Associations were determined with multiple linear regressions. RESULTS: For the 218 participants, mean age was 54 years and median Expanded Disability Status Scale was 6.0. Each additional year of prematurely achieved CVR was associated with a 2.7 mL (beta coefficient; 95% confidence interval 0.8-4.7; p = 0.006) smaller normalized whole brain volume. The strongest relationship was seen for the cortical grey matter (beta coefficient 1.6 mL per year; 95% confidence interval 0.5-2.7; p = 0.003), and associations were also found with poorer verbal working memory performance. Body mass index demonstrated the strongest relationships with normalized brain volumes, whilst serum lipid ratios demonstrated strong relationships with verbal and visuospatial working memory performance. CONCLUSIONS: Prematurely achieved CVR is associated with lower normalized brain volumes in SPMS. Future longitudinal analyses of this clinical trial dataset will be important to determine whether CVR predicts future disease worsening.

Investigating the relationship between thalamic iron concentration and disease severity in secondary progressive multiple sclerosis using quantitative susceptibility mapping: Cross-sectional analysis from the MS-STAT2 randomised controlled trial.

Background: Deep grey matter pathology is a key driver of disability worsening in people with multiple sclerosis. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique which quantifies local magnetic susceptibility from variations in phase produced by changes in the local magnetic field. In the deep grey matter, susceptibility has previously been validated against tissue iron concentration. However, it currently remains unknown whether susceptibility is abnormal in older progressive MS cohorts, and whether it correlates with disability. Objectives: To investigate differences in mean regional susceptibility in deep grey matter between people with secondary progressive multiple sclerosis (SPMS) and healthy controls; to examine in patients the relationships between deep grey matter susceptibility and clinical and imaging measures of disease severity. Methods: Baseline data from a subgroup of the MS-STAT2 trial (simvastatin vs. placebo in SPMS, NCT03387670) were included. The subgroup underwent clinical assessments and an advanced MRI protocol at 3T. A cohort of age-matched healthy controls underwent the same MRI protocol. Susceptibility maps were reconstructed using a robust QSM pipeline from multi-echo 3D gradient-echo sequence. Regions of interest (ROIs) in the thalamus, globus pallidus and putamen were segmented from 3D T1-weighted images, and lesions segmented from 3D fluid-attenuated inversion recovery images. Linear regression was used to compare susceptibility from ROIs between patients and controls, adjusting for age and sex. Where significant differences were found, we further examined the associations between ROI susceptibility and clinical and imaging measures of MS severity. Results: 149 SPMS (77% female; mean age: 53 yrs; median Expanded Disability Status Scale (EDSS): 6.0 [interquartile range 4.5-6.0]) and 33 controls (52% female, mean age: 57) were included.Thalamic susceptibility was significantly lower in SPMS compared to controls: mean (SD) 28.6 (12.8) parts per billion (ppb) in SPMS vs. 39.2 (12.7) ppb in controls; regression coefficient: -12.0 [95% confidence interval: -17.0 to -7.1], p < 0.001. In contrast, globus pallidus and putamen susceptibility were similar between both groups.In SPMS, a 10 ppb lower thalamic susceptibility was associated with a +0.13 [+0.01 to +0.24] point higher EDSS (p < 0.05), a -2.4 [-3.8 to -1.0] point lower symbol digit modality test (SDMT, p = 0.001), and a -2.4 [-3.7 to -1.1] point lower Sloan low contrast acuity, 2.5% (p < 0.01).Lower thalamic susceptibility was also strongly associated with a higher T2 lesion volume (T2LV, p < 0.001) and lower normalised whole brain, deep grey matter and thalamic volumes (all p < 0.001). Conclusions: The reduced thalamic susceptibility found in SPMS compared to controls suggests that thalamic iron concentrations are lower at this advanced stage of the disease. The observed relationships between lower thalamic susceptibility and more severe physical, cognitive and visual disability suggests that reductions in thalamic iron may correlate with important mechanisms of clinical disease progression. Such mechanisms appear to intimately link reductions in thalamic iron with higher T2LV and the development of thalamic atrophy, encouraging further research into QSM-derived thalamic susceptibility as a biomarker of disease severity in SPMS.