Stable Multiple Sclerosis Research Articles

Neutrophil/lymphocyte ratio as an indicator of radiological disease activity in clinically stable multiple sclerosis

Purpose: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system and the most common neurological disorder causing disability in young people. There is no sensitive and specific marker for both diagnosis and follow-up. Neutrophil to lymphocyte ratio is an easily applicable method and in this study we aimed to observe the changes in this ratio in the presence of isolated radiologic activity in MS. Materials and Methods: We compared 20 MS active patients with no clinical attack or neurologic progression and only radiologic activity with 20 age- and sex-matched clinically and radiologically stable MS patients in terms of NLR. Results: Mean NLR value was 2.22±0.87 in radiologically active patient group (Min 1.08-Max 4.28) and mean NLR value was 2.31±1.37 in control group (Min 0.96-Max 5.92). We observed that NLR values in patients with radiologic activity only were not significantly different from NLR values in patients with both clinical and radiologic stability. Conclusion: Marker studies in the diagnosis and follow-up of MS continue rapidly. Prospective studies involving a much larger cohort may be instructive in order to demonstrate the association of simple, easily applicable, non-invasive, inexpensive methods such as NLR with MS disease activity.

The Evolving Use of Gold Nanoparticles as a Possible Reversal Agent for the Symptoms of Neurodegenerative Diseases: A Narrative Review.

Neurodegenerative diseases are broadly hallmarked by impaired energy metabolism and toxic intracellular accumulations such as damaged organelles or reactive oxygen species (ROS). Gold nanoparticles readily cross the blood-brain barrier and increase nicotinamide adenine dinucleotide + hydrogen (NADH) oxidation to nicotinamide adenine dinucleotide (NAD+), which is vital for intracellular energy generation, cellular repair, and protection from ROS. Thus, the use of gold nanoparticles to treat and potentially reverse cellular injury seen in neurodegenerative disease has been an area of ongoing research. This systematic review explores current literature regarding the use of gold nanoparticle therapy in the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). In vitro studies of CNM-Au8 (Clene Nanomedicine, Salt Lake City, UT) have been shown to reduce TDP-43 aggregates associated with ALS. These studies also exhibited the neuroprotective effects of CNM-Au8 in rat primary neurons exposed to amyloid-beta peptides, which are associated with Alzheimer's disease. In animal models of MS, oral delivery of CNM-Au8 was demonstrated to produce robust and significant remyelination activity, oligodendrocyte maturation, and expression of myelin markers. In these same MS animal models, CNM-Au8 improved the motor function of cuprizone-treated mice in both open-field and kinematic gait studies. Recent phase II trials of CNM-Au8 in 13 patients with Parkinson's disease and 11 patients with stable relapsing MS demonstrated a statistically significant increase in the NAD+/NADH ratio across two cohorts. As the current data repeatedly suggest, these gold nanoparticles are efficacious for the treatment and reversal of symptoms across these varying neurodegenerative pathologies. Further opportunities exist for increasing human trials and eventually incorporating this new technology into existing treatment regimens.

Evidence of brain target engagement in Parkinson’s disease and multiple sclerosis by the investigational nanomedicine, CNM-Au8, in the REPAIR phase 2 clinical trials

BackgroundImpaired brain energy metabolism has been observed in many neurodegenerative diseases, including Parkinson’s disease (PD) and multiple sclerosis (MS). In both diseases, mitochondrial dysfunction and energetic impairment can lead to neuronal dysfunction and death. CNM-Au8® is a suspension of faceted, clean-surfaced gold nanocrystals that catalytically improves energetic metabolism in CNS cells, supporting neuroprotection and remyelination as demonstrated in multiple independent preclinical models. The objective of the Phase 2 REPAIR-MS and REPAIR-PD clinical trials was to investigate the effects of CNM-Au8, administered orally once daily for twelve or more weeks, on brain phosphorous-containing energy metabolite levels in participants with diagnoses of relapsing MS or idiopathic PD, respectively.ResultsBrain metabolites were measured using 7-Tesla 31P-MRS in two disease cohorts, 11 participants with stable relapsing MS and 13 participants with PD (n = 24 evaluable post-baseline scans). Compared to pre-treatment baseline, the mean NAD+/NADH ratio in the brain, a measure of energetic capacity, was significantly increased by 10.4% after 12 + weeks of treatment with CNM-Au8 (0.584 units, SD: 1.3; p = 0.037, paired t-test) in prespecified analyses of the combined treatment cohorts. Each disease cohort concordantly demonstrated increases in the NAD+/NADH ratio but did not reach significance individually (p = 0.11 and p = 0.14, PD and MS cohorts, respectively). Significant treatment effects were also observed for secondary and exploratory imaging outcomes, including β-ATP and phosphorylation potential across both cohorts.ConclusionsOur results demonstrate brain target engagement of CNM-Au8 as a direct modulator of brain energy metabolism, and support the further investigation of CNM-Au8 as a potential disease modifying drug for PD and MS.

Non-lesional white matter in relapsing-remitting multiple sclerosis assessed by multicomponent T2 relaxation.

The purpose of the study is to investigate, by T2 relaxation, non-lesional white matter (WM) in relapsing-remitting (RR) multiple sclerosis (MS). Twenty stable RR MS patients underwent 1.5T Magnetic Resonance Imaging (MRI) with 3D Fluid-Attenuated Inversion-Recovery (FLAIR), 3D-T1-weighted, and T2-relaxation multi-echo sequences. The Lesion Segmentation Tool processed FLAIR images to identify focal lesions (FLs), whereas T1 images were segmented to identify WM and FL sub-volumes with T1 hypo-intensity. Non-lesional WM was obtained as the segmented WM, excluding FL volumes. The multi-echo sequence allowed decomposition into myelin water, intra-extracellular water, and free water (Fw), which were evaluated on the segmented non-lesional WM. Correlation analysis was performed between the non-lesional WM relaxation parameters and Expanded Disability Status Scale (EDSS), disease duration, patient age, and T1 hypo-intense FL volumes. The T1 hypo-intense FL volumes correlated with EDSS. On the non-lesional WM, the median Fw correlated with EDSS, disease duration, age, and T1 hypo-intense FL volumes. Bivariate EDSS correlation of FL volumes and WM T2-relaxation parameters did not improve significance. T2 relaxation allowed identifying subtle WM alterations, which significantly correlated with EDSS, disease duration, and age but do not seem to be EDSS-predictors independent from FL sub-volumes in stable RR patients. Particularly, the increase in the Fw component is suggestive of an uninvestigated prodromal phenomenon in brain degeneration.

Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis

Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting. To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW). This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate. Association between NfL z scores and CDW. CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(-2) for 2 visits preceding event, CDW(-1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively. A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(-1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(-2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(-1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years). This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.

Successful epilepsy surgery in two cases with multiple sclerosis.

Brain surgery is the only curative treatment for people with focal epilepsy, but it is unclear whether this induces active disease in multiple sclerosis (MS). This creates a barrier to evaluate MS patients for epilepsy surgery. We present two cases of successful epilepsy surgery in patients with pharmacoresistant epilepsy and stable MS and give an overview of the existing literature. (1) a 28-year-old woman with seizures arising from a right basal temporo-occipital ganglioglioma was seizure-free after surgery, without MS relapse but with one new MS lesion postsurgically. (2) a 46-year-old woman with seizures arising from a natalizumab-associated progressive multifocal leukoencephalopathy (PML) lesion in the right frontal lobe was seizure-free after surgery preceded by extraoperative subdural electrocorticography, with new subclinical MS lesions. We are the first to report brain surgery in a PML survivor. Both patients stabilized radiologically after initiating second-line therapies. Successful epilepsy surgery can substantially increase the quality of life in patients with pharmacoresistant epilepsy and MS. With increasing survival rates of brain tumors and PML, the risk-benefit ratio of epilepsy surgery compared to a potential MS relapse after surgery becomes critically important. Shared decision-making is valuable for balancing the risks related to both diseases.

Neurofilament Light Chain in Adult and Pediatric Multiple Sclerosis: A Promising Biomarker to Better Characterize Disease Activity and Personalize MS Treatment.

Many biological markers have been explored in multiple sclerosis (MS) to better quantify disease burden and better evaluate response to treatments, beyond clinical and MRI data. Among these, neurofilament light chain (Nf-L), although non-specific for this disease and found to be increased in other neurological conditions, has been shown to be the most promising biomarker for assessing axonal damage in MS, with a definite role in predicting the development of MS in patients at the first neurological episode suggestive of MS, and also in a preclinical phase. There is strong evidence that Nf-L levels are increased more in relapsing versus stable MS patients, and that they predict future disease evolution (relapses, progression, MRI measures of activity/progression) in MS patients, providing information on response to therapy, helping to anticipate clinical decisions in patients with an apparently stable evolution, and identifying patient non-responders to disease-modifying treatments. Moreover, Nf-L can contribute to the better understanding of the mechanisms of demyelination and axonal damage in adult and pediatric MS. A fundamental requirement for its clinical use is the accurate standardization of normal values, corrected for confounding factors, in particular age, sex, body mass index, and presence of comorbidities. In this review, a guide is provided to update clinicians on the use of Nf-L in clinical activity.

Long-term potentiation-like plasticity is retained during relapse in patients with Multiple Sclerosis

ObjectiveTo investigate the degree of synaptic plasticity in Multiple Sclerosis (MS) patients during acute relapses compared to stable MS patients and healthy controls (HCs) and to analyze its functional relevance. MethodsFacilitatory quadripulse stimulation (QPS) was applied to the primary motor cortex in 18 acute relapsing and 18 stable MS patients, as well as 18 HCs. The degree of synaptic plasticity was measured by the change in motor evoked potential amplitude following QPS. Symptom recovery was assessed three months after relapse. ResultsSynaptic plasticity was induced in all groups. The degree of induced plasticity did not differ between acute relapsing patients, HCs, and stable MS patients. Plasticity was significantly higher in relapsing patients with motor disability compared to relapsing patients without motor disability. In most patients (n = 9, 50%) symptoms had at least partially recovered three months after the relapse, impeding meaningful analysis of the functional relevance of baseline synaptic plasticity. ConclusionsQPS-induced synaptic plasticity is retained during acute MS relapses. Subgroup analyses suggest that stabilizing metaplastic mechanisms may be more important to prevent motor disability but its functional relevance needs to be verified in larger, longitudinal studies. SignificanceNew insights into synaptic plasticity during MS relapses are provided.

Health related quality of life in the domain of physical activity predicts confirmed disability progression in people with relapsing remitting multiple sclerosis.

The diagnosis of the progression phase of Multiple Sclerosis (MS) is still retrospective and based on the objectivation of clinical disability accumulation. To assess whether the Patient Reported Outcomes Measures (PROMs) scores predict the occurrence of disease progression within three years of follow-up. Observational prospective multicenter study. Stable Relapsing-Remitting MS (RRMS) patients were enrolled. At enrollment, patients completed the following PROMs: Beck Depression Inventory- II, The Treatment Satisfaction Questionnaire for Medications, Medical Outcomes Study Short Form 36- Item (SF36), Fatigue Severity Scale. EDSS was assessed at enrollment and three years later. The outcome measure was defined as the occurrence of confirmed disability progression (CDP) within three years of follow-up. Univariable and multivariable logistic regression models were performed to study the association between the final score of each test and the outcome. SF36-Physical Functioning (SF36-PF) was the only independent variable associated with the outcome. The ROC curve analysis determined a score of 77.5 at SF36-PF as the cut-off point identifying patients experiencing CDP within three years of follow-up [AUC: 0.66 (95% CI: 0.56-0.75)]. RRMS patients scoring higher (>77.5) at SF36-PF subscale have a higher likelihood to experience CDP within the next three years.

Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non-inferiority trial

Multiple sclerosis typically has onset in young adults and new disease activity diminishes with age. Most clinical trials of disease-modifying therapies for multiple sclerosis have not enrolled individuals older than 55 years. Observational studies suggest that risk of return of disease activity after discontinuation of a disease-modifying therapies is greatest in younger patients with recent relapses or MRI activity. We aimed to determine whether risk of disease recurrence in older patients with no recent disease activity who discontinue disease-modifying therapy is increased compared to those who remain on disease-modifying therapy. DISCOMS was a multicentre, randomised, controlled, rater-blinded, phase 4, non-inferiority trial. Individuals with multiple sclerosis of any subtype, 55 years or older, with no relapse within the past 5 years or new MRI lesion in the past 3 years while continuously taking an approved disease-modifying therapy were enrolled at 19 multiple sclerosis centres in the USA. Participants were randomly assigned (1:1 by site) with an interactive response technology system to either continue or discontinue disease-modifying therapy. Relapse assessors and MRI readers were masked to patient assignment; patients and treating investigators were not masked. The primary outcome was percentage of individuals with a new disease event, defined as a multiple sclerosis relapse or a new or expanding T2 brain MRI lesion, over 2 years. We assessed whether discontinuation of disease-modifying therapy was non-inferior to continuation using a non-inferiority, intention-to-treat analysis of all randomly assigned patients, with a predefined non-inferiority margin of 8%. This trial is registered at ClinicalTrials.gov, NCT03073603, and is completed. 259 participants were enrolled between May 22, 2017, and Feb 3, 2020; 128 (49%) were assigned to the continue group and 131 (51%) to the discontinue group. Five participants were lost to follow-up (continue n=1, discontinue n=4). Six (4·7%) of 128 participants in the continue group and 16 (12·2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years. The difference in event rates was 7·5 percentage points (95% CI 0·6-15·0). Similar numbers of participants had adverse events (109 [85%] of 128 vs 104 [79%] of 131) and serious adverse events (20 [16%] vs 18 [14%]), but more adverse events (422 vs 347) and serious adverse events (40 vs 30) occurred in the discontinue group. The most common adverse events were upper respiratory infections (20 events in 19 [15%] participants in the continue group and 37 events in 30 [23%] participants in the discontinue group). Three participants in the continue group and four in the discontinue group had treatment-related adverse events, of which one in each group was a serious adverse event (multiple sclerosis relapse requiring admission to hospital). One participant in the continue group and two in the discontinue group died; no deaths were deemed to be related to treatment. We were unable to reject the null hypothesis and could not conclude whether disease-modifying therapy discontinuation is non-inferior to continuation in patients older than 55 years with multiple sclerosis and no recent relapse or new MRI activity. Discontinuation of disease-modifying therapy might be a reasonable option in patients older than 55 years who have stable multiple sclerosis, but might be associated with a small increased risk of new MRI activity. Patient-Centered Outcomes Research Institute and the National Multiple Sclerosis Society.

Functional and structural brain MRI changes associated with cognitive worsening in multiple sclerosis: a 3-year longitudinal study.

Heterogeneous processes may contribute to cognitive impairment in multiple sclerosis (MS). To apply a longitudinal multiparametric MRI approach to identify mechanisms associated with cognitive worsening in MS patients. 3T brain functional and structural MRI scans were acquired at baseline and after a median follow-up of 3.4years in 35 MS patients and 22 healthy controls (HC). Associations between cognitive worsening (reliable change index score < -1.25 at the Rao's battery) and longitudinal changes in regional T2-hyperintense white matter (WM) lesions, diffusion tensor microstructural WM damage, gray matter (GM) atrophy and resting state (RS) functional connectivity (FC) were explored. At follow-up, HC showed no clusters of significant microstructural WM damage progression, GM atrophy or changes in RS FC. At follow-up, 10 MS patients (29%) showed cognitive worsening. Compared to cognitively stable, cognitively worsened MS patients showed more severe GM atrophy of the right anterior cingulate cortex and bilateral supplementary motor area (p < 0.001). Cognitively worsened vs cognitively stable MS patients showed also decreased RS FC in the right hippocampus of the right working memory network and in the right insula of the default mode network. Increased RS FC in the left insula of the executive control network was found in the opposite comparison (p < 0.001). No significant regional accumulation of focal WM lesions nor microstructural WM abnormalities occurred in both patients' groups. GM atrophy progression in cognitively relevant brain regions combined with functional impoverishment in networks involved in cognitive functions may represent the substrates underlying cognitive worsening in MS.

Longitudinal Brain Volume Findings in an Outpatient Practice of Young People with MS (P11-3.001)

<h3>Objective:</h3> To assess in an outpatient setting the application of volumetrics with brain MRI among young people with multiple sclerosis (MS). <h3>Background:</h3> Research on brain atrophy in MS has illuminated how inflammation and neurodegenerative processes lead to cognitive and neurologic declines. However, brain volume assessment is rarely used in routine practice. Here, we examined predominantly pediatric onset MS and some younger adult-onset MS patients who underwent routine brain MRI including volumetrics. Our goal was to assess the impact of brain volume change on clinical outcomes including SDMT in this relatively young and stable MS subset. <h3>Design/Methods:</h3> 77 patients with pediatric or adult onset RRMS or CIS, 31 years of age or younger, were evaluated with at least two MRI studies. Volume data was computed on MRI images with icobrain ms software, compared to age- and sex-related norms and adjusted for differences across the various Siemens 3T scanners. Changes in volumes of whole brain (WB), white matter (WM), grey matter (GM), lateral ventricles (LV), and thalamus were calculated as an average annualized percent brain volume change per year. <h3>Results:</h3> The mean patient age was 21.6 years (range 12–31); 70% were female. The annual mean decrease of WB volume: −0.473%, WM: −0.390%, GM: −0.517%, thalamus: −0.552%, and annual LV volume increase: 1.78%. A total of 32.5% of patients had an annual decrease in GM volume &gt;0.8% (the 90% threshold for measurement error). 29.9% of patients had LV volumes increase &gt;3.5%. Whole brain volume loss and lateral ventricle increase was significantly correlated, r=−0.34 (p=0.002). Clinical and demographic features between those whose brain volume declined and those whose brain volumes remained stable will be presented. <h3>Conclusions:</h3> Quantitative MRI is a useful technique which has only begun to be incorporated into clinical practice. A proportion of young otherwise stable patients with RRMS show brain volume loss under computer-assisted analyses. <b>Disclosure:</b> Dr. O’Neill has nothing to disclose. Dr. Couvreur has received personal compensation in the range of $10,000-$49,999 for serving as a Intern Clinical application specialist at icometrix with The Prince Albert Fund. Dr. Hu has nothing to disclose. Mr. Zhang has nothing to disclose. Ms. Pehel has nothing to disclose. Ms. Sosa has nothing to disclose. Ms. Fade has nothing to disclose. Elayne Feld has nothing to disclose. Dr. Chen has received personal compensation for serving as an employee of icometrix. Dr. De Barros has received personal compensation for serving as an employee of Icometrix. Thibo Billiet has received personal compensation for serving as an employee of icometrix. Annemie Ribbens, 9599 has received personal compensation for serving as an employee of icometrix. Annemie Ribbens, 9599 has stock in icometrix. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gerson Lerhman. Dr. Krupp has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for medscape. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuroLive. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Krupp has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for Cleveland Clinic. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for MCIC. The institution of Dr. Krupp has received research support from Biogen. The institution of Dr. Krupp has received research support from National Multiple Sclerosis Society. Dr. Krupp has received intellectual property interests from a discovery or technology relating to health care.

Functional and Structural MRI Changes Associated With Cognitive Worsening in Multiple Sclerosis: A 3-Year Longitudinal Study (P11-3.003)

<h3>Objective:</h3> To apply a multiparametric MRI approach to identify mechanisms associated with cognitive worsening in multiple sclerosis (MS). <h3>Background:</h3> Heterogeneous processes may contribute to cognitive impairment in MS; however, its association with brain structural and functional MRI changes still need to be fully explored. <h3>Design/Methods:</h3> Brain dual-echo, 3D T1-weighted, diffusion-weighted imaging, and resting state (RS) functional MRI scans were acquired at baseline and after median follow up of 3.4 years in 35 MS patients and 22 healthy controls (HC). Associations between cognitive worsening at Rao’s battery and longitudinal changes in T2-hyperintense lesion location, WM microstructural damage, gray matter (GM) atrophy and RS functional connectivity (FC) were explored using tract-based spatial statistic, tensor-based morphometry and independent component analysis. <h3>Results:</h3> Fifteen (43%) MS patients were cognitively impaired at baseline and 10 (29%) showed cognitive deterioration at follow-up. At baseline, compared to HC, MS patients showed widespread WM damage and GM atrophy, and decreased RS FC in some clusters of executive control (ECN) and working memory networks (WMN). At follow-up, annualized volume loss of caudate nucleus was significantly higher in MS patients with vs without cognitive deterioration (−1.2% vs −0.2%, p&lt;0.05). No significant between-group differences in lesion location, WM microstructural changes or GM atrophy were found. Compared to stable MS patients, worsened patients showed decreased RS FC in right hippocampus of right WMN and in right insula of default mode network. In the opposite comparison, increased RS FC in left insula of ECN was found. <h3>Conclusions:</h3> While cognitively-stable MS patients showed increased RS FC in left insula, possibly reflecting a compensatory mechanism, cognitive deterioration in MS patients was associated with decreased RS FC in several functional brain networks, with limited GM atrophy progression. Our study suggests that, in MS patients already characterized by substantial structural damage, cognitive deterioration might be secondary to functional network collapse. <b>Disclosure:</b> Dr. Azzimonti has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Paola Valsasina has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACCMED. Elisabetta Pagani has nothing to disclose. Olga Marchesi has nothing to disclose. Dr. Tedone has nothing to disclose. Carmen Vizzino has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla.

Longitudinal Changes of Functional Connectivity Dynamism Are Relevant for Disability Worsening in Multiple Sclerosis: A 2.5-Year Study (P10-3.018)

<h3>Objective:</h3> To investigate changes in time-varying functional connectivity (TVFC) over 2.5 years of follow-up in multiple sclerosis (MS) patients and their association with disability progression. <h3>Background:</h3> In MS patients, TVFC analysis showed abnormalities of the main functional networks, correlated with more severe clinical and cognitive disability. Preliminary evidence showed that MS-related cognitive decline was associated with progressive TVFC destabilization. However, the clinical relevance of longitudinal TVFC changes has not been investigated yet. <h3>Design/Methods:</h3> 3T-MRI scans and clinical evaluations were obtained at baseline and at median follow-up of 2.5 years from 129 right-handed MS patients (103 relapsing-remitting [RR] and 26 progressive [P]) and 28 matched healthy controls (HC). At 2.5-year follow-up, patients were classified as clinically stable/worsened according to their disability change. TVFC was quantified at voxel-wise level as the coefficient of variation (CoV) across sliding-windows of degree centrality. <h3>Results:</h3> At follow-up, 25/129 (19.3%) MS patients worsened clinically. At baseline, MS patients showed reduced TVFC <i>vs</i> HC in the bilateral orbitofrontal cortex (p&lt;0.05, family-wise error corrected), left cerebellum, right precuneus and left thalamus. At 2.5-year follow-up, a widespread reduction of TVFC over time (p&lt;0.05, family-wise error corrected) was found in MS patients in temporal, parietal, occipital and frontal lobes, as well as in the cerebellum. Such a pattern of TVFC reduction was also found when looking at clinically stable MS patients. Clinically worsened MS presented peculiar TVFC reductions in areas of the default-mode network and basal ganglia. Reduced TVFC in the left putamen in clinically worsened <i>vs</i> stable MS patients was significant at time <i>x</i> group interaction analysis. <h3>Conclusions:</h3> After 2.5 years of follow-up, MS patients showed widespread TVFC reduction in cortical lobes and cerebellum. A peculiar involvement of deep grey matter was found in clinically worsened MS patients. Accrual of TVFC abnormalities in deep grey matter regions may represent a biological substrate of disability worsening. <b>Disclosure:</b> Dr. D’Amore has nothing to disclose. Paola Valsasina has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACCMED. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Monica Margoni has received research support from MAGNIMS. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla.

Adaptive and innate immune responses in multiple sclerosis with anti-CD20 therapy: Gene expression and protein profiles.

Anti-CD20 is a highly effective therapy for multiple sclerosis (MS), a disease with multiple abnormalities in function of B and T cells and innate immune cells. Anti-CD20 therapy depletes B cells, which alters antibody production and has diverse effects on B cell immunity. These changes potentially affect immunity beyond B cells in MS. Determine if anti-CD20 therapy effects non-B cell, as well as B cell, gene expression, and serum protein levels. Samples were collected from 10 healthy controls and from clinically stable relapsing-remitting MS - 10 untreated, 9 interferon-β-treated, and 15 ocrelizumab-treated patients were studied before, and 2 weeks and 6 months after, the first anti-CD20 infusion. Peripheral blood mononuclear cells (PBMC) were analyzed with sensitive, 135,000-transcript RNA expression microarrays, using stringent criteria. Gene expression was compared to 43 MS-relevant serum immune and neurotrophic proteins, using multiplex protein assays. Anti-CD20 therapy reduced expression of 413 total genes and 185 B-cell-regulated genes at 2 weeks vs. pre-therapy. Expression of 19 (15%) of these B cell genes returned toward baseline by 6 months, including genes for the B cell activation protein, CD79A, and for immunoglobulin A, D, and G heavy chains. Expression pathways for Th17 and CD4 regulatory T-cell (Treg) development, differentiation, and proliferation also quieted. In contrast, expression increased in Th1 and myeloid cell antiviral, pro-inflammatory, and toll-like receptor (TLR) gene pathways. These findings have clinical implications. B cell gene expression diminishes 2 weeks after anti-CD20 antibody infusion, but begins to rebound by 6 months. This suggests that the optimum time for vaccination is soon before reinfusion of anti-CD20 therapy. In addition, at 6 months, there is enhanced Th1 cell gene expression and induction of innate immune response genes and TLR expression, which can enhance anti-viral and anti-tumor immunity. This may compensate for diminished B cell gene expression after therapy. These data suggest that anti-CD20 therapy has dynamic effect on B cells and causes a compensatory rise in Th1 and myeloid immunity.

Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis

There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS). To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression. Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell-depleting treatment (ie, ocrelizumab or rituximab). Patients received standard immunotherapies or were untreated. In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally. This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (-1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [-0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001). Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

Multiple Sklerose: Änderung im Patientenmanagement während der COVID-19-Pandemie

The coronavirus disease 2019 (COVID-19) pandemic has been a worldwide challenge for the health system. Beside direct effects, it influenced the medical care and treatment of chronic diseases such as multiple sclerosis (MS). During the beginning of the pandemic, the prescription of disease-modifying treatments (DMT) in particular highly effective immunosuppressive drugs was also reduced in Austria and other European countries. Due to increasing evidence, several recommendations were published by national and international societies regarding COVID-19, DMT, and COVID-19 vaccination. In the case of a stable MS disease course, ongoing DMT should be continued. If a new DMT is started or treatment has to be changed, as before the pandemic, the individual risk–benefit has to be evaluated. Furthermore, COVID-19 vaccination is also recommended in untreated and treated patient (currently available vaccine, November 2022). Several healthcare centers have implemented telemedicine during the pandemic and in addition to regular visits, it has been proven to be successful.

Analysis of the extent of limbic system changes in multiple sclerosis using FreeSurfer and voxel-based morphometry approaches.

Background and purposeThe limbic brain is involved in diverse cognitive, emotional, and autonomic functions. Injury of the various parts of the limbic system have been correlated with clinical deficits in MS. The purpose of this study was to comprehensively examine different regions of the subcortical limbic system to assess the extent of damage within this entire system as it may be pertinent in correlating with specific aspects of cognitive and behavioral dysfunction in MS by using a fully automated, unbiased segmentation approach.MethodsSixty-seven subjects were included in this study, including 52 with multiple sclerosis (MS) and 15 healthy controls. Only patients with stable MS disease, without any relapses, MRI activity, or disability progression were included. Subcortical limbic system segmentation was performed using the FreeSurfer pipeline ScLimbic, which provides volumes for fornix, mammillary bodies, hypothalamus, septal nuclei, nucleus accumbens, and basal forebrain. Hippocampus and anterior thalamic nuclei were added as additional components of the limbic circuitry, also segmented through FreeSurfer. Whole limbic region mask was generated by combining these structures and used for Voxel-based morphometry (VBM) analysis.ResultsThe mean [95% confidence interval] of the total limbic system volume was lower (0.22% [0.21–0.23]) in MS compared to healthy controls (0.27%, [0.25–0.29], p < .001). Pairwise comparisons of individual limbic regions between MS and controls was significant in the nucleus accumbens (0.046%, [0.043–0.050] vs. 0.059%, [0.051–0.066], p = .005), hypothalamus (0.062%, [0.059–0.065] vs. 0.074%, [0.068–0.081], p = .001), basal forebrain (0.038%, [0.036–0.040] vs. 0.047%, [0.042–0.051], p = .001), hippocampus (0.47%, [0.45–0.49] vs. 0.53%, [0.49–0.57], p = .004), and anterior thalamus (0.077%, [0.072–0.082] vs. 0.093%, [0.084–0.10], p = .001) after Bonferroni correction. Volume of several limbic regions was significantly correlated with T2 lesion burden and brain parenchymal fraction (BPF). Multiple regression model showed minimal influence of BPF on limbic brain volume and no influence of other demographic and disease state variables. VBM analysis showed cluster differences in the fornix and anterior thalamic nuclei at threshold p < 0.05 after adjusting for covariates but the results were insignificant after family-wise error corrections.ConclusionsThe results show evidence that brain volume loss is fairly extensive in the limbic brain. Given the significance of the limbic system in many disease states including MS, such volumetric analyses can be expanded to studying cognitive and emotional disturbances in larger clinical trials. FreeSurfer ScLimbic pipeline provided an efficient and reliable methodology for examining many of the subcortical structures related to the limbic brain.

Altered bladder-related brain network in multiple sclerosis women with voiding dysfunction.

A number of neurourology imaging studies have mainly focused on investigating the brain activations during micturition in healthy and neuropathic patients. It is, however, also necessary to study brain functional connectivity (FC) within bladder-related regions to understand the brain organization during the execution of bladder function. This study aims to identify the altered brain network associated with bladder function in multiple sclerosis (MS) women with voiding dysfunction through comparisons with healthy subjects via concurrent urodynamic study(UDS)/functional magnetic resonance imaging(fMRI). Ten healthy adult women and nine adult ambulatory women with clinically stable MS for ≥6 months and symptomatic voiding phase neurogenic lower urinary tract dysfunction (NLUTD) underwent UDS/fMRI evaluation with a task of bladder filling/emptying that was repeated three to five times. We quantitatively compared their FC within 17 bladder-related brain regions during two UDS phases: "strong desire to void" and "(attempt at) voiding initiation." At "strong desire to void," the healthy group showed significantly stronger FC in regions involved in bladder filling and suppression of voiding compared to the patient group. These regions included the bilateral anterior cingulate cortex, right supplementary motor area, and right middle frontal gyrus. During "(attempt at) voiding initiation," healthy subjects exhibited stronger FC in the right inferior frontal gyrus compared to MS patients. Our study offers a new way to identify alterations in the neural mechanisms underlying NLUTD and provides potential targets for clinical interventions (such as cortical neuromodulation) aimed at restoring bladder functions in MS patients.

A double-blind, placebo-controlled, single-ascending-dose intravenous infusion study of rHIgM22 in subjects with multiple sclerosis immediately following a relapse

BackgroundRecombinant human immunoglobulin M22 (rHIgM22) has promoted remyelination in animal models and was well tolerated in people with clinically stable multiple sclerosis.ObjectiveSafety/tolerability of a single rHIgM22 dose was investigated following an acute relapse and to determine whether this enhanced CNS/CSF concentrations.MethodsAdults (N = 27) with acute relapse were assigned to rHIgM22 (0.5 or 2.0 mg/kg) or placebo. Study included screening/steroid administration periods and 10 study visits over 6 months. rHIgM22 CSF concentrations were assessed on days 2 and 29. Pharmacokinetic and safety samples were taken for up to 60 days. Assessments included adverse events and other clinical measures. Brain magnetic resonance imaging was performed with/without gadolinium.ResultsrHIgM22 CSF levels were consistent with dose-dependent concentration on both days 2 and 29. Infusion was generally well tolerated during an acute relapse. Immunogenicity was mild. Most adverse events did not appear to be dose dependent, were mild/moderate, and were events often associated with multiple sclerosis.ConclusionAlthough limited by high variability and small sample size, the data suggest enhanced CNS uptake associated with a drop in CSF levels. This study demonstrated safety of an antibody directed to myelin and oligodendrocytes in the course of active demyelinating disease. Further research into rHIgM22 is warranted.ClinicalTrials.gov: NCT02398461 https://clinicaltrials.gov/ct2/show/study/NCT02398461?term=M22&draw=2&rank=8