Functional Characterization of the Left Ventrolateral Premotor Cortex in Humans: A Direct Electrophysiological Approach.

In monkeys, motor outputs from premotor cortex (PM) involve cortico-cortical connections with primary motor cortex (M1). However, in humans, the functional organization of PM and its relationship with the corticospinal tract (CST) is still uncertain. This study was carried out in 21 patients undergoing intraoperative brain mapping prior to tumor resection. The left ventrolateral premotor cortex (vlPM-BA6) was identified preoperatively by functional magnetic resonance imaging, and then investigated intraoperatively using high frequency direct electrical stimulation (HF-DES) of the convexity of M1 and vlPM-BA6, with simultaneous recording of motor-evoked potentials (MEPs) from oro-facial, hand and arm muscles. The somatotopy, organization of evoked responses, latency of MEPs, and cortical excitability of vlPM-BA6 were compared with reference data from M1. vlPM-BA6 was found to be less excitable, with significantly longer MEP latencies than M1. In addition to the pure oro-facial and hand-arm muscle representation, a "transition oro-hand zone" was identified in vlPM-BA6. The longer latency of vlPM-BA6 MEPs suggests that human vlPM could act on spinal motoneurons either directly through more slowly conducting CST fibers or via less direct pathways through M1, brainstem, or spinal mechanisms. The results help in disclosing the very different roles of vlPM and M1 in motor control.

Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis.

BACKGROUND AND PURPOSE: Nabiximols (Sativex® ) is a cannabinoid-based compound used for the treatment of moderate to severe spasticity in multiple sclerosis (MS). The aim of the study was to investigate the effect of the administration of Nabiximols on blood transcriptome profile of patients with MS and to interpret it in the context of pathways and networks. METHODS: Whole-genome expression profiling was performed in whole blood of 33 subjects with MS at baseline and after 4 weeks of drug treatment. Patients were classified as responders (n = 19) and non-responders (n = 14). Pathway and network analyses on genes modulated by the drug were performed, followed by in vitro stimulation of peripheral blood mononuclear cells with pro-inflammatory agents to support the immunomodulatory properties of the drug. RESULTS: Individual effect size was modest; however, we observed a downregulation of several immune-related pathways after 4 weeks of treatment, which was more pronounced when restricting analyses to responders. Interesting hub molecules functionally related to the immune system emerged from network analysis, including NFKB1, FYN, MAP14 and TP53. The immunomodulatory properties of the drug were confirmed through in vitro assays in peripheral blood mononuclear cells collected from patients with MS. CONCLUSIONS: Our findings support the immunomodulatory activity of cannabinoids in patients with MS. Further studies in more specific cell types are needed to refine these results.

Basal vitamin D levels and disease activity in multiple sclerosis patients treated with fingolimod.

BACKGROUND: Several studies have shown an association between 25-hydroxyvitamin D (25[OH]D) levels and multiple sclerosis (MS) susceptibility and/or level of disease activity in patients treated with first line drugs. AIMS: To investigate whether baseline 25[OH]D values could influence disease activity also during treatment with the second-line drug fingolimod (FTY). PATIENTS AND METHODS: We enrolled 176 MS patients who started FTY at the San Raffaele Hospital (OSR) MS center with available 25[OH]D measurement at the time of treatment start. We then prospectively followed them for 2 years with periodic clinical examinations and MRI scans. RESULTS: We found no linear correlation between baseline 25[OH]D levels and annualized relapse rate (ARR) or time to first relapse. However, we observed that patients with serum 25[OH]D ≥ 100 nmol/l showed a lower number of Gd+ and combined unique activity (CUA) lesions at baseline compared to patients with the lowest 25[OH]D levels (less than 50 nmol/l, p value < 0.05). Moreover, they showed fewer CUA lesions at 2-year follow-up also when accounting for baseline level of disease activity (p value < 0.05). CONCLUSIONS: In patients treated with FTY, those with the highest baseline 25(OH)D levels had a significantly lower number of active lesions at baseline; the same effect, even if weaker, was observed also at 2-year follow-up when adjusting for baseline disease activity. Given Vitamin D supplementation safety profile, also if a causal effect has not yet been shown, most of MS patients could probably benefit from 25[OH]D levels above those currently considered to be sufficient.

Pharmacogenetic study of long-term response to interferon-ß treatment in multiple sclerosis.

The aim of the study is the identification of genetic factors that influence the long-term response to interferon-ß (IFNß) (4-year follow-up). We performed a genome-wide association study in 337 IFNß-treated Italian multiple sclerosis patients at the extreme of treatment response, and we meta-analyzed association effects, integrating results with pathway analysis, gene-expression profiling of IFNß-stimulated peripheral blood mononuclear cells from 20 healthy controls (HC) and expression quantitative locus (eQTL) analyses. From meta-analysis, 43 markers were associated at P<10-4, and two of them (rs7298096 and rs4726460) pointed to two genes, NINJ2 and TBXAS1, that were significantly downregulated after IFNß stimulation in HC (P=3.1 × 10-9 and 5.6 × 10-10). We also observed an eQTL effect for the allele associated with favorable treatment response (rs4726460A); moreover, TBXAS1 appeared downregulated upon IFNß administration (ß=-0.39; P=0.02). Finally, we found an enrichment of pathways related to inflammatory processes and presynaptic membrane, the latter with involvement of genes related to glutamatergic system (GRM3 and GRIK2), confirming its potential role in the response to IFNß.

Analysis of genes, pathways and networks involved in disease severity and age at onset in primary-progressive multiple sclerosis.

BACKGROUND: The role of genetic factors in influencing the clinical expression of multiple sclerosis (MS) is unclear. OBJECTIVE: The objective of this paper is to identify genes, pathways and networks implicated in age at onset (AAO) and severity, measured using the Multiple Sclerosis Severity Score (MSSS), of primary-progressive MS (PPMS). METHODS: We conducted a genome-wide association study (GWAS) of 470 PPMS patients of Italian origin:. Allelic association of 296,589 SNPs with AAO and MSSS was calculated. Pathway and network analyses were also conducted using different tools. RESULTS: No single association signal exceeded genome-wide significance in AAO and MSSS analyses. Nominally associated genes to AAO and MSSS were enriched in both traits for 10 pathways, including: "oxidative phosphorylation" (FDRAAO=9*10(-4); FDRMSSS=3.0*10(-2)), "citrate (TCA) cycle" (FDRAAO=1.6*10(-2); FDRMSSS=3.2*10(-3)), and "B cell receptor signaling" (FDRAAO=3.1*10(-2); FDRMSSS=2.2*10(-3)). In addition, an enrichment of "chemokine signaling pathway" (FDR=9*10(-4)) for AAO and of "leukocyte transendothelial migration" (FDR=2.4*10(-3)) for MSSS trait was observed, among others. Network analysis revealed that p53 and CREB1 were central hubs for AAO and MSSS traits, respectively. CONCLUSIONS: Despite the fact that no major effect signals emerged in the present GWAS, our data suggest that genetic variants acting in the context of oxidative stress and immune dysfunction could modulate the onset and severity of PPMS.

Predictors of effectiveness of multidisciplinary rehabilitation treatment on motor dysfunction in multiple sclerosis.

OBJECTIVES: To identify clinical predictors of effectiveness of a motor rehabilitation treatment in a cohort of multiple sclerosis (MS) patients. MATERIALS AND METHODS: We analysed 212 consecutive patients who underwent a short-term (3-7 weeks) intensive (two hours per day, five days per week), individualised, goal-oriented inpatient rehabilitation program. Activity limitation and impairment were measured on admission and discharge of the rehabilitation trial using the motor sub-items of the Functional Independence Measure (mFIM) and the Expanded Disability Status Scale (EDSS) score. Multivariate logistic regression models have been tested to evaluate the role of clinical baseline features on rehabilitation effectiveness. RESULTS: According to pre-defined outcome measures, 75.1% of MS patients improved in either activity limitation (≥5 points delta mFIM) or impairment (≥1.0 delta EDSS score if baseline EDSS was ≤5.5, or ≥0.5 if baseline EDSS was >5.5), and 35.4% of MS patients improved in both outcomes. A relapsing-remitting course of disease, a more severe baseline impairment and activity limitation level, a shorter disease duration and a less severe balance dysfunction were predictive of the effectiveness of rehabilitation. DISCUSSION: These data confirm that an intensive inpatient rehabilitation program is able to produce a short-term relevant improvement on clinical and functional outcome measures and suggest some clinical features which can be considered as potential predictors of the outcome of rehabilitative intervention.

Forceps minor damage and co-occurrence of depression and fatigue in multiple sclerosis.

OBJECTIVE: Using diffusion tensor magnetic resonance imaging (DT MRI), we analyzed the architectural integrity of the brain white matter (WM) from a large cohort of MS patients to identify the structural substrates of the concomitant presence of depression and fatigue. METHODS: Brain dual-echo, 3D T1-weighted and DT MRI scans were acquired from 147 MS patients and 90 gender- and age-matched healthy controls (HCs). Patients were stratified by the presence of depression (92 depressed (D), 55 not depressed (nD)) and fatigue (81 fatigued (F), 66 not fatigued (nF)). Sixty-five patients had co-occurrence of depression and fatigue (DF). Whole-brain voxel-wise comparisons of WM DT MRI abnormalities were performed using tract-based-spatial-statistics (TBSS). Tract-specific analyses were run in brain WM tracts using standard-space templates. RESULTS: Whole-brain voxel-wise analysis yielded no significant differences between patient subgroups. At tract-specific analysis, DF patients had reduced fractional anisotropy (FA) of the forceps minor. Reduced FA of the right anterior thalamic radiation and right uncinate fasciculus was found in F-MS vs not F-MS patients after correcting for depression. No significant differences were found between D vs not D-MS patients, after correcting for fatigue. CONCLUSIONS: This study provides evidence for partially overlapping damage to frontal and fronto-temporal pathways underlying depression and fatigue in MS.

Clinical and MRI predictors of response to interferon-beta and glatiramer acetate in relapsing-remitting multiple sclerosis patients.

BACKGROUND AND PURPOSE: It is still unclear which patients benefit more from available disease-modifying treatments (DMTs) in multiple sclerosis (MS). Our objective is to identify the baseline clinical and magnetic resonance imaging (MRI) predictors of response to first-line DMTs in a cohort of relapsing-remitting (RR) MS patients in a real-world clinical setting. METHODS: Consecutive naïve RRMS patients treated with interferon-beta or glatiramer acetate have been included and followed for 2 years. Patients were grouped into responders (R) in case of absence of clinical and MRI activity, and non-responders (NR) if the on-treatment annualized relapse rate (ARR) reduction was < 50% of the ARR in the 2 years before treatment or in the presence of MRI activity (≥ 2 active lesions at 1-year MRI or ≥ 4 active lesions at 1 + 2-year MRI). RESULTS: At 2-year follow-up, 272 patients were R (34.6%) and 322 NR (40.9%), and multivariate analysis revealed that a later age at onset of the disease (P < 0.0001), a lower disability (P < 0.0001) and a lower number of gadolinium-enhancing lesions at baseline MRI (P = 0.002) were predictors of efficacy of DMTs. Moreover, the first year response had a good predictive power on the second year, as 73.7% of 1-year R had no evidence of clinical and MRI activity within the ensuing year. CONCLUSION: A lower baseline MRI and clinical activity have been identified as predictors of DMT efficacy in patients with RRMS in routine clinical practice. Evaluation of clinical and MRI activity at 1 year is recommended to monitor patients over time.

Burden of rare coding variants in an Italian cohort of familial multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative demyelinating disease of the central nervous system. It is a complex and heterogeneous disease caused by a combination of genetic and environmental factors, and it can cluster in families. OBJECTIVE: to evaluate at gene-level the aggregate contribution of predicted damaging low-frequency and rare variants to MS risk in multiplex families. METHODS: We performed whole exome sequencing (WES) in 28 multiplex MS families with at least 3 MS cases (81 affected and 42 unaffected relatives) and 38 unrelated healthy controls. A gene-based burden test was then performed, focusing on two sets of candidate genes: i) literature-driven selection and ii) data-driven selection. RESULTS: We identified 11 genes enriched with predicted damaging low-frequency and rare variants in MS compared to healthy individuals. Among them, UBR2 and DST were the two genes with the strongest enrichment (p = 5 × 10-4 and 3 × 10-4, respectively); interestingly enough the association signal in UBR2 is driven by rs62414610, which was present in 25% of analysed families. CONCLUSION: Despite limitations, this is one of the first studies evaluating the aggregate contribution of predicted damaging low-frequency and rare variants in MS families using WES data. A replication effort in independent cohorts is warranted to validate our findings and to evaluate the role of identified genes in MS pathogenesis.

Oxidative imbalance in different neurodegenerative diseases with memory impairment.

BACKGROUND: Byproducts of oxidative metabolic reactions could play a role in the pathogenesis of several neurodegenerative diseases (ND) including Alzheimer's disease (AD). We designed a study aimed at investigating a large set of oxidative and antioxidant markers in a sample of patients affected by different forms of dementia or memory impairment. METHODS: Serum levels of coenzyme Q(10), malondialdehyde (MDA), the total, oxidized and reduced forms of glutathione (GStot, GSSG and GSH, respectively), reactive oxygen species, anti-oxidized low-density lipoprotein antibodies and antioxidant power (PAO) were investigated in patients affected by AD, mild cognitive impairment, dementia with Lewy bodies and Parkinson's disease with dementia. The patient sample (n = 66) was compared with healthy subjects (HC; n = 62), and a comparison across pathological subgroups was also performed. A multivariate logistic regression model was implemented in order to calculate an algorithm model for predicting the risk of developing a neurodegenerative disorder. RESULTS: The comparison between the memory deficit (MD) group and HC showed a significant difference for MDA (MD: 6.3 ± 2.8 µg/l; HC: 9.1 ± 4.9 µg/l; p = 1.7 × 10(-6)), GStot (MD: 260.4 ± 62.6 mg/l; HC: 306.5 ± 60.7 mg/l; p = 2.2 × 10(-5)), GSH (MD: 208.9 ± 68.4 mg/l; HC: 295.3 ± 101.3 mg/l; p = 2.2 × 10(-7)) and PAO (MD: 1,066.5 ± 247.7 µmol; HC: 954.9 ± 200.4 µmol; p = 0.8 × 10(-3)). By contrast, no differences in the levels of the studied markers were detected across the different forms of ND. An older age, higher levels of PAO, lower levels of GSH and MDA and the use of cardiovascular or antidepressant drugs were the most important factors associated with the carrier ship of neurodegenerative disorder. CONCLUSION: To our knowledge, this is the first study reporting similar oxidative imbalance in different forms of memory impairment, regardless of the specific etiology. Low GSH levels could be considered as a favorable factor in ND; at the same time it could be suggested that higher levels of PAO represent a counteracting mechanism against an increased oxidative stress. The association between vascular risk factors, depressive status and cognitive impairment is in line with findings in the literature.

Transcriptomic Analysis of Peripheral Monocytes upon Fingolimod Treatment in Relapsing Remitting Multiple Sclerosis Patients.

Fingolimod (FTY), a second-line oral drug approved for relapsing remitting Multiple Sclerosis (RRMS) acts in preventing lymphocyte migration outside lymph nodes; moreover, several lines of evidence suggest that it also inhibits myeloid cell activation. In this study, we investigated the transcriptional changes induced by FTY in monocytes in order to better elucidate its mechanism of action. CD14+ monocytes were collected from 24 RRMS patients sampled at baseline and after 6 months of treatment and RNA profiles were obtained through next-generation sequencing. We conducted pathway and sub-paths analysis, followed by centrality analysis of cell-specific interactomes on differentially expressed genes (DEGs). We investigated also the predictive role of baseline monocyte transcription profile in influencing the response to FTY therapy. We observed a marked down-regulation effect (60 down-regulated vs. 0 up-regulated genes). Most of the down-regulated DEGs resulted related with monocyte activation and migration like IL7R, CCR7 and the Wnt signaling mediators LEF1 and TCF7. The involvement of Wnt signaling was also confirmed by subpaths analyses. Furthermore, pathway and network analyses showed an involvement of processes related to immune function and cell migration. Baseline transcriptional profile of the HLA class II gene HLA-DQA1 and HLA-DPA1 were associated with evidence of disease activity after 2 years of treatment. Our data support the evidence that FTY induces major transcriptional changes in monocytes, mainly regarding genes involved in cell trafficking and immune cell activation. The baseline transcriptional levels of genes associated with antigen presenting function were associated with disease activity after 2 years of FTY treatment.

Identification of differential DNA methylation associated with multiple sclerosis: A family-based study.

Multiple Sclerosis (MS) is caused by a still unknown interplay between genetic and environmental factors. Epigenetics, including DNA methylation, represents a model for environmental factors to influence MS risk. Twenty-six affected and 26 unaffected relatives from 8 MS multiplex families were analysed in a multicentric Italian study using MeDIP-Seq, followed by technical validation and biological replication in two additional families of differentially methylated regions (DMRs) using SeqCap Epi Choice Enrichment kit (Roche®). Associations from MeDIP-Seq across families were combined with aggregation statistics, yielding 162 DMRs at FDR ≤ 0.1. Technical validation and biological replication led to 2 hypo-methylated regions, which point to NTM and BAI3 genes, and to 2 hyper-methylated regions in PIK3R1 and CAPN13. These 4 novel regions contain genes of potential interest that need to be tested in larger cohorts of patients.

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males.

Progranulin (GRN) gene variability has been analyzed in a sample of 354 patients with multiple sclerosis (MS) compared with 343 controls. No significant differences were observed, but by stratifying according to MS subtypes, a significant increased frequency of the rs2879096 TT genotype was found in primary progressive MS (PPMS) patients versus controls (16.0 vs 3.5%, P=0.023, odds ratio (OR) 5.2, 95% confidence interval (CI) 1.2-21.4). In addition, in PPMS, an association with the C allele of rs4792938 was observed (55.3 vs 33.5%, P=0.011, OR 2.4, 95% CI 1.2-4.7). An independent population was studied as replication, failing to confirm results previously obtained. Stratifying according to gender, an association with rs4792938 C allele was found in male PPMS patients compared with controls (40.7 vs 26.9%, P=0.002, OR 1.87, 95% CI 1.2-2.8). An association with the rs2879096T allele was observed (29.2 in patients compared with 18.9% in controls, P=0.012, OR 1.77, 95% CI 1.1-2.8). Haplotype analysis showed that TC haplotype frequency is increased in PPMS male patients compared with male controls (25.7 vs 16.6%; P=0.02, OR 1.69, 95% CI 1.1-2.7), whereas the respective GC haplotype seems to exert a protective effect, as its frequency is decreased in patients compared with controls (55.8% vs 70.9%; P=0.001, OR 0.52, 95% CI 0.4-0.8). Therefore, GRN haplotypes likely influence the risk of developing PPMS in males.

Lack of replication of KIF1B gene in an Italian primary progressive multiple sclerosis cohort.

BACKGROUND: KIF1B gene represents the first non-inflammatory gene with a putative role on axonal loss and neurodegeneration found to be associated with multiple sclerosis (MS). The objective of this study is to test the association of the rs10492972 C allelic variant of KIF1B gene in a large Italian cohort of patients with primary progressive and progressive relapsing MS (PPMS and PRMS), which represents a subtype of MS mainly driven by neurodegenerative phenomena. METHODS: rs10492972 has been genotyped in an outbred sample of 222 primary PPMS and PRMS and 221 healthy controls of unique northern Italian origin using the TaqMan assay. RESULTS: A non-significant age- and sex-adjusted odds ratio of 0.96 [95% confidence interval (CI) 0.71-1.31] has been found in C carriers, and a non-significant risk of 0.99 [95% CI 0.77-1.63] in C carriers according to a dominant model. Stratification by sex, age at onset younger than 35 years and symptoms at the onset of the disease did not reveal any significant findings. No influence on disability progression, measured with the multiple sclerosis severity score, was found in C carriers. CONCLUSIONS: These results suggest that there is no effect in carrying the rs10492972 C variant on the risk of disease as well as on the rate of disability progression in a cohort of Italian patients with PPMS and patients with PRMS. These data need to be confirmed in an independent sample of patients with progressive MS.

The WNT receptor ROR2 drives the interaction of multiple myeloma cells with the microenvironment through AKT activation.

Multiple myeloma is the second most frequent hematological cancer after lymphoma and remains an incurable disease. The pervasive support provided by the bone marrow microenvironment to myeloma cells is crucial for their survival. Here, an unbiased assessment of receptor tyrosine kinases overexpressed in myeloma identified ROR2, a receptor for the WNT noncanonical pathway, as highly expressed in myeloma cells. Its ligand, WNT5A is the most abundant growth factor in the bone marrow of myeloma patients. ROR2 mediates myeloma cells interactions with the surrounding bone marrow and its depletion resulted in detachment of myeloma cells from their niche in an in vivo model, triggering apoptosis and thus markedly delaying disease progression. Using in vitro and ex vivo 3D-culture systems, ROR2 was shown to exert a pivotal role in the adhesion of cancer cells to the microenvironment. Genomic studies revealed that the pathways mostly deregulated by ROR2 overexpression were PI3K/AKT and mTOR. Treatment of cells with specific PI3K inhibitors already used in the clinic reduced myeloma cell adhesion to the bone marrow. Together, our findings support the view that ROR2 and its downstream targets represent a novel therapeutic strategy for the large subgroup of MM patients whose cancer cells show ROR2 overexpression.

DCUN1D1 is a risk factor for frontotemporal lobar degeneration.

BACKGROUND AND PURPOSE: Frontotemporal lobar degeneration (FTLD) is considered as a proteinopathy; therefore, it is conceivable that genes encoding for factors involved in protein misfolding and/or degradation could play a role in its pathogenesis. METHODS: An association study of defective in cullin neddylation 1 (DCN-1)-domain containing 1 (DCUN1D1), which is involved in protein degradation, was carried out in a population of 220 patients with FTLD as compared with 229 age-matched controls. RESULTS: A statistically significant increased frequency of the GG genotype of the DCUN1D1 rs4859146 single nucleotide polymorphism (SNP) was observed in patients compared with controls (6.9 vs. 1.7%, P = 0.011, adjusted OR: 4.39, 95% CI: 1.40-13.78). Stratifying according to the clinical syndrome, significant differences were observed between the behavioral variant of frontotemporal dementia and controls (GG frequency: 6.3 vs. 1.7%, P = 0.02, OR:4.0, 95%, CI = 1.24-12.92), as well as between patients with progressive aphasia compared with controls (15.4 vs. 1.7%, P = 0.014, OR = 11.30, 95%, CI = 1.63-78.45), but not in patients with SD versus controls (8.3 vs. 1.7%, P = 0.18, OR = 5.24, 95% C.I. = 0.45-60.63). No significant differences in allelic and genotypic frequencies of the DCUN1D1 rs4859147 SNP were found. CONCLUSIONS: The GG genotype of the DCUN1D1 rs4859147 SNP represents a risk factor for the development of FTLD, increasing the risk of about fourfold.

HLA-DRB1 polymorphisms distribution in chronic dysimmune polyneuropathy.

The frequency of HLA-DRB1*15 polymorphism, which is strongly associated to multiple sclerosis, was investigated in 84 adult patients with chronic dysimmune polyneuropathy and 272 healthy controls. No significant differences were detected between cases and controls and, among patients, according to gender, peripheral nerve antigen antibody seropositivity, and electrophysiological features. A trend towards an increase of HLA-DRB1*11 in anti-MAG neuropathy was detected.

Effectiveness and baseline factors associated to fingolimod response in a real-world study on multiple sclerosis patients.

BACKGROUND: Treatment choice in multiple sclerosis (MS) is crucial for optimizing risk-benefit profile. OBJECTIVE: To assess fingolimod (FTY) effectiveness and identify baseline features associated to disease activity in a large Italian cohort of Relapsing-Remitting (RR) MS patients. METHODS: Three-hundred sixty-seven RRMS patients starting FTY treatment at San Raffaele Hospital (Milan-Italy) underwent clinical and MRI evaluations for 2 years. Treatment response was assessed considering the proportion of patients with no evidence of disease activity (NEDA) and recording the time to first relapse. Primary analyses were performed stratifying for Natalizumab (NTZ) treatment in the year before (NO_NTZ vs NTZ group), to account for post-NTZ reactivation. RESULTS: Almost half of patients were NEDA after 2 years, 53.4% in the NO_NTZ group and 36.2% in the NTZ group. Despite an opposite trend during the first 6-12 months, at 2-year follow-up the two groups were comparable for relapses and number of new/enlarging T2 and Gd-enhancing lesions. Baseline parameters of higher disease activity (ARR, Gd enhancing lesions and age at onset) were associated with increased likelihood of failing NEDA criteria or with shorter time to relapse (p < 0.05). CONCLUSIONS: Our data strengthen FTY effectiveness in everyday clinical practice, even in patients switching from NTZ treatment. Baseline parameters of inflammatory activity are the most important prognostic factors for mid-term disease reactivation also during second-line treatment with FTY, providing hints on how to select therapies towards a more personalized management.

Neuromyelitis optica spectrum disorder and multiple sclerosis in a Sardinian family.

The coexistence of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) in the same family is a rare event. We report a familial case originating from Sardinia of two siblings: one with NMOSD and one with MS. Human leukocyte antigen (HLA) typing showed that the two affected siblings were HLA-identical, sharing risk-increasing alleles, while a younger unaffected sister was haploidentical to her siblings but she also carried protective alleles. Our findings confirm the role of HLA in raising the risk to develop CNS inflammatory diseases and provide further knowledge on the relationship between NMOSD and MS.

Movement preparation is affected by tissue damage in multiple sclerosis: evidence from EEG event-related desynchronization.

OBJECTIVE: To investigate the impact of brain tissue damage in Multiple Sclerosis (MS) on the efficiency of programming of voluntary movement, assessed using event-related desynchronization of the EEG. METHODS: The onset latency of mu ERD (percent desyncronization of the mu rhythm preceding movement onset) to hand movement was studied in 34 MS patients. ERD onset was compared with normative data and correlated with T1 and T2 total lesion volume (TLV) at magnetic resonance imaging (MRI). RESULTS: ERD onset latency was significantly correlated with T1-TLV (r = 0.53, P = 0.001) and T2 lesion load (r = 0.5, P = 0.003), even after correcting for disability. Patients with higher T1-TLV had significantly delayed ERD onset compared with normal subjects and with patients with lower T1-TLV; patients with higher T2-TLV had significantly delayed ERD compared with normal subjects only. ERD onset latency was not correlated to clinical disability. CONCLUSIONS: Our finding of delayed ERD onset in patients with more severe measures of brain damage, independently from clinical disability, suggests that functional cortico-cortical and cortico-subcortical connections underlying the expression of ERD during programming of voluntary movement are disrupted by the MS related pathological process. Further, studies are needed to evaluate the role of specific anatomical cortico-subcortical circuits in determining this abnormality. SIGNIFICANCE: The extent of brain lesion load in multiple sclerosis affects cortical changes related to motor preparation, detected by analysis of onset latency of event-related desynchronization (ERD) of the mu rhythm to self-paced movement.