MS symptoms affect many functional domains. Knowing the specific impact of symptoms on health-related quality of life (HRQoL) is vital for successful disease and symptom management in MS. We aimed at investigating how specific MS symptoms contribute to the disease burden in individuals and from a population perspective. We included 855 Swiss Multiple Sclerosis Registry participants with a relapsing-remitting form (RRMS) or a progressive form (PMS). HRQoL was measured with the EuroQol 5-Dimension EQ-5D-index and EQ-Visual Analogue Scale (EQ-VAS) on 0-100% scales. Their associations with 20 symptoms, socio-demographic and clinical information were explored in median regression models, stratified by RRMS and PMS. We included 611 participants with RRMS and 244 with PMS. In RRMS, gait (-6.5%) and balance problems (-5.1%) had the largest EQ-5D-index reductions, and were also important at the population level (frequencies 45% and 52%). Fatigue, depression, and spasticity (frequencies 74.1%, 31%, 38%) also contributed to the population disease burden. In PMS, spasticity, paralysis, and bowel problems had the largest impact on EQ-5D-index, both at the individual and population levels. The largest impact on EQ-VAS at population level was associated in RRMS with balance problems, depression, dizziness, and spasticity, while in PMS with weakness, pain, and paralysis. While HRQoL at population level is most affected by balance problems, spasticity, and depression in RRMS, the biggest HRQoL losses in PMS are caused by spasticity, paralysis, weakness, and pain. Many symptoms with the largest effects in individuals substantially contribute to the population disease burden.

Background: Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin HTT (HD) gene. The primary genetic determinant of the age at onset (AO) is the length of the HTT CAG repeat; however, the remaining genetic contribution to the AO of HD has largely not been elucidated. Recent studies showed that impaired functioning of the peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1alpha) contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1alpha in HD pathogenesis was generated by the findings that sequence variations in the PPARGC1A gene encoding PGC-1alpha exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO. Results: In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD. When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively. Conclusions: These results underscore that impairment of mitochondrial function plays a critical role in the pathogenesis of HD and that upstream transcriptional activators of PGC-1alpha may be useful targets in the treatment of HD.

BACKGROUND AND PURPOSE The involvement of astrocytes as immune‐competent players in inflammation and the pathogenesis of epilepsy and seizure‐induced brain damage has recently been recognized. In clinical trials and practice, levetiracetam (LEV) has proven to be an effective antiepileptic drug (AED) in various forms of epileptic seizures, when applied as mono‐ or added therapy. Little is known about the mechanism(s) of action of LEV. Evidence so far suggests a mode of action different from that of classical AEDs. We have shown that LEV restored functional gap junction coupling and basic membrane properties in an astrocytic inflammatory model in vitro.EXPERIMENTAL APPROACH Here, we used neonatal rat astrocytes co‐cultured with high proportions (30%) of activated microglia or treated with the pro‐inflammatory cytokine interleukin‐1β to provoke inflammatory responses. Effects of LEV (50 µg·mL⁻¹) on electrophysiological properties of astrocytes (by whole cell patch clamp) and on secretion of TGFβ1 (by elisa) were studied in these co‐cultures.KEY RESULTS LEV restored impaired astrocyte membrane resting potentials via modification of inward and outward rectifier currents, and promoted TGFβ1 expression in inflammatory and control co‐cultures. Furthermore, LEV and TGFβ1 exhibited similar facilitating effects on the generation of astrocyte voltage‐gated currents in inflammatory co‐cultures and the effects of LEV were prevented by antibody to TGFβ1.CONCLUSIONS AND IMPLICATIONS Our data suggest that LEV is likely to reduce the harmful spread of excitation elicited by seizure events within the astro‐glial functional syncytium, with stabilizing consequences for neuronal–glial interactions.

The limited efficacy of glucocorticoids (GCs) during therapy of acute relapses in multiple sclerosis (MS) leads to long-term disability. We investigated the potential of vitamin D (VD) to enhance GC efficacy and the mechanisms underlying this VD/GC interaction. In vitro, GC receptor (GR) expression levels were quantified by ELISA and induction of T cell apoptosis served as a functional readout to assess synergistic 1,25(OH)₂D₃ (1,25D)/GC effects. Experimental autoimmune encephalomyelitis (MOG_35–55 EAE) was induced in mice with T cell-specific GR or mTORc1 deficiency. 25(OH)D (25D) levels were determined in two independent cohorts of MS patients with stable disease or relapses either responsive or resistant to GC treatment (initial cohort: n = 110; validation cohort: n = 85). Gene expression of human CD8⁺ T cells was analyzed by microarray (n = 112) and correlated with 25D serum levels. In vitro, 1,25D upregulated GR protein levels, leading to increased GC-induced T cell apoptosis. 1,25D/GC combination therapy ameliorated clinical EAE course more efficiently than respective monotherapies, which was dependent on GR expression in T cells. In MS patients from two independent cohorts, 25D deficiency was associated with GC-resistant relapses. Mechanistic studies revealed that synergistic 1,25D/GC effects on apoptosis induction were mediated by the mTOR but not JNK pathway. In line, 1,25D inhibited mTORc1 activity in murine T cells, and low 25D levels in humans were associated with a reduced expression of mTORc1 inhibiting tuberous sclerosis complex 1 in CD8⁺ T cells. GR upregulation by 1,25D and 1,25D/GC synergism in vitro and therapeutic efficacy in vivo were abolished in animals with a T cell-specific mTORc1 deficiency. Specific inhibition of mTORc1 by everolimus increased the efficacy of GC in EAE. 1,25D augments GC-mediated effects in vitro and in vivo in a T cell-specific, GR-dependent manner via mTORc1 inhibition. These data may have implications for improvement of anti-inflammatory GC therapy.

The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood–brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens. We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy. In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro. Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.

MS is the most common autoimmune demyelinating disease of the CNS. For the past decades, several immunomodulatory disease‐modifying treatments with multiple presumed mechanisms of action have been developed, but MS remains an incurable disease. Whereas high efficacy, at least in early disease, corroborates underlying immunopathophysiology, there is profound heterogeneity in clinical presentation as well as immunophenotypes that may also vary over time. In addition, functional plasticity in the immune system as well as in the inflamed CNS further contributes to disease heterogeneity. In this review, we will highlight immune‐pathophysiological and associated clinical heterogeneity that may have an implication for more precise immunomodulatory therapeutic strategies in MS.