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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.

Some clinical and biological characteristics have been described as prognostic factors for clinical conversion into clinically definite multiple sclerosis in radiologically isolated syndrome (RIS) population. The aim of this study was to assess signatures of circulating miRNAs in those patients according to their conversion status after 5 years of follow-up. OpenArray plates assessing 216 miRNA candidates were run in 15 RIS patients, and their relative abundances were analyzed. A specific profile of deregulated circulating miRNAs (miR-144-3p, miR-448 and miR-653-3p in cerebrospinal fluid and miR-142-3p, miR-338-3p, miR-363-3p, miR-374b-5p, miR-424-5p, miR-483-3p in plasma) differentiated individuals who remained as RIS after 5 years of follow-up. Circulating miRNAs might be used as prognostic biomarkers for RIS patients.

Purpose To describe the pattern of drug consumption among patients with dementia in a geographically defined general population in Catalonia (Spain), and to determine its association with age, gender, type of dementia and severity indicators. Methods Cross-sectional study that included 1,894 cases of dementia registered by the Registry of Dementias of Girona from 2007 to 2009. Prescribed drugs were categorized according to the Anatomical Therapeutic Chemical (ATC) classification. A descriptive analysis of drug consumption was stratified according to age, gender, dementia subtypes and dementia severity. Binary logistic regression models were adjusted to detect the association of these variables with drug consumption according to the ATC groups. Results The most commonly prescribed drugs were for the central nervous system (CNS) (96.4 %), cardiovascular system (79.4 %) and digestive and metabolic system categories (77.7 %). No significant differences were found between the use of nervous system drugs and age, gender, dementia subtypes or dementia severity. The use of alimentary tract and metabolism related drugs, as well as cardiovascular and blood system drugs, were positively correlated with age and secondary dementia. The prevalence of use of cardiovascular and musculoskeletal drugs was higher in women than in men (OR: 1.34; OR: 1.26 respectively). A negative association was found between the severity of dementia and the use of musculoskeletal drugs (OR: 0.71), while its use was significantly higher in the youngest patients (OR: 1.71). Conclusions Almost all patients with dementia received a CNS drug, being at risk of inappropriate treatment. Treatment for comorbidities in patients with dementia should not be withheld on the basis of age or dementia severity, but rather on the benefit/risk ratio of its prescription. Further studies are needed to evaluate potentially inappropriate drug use and possible untreated conditions in this population.

Aims: To describe central nervous system (CNS) drug consumption patterns depending on the time to diagnosis of Alzheimer’s disease (AD), and to check whether the cases diagnosed later are associated with greater severity and consuming more CNS drugs. Methods: Cross-sectional study using 952 cases of the Registry of Dementias of Girona. A binary logistic regression was used to detect variables associated with the use of CNS drugs depending on the time to diagnosis. Results: CNS drugs were consumed by 95.8% of the AD patients. Only antipsychotics presented a statistically significant increase in the frequency of prescription to patients with longer time elapsed from symptom onset to AD diagnosis. Conclusion: Longer time elapsed from the onset of symptoms to the diagnosis resulted in increased probability of antipsychotic consumption.

Knowledge on survival after diagnosis is important for all stakeholders. We aimed to estimate the survival and life expectancy after a dementia diagnosis, and to quantify the impact of dementia subtypes on mortality. Retrospective matched cohort study using a linkage between a dementia-specific registry and two primary care electronic medical records databases. Between 1 January 2007 and 31 December 2015 there were 5,156 subjects aged 60 years and over registered by the Registry of Dementia of Girona and matched to 15,468 age-sex and comorbidity individuals without dementia attended by general practitioners in the province of Girona (Catalonia, Spain). The median survival was 5.2 years (95% CI 5.0 to 5.4), the median life expectancy was 74.7 years (95% CI 71.9 to 76.5), and there were differences by gender. The mortality rate was 127.1 per 1,000 person-years (95% CI 121.6 to 132.7), and the hazard ratio for mortality in persons with dementia ranged between 1.63 (95% CI 1.52 to 1.76) for Alzheimer's disease and 2.52 (95% CI 1.90 to 3.35) for Parkinson-plus syndromes. There was one death per year attributable to dementia for every 18.6 persons with dementia, and for every 2.4 persons with dementia who die, one death was attributable to dementia. The prognosis after dementia diagnosis is conditioned by demographic and clinical features. Although survival is larger for women, they also experience a higher number of years of life lost. Parkinson-plus syndromes and dementia due to multiple etiologies are among the most malignant subtypes regarding mortality.

Background Acetylcholinesterase inhibitors (AChEIs) and the N -methyl d -aspartate-antagonist memantine are indicated for the symptomatic treatment of Alzheimer’s disease (AD). Objectives Our aims were to describe the baseline characteristics of patients with AD according to prescription of these treatments after the diagnostic work-up to describe long-term trends in the use of these medications and to identify baseline characteristics associated with the frequency of use of each treatment. Methods This was a cohort study with a sample of 2992 patients with AD recorded in the Registry of Dementias of Girona (ReDeGi) between 2007 and 2014. Consumption of AChEIs and memantine was assessed using the Pharmacy Unit database from the Public Catalan Healthcare Service. We used generalized estimating equation analyses to identify the baseline characteristics associated with the consumption of AChEIs and memantine over time. Results Most of the patients (70.4%; 95% confidence interval [CI] 68.7–72.0) were prescribed antidementia medication at the time of diagnosis. Of these, 75.0% (95% CI 73.1–76.8) were prescribed AChEIs, 14.7% (95% CI 13.2–16.3) were prescribed an AChEI plus memantine, and 10.3% (95% CI 9.0–11.6) were prescribed memantine. Advanced age reduced the likelihood of AChEI consumption. Mild dementia severity increased the use of AChEIs, and moderate–advanced dementia increased the likelihood of memantine consumption. After diagnosis, the likelihood of AChEI consumption decreased from the first year until the fifth, whereas the likelihood of memantine consumption, either alone or in combination with AChEIs, increased. Conclusions Antidementia drug use in this study showed the initial use of AChEIs alone with later use of AChEIs in combination with memantine and memantine alone in older patients with severe AD. Our findings are in agreement with current clinical practice guidelines for the pharmacological treatment of AD.

Tumor necrosis factor (TNF)-alpha converting enzyme (TACE, also called ADAM17) is a key sheddase that releases TNF-alpha from its inactive cell-bound precursor. TACE protein expression levels in peripheral blood mononuclear cells were measured by Western blot analysis in 20 healthy controls and 80 multiple sclerosis (MS) patients before and after treatment with IFNbeta [20 patients with primary progressive (PP) MS, 20 patients with secondary progressive (SP) MS, and 40 patients with relapsing- remitting (RR) MS (20 patients during clinical remission and 20 patients in relapse)]. TNF-alpha serum levels were also measured by enzyme-linked immunoassay in the MS patients and healthy controls. TACE protein expression levels were lower in healthy controls and PPMS patients compared with SPMS patients and RRMS patient during clinical remission. No differences in TACE protein levels were observed between RRMS patients in relapse and during remission. TACE protein levels were increased in PPMS patients treated with IFNbeta. Serum TNF-alpha levels were higher in RRMS patients in relapse compared with RRMS patients during remission, and positive and negative correlations were found between TACE protein expression and serum TNF-alpha levels in RRMS patients during relapse and during remission respectively. These findings point to different regulatory mechanisms of the TACE-TNF-alpha pathway in the clinical MS subtypes and expand the role of TACE in MS pathogenesis.

Multiple sclerosis (MS) is a disease supposedly of autoimmune origin, with reactivity directed against myelin antigens. From the neuropathological point of view, MS produces inflammation, demyelination and axonal and neuronal degeneration. Inflammatory phenomena are predominant in the initial phase of the disease, followed later by neurodegenerative processes. Over the last decade, early treatment, during the most inflammatory phase of the disease, has been considered the best strategy to treat MS. Accordingly, we decided to determine the periods of delay between the first symptoms and the time to the first medical visit, the time to referral to a specialised MS unit, the delay in undertaking clinical and paraclinical tests, the diagnostic criteria used and the overall delay in diagnosis and treatment. The median time from onset of first symptoms to the first visit to a physician was 19.2 months, which represented the greatest delay. The median time between this initial medical consultation and the confirmation of the diagnosis by a specialised MS unit was 5.7 months, and the overall time from symptom onset to diagnosis was 24.9 months (2.08 years). The median time between onset of the first symptoms and the decision to give the first treatment was 2 years. The most important delay was that from symptom onset to the first medical visit, with the other delays being less. Thus, it is during this initial period that greater effort is required in order to reduce the time to diagnosis, by increasing awareness of the problem of MS among the general population and primary care physicians.