Secondary Progressive Patients Research Articles

Diffusion-based structural connectivity patterns of multiple sclerosis phenotypes

BackgroundWe aimed to describe the severity of the changes in brain diffusion-based connectivity as multiple sclerosis (MS) progresses and the microstructural characteristics of these networks that are associated with distinct...

Genetic Variants in Iron Metabolism impact Disease Progression in MS through HIF1A (S9.006)

Genetic Variants in Iron Metabolism impact Disease Progression in MS through HIF1A (S9.006)

Neuroaxonal and Glial Markers in Patients of the Same Age With Multiple Sclerosis.

The specificity of novel blood biomarkers for multiple sclerosis (MS)-related neurodegeneration is unclear because neurodegeneration also occurs during normal aging. To understand which aspects of neurodegeneration the serum biomarkers neurofilament light (sNfL), serum glial fibrillary acidic protein (sGFAP), and serum contactin-1 (sCNTN1) reflect, we here explore their cross-sectional association with disability outcome measures and MRI volumes in a unique cohort of people with MS (PwMS) of the same age. sNfL, sGFAP (both singe-molecule array technology) and sCNTN1 (Luminex) were measured in serum samples of 288 PwMS and 125 healthy controls (HCs) of the Project Y cohort, a population-based cross-sectional study of PwMS born in the Netherlands in 1966 and age-matched HC. sNfL (9.83 pg/mL [interquartile range {IQR}: 7.8-12.0]) and sGFAP (63.7 pg/mL [IQR: 48.5-84.5]) were higher in PwMS compared with HC (sNfL: 8.8 pg/mL [IQR: 7.0-10.5]; sGFAP: 51.7 pg/mL [IQR: 40.1-68.3]) (p < 0.001), whereas contactin-1 (7,461.3 pg/mL [IQR: 5,951.8-9,488.6]) did not significantly differ between PwMS compared with HC (7,891.2 pg/mL [IQR: 6,120.0-10,265.8]) (p = 0.068). sNfL and sGFAP levels were 1.2-fold higher in secondary progressive patients (SPMS) compared with relapsing remitting patients (p = 0.009 and p = 0.043). Stratified by MS subtype, no relations were seen for CNTN1, whereas sNfL and sGFAP correlated with the Expanded Disability Status Scale (ρ = 0.43 and ρ = 0.39), Nine-Hole Peg Test, Timed 25-Foot Walk Test, and Symbol Digit Modalities Test (average ρ = 0.38) only in patients with SPMS. Parallel to these clinical findings, correlations were only found for sNfL and sGFAP with MRI volumes. The strongest correlations were observed between sNfL and thalamic volume (ρ = -0.52) and between sGFAP with deep gray matter volume (ρ = - 0.56) in primary progressive patients. In our cohort of patients of the same age, we report consistent correlations of sNfL and sGFAP with a range of metrics, especially in progressive MS, whereas contactin-1 was not related to clinical or MRI measures. This demonstrates the potential of sNfL and sGFAP as complementary biomarkers of neurodegeneration, reflected by disability, in progressive MS.

Effect of Rituximab on the cognitive impairment in patients with secondary progressive multiple sclerosis.

Background:The present study aimed to address the effect of Rituximab on the cognitive impairment in patients with secondary progressive MS (SPMS).Methods:The present interventional study used a convenience sampling method to select the study participants from SPMS patients. All these patients had progressive disability over the last two years before being admitted in the study. Prior to the administration of Rituximab, the minimal assessment of cognitive function in the multiple sclerosis (MACFIMS) test was performed for each patient who was a candidate to be included in this study. This test was repeated by passing 6 and 12 months from the initial treatment with Rituximab. Since the data needed for this study were obtained at different time intervals, so a linear mixed model was used for their analysis. Analysis of variance (ANOVA) was also used to investigate whether time and sex generally affect the cognitive impairments in SPMS patients. A p-value <0.05 was considered as statistically significant in this study. Results:Of the total 35 patients, 34% and 66% were men and women with a mean age of 41.33 and 41.39 years old, respectively. Rituximab showed a significant positive effect on a number of subgroups of MACFIMS test, including Controlled Oral Word Association Test (COWAT) (P-value: 0.038) and Brief Visuospatial Memory Test (BVMT-total) (P: 0.019).Conclusion:The present study revealed that Rituximab has a positive effect on the cognitive impairment resulted from MS in secondary progressive patients.

Phenotyping of multiple sclerosis lesions according to innate immune cell activation using 18 kDa translocator protein-PET.

Chronic active lesions are promotors of neurodegeneration and disease progression in multiple sclerosis. They harbour a dense rim of activated innate immune cells at the lesion edge, which promotes lesion growth and thereby induces damage. Conventional MRI is of limited help in identifying the chronic active lesions, so alternative imaging modalities are needed. Objectives were to develop a PET-based automated analysis method for phenotyping of chronic lesions based on lesion-associated innate immune cell activation and to comprehensively evaluate the prevalence of these lesions in the various clinical subtypes of multiple sclerosis, and their association with disability. In this work, we use 18 kDa translocator protein-PET imaging for phenotyping chronic multiple sclerosis lesions at a large scale. For this, we identified 1510 white matter T1-hypointense lesions from 91 multiple sclerosis patients (67 relapsing–remitting patients and 24 secondary progressive patients). Innate immune cell activation at the lesion rim was measured using PET imaging and the 18 kDa translocator protein-binding radioligand 11C-PK11195. A T1-hypointense lesion was classified as rim-active if the distribution volume ratio of 11C-PK11195-binding was low in the plaque core and considerably higher at the plaque edge. If no significant ligand binding was observed, the lesion was classified as inactive. Plaques that had considerable ligand binding both in the core and at the rim were classified as overall-active. Conventional MRI and disability assessment using the Expanded Disability Status Scale were performed at the time of PET imaging. In the secondary progressive cohort, an average of 19% (median, interquartile range: 11–26) of T1 lesions were rim-active in each individual patient, compared to 10% (interquartile range: 0–20) among relapsing–remitting patients (P = 0.009). Secondary progressive patients had a median of 3 (range: 0–11) rim-active lesions, versus 1 (range: 0–18) among relapsing–remitting patients (P = 0.029). Among those patients who had rim-active lesions (n = 63), the average number of active voxels at the rim was higher among secondary progressive compared to relapsing–remitting patients (median 158 versus 74; P = 0.022). The number of active voxels at the rim correlated significantly with the Expanded Disability Status Scale (R = 0.43, P < 0.001), and the volume of the rim-active lesions similarly correlated with the Expanded Disability Status Scale (R = 0.45, P < 0.001). Our study is the first to report in vivo phenotyping of chronic lesions at large scale, based on 18 kDa translocator protein-PET. Patients with higher disability displayed a higher proportion of rim-active lesions. The in vivo lesion phenotyping methodology offers a new tool for individual assessment of smouldering (rim-active) lesion burden.

IMPACT OF RELAPSING REMITTING MULTIPLE SCLEROSIS ON COGNITIVE FUNCTION AND SLEEP PROFILE IN PATIENTS AT ALEXANDRIA UNIVERSITY HOSPITALS

Introduction Multiple sclerosis (MS) is the most common, chronic neuroinflammatory, demyelinating and neurodegenerative disease of CNS affecting individuals in their early adult life Prevalence estimates of cognitive impairment in MS have markedly increased, 40–70% of people with MS experience neuropsychological dysfunction in one or more cognitive domains at every stage of the disease. UP to 42- 65 % of MS patients are believed to have sleep disorders. Sleep abnormalities have a deleterious impact on cognitive functions in MS patients. It is critical to assess the cognitive and sleep affection as well as the bidirectional relationship in patients with multiple sclerosis thus improve overall health and quality of life. Aim of the work: To assess the effect of different clinical variables of RRMS on cognition and sleep, as well as the relation between sleep disturbance and cognitive dysfunction in RRMS patients presented to Alexandria university hospitals..Subjects:The study was carried out on 50 subjects of confirmed Remitting relapsing MS patients with excluding Primary progressive and secondary progressive patients and patients with other associated autoimmune diseases, attending at Alexandria university hospitals.

Italian translation and psychometric validation of the ABILHAND-26 and its correlation with upper limb objective and subjective measures in multiple sclerosis subjects

BackgroundUpper limb (UL) function is affected in about 50% of people with Multiple Sclerosis (PwMS). In the last decade, Patient Reported Outcome Measures (PROM) are playing an important role in clinical trial and practice. ABILIHAND-26 is a PROM that assess self-perceived manual ability defined as the capacity to manage daily activities using the upper limbs. The aim of the study is to translate the ABILHAND-26 into Italian, to explore its psychometric properties examining the associations with demographics, clinical variables, 9-Hole Peg Test (9-HPT) and Manual Ability Measures-36 (MAM-36). Materials and methodsSubjects were recruited in five Italian neurological centers. They were evaluated through ABILHAND-26, 9-HPT and MAM-36. Confirmatory factor analysis and Rasch analysis were adopted to investigate the psychometric properties of the ABILHAND-26. ResultsTwo hundred and forty-five patients were recruited. Rasch analyses showed adequate functioning and supported the unidimensionality of the scale. ABILHAND-26 showed negative correlations with age and disease duration, moderate negative correlation with EDSS and the 9-HPT scores for both arms and strong positive associations (ρ ≥ .84) with the MAM-36. Difference in ABILHAND-26 scores only emerged when comparing patients with severe disability (EDSS ≥ 6) with patients with either mild or moderate disability. t) and when comapring relapsing-remitting and secondary progressive patients. ConclusionThe Italian version of the ABILHAND-26 is now available. It shows adequate reliability of the score, moderate criterion validity and strong convergent validity. ABILHAND-26 could represent a valid assessment for self-perceived ability to perform manual activity, especially for PwMS with moderate-to-high level of disability.

PND10 The Disability Progression of Multiple Sclerosis Progressive Course: A Markov MODEL Approach

Understanding disability progression in multiple sclerosis (MS) patients is essential to estimate the impact of clinical interventions. Detailed assessment of annual changes of patients Expanded Disability Status Scale (EDSS) level is necessary to model EDSS level distribution over time and project the effectiveness and cost of clinical interventions. This data are widely available for relapsing remitting MS, while poor or no data are available for progressive courses. This study aims to fill this gap. MS Primary Progressive (PPMS) and Secondary Progressive (SPMS) patients, with EDSS between 3.0 and 7.0 at first visit, were enrolled in two big MS centers registries in Italy. The registries collected demographic, clinical and treatment data at each visit performed in the centers from 1983 to 2017. Cox proportional hazard models were used to identify clinical characteristic associated to disability progression. Annual EDSS transition probabilities for PPMS and SPMS were estimated using continuous Markov models. Goodness of fit and sensitivity analyses were performed. The study cohort included 758 patients (274 PPMS and 434 SPMS) with a median follow-up of 8.2 years. Relapse rate and EDSS level at first visit were significantly associated to EDSS progression in both progressive courses; while in SPMS disease-modifying treatment in the observational period was also significantly associated. Annual transition probability matrix from EDSS 3.0 to 9.0 were estimated for both MS courses separately, with SPMS reporting a higher annual probability to move within EDSS levels. Goodness of fit was acceptable when comparing predicted and observed EDSS profiles. This study provides for the first time a detailed description of EDSS changes over time for PPMS and SPMS patients. These results could be a useful tool for healthcare decision makers and clinicians to assess the impact of interventions on disability progression in order to select the most valuable ones.

Retrospective unbiased plasma lipidomic of progressive multiple sclerosis patients-identifies lipids discriminating those with faster clinical deterioration

The disease course of patients with a confirmed diagnosis of primary progressive multiple sclerosis (PPMS) is uncertain. In an attempt to identify potential signaling pathways involved in the evolution of the disease, we conducted an exploratory unbiased lipidomic analysis of plasma from non-diseased controls (n = 8) and patients with primary progressive MS (PPMS, n = 19) and either a rapid (PPMS-P, n = 9) or slow (PPMS-NP, n = 10) disease course based on worsening disability and/or MRI-visible appearance of new T2 lesions over a one-year-assessment. Partial least squares-discriminant analysis of the MS/MSALL lipidomic dataset, identified lipids driving the clustering of the groups. Among these lipids, sphingomyelin-d18:1/14:0 and mono-hexosylceramide-d18:1/20:0 were differentially abundant in the plasma of PPMS patients compared to controls and their levels correlated with MRI signs of disease progression. Lyso-phosphatidic acid-18:2 (LPA-18:2) was the only lipid with significantly lower abundance in PPMS patients with a rapidly deteriorating disease course, and its levels inversely correlated with the severity of the neurological deficit. Decreased levels of LPA-18:2 were detected in patients with more rapid disease progression, regardless of therapy and these findings were validated in an independent cohort of secondary progressive (SPMS) patients, but not in a third cohorts of relapsing–remitting (RRMS) patients. Collectively, our analysis suggests that sphingomyelin-d18:1/14:0, mono-hexosylceramide-d18:1/20:0, and LPA-18:2 may represent important targets for future studies aimed at understanding disease progression in MS.

Prevalence of disability improvement as a potential outcome for multiple sclerosis trials

Background: The concept of improvement of disability recently emerged as a new target in multiple sclerosis (MS) studies since the approval of new potent drugs and for testing drugs for neuroprotection and repair. Objective: To propose a simple estimator for assessing and comparing the prevalence of improvement over time between groups. Methods: The prevalence of a transient condition takes into account the incidence and the duration of such condition. We propose here the application of a modified Kaplan–Meier estimator to evaluate and compare between groups the prevalence of improvement over time in a cohort of 121 patients treated with autologous hematopoietic stem cell transplantation. Results: The prevalence of improvement after 5 years from transplant was 50.3% (95%CI: [38.0–63.0]) in relapsing–remitting patients and 6.5% (95%CI: [0–17.8]) in secondary-progressive patients (p < 0.001). Such a difference wouldn’t be evident considering the traditional cumulative probability of improvement at 5 years (55.5% in relapsing–remitting vs 33.4% in secondary-progressive patients, p = 0.10). Conclusion: This study shows the relevance of a new estimator of prevalence of improvement in MS. This estimator gives simple information on whether a drug can induce a durable improvement in disability and can be considered a potential outcome for trials assessing drugs for neuroprotection or repair.

Multiple sclerosis lesions in motor tracts from brain to cervical cord: spatial distribution and correlation with disability.

Despite important efforts to solve the clinico-radiological paradox, correlation between lesion load and physical disability in patients with multiple sclerosis remains modest. One hypothesis could be that lesion location in corticospinal tracts plays a key role in explaining motor impairment. In this study, we describe the distribution of lesions along the corticospinal tracts from the cortex to the cervical spinal cord in patients with various disease phenotypes and disability status. We also assess the link between lesion load and location within corticospinal tracts, and disability at baseline and 2-year follow-up. We retrospectively included 290 patients (22 clinically isolated syndrome, 198 relapsing remitting, 39 secondary progressive, 31 primary progressive multiple sclerosis) from eight sites. Lesions were segmented on both brain (T2-FLAIR or T2-weighted) and cervical (axial T2- or T2*-weighted) MRI scans. Data were processed using an automated and publicly available pipeline. Brain, brainstem and spinal cord portions of the corticospinal tracts were identified using probabilistic atlases to measure the lesion volume fraction. Lesion frequency maps were produced for each phenotype and disability scores assessed with Expanded Disability Status Scale score and pyramidal functional system score. Results show that lesions were not homogeneously distributed along the corticospinal tracts, with the highest lesion frequency in the corona radiata and between C2 and C4 vertebral levels. The lesion volume fraction in the corticospinal tracts was higher in secondary and primary progressive patients (mean = 3.6 ± 2.7% and 2.9 ± 2.4%), compared to relapsing-remitting patients (1.6 ± 2.1%, both P < 0.0001). Voxel-wise analyses confirmed that lesion frequency was higher in progressive compared to relapsing-remitting patients, with significant bilateral clusters in the spinal cord corticospinal tracts (P < 0.01). The baseline Expanded Disability Status Scale score was associated with lesion volume fraction within the brain (r = 0.31, P < 0.0001), brainstem (r = 0.45, P < 0.0001) and spinal cord (r = 0.57, P < 0.0001) corticospinal tracts. The spinal cord corticospinal tracts lesion volume fraction remained the strongest factor in the multiple linear regression model, independently from cord atrophy. Baseline spinal cord corticospinal tracts lesion volume fraction was also associated with disability progression at 2-year follow-up (P = 0.003). Our results suggest a cumulative effect of lesions within the corticospinal tracts along the brain, brainstem and spinal cord portions to explain physical disability in multiple sclerosis patients, with a predominant impact of intramedullary lesions.

Increased plasma levels of mitochondrial DNA and pro-inflammatory cytokines in patients with progressive multiple sclerosis

The role of damage-associated molecular patterns in multiple sclerosis (MS) is under investigation. Here, we studied the contribution of circulating high mobility group box protein 1 (HMGB1) and mitochondrial DNA (mtDNA) to neuroinflammation in progressive MS. We measured plasmatic mtDNA, HMGB1 and pro-inflammatory cytokines in 38 secondary progressive (SP) patients, 35 primary progressive (PP) patients and 42 controls. Free mtDNA was higher in SP than PP. Pro-inflammatory cytokines were increased in progressive patients. In PP, tumor necrosis factor-α correlated with MS Severity Score. Thus, in progressive patients, plasmatic mtDNA and pro-inflammatory cytokines likely contribute to the systemic inflammatory status.

Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression.

BackgroundMultiple Sclerosis (MS) is a chronic inflammatory disease and a leading cause of progressive neurological disability among young adults. DNA methylation, which intersects genes and environment to control cellular functions on a molecular level, may provide insights into MS pathogenesis.MethodsWe measured DNA methylation in CD4+ T cells (n = 31), CD8+ T cells (n = 28), CD14+ monocytes (n = 35) and CD19+ B cells (n = 27) from relapsing-remitting (RRMS), secondary progressive (SPMS) patients and healthy controls (HC) using Infinium HumanMethylation450 arrays. Monocyte (n = 25) and whole blood (n = 275) cohorts were used for validations.FindingsB cells from MS patients displayed most significant differentially methylated positions (DMPs), followed by monocytes, while only few DMPs were detected in T cells. We implemented a non-parametric combination framework (omicsNPC) to increase discovery power by combining evidence from all four cell types. Identified shared DMPs co-localized at MS risk loci and clustered into distinct groups. Functional exploration of changes discriminating RRMS and SPMS from HC implicated lymphocyte signaling, T cell activation and migration. SPMS-specific changes, on the other hand, implicated myeloid cell functions and metabolism. Interestingly, neuronal and neurodegenerative genes and pathways were also specifically enriched in the SPMS cluster.InterpretationWe utilized a statistical framework (omicsNPC) that combines multiple layers of evidence to identify DNA methylation changes that provide new insights into MS pathogenesis in general, and disease progression, in particular.FundThis work was supported by the Swedish Research Council, Stockholm County Council, AstraZeneca, European Research Council, Karolinska Institutet and Margaretha af Ugglas Foundation.

Safety of long-term intrathecal methotrexate in progressive forms of MS.

Background:There are few treatment options for multiple sclerosis (MS) patients with advanced disability [expanded disability status scale (EDSS) ⩾ 6.0]. In 2010, we reported initial results of using intrathecal methotrexate (ITMTX) in patients with progressive MS. We now report on long-term use of ITMTX. We performed a retrospective chart analysis of patients who have had 18 or more treatments to establish the ongoing safety and tolerability of ITMTX. Thus, the objective of this study was to establish the safety and tolerability of long-term therapy with (ITMTX) in patients with treatment-resistant, progressive forms of MS.Methods:We studied 83 patients (67 secondary and 16 primary progressive) who received ITMTX 12.5 mg every 8–11 weeks for 3–10 years (range: 18–57 treatments). All patients were evaluated neurologically, and their EDSS was assessed at every treatment. In addition, all adverse events, frequency of infections, and any hospitalizations, were noted.Results:There were no deaths, hospitalizations, or other serious adverse effects related to ITMTX. Headaches occurred at least once in 12% of patients, and transient fatigue occurred in 53% of patients. As determined by EDSS, there was no significant change from baseline status to post-treatment scores in both primary progressive MS (PPMS) and secondary progressive (SPMS) patients.Conclusions:Pulsed ITMTX was well tolerated for up to 10 years in PPMS patients with no serious adverse effects. Although this was an open-label, retrospective analysis, and efficacy could not be studied, there was evidence of disease stabilization in many patients receiving ITMTX. It appears that long-term ITMTX is a safe therapeutic option in advanced progressive MS.

Therapeutic Use of Intrathecal Mesenchymal Stem Cells in patients with Multiple Sclerosis: A Pilot Study with Booster Injection

ABSTRACTBackground: Mesenchymal stem cells (MSCs) are a potential therapy for various diseases. Here, the results of intrathecal injection of MSCs in multiple sclerosis (MS) patients are reported.Materials and methods: Four patients were enrolled in the study. Three were male and one was female. There were three secondary-progressive MS patients and one relapsing-remitting MS patient. An amount of 50–80 ml of bone marrow was collected from the patients. MSC cultures were collected for each microbiological examination at each change of medium and passage as well as at the time of sample injection. Then, MSCs were injected into the patients by the intrathecal method. In two patients, the injection was replicated in 1 year.Results: All the patients were followed up for 2 years. Three patients who had secondary progression did not show disease progress after the injection, and the disease entered a stable state. A degree of recovery was observed in two patients. The relapsing-remitting patient suffered an attack that led to corticosteroid injection. None of the patients reported side effects. In terms of magnetic resonance imaging, there were no new plaques or enhanced plaques.Conclusion: This study suggests that injection of MSC can be a suitable method, especially for secondary-progressive patients. It seems that reinjection of these stem cells can be safe and sustaining it positively increases the effects of this therapeutic approach.

Predicting cognitive decline in multiple sclerosis: a 5-year follow-up study.

Cognitive decline is common in multiple sclerosis and strongly affects overall quality of life. Despite the identification of cross-sectional MRI correlates of cognitive impairment, predictors of future cognitive decline remain unclear. The objective of this study was to identify which MRI measures of structural damage, demographic and/or clinical measures at baseline best predict cognitive decline, during a 5-year follow-up period. A total of 234 patients with clinically definite multiple sclerosis and 60 healthy control subjects were examined twice, with a 5-year interval (mean = 4.9 years, standard deviation = 0.9). An extensive neuropsychological evaluation was performed at both time points and the reliable change index was computed to evaluate cognitive decline. Both whole-brain and regional MRI (3 T) measures were assessed at baseline, including white matter lesion volume, diffusion-based white matter integrity, cortical and deep grey matter volume. Logistic regression analyses were performed to determine which baseline measures best predicted cognitive decline in the entire sample as well as in early relapsing-remitting (symptom duration <10 years), late relapsing-remitting (symptom duration ≥10 years) and progressive phenotypes. At baseline, patients with multiple sclerosis had a mean disease duration of 14.8 (standard deviation = 8.4) years and 96/234 patients (41%) were classified as cognitively impaired. A total of 66/234 patients (28%) demonstrated cognitive decline during follow-up, with higher frequencies in progressive compared to relapsing-remitting patients: 18/33 secondary progressive patients (55%), 10/19 primary progressive patients (53%) and 38/182 relapsing-remitting patients (21%). A prediction model that included only whole-brain MRI measures (Nagelkerke R2 = 0.22, P < 0.001) showed cortical grey matter volume as the only significant MRI predictor of cognitive decline, while a prediction model that assessed regional MRI measures (Nagelkerke R2 = 0.35, P < 0.001) indicated integrity loss of the anterior thalamic radiation, lesions in the superior longitudinal fasciculus and temporal atrophy as significant MRI predictors for cognitive decline. Disease stage specific regressions showed that cognitive decline in early relapsing-remitting multiple sclerosis was predicted by white matter integrity damage, while cognitive decline in late relapsing-remitting and progressive multiple sclerosis was predicted by cortical atrophy. These results indicate that patients with more severe structural damage at baseline, and especially cortical atrophy, are more prone to suffer from cognitive decline. New studies now need to further elucidate the underlying mechanisms leading to cortical atrophy, evaluate the value of including cortical atrophy as a possible outcome marker in clinical trials as well as study its potential use in individual patient management.

Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis.

Brain magnetic resonance imaging is an important tool in the diagnosis and monitoring of multiple sclerosis patients. However, magnetic resonance imaging alone provides limited information for predicting an individual patient's disability progression. In part, this is because magnetic resonance imaging lacks sensitivity and specificity for detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. The aim of this study was to test for an association between 18 kDa translocator protein brain positron emission tomography signal, which arises largely from microglial activation, and measures of subsequent disease progression in multiple sclerosis patients. Twenty-one patients with multiple sclerosis (seven with secondary progressive disease and 14 with a relapsing remitting disease course) underwent T1- and T2-weighted and magnetization transfer magnetic resonance imaging at baseline and after 1 year. Positron emission tomography scanning with the translocator protein radioligand 11C-PBR28 was performed at baseline. Brain tissue and lesion volumes were segmented from the T1- and T2-weighted magnetic resonance imaging and relative 11C-PBR28 uptake in the normal-appearing white matter was estimated as a distribution volume ratio with respect to a caudate pseudo-reference region. Normal-appearing white matter distribution volume ratio at baseline was correlated with enlarging T2-hyperintense lesion volumes over the subsequent year (ρ = 0.59, P = 0.01). A post hoc analysis showed that this association reflected behaviour in the subgroup of relapsing remitting patients (ρ = 0.74, P = 0.008). By contrast, in the subgroup of secondary progressive patients, microglial activation at baseline was correlated with later progression of brain atrophy (ρ = 0.86, P = 0.04). A regression model including the baseline normal-appearing white matter distribution volume ratio, T2 lesion volume and normal-appearing white matter magnetization transfer ratio for all of the patients combined explained over 90% of the variance in enlarging lesion volume over the subsequent 1 year. Glial activation in white matter assessed by translocator protein PET significantly improves predictions of white matter lesion enlargement in relapsing remitting patients and is associated with greater brain atrophy in secondary progressive disease over a period of short term follow-up.

Sativex® effects on promoter methylation and on CNR1/CNR2 expression in peripheral blood mononuclear cells of progressive multiple sclerosis patients

Multiple sclerosis (MS) is a chronic demyelinating central nervous system (CNS) disease that involve oligodendrocyte loss and failure to remyelinate damaged brain areas causing a progressive neurological disability. Studies in MS mouse model suggest that cannabinoids ameliorate symptoms as spasticity, tremor and pain reducing inflammation via cannabinoid-mediated system.The aim of our study is to investigate the changes in cannabinoid type 1 (CNR1) and 2 (CNR2) receptors mRNA expression levels and promoter methylation in peripheral blood mononuclear cells (PBMCs) of MS secondary progressive (MSS-SP) patients treated with Sativex®.Our cohort included MSS-SP patients, that at the time of Sativex® treatment, are treated (n=7), not treated (n=11) or that had terminated interferon-β-1b (IFN-β-1b) therapy (n=12).By Methylation Sensitive High Resolution Melting (MS-HRM), we characterized the methylation profile of CNR1 and CNR2 promoter region, while the relative mRNA transcript levels of these two genes were evaluated in the same samples by Quantitative Real-Time PCR (qRT-PCR) analysis. We did not find different pattern of cytosine-phosphate-guanine (CpG) methylation in the CNR1/CNR2 promoter region of all MSS-SP patients treated with Sativex®.In addition, CNR1 and CNR2 expression did not significantly differ in MSS-SP patients not treated with IFN-β-1b vs. them that have suspended, while in MSS-SP patients treated with IFN-β-1b during Sativex® therapy we found a specific decrease of the CNR2 expression levels.These results suggest that the different expression of cannabinoid receptors by Sativex® treatment in leukocytes might be regulated through a molecular mechanism that involve interferon modulation.

Sexual functioning in multiple sclerosis: Relationships with depression, fatigue and physical function

Background: Sexual dysfunction (SD) is common among people with multiple sclerosis, but there is limited information on its relationships. Objective: This national study examines the relationships between sexual function with demographic factors, physical function, fatigue and depression. Methods: Participants in the Trajectories of Outcomes in Neurological Conditions (TONiC) study completed the measures of fatigue, physical function and depression together with the Multiple Sclerosis Intimacy and Sexuality Questionnaire-15 (MSISQ-15), which covers sexual function (primary), symptoms that interfere with sexual function (secondary) and psychological issues (tertiary). All ordinal scores from the measures were converted to interval scale latent estimates via the Rasch model and used as single indicator latent variables in path analysis. Results: From 722 patients, 538 were sexually active of whom 431 (80.1%) answered questions on sexual functioning. Of these, only 18.5% reported no impact on any aspect of sexual function. Dysfunction was linked to disease subtype and Expanded Disability Status Scale (EDSS). Subtype influenced the relationship between symptoms and sexual function, which was fully mediated by psychological factors in secondary progressive patients. Depression was not directly associated with sexual functioning, but appeared as a consequence of the psychological issues associated with SD. Conclusion: SD is common among participants in this UK-wide study, and psychological aspects of SD contributed to depression.

Brain Metabolite Changes in Patients with Relapsing-Remitting and Secondary Progressive Multiple Sclerosis: A Two-Year Follow-Up Study.

Magnetic resonance spectroscopy (MRS) provides the unique ability to monitor several disease-related pathological processes via their characteristic metabolic markers in vivo. In the present study metabolic compositions were assessed every six months over the period of two years in 36 patients with Multiple Sclerosis (MS) including 21 relapsing-remitting (RR), 15 secondary progressive (SP) patients and 12 normal subjects. The concentrations of the main MRS-detectable metabolites N-acetylaspartate and N-acetylaspartylglutamate (tNAA), creatine and phosphocreatine (tCr), choline containing compounds (Cho), myo-Inositol (Ins), glutamine and glutamate (Glx) and their ratios were calculated in the normal appearing white matter (NAWM) and in selected non-enhancing white matter (WM) lesions. Association between metabolic concentrations in the NAWM and disability were investigated. Concentration of tNAA, a marker for neuroaxonal integrity, did not show any difference between the investigated groups. However, the patients with SPMS showed significant reduction of tNAA in the NAWM over the investigation period of two years indicating diffuse neuroaxonal loss during the disease course. Furthermore, we found a significant increase of Ins, Ins/tCr and Ins/tNAA in WM lesions independently from the course of the disease suggesting ongoing astrogliosis in silent-appearing WM lesions. Analyzing correlations between MRS metabolites in the NAWM and patients clinical status we found the positive correlation of Ins/tNAA with disability in patients with RRMS. In SPMS positive correlation of Cho with disability was found.