Role of inflammatory monocytes in adolescent metabolic syndrome

Metabolic syndrome (MetSyn) is a cluster of risk factors for cardiovascular disease and diabetes that affects 1 in 3 obese children. Inflammatory cytokines secreted from macrophages are thought to be partly responsible for the metabolic abnormalities associated with MetSyn. This study aimed to determine whether peripheral blood monocytes (macrophage precursors) from overweight individuals with MetSyn (Overwt-MetSyn) demonstrate enhanced activation of inflammatory signaling pathways when compared to metabolically normal overweight (Overwt-Healthy) or lean individuals. We conducted a cross sectional pilot study involving 24 adolescents (six boys and eighteen girls) recruited from the University of Massachusetts Boston and Worcester campuses. Six subjects were classified as Overwt-MetSyn using a modified definition proposed by the International Diabetes Federation. The Overwt-MetSyn group demonstrated an elevated expression of TLR2 and TLR4 in peripheral monocytes, and increased circulating levels of TNFa and IL6. Expression of TLR2 and TLR4 showed a positive correlation with circulating cytokines, and expression of TNFa correlated with waist circumference and BMI. Metabolic syndrome in adolescents is associated with increased activation of the TLR signaling pathway in monocytes. The knowledge gained from this study will advance our understanding of the contribution of monocytes to the pathophysiology of MetSyn

Association between early treatment of multiple sclerosis and patient-reported outcomes: a nationwide observational cohort study

Background Timing of disease-modifying therapy affects clinical disability in multiple sclerosis, but it is not known whether patient reported outcomes are also affected. This study investigates the relationship between treatment timing and patient-reported symptoms and health-related quality of life. Methods This was a nationwide observational cohort study of adults with relapsing multiple sclerosis, with disease onset between 2001 and 2016, and commenced on disease-modifying treatment within 4 years from disease onset. Patients commencing treatment within 0–2 years were compared with patients commencing treatment at 2–4 years. Indication bias was mitigated by propensity matching. Outcomes were patient-reported symptoms and health-related quality of life as measured by the Multiple Sclerosis Impact Scale (MSIS-29) and EuroQol-5 Dimensions-3 Level (EQ-5D). The follow-up period was 4–10 years from disease onset. Results There were 2648 patients (69% female, median age 32.8) eligible for matching. Mean follow-up time was 3.7 years. Based on 780 matched patients, each year of treatment delay was associated with a worse MSIS physical score by 2.75 points (95% CI 1.29 to 4.20), and worse MSIS psychological score by 2.02 points (95% CI 0.03 to 3.78), in the adjusted models. Among 690 matched patients, earlier treatment start was not associated with EQ-5D score during the follow-up. Conclusions Earlier commencement of disease-modifying treatment was associated with better patient-reported physical symptoms when measured using a disease-specific metric; however, general quality of life was not affected. This indicates that other factors may inform patients’ overall quality of life

Slowly expanding lesions relate to persisting black-holes and clinical outcomes in relapse-onset multiple sclerosis

Black holes; Chronic active lesions; Volumetric MRIAgujeros negros; Lesiones activas crónicas; Resonancia magnética volumétricaForats negres; Lesions actives cròniques; Ressonància magnètica volumètricaBackground Slowly expanding lesions (SELs) are MRI markers of chronic active lesions in multiple sclerosis (MS). T1-hypointense black holes, and reductions in magnetization transfer ratio (MTR) are pathologically correlated with myelin and axonal loss. While all associated with progressive MS, the relationship between these lesion’s metrics and clinical outcomes in relapse-onset MS has not been widely investigated. Objectives To explore the relationship of SELs with T1-hypointense black holes, and longitudinal T1 intensity contrast ratio and MTR, their correlation to brain volume, and their contribution to MS disability in relapse-onset patients. Methods 135 patients with relapsing-remitting MS (RRMS) were studied with clinical assessments and brain MRI (T2/FLAIR and T1-weighted scans at 1.5/3 T) at baseline and two subsequent follow-ups; a subset of 83 patients also had MTR acquisitions. Early-onset patients were defined when the baseline disease duration was ≤ 5 years (n = 85). SELs were identified using deformation field maps from the manually segmented baseline T2 lesions and differentiated from the non-SELs. Persisting black holes (PBHs) were defined as a subset of T2 lesions with a signal below a patient-specific grey matter T1 intensity in a semi-quantitative manner. SELs, PBH counts, and brain volume were computed, and their associations were assessed through Spearman and Pearson correlation. Clusters of patients according to low (up to 2), intermediate (3 to 10), or high (more than 10) SEL counts were determined with a Gaussian generalised mixture model. Mixed-effects and logistic regression models assessed volumes, T1 and MTR within SELs, and their correlation with Expanded Disability Status Scale (EDSS) and confirmed disability progression (CDP). Results Mean age at study onset was 35.5 years (73% female), disease duration 5.5 years and mean time to last follow-up 6.5 years (range 1 to 12.5); median baseline EDSS 1.5 (range 0 to 5.5) and a mean EDSS change of 0.31 units at final follow-up. Among 4007 T2 lesions, 27% were classified as SELs and 10% as PBHs. Most patients (n = 65) belonged to the cluster with an intermediate SEL count (3 to 10 SELs). The percentage of PBHs was higher in SELs than non-SELs (up to 61% vs 44%, p < 0.001) and within-patient SEL volumes positively correlated with PBH volumes (r = 0.53, p < 0.001). SELs showed a decrease in T1 intensity over time (beta = -0.004, 95%CI −0.005 to −0.003, p < 0.001), accompanied by lower cross-sectional baseline and follow-up MTR. In mixed-effects models, EDSS worsening was predicted by the SEL log-volumes increase over time (beta = 0.11, 95%CI 0.03 to 0.20, p = 0.01), which was confirmed in the sub-cohort of patients with early onset MS (beta = 0.14, 95%CI 0.04 to 0.25, p = 0.008). In logistic regressions, a higher risk for CDP was associated with SEL volumes (OR = 5.15, 95%CI 1.60 to 16.60, p = 0.006). Conclusions SELs are associated with accumulation of more destructive pathology as indicated by an association with PBH volume, longitudinal reduction in T1 intensity and MTR. Higher SEL volumes are associated with clinical progression, while lower ones are associated with stability in relapse-onset MS

Periventricular lesions and MS diagnostic criteria in young adults with typical clinically isolated syndromes.

In patients who present with a clinically isolated syndrome (CIS), whose features are suggestive of multiple sclerosis (MS), fulfilling McDonald 2010 magnetic resonance imaging (MRI) criteria for dissemination in space (DIS) and dissemination in time (DIT) enables a diagnosis of MS. While ⩾1 periventricular lesion is included in the 2010 DIS criteria, earlier McDonald criteria required ⩾3 periventricular lesions to confirm DIS and recent Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS)-recommended DIS criteria also require ⩾3 lesions. We investigated the effect of varying the required number of periventricular lesions and found that the best combination of specificity and sensitivity for clinically definite MS was seen for ⩾1 periventricular lesion using both the McDonald 2010 and MAGNIMS 2016 criteria

Grey matter involvement by focal cervical spinal cord lesions is associated with progressive multiple sclerosis.

BACKGROUND: The in vivo relationship of spinal cord lesion features with clinical course and function in multiple sclerosis (MS) is poorly defined. OBJECTIVE: The objective of this paper is to investigate the associations of spinal cord lesion features on MRI with MS subgroup and disability. METHODS: We recruited 120 people: 25 clinically isolated syndrome, 35 relapsing-remitting (RR), 30 secondary progressive (SP), and 30 primary progressive (PP) MS. Disability was measured using the Expanded Disability Status Scale. We performed 3T axial cervical cord MRI, using 3D-fast-field-echo and phase-sensitive-inversion-recovery sequences. Both focal lesions and diffuse abnormalities were recorded. Focal lesions were classified according to the number of white matter (WM) columns involved and whether they extended to grey matter (GM). RESULTS: The proportion of patients with focal lesions involving at least two WM columns and extending to GM was higher in SPMS than in RRMS (p = 0.03) and PPMS (p = 0.015). Diffuse abnormalities were more common in both PPMS and SPMS, compared with RRMS (OR 6.1 (p = 0.002) and 5.7 (p = 0.003), respectively). The number of lesions per patient involving both the lateral column and extending to GM was independently associated with disability (p < 0.001). CONCLUSIONS: More extensive focal cord lesions, extension of lesions to GM, and diffuse abnormalities are associated with progressive MS and disability

The relation of sarcopenia and disability in multiple sclerosis

Background: The relation of sarcopenia and disability in MS is unknown. Objective: To investigate the relation of temporal muscle thickness (TMT) and disability. Methods: A cohort of 132 people who presented with a clinically isolated syndrome (CIS) suggestive of MS at a mean age of 30.0 years, were prospectively followed clinically and with MRI over 30-years. TMT and expanded disability status scale (EDSS) were assessed at baseline, one- five- ten- fourteen- twenty- and thirty-year follow-up. Results: At 30-years, 27 participants remained classified as having had a CIS, 34 converted to relapsing remitting MS, 26 to secondary progressive MS, and 16 had died due to MS. Using linear mixed effect models with subject nested in time, greater annualized TMT-thinning was seen in individuals who developed MS (-0.04 mm/a, 95%CI: -0.07 to -0.01, p = 0.023). In those who converted to MS, a thinner TMT was reached at 14- (p = 0.008), 20- (p = 0.002) and 30-years (p< 0.001). TMT was negatively correlated with EDSS at 20-years (R=-0.18, p = 0.032) and 30-years (R-0.244, p = 0.005). Longitudinally, TMT at earlier timepoints was not predictive for 30-year clinical outcomes. Conclusion: TMT thinning is accelerated in MS and correlated with disability in later disease stages, but is not predictive of future disability

Association between clinic-level quality of care and patient-level outcomes in multiple sclerosis

Background: Multiple sclerosis (MS) quality of care guidelines are consensus-based. The effectiveness of the recommendations is unknown.// Objective: To determine whether clinic-level quality of care affects clinical and patient-reported outcomes.// Methods: This nationwide observational cohort study included patients with adult-onset MS in the Swedish MS registry with disease onset 2005–2015. Clinic-level quality of care was measured by four indicators: visit density, magnetic resonance imaging (MRI) density, mean time to commencement of disease-modifying therapy, and data completeness. Outcomes were Expanded Disability Status Scale (EDSS) and patient-reported symptoms measured by the Multiple Sclerosis Impact Scale (MSIS-29). Analyses were adjusted for individual patient characteristics and disease-modifying therapy exposure.// Results: In relapsing MS, all quality indicators benefitted EDSS and physical symptoms. Faster treatment, frequent visits, and higher data completeness benefitted psychological symptoms. After controlling for all indicators and individual treatment exposures, faster treatment remained independently associated with lower EDSS (−0.06, 95% confidence interval (CI): −0.01, −0.10) and more frequent visits were associated with milder physical symptoms (MSIS-29 physical score: −16.2%, 95% CI: −1.8%, −29.5%). Clinic-level quality of care did not affect any outcomes in progressive-onset disease.// Conclusion: Certain quality of care indicators correlated to disability and patient-reported outcomes in relapse-onset but not progressive-onset disease. Future guidelines should consider recommendations specific to disease course..