Objective
The aims of the study were to determine the immune responses to candidate viral triggers of multiple sclerosis (MS) in patients with clinically isolated syndromes (CISs), and to evaluate ...their potential value in predicting conversion to MS.
Methods
Immune responses to Epstein–Barr virus (EBV), human herpesvirus 6, cytomegalovirus (HCMV), and measles were determined in a cohort of 147 CIS patients with a mean follow‐up of 7 years and compared with 50 demographically matched controls.
Results
Compared with controls, CIS patients showed increased humoral (p < 0.0001) and cellular (p = 0.007) immune responses to the EBV‐encoded nuclear antigen‐1 (EBNA1), but not to other EBV‐derived proteins. Immunoglobulin G (IgG) responses to other virus antigens and frequencies of T cells specific for HCMV and influenza virus gene products were unchanged in CIS patients. EBNA1 was the only viral antigen with which immune responses correlated with number of T2 lesions (p = 0.006) and number of Barkhof criteria (p=0.001) at baseline, and with number of T2 lesions (p = 0.012 at both 1 and 5 years), presence of new T2 lesions (p = 0.003 and p = 0.028 at 1 and 5 years), and Expanded Disability Status Scale score (p = 0.015 and p = 0.010 at 1 and 5 years) during follow‐up. In a univariate Cox regression model, increased EBNA1‐specific IgG responses predicted conversion to MS based on McDonald criteria (hazard ratio 95% confidence interval, 2.2 1.2‐4.3; p = 0.003).
Interpretation
Our results indicate that elevated immune responses toward EBNA1 are selectively increased in CIS patients and suggest that EBNA1‐specific IgG titers could be used as a prognostic marker for disease conversion and disability progression. ANN NEUROL 2010;67:159–169
Background:
MicroRNAs (miRNAs) are non-coding RNAs that regulate cellular processes by controlling protein translation and mRNA degradation.
Objective:
We aimed to explore the miRNA signature of ...multiple sclerosis (MS) patients versus controls and the possibility that patients with lipid-specific oligolconal IgM bands (LS_OCMB), a predictor of a more severe disease course, may have a distinct profile.
Methods:
An extensive profile of 754 miRNAs was evaluated in the cerebrospinal fluid (CSF) of 14 women using TaqMan low-density arrays. Differentially expressed miRNAs together with others previously identified in the literature were validated in an extended sample of 86 MS patients (39 LS_OCMB+) and 55 controls.
Results:
We detected higher levels of miR-150 in MS patients and especially in those with LS_OCMB+. Other miRNAs (miR-328, miR-30a-5p and miR-645) were up-regulated in MS patients compared to controls while miR-21, miR-199a-3p, miR-191, miR-365, miR-106a and miR-146a showed down-regulated expression. Considering only patients with LS_OCMB+, we also detected up-regulation of miR-30a-5p, miR-150 and miR-645 and down-regulation of miR-191 compared to controls.
Conclusion:
Our study confirms the recent findings regarding the deregulated expression of miR-150 not only with MS but also with the presence of LS_OCMB. This study highlights the potential utility of miRNAs in CSF as biomarkers for MS.
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.
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.
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).
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.
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.
There are several position statements and clinical practice guidelines (CPG) for diagnosing dementia.
Our aims were to evaluate the adherence to CPG among specialists in the 7 memory clinics included ...in the Registry of Dementias of Girona (ReDeGi), and to compare the results between 2007-2011 and 2012-2015. We also determined the time and number of visits required to achieve a diagnosis, the supplementary tests ordered, and the drugs prescribed according to dementia subtypes.
Medical charts of a stratified random sample of 475 ReDeGi cases were reviewed. Basic dementia work-up was evaluated using as a reference evidence-based CPG. An Index of Adherence (AI) was calculated using the following items in the medical chart: cognitive symptomatology; functional disability evaluation; physical examination; neurological examination; psychiatric examination; brief cognitive examination; activities of daily living performance examination; blood test; structural neuroimaging (CT-scan or MRI).
The mean AI to CPG among specialists was of 8.2 points, and it improved from 7.9 points in 2007-2011 to 8.5 points in 2012-2015 (Cohen's d = 0.46). A lower adherence was detected in the most severe cases. A dementia diagnosis required 3.5 visits, regardless of the subtype of dementia, although milder cases required more time, more visits, and more supplementary tests than severe cases.
The adherence to CPG in the catchment area of the ReDeGi is high, and an epidemiological surveillance system such as the ReDeGi may help in improving it. Dementia guidelines should establish procedures adapted to clinical practice, with simplified recommendations for most severe cases.
Age- and sex-stratified incidence rates of uncommon dementia subtypes are imprecise and scarce.
We used data from 7357 newly diagnosed individuals aged between 30.6 and 101.0 years from the Registry ...of Dementia of Girona during 2007-2016 to determine the incidence rates of uncommon dementia subtypes stratified by sex and age groups and to describe their clinical characteristics.
Uncommon dementia subtypes were classified according to their etiology. The incidence rate of uncommon dementia subtypes was 27.8 cases per 100,000 person-years for those aged 30 years and older, 3.7 cases per 100,000 person-years for people aged less than 65 years, and 110.9 per 100,000 person-years for those aged 65 years and older. Age, sex, dementia severity, and medical comorbidities were different depending on the dementia subtype.
There are differences in the incidence rates and the demographic and clinical characteristics among uncommon dementia subtypes for age and sex groups.
•Uncommon dementia in aged <65 years was 3.7 cases per 100,000 person-years.•Uncommon dementia in aged ≥65 years was 110.9 cases per 100,000 person-years.•Clinical characteristics of uncommon dementias differ at the moment of diagnosis.•The ratio of uncommon dementia between aged <65 years vs. ≥65 years was 1:30 cases.
Psychotropic drugs are usually prescribed to deal with behavioral and psychological symptoms of dementia, especially when nonpharmacologic approaches are not available or have limited efficacy. Poor ...outcomes and serious adverse events of the drugs used must be addressed, and risk-benefit ratios need to be considered. The aim of this longitudinal study was to describe the evolution of dispensation of psychotropic drugs in patients with Alzheimer's disease (AD) and to identify the associated demographic and clinical variables.
Longitudinal study using 698 cases with AD included in the Registry of Dementias of Girona in 2007 and 2008 and followed up during 3 years. Drugs were categorized according to the Anatomical Therapeutic Chemical classification. Binary logistic regression analyses were used to detect the variables associated with the use of antipsychotics, selective serotonin reuptake inhibitors (SSRIs), anxiolytics, and hypnotics.
Of the patients, 51.2% consumed antipsychotics at least once during the three years of the study, whereas 73.3% and 58.2% consumed SSRIs and anxiolytics, respectively; 32.8% used hypnotics. Antipsychotic use was associated with a diagnosis of AD with delusions) odds ratio (OR) = 5.7 and with increased behavior disorders (OR = 1.2). Patients with AD with depressed mood were more likely to be treated with SSRIs (OR = 3.1), while being a woman was associated with increased dispensation of anxiolytics (OR = 1.9) and SSRIs (OR = 2.2).
Consumption of psychotropic drugs by the patients with AD registered in the Registry of Dementias of Girona is very high. Despite all the described adverse effects and recommendations of caution in their use, antipsychotics still are extensively used.
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.
Acetylcholinesterase inhibitors (AChEIs) and the N-methyl D-aspartate-antagonist memantine are indicated for the symptomatic treatment of Alzheimer's disease (AD).
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.
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.
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.
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.
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