Each year, the Forum of the Americas Committee for Treatment and Research in Multiple Sclerosis explores the dynamic environment of the disease in a unique series of scientific and clinical presentations. This year’s theme was “Breaking Barriers in MS”. The scientific program included discussions on barriers such as healthcare disparities and access to care, CNS boundaries and associated cells, barriers to nerve repair, rehabilitation barriers, and clinical trial design considerations.
Paramagnetic rim lesions (PRL) are considered a biomarker for chronic active lesions (CAL) in multiple sclerosis (MS). However, the link between CAL and neurodegeneration in MS is still unclear. PRLs are one way of investigating this relationship in vivo. Evidence of such a link would support the importance of a pharmacological attack on PRL. Therefore, the relationship between PRL and measures of neurodegeneration and clinical disability was analyzed at the time of diagnosis of MS, clinically isolated syndrome (CIS) or radiologically isolated syndrome (RIS) [1]. To this end, 47 treatment-naïve individuals with newly diagnosed MS, CIS or RIS underwent magnetic resonance imaging (MRI) at 7.0 Tesla (7T) as well as clinical and neurocognitive examinations. PRL were detected in 27 people (57.4%). The PSR values in the NAWM adjacent to the PRL were lower than in the contralateral NAWM and the NAWM adjacent to rimless lesions. The PSR values measured in the PRL core correlated with the values measured in the NAWM near the PRL. PRL+ individuals had smaller normalized volumes of thalamus, caudate, globus pallidum, hippocampus and amygdala and reduced thickness in some cortical regions. They also performed worse in the 9-hole pencil test and the cued recall test. However, the results of the Expanded Disability Status Scale, the brain volume, PSR and R1f of the NAWM and the deep gray matter (GM) of the whole brain did not differ between the groups. Thus, PRL was found to be significantly associated with GM atrophy and poor health of the surrounding NAWM, likely leading to some degree of cognitive and physical disability. However, this relationship between PRL and GM atrophy is not reflected in regional myelin loss. The scientists suspect that PRL+ individuals have a widespread microglia-driven process that ultimately leads to neurodegeneration. This could indirectly indicate a more advanced stage of the disease at the time of diagnosis.
What role does white matter play in fatigue?
Fatigue is one of the most important and disabling symptoms of MS patients and occurs in 80% of cases with relapsing-remitting multiple sclerosis (RRMS). Many studies have linked gray matter atrophy to fatigue, but white matter lesion burden (WM-LL) has received less attention. This has now been investigated in more detail in a study involving 63 RRMS patients [2]. Each patient provided demographic information and was assessed using the Expanded Disability Status Scale (EDSS) and the Fatigue Severity Scale (FSS). VolBrain, a fully automated, operator-independent instrument, was used to assess WM-LL and total brain volume. The patients were divided into three groups: no fatigue (FSS <4), leichte bis mittlere Fatigue (FSS ≥4 ≤5) und starke Fatigue (FSS>5). 33.3% of patients had no significant fatigue, 25.4% had mild to moderate fatigue and 41.3% had significant fatigue. Age, disease duration, relapses and EDSS were positively correlated with the severity of fatigue. Total brain volume, total and regional WM-LL (juxtacortical, periventricular, infratentorial) were also correlated with the severity of fatigue. Ordinal regression analysis for the severity of fatigue showed that EDSS and infratentorial lesion volume were the best predictors. The present results emphasize the importance of EDSS and infratentorial lesion volume (cerebellum and brainstem) as predictors of fatigue severity in RRMS.
MS or a metabolic disorder?
Demystifying multiple sclerosis (MS) requires an understanding of its hereditary “disease mimics”, i.e. mimicry. To date, several single-gene disorders in both adults and children have been reported to have clinical and radiologic features that overlap with primary progressive MS. From this group, there is increasing evidence that metabolic and mitochondrial disorders (MDs) are common, so that special attention must be paid to these disorders in the diagnosis, treatment and care of patients. Due to the involvement of several systems and the great genetic and clinical heterogeneity, the diagnosis of MS and metabolic disorders is often a challenge. However, the list of MS mimics is growing, new disease-causing genes are being identified and the reported phenotypes are broadening, enabling precise and accurate diagnosis of MS mimics. One study aimed to characterize the genetic, neurological and clinical features of 8 adults suspected of having genetic MS mimicry [3].
Eight adult subjects with atypical primary progressive MS features referred to the Undiagnosed White Matter Disease Clinic at the Montreal Neurological Institute were recruited. There, next-generation sequencing (NGS) data was generated: A targeted NGS panel for the genes associated with known forms of genetic leukoencephalopathies was performed in all patients, followed by whole-exome sequencing (WES, in one patient) or whole-genome sequencing (WGS, in five patients) if the targeted panel was negative. The NGS data was analyzed using a filter strategy aimed at identifying rare pathogenic variants. By using a targeted panel, variants in the candidate genes POLG and MT-CO2 were detected in two subjects, resulting in a diagnostic yield of 25%. In addition, probable pathogenic variants in ABCD1 were identified in one patient with available WES data and variants in PEX5 were identified in one patient with available WGS data. The WGS analysis of four patients has not yet been completed. All identified genes proved to be strong disease causative agents in accordance with the clinical and radiological characteristics of the affected individuals. The MT-CO2 and POLG genes are involved in mitochondrial function, while ABCD1 and PEX5 are peroxisomal genes.
Significance of the blood-brain barrier in pathogenesis
MS is a neuroinflammatory disease of the central nervous system (CNS) characterized by breakdown of the blood-brain barrier (BBB), infiltration of immune cells across CNS barriers and demyelination. The orchestrated immune response in MS involves the activation and differentiation of immune cells into pro- or anti-inflammatory phenotypes and modulates inflammation. Stra6 is a known regulator of retinol transport, the downstream active metabolite of vitamin A, and a precursor of the active signaling molecule retinoic acid (RA). RA has been shown to induce a regulatory T-cell response and suppresses the pathogenic response in the steady state. However, it has been shown that RA promotes T-cell activation during ongoing inflammation and enhances the pathogenic T-helper cell response in a dose-dependent manner. While most studies have primarily investigated the peripheral role of vitamin A, retinol and RA, our understanding of the transport of these molecules into the CNS and their immunomodulatory effects within the CNS compartment in neuroinflammation is still rudimentary. The aim was therefore to understand the mechanisms that regulate brain endothelial transport of retinol from the blood into the CNS parenchyma in the healthy state and in a mouse model of MS, and to determine whether changes in RA concentrations in the CNS compartments control the local pro- or anti-inflammatory immune response [4].
To this end, RNA sequencing was performed on FACS-purified BBB endothelial cells from the spinal cord of mice suffering from experimental autoimmune encephalomyelitis (EAE) and from healthy control mice. It has been shown that Stra6 (Stimulated by Retinoic Acid 6) is strongly upregulated at the BBB at the peak of EAE at both transcript and protein levels in the spinal cord. In addition, the results showed a similar increase in Stra6 protein expression in ECs in the brain as in ECs in the spinal cord. The absence of Stra6 led to a delay and improvement in the progression of EAE. In addition, the absence of Stra6 in the endothelial cells led to a significant reduction in the severity of EAE compared to their littermates. The preliminary results suggest that the absence of Stra6 in the ECs and thus the altered RA levels in the CNS parenchyma modulate the CNS-specific immune response in an anti-inflammatory manner.
Prognosis factor patients over 50 years of age
In multiple sclerosis, relapses and MRI activity generally decrease with increasing age, but are replaced by relapse-independent progression (PIRA). However, several older patients with MS (PwMS) continue to experience clinical relapses and the impact on their disease remains undetermined. The aim was therefore to determine the effects of an index relapse on the course of the disease in patients over 50 years of age and to identify risk factors for unfavorable courses [5]. For this purpose, a secondary analysis of three local prospective cohorts in Germany was conducted. All people with disabilities aged ≥50 years who had a relapse ≤60 days before the initial examination and 18 months after the examination were examined and compared with a control group of people with disabilities without a relapse. The patients were stratified according to age or disease progression. Relapses, MRI activity, relapse-associated worsening (RAW) and PIRA were analyzed. A regression analysis was performed to assess the impact of specific baseline risk factors and treatment regimen changes on the various disease outcomes at month 18.
681 patients were included in the “relapse cohort”. The control cohort comprised 232 patients. The epidemiologic baseline parameters were balanced between the cohorts and subgroups. Increased inflammatory activity and relapse-independent progression of disability was observed in the relapse cohort compared to the control cohort. In the relapse cohort, 393 patients were classified as stable (57.7%), 164 patients as active (24.1%) and 124 patients as progressive (18.2%) during follow-up. Cardiovascular risk factors and older age at baseline were identified as risk factors for progressive disease, while DMT administration at baseline favored stable disease. Initiation or escalation of treatment was useful to prevent active but non-progressive disease. Relapse in people with disabilities older than 50 years was associated with further inflammatory disease activity and worsening of disability. The study shows that relapses drive PIRA and disease progression in people with disabilities. These results support the continuation of DMT in older patients with stable disease, as the reintroduction of DMT in response to relapse did not help prevent disease progression.
Effects of COVID-19 on sleep
There is some, albeit contradictory, evidence that sleep and mental health have deteriorated in the general population as a result of the COVID-19 pandemic and the associated social restrictions. A study has now investigated whether and to what extent the symptoms of insomnia, depression, fatigue and paraesthesia in women diagnosed with multiple sclerosis (MS) have changed before and during the COVID-19 pandemic [6]. To this end, a total of 90 women with MS completed a series of self-assessment scales at two time points. Nine months before the COVID-19 outbreak in May 2019 (baseline) and during the COVID-19 pandemic (end of study; 12 months after baseline: May 2020). The self-assessment questionnaires included sociodemographic and disease-related information as well as symptoms of insomnia, depression, fatigue and paresthesia.
The symptoms of depression increased over time, while the symptoms of insomnia, fatigue and paraesthesia did not. The only predictor of insomnia during the COVID-19 pandemic was insomnia before the COVID-19 pandemic; the only predictor of depression during the COVID-19 pandemic was insomnia before the COVID-19 pandemic. Accordingly, a modest influence – if any – on the participants’ main problems, namely insomnia, depression, fatigue and paraesthesia, can possibly be assumed.
Taking disease modification further
Disease-modifying therapies have revolutionized the treatment of relapsing-remitting MS by largely preventing the influx of peripheral immune cells into the central nervous system (CNS). However, the relapsing-remitting pathology of MS is driven by chronic, compartmentalized processes in the CNS for which there are no effective therapies. Meningeal aggregates play an essential role in this pathology by supporting chronic active lesions in the CNS parenchyma. Tregs are well suited to address this aspect of MS pathophysiology due to their ability to suppress immune-mediated inflammation through multiple mechanisms and their phenotypic stability. It has been hypothesized that Tregs targeting the CNS will destroy the meningeal aggregates [7]. The aim is to develop a therapy based on regulatory T cells (Treg) for the treatment of progressive multiple sclerosis (MS).
A TCR-engineered Treg product was developed to target the CNS antigen myelin basic protein (MBP) in connection with HLA-DRB1*15:01. The T cell receptors (TCRs) in question were examined in a series of tests for their MBP reactivity and their ability to induce suppressive activity in human Tregs. The best TCR was introduced into Tregs isolated from leukopaks from healthy donors and MS patients. The suppressive activity, phenotypic stability and producibility of TCR-engineered Tregs from healthy donor and MS patient materials were characterized.
Results: The selected MBP-specific TCR induced activation, suppressive activity towards conventional T cells and suppressive cytokine expression in primary Tregs after exposure to MBP peptide and antigen-presenting cells. A highly purified Treg product could be produced from leukopaks from both healthy donors and MS patients, as measured by flow cytometry and demethylation assays for Treg-specific demethylated regions (TSDR). The functional stability of the Treg cell product was tested during the entire manufacturing process as well as during activation and exposure to inflammatory cytokines. Accordingly, TCR-derived Tregs were shown to exhibit suppressive activity when exposed to MBP peptide/MHC and can be produced in high purity for both healthy donors and MS patients. This Treg product is phenotypically stable under inflammatory conditions.
Age in view
Age is the strongest factor determining disease severity in multiple sclerosis, with both chronological and biological age being associated with relapse rate and disability accumulation. Both normal ageing and accelerated ageing due to MS pathology can contribute to this. Studying age extremes in the MS population, including children, may help to better understand these aspects of aging in MS. If children with MS show signs of accelerated aging, this would strongly support the hypothesis that MS pathology drives premature aging.
An attempt was made to measure differences in the epigenetic clock between participants with pediatric MS (POMS) and age-matched pediatric controls to determine whether people with POMS exhibit accelerated aging [8]. A cross-sectional case-control study was conducted using DNA samples and clinical data from the US network of pediatric MS centers. All samples were collected from whole blood and processed using Illumina’s Infinium Methylation EPIC BeadChip technology to generate quantitative methylation scores. The methylation values were preprocessed with the minfi package in R for noob normalization. This data was then processed using standard R packages to calculate epigenetic age based on various published epigenetic clocks for lifespan and health, including Horvath, Hannum, PhenoAge and GrimAge. The epigenetic age from each model was regressed on chronological age to generate an age acceleration residual representing the divergence between epigenetic and chronological age. The residuals of age acceleration were compared between cases and controls using standard statistical tests in R.
In total, samples from 164 POMS cases and 112 pediatric controls were analyzed. The mean chronological age was 15.2 years in the POMS group and 14.0 years in the control group. The residuals of the age acceleration were significantly larger for the POMS participants compared to the controls for each of the watches used: Horvath acceleration difference = 0.85, 95% CI 0.13-1.59, p=0.02; Hannum acceleration difference = 2.36, 95% CI 0.91-3.81, p=0.002; Phenoage acceleration difference = 3.9, 95% CI 1.85-6.04, p=0.0003; GrimAge acceleration difference = 1.05, 95% CI 0.34-1.76, p=0.004. This difference in age acceleration remained significant even after taking biological sex into account. Because children are chronologically young and have fewer comorbidities, these data suggest that the MS disease state may drive accelerated biological aging.
Congress: Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS)
Literature:
- Kazimuddin HF, et al.: Paramagnetic Rim Lesions and Their Relationship With Neurodegeneration and Clinical Disability at the Time of Multiple Sclerosis Diagnosis. Poster P038. ACTRIMS Forum 2024, West Palm Beach, 29. Februar–2. März 2024.
- Hassan SS, et al.: EDSS and Infratentorial White Matter Lesion Volume and Fatigue in MS. Poster P069. ACTRIMS Forum 2024, West Palm Beach, 29. Februar–2. März 2024.
- Hasan H, et al.: Next-Generation Sequencing Analysis in a Series of Subjects With Multifocal White Matter Disease Initially Suspected as Having PPMS. Poster P129. ACTRIMS Forum 2024, West Palm Beach, 29. Februar–2. März 2024.
- Aydin S, et al.: The Role of Endothelial Stra6 in Modulating the Neuroinflammation. Poster P426. ACTRIMS Forum 2024, West Palm Beach, 29. Februar–2. März 2024.
- Pfeuffer S, et al.: Association of Clinical Relapse on Disease Outcomes in People With Multiple Sclerosis Older Than 50 years. Poster P458. ACTRIMS Forum 2024, West Palm Beach, 29. Februar–2. März 2024.
- Sadeghi Bahmani, et al.: Symptoms of Insomnia and Depression Among Individuals With Multiple Sclerosis Before and During the COVID-19 Poster P503. ACTRIMS Forum 2024, West Palm Beach, 29. Februar–
2. März 2024. - Moodley D, et al.: Preclinical Development of a T Cell Receptor Engineered Regulatory T Cell Therapy for Progressive Pathology in MS Poster P136. ACTRIMS Forum 2024, West Palm Beach, 29. Februar–2. März 2024.
- Goyne C, et al.: Accelerated Epigenetic Aging in Pediatric Onset Multiple Sclerosis Poster P211. ACTRIMS Forum 2024, West Palm Beach, 29. Februar–2. März 2024.
InFo NEUROLOGIE & PSYCHIATRIE 2024; 22(2): 28–30 (published on 12.4.24, ahead of print)