Latest developments in multiple sclerosis (MS) research:
- Read about the association between synaptic loss in the inner plexiform layer (IPL) of the retina and progression in MS.
- Learn about the potential to personalise treatment selection based on individual endophenotypes.
- Know more about the association between brain microstructure and cognitive fatigue in early MS.
These noteworthy MS news highlights and more are included in this month’s ECTRIMS Bulletin – a 30-day snapshot of global news and publications on MS research, treatment, and care.
ECTRIMS Bulletins can be sent to you every month, delivered straight to your inbox, via our free subscription service. Simply select all “topics” that are of interest to you, and when one of those appears in our news and publication cycle, you’ll be sure to hear from us.
Imaging and non-imaging biomarkers
Neurofilaments as biomarkers in neurological disorders — towards clinical application
Nature Reviews Neurology | 12 April 2024
The present review article discusses the clinical application of neurofilaments as biomarkers in several neurological disorders, including MS, neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendtrocyte glycoprotein antibody-associated disease (MOGAD). Measuring both serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels can help predict progression in patients with MS, more effectively than standard magnetic resonance imaging (MRI) and clinical assessments. In the clinical practice, these biomarkers have the potential to be used to quantify disease activity and monitor drug response. Neurofilament light and heavy chain – NfL and NfH – are also markers of disease activity and progression in NMOSD and MOGAD. GFAP seems to be more appropriate than NfL to monitor NMOSD over time.
Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis
Cell Reports Medicine | 16 April 2024
Identifying potential biomarkers of progression in MS would assist in making timely treatment decisions. Can synaptic loss be a potential marker of progression in MS? This hypothesis is investigated in this study using an animal model of chronic MS, investigating a dataset of MS patients, and finally examining the biological substrate of synaptic loss. Mice with experimental autoimmune encephalomyelitis (EAE) presented with synaptic loss in the inner plexiform layer (IPL) of the retina at a very early stage, during the first day of symptoms. The authors then analysed a longitudinal cohort – Expressions, Proteomics, Imaging, Clinical (EPIC) of the University of California, San Francisco (UCSF) – with more than 800 patients, who were followed for more than 12 years. The dataset includes measures of IPL thickness via optical coherence tomography (OCT). 70 Patients with MS of the EPIC cohort, who were initially registered as relapsing-remitting (RRMS), transitioned to secondary progressive MS (SPMS). For 19 of these patients, two retinal imaging in different points of time – more than 6 months apart – were available in the year before the transition to SPMS. Their retinal imaging revealed a loss of a mean of 0.259 µm of IPL thickness per year. On the contrary, the retina layers of patients with a stable relapsing-remitting disease did not change. These results suggest that IPL thickness, a measure of in vivo synaptic loss, can serve as a predictive marker of disease progression in MS. A serum proteome-wide analysis revealed that demyelination, glial activation, and synaptic loss are strongly associated and are independent from axonal injury.
Therapeutics
Multiple sclerosis endophenotypes identified by high-dimensional blood signatures are associated with distinct disease trajectories
Science Translational Medicine | 27 March 2024
Personalised treatment in MS represents today an important challenge. Peripheral immune signatures may allow stratify patients and support more appropriate treatment decisions. The authors of the present study analysed peripheral blood mononuclear cells (PBMCs) and serum of 309 patients with early MS from the NationMS cohort. Using a combination of high-dimensional flow cytometry and serum proteomics, they identified three distinct immunological endophenotypes. The presence of the three immunological phenotypes was confirmed in a second independent cohort of 232 patients. Each immunological phenotype was characterised by alterations of distinct immune compartments and was associated with a different disease trajectory. The “degenerative” endophenotype was linked to early disability progression, while the “inflammatory” endophenotype was associated with inflammatory disease features. Furthermore, standard immune therapies for MS had different capacities to normalise the immune alterations specific for each endophenotype. Identifying the individual endophenotype has a potential to assist optimal treatment selection in MS.
One-year Analysis of Efficacy and Safety Data from Black/African American and Hispanic/Latino People with Relapsing Multiple Sclerosis Receiving Ocrelizumab Treatment in the CHIMES Trial (PL5.005)
Characterization of Ocrelizumab in Minorities With Multiple Sclerosis (CHIMES) is an open-label, single-arm, multicenter, phase-IV study, conducted in US and Kenya and developed in collaborations with clinical researchers, patients with multiple sclerosis and national advocacy groups. CHIMES enrolled 113 Black/African American patients and 69 Hispanic/Latino patients with multiple sclerosis (MS) – with a mean age of 35.5 years. They received two 300-mg ocrelizumab infusions with a 14-day interval and 600 mg every 24 weeks for 1 year. Approximately half of the participants showed no evidence of disease activity during a 48-week period of treatment. No safety signals were observed. Most patients (80.2%) experienced 1 or less adverse event, 5.5% had 1 or less serious adverse event, and 29.1% experienced reactions related to the infusions.
Reviews
Determinants and biomarkers of progression independent of relapses in multiple sclerosis
Annals of Neurology | 3 April 2024
The review focuses on the latest evidence regarding the mechanisms underlying smouldering disease activity – also known as silent progression or progression independent of relapsing activity (PIRA). PIRA can occur from the early stages of MS. However, detecting it at the beginning can be challenging. Individuals with paediatric-onset may not show clinical manifestations of PIRA for over 10 years. There is a need to improve the detection of PIRA in clinical settings. Some measures can be very effective in detecting disability accrual, such as the Timed 25-Foot Walk (T25FW) and the 9-Hole Peg Test (9-HPT) – two quantitative and timed tests measuring mobility and leg function and arm and hand function, respectively. Cognitive functions, especially processing speed as measured by the Symbol Digit Modalities Test (SDMT), should be regularly assessed. Promising imaging markers of PIRA include longitudinal measures of cortical grey matter and lesions with a paramagnetic rim (PRL). Additionally, serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) are still under investigation as potential fluid biomarkers to predict PIRA. Furthermore, several markers of inflammation in the cerebrospinal fluid (CSF) have been associated to cortical damage and are effective in predicting cortical thinning.
Pathogenesis
Brain microstructure is linked to cognitive fatigue in early multiple sclerosis
Journal of Neurology | 28 March 2024
The present study suggests that the integrity of brain microstructure can already be altered during the first years of the disease. Alterations, measured with multiparametric quantitative magnetic resonance imaging (MRI), occur in normal appearing white matter (NAWM) and cortical grey matter (NACGM) and are associated with cognitive fatigue. Eighteen patients – with an average age of 31 years – living with relapsing remitting multiple sclerosis (RRMS) or clinically isolated syndrome (CIS) were recruited from the University Hospital in Liège. Cognitive fatigue was severe in 7 individuals with MS, moderate in 3, and normal to mild in 10. The results suggest that cognitive fatigue in patients with MS can be linked to global integrity within the NAWM and the NACGM, but not within the normal appearing deep grey matter. Interestingly, cognitive fatigue was associated with brain microstructure within the NAWM both in patients and healthy controls.
Research Highlights
EBV-specific T cells in multiple sclerosis
Nature Reviews Neurology | 10 April 2024
F Hayashi presented a study during the ACTRIMS Forum that supports the role of the Epstein-Barr virus (EBV) infection in multiple sclerosis (MS). Using single-cell analysis, the researchers identified an increased number of CD8+ T cells clonally expanded in the cerebrospinal fluid (CSF) of 13 individuals living with MS. In 2 out of 13 people with MS the T cell receptors (TCRs) were EBV-specific.