Stable Multiple Sclerosis Patients Research Articles

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 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.

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 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.

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.

Stable multiple sclerosis patients on anti-CD20 therapy should go on extended interval dosing—Commentary

Stable multiple sclerosis patients on anti-CD20 therapy should go on extended interval dosing—Commentary

Stable multiple sclerosis patients on anti-CD20 therapy should go on extended interval dosing: NO

Stable multiple sclerosis patients on anti-CD20 therapy should go on extended interval dosing: NO

Stable multiple sclerosis patients on anti-CD20 therapy should go on extended interval dosing—“Yes”

Stable multiple sclerosis patients on anti-CD20 therapy should go on extended interval dosing—“Yes”

Thalamus Atrophy in the Peri-Pregnancy Period in Clinically Stable Multiple Sclerosis Patients: Preliminary Results.

Radiological activity in the post-partum period in MS patients is a well-known phenomenon, but there is no data concerning the influence of pregnancy on regional brain atrophy. The aim of this article was to investigate local brain atrophy in the peri-pregnancy period (PPP) in patients with MS. Thalamic volume (TV); corpus callosum volume (CCV) and classical MRI activity (new gadolinium enhancing lesions (Gd+), new T2 lesions, T1 lesions volume (T1LV) and T2 lesions volume (T2LV)) were analyzed in 12 clinically stable women with relapsing–remitting MS and with MRI performed in the PPP. We showed that there was a significant decrease in TV (p = 0.021) in the PPP. We also observed a significant increase in the T1 lesion volume (p = 0.028), new gadolinium-enhanced and new T2 lesions (in 46% and 77% of the scans, respectively) in the post-partum period. Our results suggest that the PPP in MS may be associated not only with classical MRI activity but, also, with regional brain atrophy.

Recurrence and Prognostic Value of Asymptomatic Spinal Cord Lesions in Multiple Sclerosis.

Spinal magnetic resonance imaging (MRI) is currently not recommended for the routine monitoring of clinically stable multiple sclerosis (MS) patients. We aimed to investigate the occurrence of asymptomatic spinal lesions (a-SL) in clinically stable MS patients, and their association with clinical and radiological outcomes, including the recurrence of spinal lesions. The hospital MS registry was searched for clinically stable MS patients (no relapses, no disability progression) with spinal MRIs performed at T1 (baseline) and T2 (9–36 months after T1). Information on relapses, disability and new brain/spinal MRI lesions at T3 (≥6 months after T2) was collected and analyzed. Out of 300 MS patients, 45 showed a-SL between T1 and T2. The presence of a-SL was not associated with the subsequent occurrence of relapses or disability progression at T3, but did correlate with the risk of new brain (rate ratio (RR) = 1.63, 95% CI = 1.16−2.25, p = 0.003) and recurrent spinal lesions (RR = 7.28, 95% CI = 4.02–13.22, p < 0.0001). Accounting for asymptomatic brain lesions (a-BL), the presence of either a-BL or a-SL was associated with subsequent risk for new brain (OR = 1.81, 95% CI = 1.25–2.60, p = 0.001) or spinal (RR = 2.63, 95% CI = 1.27–5.45, p = 0.009) lesions. Asymptomatic spinal demyelinating lesions occurred in 15% of clinically stable MS patients within a median period of 14 months and conferred an increased risk of future radiological activity at the brain and spinal level.

Brain Atrophy Rates for Stable Multiple Sclerosis Patients on Long-Term Fingolimod versus Glatiramer Acetate.

Background: Clinically stable multiple sclerosis (MS) patients on long-term therapy often have negligible acute inflammation on MRI. Brain atrophy may provide insight into subclinical disease progression in such populations.Objective: This study aims to compare brain atrophy for age- and gender-matched MS patients treated for >2 years with fingolimod (FTY) or glatiramer acetate (GA), examining brain volume, cognition, and patient-reported outcomes (PROs).Methods: Stable relapsing-MS patients, age 18–60, on FTY or GA for >2 years were followed up for 2 years. MRI brain and lesion volumes, cognitive measures, and PROs were collected at baseline and annually.Results: Forty-four FTY and forty-three GA patients completed baseline and year 2 visits. No differences in age, gender, or education were observed. Median EDSS was 2.0GA and 2.5FTY (p = 0.22). Treatment duration was longer for GA, 6.50GA vs. 3.73FTY years (p < 0.001). Baseline geometric mean T2LV were different, GA = 1,009.29 cm3 vs. FTY = 2,404.67 cm3 (p = 0.0071). Baseline brain volumes were similar, GA = 1,508 cm3 vs. FTY = 1,489 cm3 (p = 0.2381). Annualized atrophy rates, adjusted for baseline and at mean baseline value, were GA = −0.2775% vs. FTY = −0.2967% (p = 0.7979). No differences in cognitive measures or PROs were observed.Conclusions: Stable MS patients on long-term treatment with FTY and GA have similar brain volume loss rates. Differences in baseline disease severity may suggest patients with more aggressive disease treated with FTY may achieve similar brain volume loss rates as patients with milder baseline disease on GA.

IPSCs from people with MS can differentiate into oligodendrocytes in a homeostatic but not an inflammatory milieu.

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS) that results in variable severities of neurodegeneration. The understanding of MS has been limited by the inaccessibility of the affected cells and the lengthy timeframe of disease development. However, recent advances in stem cell technology have facilitated the bypassing of some of these challenges. Towards gaining a greater understanding of the innate potential of stem cells from people with varying degrees of disability, we generated induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells derived from stable and progressive MS patients, and then further differentiated them into oligodendrocyte (OL) lineage cells. We analyzed differentiation under both homeostatic and inflammatory conditions via sustained exposure to low-dose interferon gamma (IFNγ), a prominent cytokine in MS. We found that all iPSC lines differentiated into mature myelinating OLs, but chronic exposure to IFNγ dramatically inhibited differentiation in both MS groups, particularly if exposure was initiated during the pre-progenitor stage. Low-dose IFNγ was not toxic but led to an early upregulation of interferon response genes in OPCs followed by an apparent redirection in lineage commitment from OL to a neuron-like phenotype in a significant portion of the treated cells. Our results reveal that a chronic low-grade inflammatory environment may have profound effects on the efficacy of regenerative therapies.

Factors affecting MS patients' health-related quality of life and measurement challenges in Lebanon and the MENA region.

BackgroundIn the Middle East and North Africa (MENA) region, few studies explored the quality of life of multiple sclerosis patients and the factors affecting it.ObjectiveThe objective of this study was to explore studies on multiple sclerosis quality of life in the MENA area through a comprehensive literature review. To validate the Multiple sclerosis international Quality of Life (MusiQoL) and Modified Fatigue Impact Scale (MFIS) in Arabic, and investigate the impact of sociodemographic and clinical variables of Lebanese multiple sclerosis patients on quality of life.MethodsAs part of an ongoing observational prospective research study, data from 663 stable multiple sclerosis patients were analysed.ResultsIn Lebanese multiple sclerosis patients, the Arabic MusiQoL and MFIS seem to be accurate and valid tools with high reliability coefficients and confirmatory factor analytic indices. Variables such as age and disease type predicted multiple sclerosis quality of life, yet were significantly affected by psychosocial fatigue. The influence of sociodemographic and clinical variables on quality of life dimensions varied. Being a woman with multiple sclerosis, receiving medications and experiencing physical fatigue worsens the psychological wellbeing quality of life dimension.ConclusionSeveral sociodemographic and clinical variables predicted the health-related quality of life dimensions of multiple sclerosis patients in MENA. Further in-depth investigation to guide more targeted clinical management is recommended. We encourage using validated multidimensional tools to measure quality of life in MENA such as the Arabic MusiQoL.

Distinctive Pattern of Cognitive Disorders During Multiple Sclerosis Relapse and Recovery Based on Computerized CANTAB Tests

Background: Cognition may be affected at least as seriously as physical function during multiple sclerosis (MS) relapse, however MS relapse related cognitive disorders are still underdiagnosed and poorly characterized. The limited number of paper-pencil tests were used for assessment, and nevertheless, some significant changes were found. Unlike the paper-pencil tests, computerized batteries and tests are more sensitive and highly standardized, produce instant scoring and can minimize the learning and practice effects on follow-up. We investigated the cognition during MS relapse with the Cambridge Neuropsychological Test Automated Battery (CANTAB), which has shown sensitivity to cognitive dysfunction across different clinical groups, including patients with MS.Objective: The objective of the study was to assess the cognitive functions with CANTAB battery in MS patients during relapse, in stable MS patients, and healthy controls, and to establish the timing and pattern of cognitive recovery after relapse.Methods: Sixty relapsing, thirty stable MS patients, and thirty controls were assessed with CANTAB. The relapse group was assessed during multiple sclerosis relapse and 1 and 3 months after the first assessment.Results: The score of the difficult task of spatial planning was worse in MS relapse group than in MS stable group (p < 0.05). The scores of medium difficulty tasks of spatial planning, episodic visual recall and working memory were worse in the relapse group than in the control group (p < 0.05), while in stable MS and control groups, the scores of these tasks didn't differ. The most significant improvement of speed of response, spatial planning, episodic visual recall memory and spatial working memory, was established at 1 month after the first assessment, additional improvement of spatial planning and working memory was observed at 3 months after the first assessment.Conclusions: The results of this study indicate that cognitive function is affected during MS relapse. The difficult task of CANTAB battery, which assesses the spatial planning, showed MS relapse related cognitive dysfunction. The changes in scores of episodic visual recall and working memory may be related to MS relapse. A significant improvement in the speed of response, spatial planning, episodic visual recall and working memory was established at 1 month after MS relapse. The additional improvement in spatial planning for the most difficult task and working memory was observed at 3 months after MS relapse. It may be possible that the practice effect had the impact on the improvement of cognitive scores that was noted in relapsing MS patients.

Gene expression of chemokines CX3CL1 and CXCL16 and their receptors, CX3CR1 and CXCR6, in peripheral blood mononuclear cells of patients with relapsing-remitting multiple sclerosis - a pilot study

Background/Aim. In vitro and in vivo studies show that CX3CL1 and CXCL16 chemokines and their specific receptors, CX3CR1 and CXCR6, respectively, mediate mechanism of neuroinflammation during the pathogenesis of multiple sclerosis (MS). The aim of this study was to investigate relative messenger ribonucleic acid (mRNA) levels of CX3CL1, CXCL16, CX3CR1 and CXCR6 in peripheral blood mononuclear cells, as potential molecular markers of relapsing-remitting (RR) MS. Methods. The study included 43 unrelated RR MS patients, 20 of them with clinically active disease (relapse) and 23 with clinically stable disease (remission), and 28 unrelated healthy subjects as controls. Real-time polymerase chain reactions (PCR) were performed using TaqMan? gene expression assays. Relative expression (mRNA) level of each target gene in each sample of peripheral blood mononuclear cells was calculated as the mean normalized expression. Results. The levels of CX3CR1 mRNA were significantly higher in clinically active RR MS patients compared to controls [fold change = 1.38, p (Mann-Whitney U test) = 0.009], and significantly lower in clinically stable vs active RR MS patients [fold change = - 1.43, p (t-test) = 0.03]. Stable RR MS patients had significantly higher CXCL16 mRNA levels than controls [fold change = 1.33, p (Mann-Whitney U test) = 0.006]. A trend of increased CXCR6 gene expression was found in active RR MS patients compared to controls [fold change = 1.23, p (Mann-Whitney U test) = 0.08]. In either active or stable RR MS patients there were no significant correlations of the clinical parameters with expression levels of the target genes. Conclusion. The current results show that increased CX3CR1 mRNA levels in peripheral blood mononuclear cells could represent a proinflammatory molecular marker of clinically active RR MS.

Tolerability, treatment satisfaction and quality of life outcomes in stable multiple sclerosis patients switched from injectable therapies to auto injected intramuscular interferon beta 1a: The SFERA study

BackgroundInterferon beta (IFNB) and Glatiramer acetate, long-term first line disease modifying treatments (DMTs) for multiple sclerosis (MS), have different injection frequencies crucial for injection site related side effects. We aimed at investigating whether switching to intramuscular IFNB-1a injected once/week with the Avonex®Pen™ device improves treatment tolerability and quality of life in stable MS patients. MethodsClinically stable MS patients, whom their treating neurologist switched from high frequency injectable DMTs to weekly intramuscular IFNB-1a because of bothersome injection site reactions, were included. Injection site and systemic tolerability were measured by a composite 100 mm visual analogue scale at screening, months 4 and 12. Treatment satisfaction, quality of life, relapses and EDSS progression were also recorded. The primary endpoint was change in injection site tolerability from screening to Month 4. Descriptive statistics and Wilcoxon paired signed-rank tests were applied. ResultsThe median injection site tolerability and systemic tolerability were significantly improved at months 4 (n = 36) and 12 (n = 33) [change −51.60 (IQR: −60.13, −39.60) mm (p < 0.0001); −26.00 (−54.00, 2.25) mm (p = 0.002)]. Median treatment satisfaction was significantly improved at month 12 [change of 18.00 (2.00, 47.50) mm (p = 0.0003)]. Physical and mental components of the SF-36 did not change significantly, and 30/33 (90.9%) and 33/33 (100%) patients were free from relapses and EDSS progression at month 12. ConclusionsWeekly intramuscular IFNB-1a may represent an alternative treatment option for clinically stable MS patients suffering from intolerable injection-related side effects under treatment with high frequency injectable DMTs.

Phosphorylated SIRT1 as a biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis

We have previously shown that SIRT1 mRNA expression was significantly lower in relapsing MS patients compared to those in remission. Our goal was to longitudinally investigate the role of active, phosphorylated SIRT1 (p-SIRT1) as a potential biomarker of relapse and predictor for response to glatiramer acetate (GA) treatment in patients with relapsing remitting multiple sclerosis (MS). We also want to investigate the downstream effects of SIRT1 activation by measuring the trimethylation of histone 3 at lysine 9 (H3K9me3). A cohort of 15 GA-treated patients was clinically monitored using the Expanded Disability Status Scale (EDSS) and peripheral blood mononuclear cells (PBMCs) were collected at 0, 3, 6, and 12 months after initiation of the therapy. P-SIRT1 and H3K9me3 levels were assayed by Western blotting using specific antibodies. Statistically significant lower levels of p-SIRT1 protein (p < 0.0001) and H3K9me3 (p = 0.001) were found during relapses when compared to stable MS patients. Non-responders to GA treatment were defined as patients who exhibited at least two relapses following initiation of GA treatment. Statistically significant lower levels of p-SIRT1 protein (p = 0.02) and H3K9me3 (p = 0.004) were found in GA non-responders compared to responders. Using receiver operating characteristic analysis, area under the curve (AUC) for p-SIRT1 was 77% (p = 0.007) and for H3K9me3 was 81% (p = 0.002) for prediction of relapse. For predicting responsiveness to GA treatment, AUC was 75% (P = 0.01) for H3K9me3. Our data suggest that p-SIRT1 and H3K9me3 could serve as potential biomarkers for MS relapse. In addition, H3K9me3 could serve as possible biomarker to predict response to GA treatment.

Neuroinflammation following disease modifying therapy in multiple sclerosis: A pilot positron emission tomography study

IntroductionChronic activation of microglia accelerates the neurodegenerative process in multiple sclerosis (MS). Although disease modifying therapy (DMT) is reportedly effective for neuroinflammatory responses in MS, the progression of neuroinflammation after DMT remains unclear. MethodsWe evaluated microglial activation in six clinically stable relapsing-remitting MS patients after DMT by quantifying changes in translocator protein (TSPO) density using PET with [11C]DPA713, a selective TSPO tracer for microglial activation. All patients underwent [11C]DPA713 PET scans twice, and the scans were conducted one year apart. The binding potential (BPND) of the tracer was estimated using a simplified reference tissue model. Results[11C]DPA713 BPND measured at 6months after DMT was significantly higher in the MS group than that in the control group. Compared with the first PET measurement, the one-year PET measurement revealed significantly elevated [11C]DPA713 BPND in broader brain regions covering the temporal and parietal cortices after one year of DMT. ConclusionsThe current results indicate that microglial activation may proceed in the entire brain of clinically stable MS patients even after receiving DMT.