Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis

Background and ObjectivesImproved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS.MethodsThe MS-STAT trial randomized patients to 80 mg simvastatin or placebo. Serum was analyzed for NfL and NfH using Simoa technology. We used linear mixed models to investigate the treatment effects of simvastatin compared with placebo on NfL and NfH. Additional models examined the relationships between neurofilaments and MRI and clinical measures of disease severity.ResultsA total of 140 patients with SPMS were included. There was no evidence for a simvastatin treatment effect on NfL or NfH: compared with placebo, NfL was 1.2% lower (95% CI 10.6% lower to 9.2% higher; p = 0.820) and NfH was 0.4% lower (95% CI 18.4% lower to 21.6% higher; p = 0.969) in the simvastatin treatment group. Secondary analyses suggested that higher NfL was associated with greater subsequent whole brain atrophy, higher T2 lesion volume, and more new/enlarging T2 lesions in the previous 12 months, as well as greater physical disability. There were no significant associations between NfH and MRI or clinical variables.DiscussionWe found no evidence of a simvastatin treatment effect on serum neurofilaments. While confirmation of the neuroprotective benefits of simvastatin is awaited from the ongoing phase 3 study (NCT03387670), our results suggest that treatments capable of slowing the rate of whole brain atrophy in SPMS, such as simvastatin, may act via mechanisms largely independent of neuroaxonal injury, as quantified by NfL. This has important implications for the design of future phase 2 clinical trials in PMS.Trial Registration InformationMS-STAT: NCT00647348.Classification of EvidenceThis study provides class I evidence that simvastatin treatment does not have a large impact on either serum NfL or NfH, as quantified in this study, in SPMS.

Single-nucleus RNA-seq of normal-appearing brain regions in relapsing-remitting vs. secondary progressive multiple sclerosis

Multiple sclerosis (MS) is an immune-mediated demyelinating disease that alters central nervous system (CNS) functions. Relapsing-remitting MS (RRMS) is the most common form, which can transform into secondary-progressive MS (SPMS) that is associated with progressive neurodegeneration. Single-nucleus RNA sequencing (snRNA-seq) of MS lesions identified disease-related transcriptomic alterations; however, their relationship to non-lesioned MS brain regions has not been reported and which could identify prodromal or other disease susceptibility signatures. Here, snRNA-seq was used to generate high-quality RRMS vs. SPMS datasets of 33,197 nuclei from 8 normal-appearing MS brains, which revealed divergent cell type-specific changes. Notably, SPMS brains downregulated astrocytic sphingosine kinases (SPHK1/2), the enzymes required to phosphorylate and activate the MS drug, fingolimod. This reduction was modeled with astrocyte-specific Sphk1/2 null mice in which fingolimod lost activity, supporting functionality of observed transcriptomic changes. These data provide an initial resource for studies of single cells from non-lesioned RRMS and SPMS brains.

Therapeutic Benefits of Short-Arm Human Centrifugation in Multiple Sclerosis–A New Approach

Short-arm human centrifugation (SAHC) is proposed as a robust countermeasure to treat deconditioning and prevent progressive disability in a case of secondary progressive multiple sclerosis. Based on long-term physiological knowledge derived from space medicine and missions, artificial gravity training seems to be a promising physical rehabilitation approach toward the prevention of musculoskeletal decrement due to confinement and inactivity. So, the present study proposes a novel infrastructure based on SAHC to investigate the hypothesis that artificial gravity ameliorates the degree of disability. The patient was submitted to a 4-week training programme including three weekly sessions of 30 min of intermittent centrifugation at 1.5–2 g. During sessions, cardiovascular, muscle oxygen saturation (SmO2) and electroencephalographic (EEG) responses were monitored, whereas neurological and physical performance tests were carried out before and after the intervention. Cardiovascular parameters improved in a way reminiscent of adaptations to aerobic exercise. SmO2 decreased during sessions concomitant with increased g load, and, as training progressed, SmO2 of the suffering limb dropped, both effects suggesting increased oxygen use, similar to that seen during hard exercise. EEG showed increased slow and decreased fast brain waves, with brain reorganization/plasticity evidenced through functional connectivity alterations. Multiple-sclerosis-related disability and balance capacity also improved. Overall, this study provides novel evidence supporting SAHC as a promising therapeutic strategy in multiple sclerosis, based on mechanical loading, thereby setting the basis for future randomized controlled trials.

Guanidinoacetate–creatine in secondary progressive multiple sclerosis: a case report

Acute secondary progressive multiple sclerosis (SPMS) is characterized by escalating neurological disability, with limited disease-modifying therapeutic options. A 48-year-old woman with acute SPMS being treated with interferon beta-1a and oral corticosteroids presented as a clinical outpatient with no disease-modifying effects after treatment. A decision was made to treat her with a combination of guanidinoacetate and creatine for 21 days. She had made clinical progress at follow-up, with the intensity of fatigue dropping from severe to mild. Magnetic resonance spectroscopy revealed increased brain choline, creatine, N-acetylaspartate, and glutathione. Patients with SPMS may benefit from guanidinoacetate–creatine treatment in terms of patient- and clinician-reported outcomes; this requires additional study.