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Background MicroRNAs (miRNAs) have been reported as deregulated in active brain lesions derived from patients with multiple sclerosis (MS). In there, these post-transcriptional regulators may elicit very important effects but proper identification of miRNA candidates as potential biomarkers and/or therapeutic targets is scarcely available. Objective The aim of the study was to detect the presence of a set of candidate miRNAs in cell-free cerebrospinal fluid (CSF) and to determine their association with gadolinium-enhancing (Gd+) lesions in order to assess their value as biomarkers of MS activity. Methods Assessment of 28 miRNA candidates in cell-free CSF collected from 46 patients with MS (26 Gd+ and 20 Gd− patients) was performed by TaqMan assays and qPCR. Variations in their relative abundance were analyzed by the Mann-Whitney U test and further evaluated by receiver operating characteristic (ROC) analysis. Signaling pathways and biological functions of miRNAs were analyzed using bioinformatic tools (miRTarBase, Enrichr, REVIGO, and Cytoscape softwares). Results Seven out of 28 miRNA candidates were detected in at least 75% of CSF samples. Consistent increase of miR-21 and miR-146a/b was found in Gd+ MS patients. This increase was in parallel to the number of Gd+ lesions and neurofilament light chain (NF-L) levels. Gene Ontology enrichment analysis revealed that the target genes of these miRNAs are involved in biological processes of key relevance such as apoptosis, cell migration and proliferation, and in cytokine-mediated signaling pathways. Conclusion Levels of miR-21 and miR-146a/b in cell-free CSF may represent valuable biomarkers to identify patients with active MS lesions.

ObjectivesWe want to report the clinical and radiological features of our cohort of patients diagnosed with cerebral amyloid angiopathy-related inflammation (CAA-RI) according to the Boston Criteria and additionally to disclose some atypical clinical characteristics observed in some of them to provide more knowledge about this novel entity.MethodsWe describe 5 patients with probable CAA-RI according to a validation study of proposed criteria for the diagnosis of CAA-RI at University Hospital Josep Trueta of Girona. We consider some clinical characteristics which include the response to immunotherapy, CSF findings, and MRI features. The patient’s neurologic outcomes were assessed using the modified Rankin Scale (mRS).ResultsWe collected 5 patients admitted for probable CAA-RI. Most were women and the median age was 72 years. The median mRS score at the onset of disease was 1. Parietal lobes were most affected clinically as well as radiologically. Two patients had intracranial hemorrhage. Decreased levels of CSF amyloid beta 42 and 40 protein were observed. Corticosteroids were used in four patients and a remarkable improvement was observed in all of them.ConclusionsCAA-RI is a condition that predominantly affects parietal lobes according to our case series and this involvement seems to be directly related to a greater burden of microbleeds, cortical siderosis, WMH, and lobar hemorrhages on these lobes. Decreased levels of CSF amyloid beta protein plus increased total tau protein should be considered as part of the diagnostic criteria of CAA-RI. We recommend corticosteroids using, as they have been demonstrated to be very effective in managing CAA-RI.

Progressive multiple sclerosis (MS) involves heterogeneous mechanisms, and primary progressive MS without inflammatory activity (PPMS-NA) is poorly understood. To characterize the immune-oxidative profile of PPMS-NA and assess plasma IL-6, IL-8, IFNα2, and cerebrospinal fluid (CSF) reactive oxygen species (ROS) as predictors of disability and cognitive decline. We conducted a multicenter longitudinal study with two cohorts. Cohort 1 included participants across MS phenotypes (n = 146 baseline; n = 36 follow-up) and other neurological disorders, measuring plasma cytokines and CSF ROS. Cohort 2 included 40 people with MS, followed for 10 years to assess associations with cognition. Outcomes were analyzed with multivariate models. PPMS-NA showed reduced IL-6 and IFNα2 but elevated CSF ROS versus RRMS and OND, reflecting low systemic inflammation and central oxidative stress. IL-8 increased, predicting disability and 10-year processing speed decline. IL-6 had time- and domain-specific effects: initially linked to attention, later inversely with visuospatial and working memory. CSF ROS correlated with atrophy, supporting oxidative stress as neurodegeneration driver. PPMS-NA is a progressive MS subtype driven by oxidative and glial processes. IL-8 and CSF ROS are biomarkers for early stratification, and IL-6 relates to cognition, supporting therapies targeting oxidative stress and glia.

Although fingolimod, a sphingosine 1-phosphate receptor agonist, has shown to be an effective treatment reducing relapse rate and also slowing down the disability progression in relapsing-remitting multiple sclerosis (RRMS) patients, it is important to quickly identify those suboptimal responders. The main objective was to assess different clinical, radiological, genetic and environmental factors as possible early predictors of response in MS patients treated with fingolimod for 24 months. The secondary objective was to analyze the possible contribution of the environmental factors analyzed to the progression and activity of the disease along the 2-years of follow-up. A retrospective study with 151 patients diagnosed with MS, under fingolimod treatment for 24 months, with serum samples at initiation and six months later, and with clinical and radiological data at initiation and 24 months later, were included in the study. Clinical and radiological variables were collected to establish NEDA-3 (no evidence of disease activity: patients without relapses, disability progression and new T2 lesions or Gd+ lesions) and EDA (evidence of disease activity: patients with relapses and/or progression and/or new T2 lesions or gadolinium-positive [Gd+] lesions) conditions. Human leukocyte antigen II (HLA-II), EBNA-1 IgG and VCA IgG from Epstein-Barr virus (EBV) and antibody titers against Human herpesvirus 6A/B (HHV-6A/B) were also analyzed. A total of 151 MS patients fulfilled the inclusion criteria: 27.8% was NEDA-3 (37.5% among those previously treated with high efficacy therapies >24 months). The following early predictors were statistically significantly associated with NEDA-3 condition: sex (male; p=0.002), age at baseline (older; p=0.009), relapses 2-years before fingolimod initiation ≤1 (p=0.010), and absence of Gd+ lesions at baseline (p=0.006). Regarding the possible contribution of the environmental factors included in the study to the activity or the progression of the disease, we only found that EBNA-1 IgG titers decreased in 20.0% of PIRA (progression independent from relapse activity) patients vs. 73.3% of RAW (relapse-associated worsening) patients (p=0.006; O.R. = 11.0). MS patients that are male, older, and with a low clinical and radiological activity at fingolimod initiation have a greater probability to reach NEDA-3 condition after two years with this therapy. An intriguing association of EBV with the progression of the disease has also been described, but it should be further study in a larger cohort to confirm these results.

Interferon beta receptor 2 subunit (IFNAR2) can be produced as a transmembrane protein, but also as a soluble form (sIFNAR2) generated by alternative splicing or proteolytic cleavage, which has both agonist and antagonist activities for IFN-β. However, its role regarding the clinical response to IFN-β for relapsing-remitting multiple sclerosis (RRMS) is unknown. We aim to evaluate the short-term effects and after 6 and 12 months of IFN-β therapy on sIFNAR2 production and their association with the clinical response in MS patients. Ninety-four RRMS patients were included and evaluated at baseline, 6 and 12 months from treatment onset. A subset of 41 patients were classified as responders and non-responders to IFN-β therapy. sIFNAR2 serum levels were measured by ELISA. mRNA expression for IFNAR1, IFNAR2 splice variants, MxA and proteases were assessed by RT-PCR. The short-term effect was evaluated in PBMC from RRMS patients after IFN-β stimulation . Protein and mRNA levels of sIFNAR2 increased after IFN-β treatment. According to the clinical response, only non-responders increased sIFNAR2 significantly at both protein and mRNA levels. sIFNAR2 gene expression correlated with the transmembrane isoform expression and was 2.3-fold higher. While MxA gene expression increased significantly after treatment, IFNAR1 and IFNAR2 only slightly increased. After short-term IFN-β induction of PBMC, 6/7 patients increased the sIFNAR2 expression. IFN-β administration induces the production of sIFNAR2 in RRMS and higher levels might be associated to the reduction of therapeutic response. Thus, levels of sIFNAR2 could be monitored to optimize an effective response to IFN-β therapy.

To explore if baseline blood lymphocyte profile could identify relapsing remitting multiple sclerosis (RRMS) patients at higher risk of developing secondary autoimmune adverse events (AIAEs) after alemtuzumab treatment. Multicenter prospective study including 57 RRMS patients treated with alemtuzumab followed for 3.25 [3.5-4.21] years, (median [interquartile range]). Blood samples were collected at baseline, and leukocyte subsets determined by flow cytometry. We had additional samples one year after the first cycle of alemtuzumab treatment in 39 cases. Twenty-two patients (38.6%) developed AIAEs during follow-up. They had higher B-cell percentages at baseline (p=0.0014), being differences mainly due to plasmablasts/plasma cells (PB/PC, p=0.0011). Those with no AIAEs had higher percentages of CD4+ T cells (p=0.013), mainly due to terminally differentiated (TD) (p=0.034) and effector memory (EM) (p=0.031) phenotypes. AIAEs- patients also showed higher values of TNF-alpha-producing CD8+ T cells (p=0.029). The percentage of PB/PC was the best variable to differentiate both groups of patients. Baseline values >0.10% closely associated with higher AIAE risk (Odds ratio [OR]: 5.91, 95% CI: 1.83-19.10, p=0.004). When excluding the 12 patients with natalizumab, which decreases blood PB/PC percentages, being the last treatment before alemtuzumab, baseline PB/PC >0.1% even predicted more accurately the risk of AIAEs (OR: 11.67, 95% CI: 2.62-51.89, p=0.0007). The AIAEs+ group continued having high percentages of PB/PC after a year of alemtuzumab treatment (p=0.0058). A PB/PC percentage <0.1% at baseline identifies MS patients at low risk of secondary autoimmunity during alemtuzumab treatment.​.

Background An association has been found between the presence of lipid‐specific oligoclonal IgM bands (LS‐OCMB) in cerebrospinal fluid and a more severe clinical multiple sclerosis course. Objective To investigate lipid‐specific oligoclonal IgM bands as a prognostic biomarker of cognitive impairment in the early stages of multiple sclerosis. Methods Forty‐four patients underwent neuropsychological assessment at baseline and 4 years. Cognitive performance at follow‐up was compared adjusting by age, education, anxiety–depression, and baseline performance. Results LS‐OCMB+ patients only performed worse for Long‐Term Storage in the Selective Reminding Test (p = .018). Conclusion There are no remarkable cognitive differences between LS‐OCMB– and LS‐OCMB+ patients in the early stages of MS. Although an association has been reported between the presence of lipid‐specific oligoclonal IgM bands (LS‐OCMB) in cerebrospinal fluid and a more severe clinical multiple sclerosis course, no remarkable cognitive differences were found in this study between LS‐OCMB– and LS‐OCMB+ patients in the early stages of MS.

Background and purpose Evidence on regional changes resulting from neurodegenerative processes underlying primary progressive multiple sclerosis (PPMS) is still limited. We assessed brain region volumes and their relationship with disability progression and cognitive function in PPMS patients. Methods This was an MRI analysis of 43 patients from the prospective Understanding Primary Progressive Multiple Sclerosis (UPPMS) cohort study. MRI scans were performed within 3 months before enrollment and at month 12. Results Gray matter volume of declive and white matter volumes adjacent to left straight gyrus, right calcarine sulcus, and right inferior occipital gyrus significantly decreased from baseline to month 12. Baseline white matter volumes adjacent to right amygdala and left cuneus significantly differed between patients with and without disability progression, as well as baseline gray matter volumes of left cuneus, right parahippocampal gyrus, right insula, left superior frontal gyrus, declive, right inferior temporal gyrus, right superior temporal gyrus (pole), and right calcarine sulcus. Baseline gray matter volumes of right cuneus and right superior temporal gyrus positively correlated with 12‐month Selective Reminding Test and Word List Generation performance, respectively. Gray matter changes in right superior semilunar lobe and white matter adjacent to left declive and right cerebellar tonsil also positively correlated with Word List Generation scores, while white matter change in left inferior semilunar lobe positively correlated with Symbol Digit Modalities Test performance after 12 months. Conclusions White and gray matter volumes of specific brain regions could predict disability progression and cognitive performance of PPMS patients after one year. The data described in the present manuscript provide a detailed description of region volume changes exhibited by primary progressive multiple sclerosis patients over one year, including decreases in gray matter declive and white matter adjacent to left straight gyrus, right calcarine sulcus, and right inferior occipital gyrus. In addition, baseline volumes of white matter adjacent to right amygdala and left cuneus could also predict 1‐year disability progression in patients with primary progressive multiple sclerosis, as well as baseline grey matter volumes of left cuneus, right parahippocampal gyrus, right insula, left superior frontal gyrus, declive, right inferior temporal gyrus, right superior temporal gyrus (pole), and right calcarine sulcus. Furthermore, baseline volumes of certain regions such as grey matter of right cuneus and right superior temporal gyrus could also predict cognitive performance after one year, as well as volume changes in grey matter of right superior semilunar lobe and white matter of left inferior semilunar lobe and adjacent to left declive and right cerebellar tonsil were correlates of cognitive performance.

ObjectiveThis study aims to report the clinical heterogeneity of myoclonus in 6 patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).MethodsPatient data were obtained from medical records from the University Hospital Dr. Josep Trueta, Girona, Spain.ResultsSix patients (5 men and 1 woman, aged 60–76 years) presented with different myoclonus phenotypes. All of them had a medical history of hypertension and overweight. The latency of myoclonus appearance ranged from 1 to 129 days. The phenotype most observed was generalized myoclonus. Special phenotypes such as painful legs and moving toes syndrome with jerking feet, Lazarus sign-like, action myoclonus/ataxia syndrome, and segmental myoclonus secondary to myelitis have been described too. Levetiracetam and clonazepam were medications most used successfully. Two patients died for complications not related to myoclonus.ConclusionsOur 6 cases highlight the heterogeneity of the clinical spectrum of myoclonus associated to COVID-19 (MYaCO). MYaCO pathogenesis is suspected to be due to an immune-mediated para- or post-infectious phenomenon; nevertheless, further research is needed to elucidate this hypothesis.

Objectives Shapiro’s syndrome (SS) is a rare condition characterized by spontaneous periodic hypothermia. The underlying pathophysiological mechanisms and etiology of this syndrome remain controversial, and fewer than 100 cases have been reported to date. The objective of this case report is to present a unique iatrogenic case of SS and contribute additional insights into the underlying etiology of this rare disorder. Methods We conducted an analysis of existing medical literature and described a clinical case of SS secondary to a neurosurgical procedure. Results To our knowledge, we present the first iatrogenic case of SS in a 53-year-old woman who underwent a partial right parieto-occipital lobectomy in 2003 as a treatment for refractory epilepsy. Several years after the surgical procedure, she began experiencing recurrent episodes of hypothermia. Brain magnetic resonance imaging (MRI) revealed the absence of the splenium of the corpus callosum (CC) and pituitary hyperplasia. After ruling out other potential causes of hypothermia, a diagnosis of SS was made. Discussion The most plausible mechanism to explain the recurrent hypothermia associated with SS in our patient is a probable disruption of the pathways involved in thermoregulation through the CC as a consequence of the surgical procedure. This case report provides further insights into the etiology of this rare disorder.