Vasileios Siokas

The Role of TOR1A Polymorphisms in Dystonia: A Systematic Review and Meta-Analysis

Importance A number of genetic loci were found to be associated with dystonia. Quite a few studies have been contacted to examine possible contribution of TOR1A variants to the risk of dystonia, but their results remain conflicting. The aim of the present study was to systematically evaluate the effect of TOR1A gene SNPs on dystonia and its phenotypic subtypes regarding the body distribution. Methods We performed a systematic review of Pubmed database to identify all available studies that reported genotype frequencies of TOR1A SNPs in dystonia. In total 16 studies were included in the quantitative analysis. Odds ratios (ORs) were calculated in each study to estimate the influence of TOR1A SNPs genotypes on the risk of dystonia. The fixed-effects model and the random effects model, in case of high heterogeneity, for recessive and dominant mode of inheritance as well as the free generalized odds ratio (ORG) model were used to calculate both the pooled point estimate in each study and the overall estimates. Results Rs1182 was found to be associated with focal dystonia in recessive mode of inheritance [Odds Ratio, OR (95% confidence interval, C.I.): 1.83 (1.14–2.93), Pz = 0.01]. In addition, rs1801968 was associated with writer’s cramp in both recessive and dominant modes [OR (95%C.I.): 5.99 (2.08–17.21), Pz = 0.00009] and [2.48 (1.36–4.51), Pz = 0.003) respectively and in model free-approach [ORG (95%C.I.): 2.58 (1.45–4.58)]. Conclusions Our meta-analysis revealed a significant implication of rs1182 and rs1801968 TOR1A variants in the development of focal dystonia and writer’s cramp respectively. TOR1A gene variants seem to be implicated in dystonia phenotype.

Vitamin B12, folate, and homocysteine levels and multiple sclerosis: A meta-analysis

BACKGROUND Multiple sclerosis (MS) is a demyelinating and disabling inflammatory disease of the central nervous system. Several factors contribute to MS pathogenesis including genetic-environmental interactions. Case-control studies suggest that there might be associations between MS and homocysteine (Hcy), vitamin B12, and folate blood levels. AIM To meta-analyze all available data describing associations between MS and serum or plasma Hcy, vitamin B12, and folate levels. METHODS The PubMed, MEDLINE, and EMBASE databases were searched for eligible case-control studies published until June 2017. After data extraction, separate analyses using mainly random-effects models were conducted to test for associations between MS and vitamin B12, Hcy, or folate blood levels. RESULTS Twelve, 12, and 9 studies met the inclusion criteria for meta-analysis of MS and Hcy, vitamin B12, and folate levels, respectively. The standardized mean difference (SMD) between MS patients and controls was statistically significant for Hcy (SMD: 0.70, 95% CI: 0.06, 1.34). Stratification according to clinical pattern did not reveal significant differences between relapsing-remitting MS patients and controls (SMD: 0.30, 95% CI: -0.93, 1.54) or between secondary progressive MS patients and controls (SMD: 0.12, 95% CI: -1.65, 1.90). There were no significant differences in SMD between MS patients and healthy individuals for vitamin B12 (SMD: -0.09, 95% CI: -0.29, 0.10) or folate (SMD: -0.06, 95% CI: -0.17, 0.05). CONCLUSION MS patients tend to have elevated Hcy blood levels compared to healthy controls. Hcy may contribute to the pathogenesis of the disease.

Deciphering the role of DNA methylation in multiple sclerosis: emerging issues

Multiple sclerosis (MS) is an autoimmune inflammatory and neurodegenerative disease of the central nervous system that involves several not yet fully elucidated pathophysiologic mechanisms. There is increasing evidence that epigenetic modifications at level of DNA bases, histones, and micro-RNAs may confer risk for MS. DNA methylation seems to have a prominent role in the epigenetics of MS, as aberrant methylation in the promoter regions across genome may underlie several processes involved in the initiation and development of MS. In the present review, we discuss current understanding regarding the role of DNA methylation in MS, possible therapeutic implications and future emerging issues.

Genetic polymorphisms in amyotrophic lateral sclerosis: Evidence for implication in detoxification pathways of environmental toxicants

Abstract Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease of the central nervous system, characterized by progressive loss of motor neurons, and occurring in both sporadic and familial form. The origin of the disease is unknown, though increasing evidence suggests that the interaction between genetic and environmental factors may increase susceptibility to ALS, including its sporadic form. Although genetic mutations have been correlated to the familial type of ALS, relatively little is known about the sporadic type (sALS). Genetic factors concerning pesticide metabolism and heavy metal detoxification are increasing the susceptibility to sALS. This review focuses on the genes implicated in metabolic detoxification pathways of environmental toxicants and their potential role in ALS susceptibility.

Efficacy of computer-based cognitive training in neuropsychological performance of patients with multiple sclerosis: a systematic review and meta-analysis

IMPORTANCE Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by relapses and a progressive course that may lead to accumulation of physical and cognitive disability. Cognitive training interventions seem to improve the cognitive performance of MS patients. The aim of the present meta-analysis is to quantitatively investigate the effect of computer-based cognitive rehabilitation on the neuropsychological performance of patients with MS. METHODS We performed a systematic review of the PubMed database to identify available studies that performed computer-based cognitive training in MS patients. Studies should have reported pre- and post-cognitive training neuropsychological tests scores and included both intervention and placebo/no-intervention MS groups. We analyzed the effect of computer-based cognitive rehabilitation on individual neuropsychological tests, on specific functional domains, and on overall cognition performance. The effect-size of cognitive training pre- and post-treatment compared to placebo/ no-intervention was estimated using the standardized mean difference (SMD). The 95% confidence intervals (CI) were estimated using a Z test by comparing the final values. Baseline between-group differences in selected outcomes were estimated with ANOVA. RESULTS In total, 9 studies fulfilled the criteria for inclusion and were inserted in the quantitative analysis. Computer-based cognitive training was found to improve the performance in the memory domain of MS patients compared to control interventions (SMD, 0.22; 95% CI 0.01-0.43; p = 0.04). Moreover, in the subgroup analysis, cognitive training demonstrated significant effects in Selective Reminding Test (SRT) delay memory (SMD, 0.58; 95% CI 0.29-0.87; p < 0.001). CONCLUSIONS The present meta-analysis revealed a significant effect for computer-based cognitive training on the performance of the memory domain of patients with MS. This finding may have significant implications in the current treatment practice when cognitive decline is detected in MS patients.

CpG Island Methylation Patterns in Relapsing-Remitting Multiple Sclerosis

AbstractDNA methylation may predispose to multiple sclerosis (MS), as aberrant methylation in the promoter regions across the genome seems to underlie several processes of MS. We have currently determined the methylation status of eight genes in relapsing-remitting MS patients. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was used to determine the status of 31 CpG islands, located across eight genes, in 33 healthy individuals and 66 MS patients (33 in relapse and 33 in remission). The methylation levels in the examined sites ranged from 0 to 31%. Methylation positivity for RUNX3 and CDKN2A differed significantly between MS patients and healthy controls. Maximum methylation in RUNX3, CDKN2A, SOCS1, and NEUROG1 genes was significantly different between patients and controls. Roc curves demonstrated that the appropriate cut-offs to distinguish patients from healthy controls were 2% for RUNX3 (OR 3.316, CI 1.207–9.107, p = 0.024) and 3% for CDKN2A (OR 3.077, CI 1.281–7.39, p = 0.018). No difference in methylation was observed between patients in relapse and patients in remission, in any of the genes examined. Methylation patterns of RUNX3 and CDKN2A may be able to distinguish between MS patients and healthy controls, but not between MS patients in relapse and in remission. Graphical AbstractMethylation patterns of RUNX3 and CDKN2A may be able to discriminate healthy individuals from MS patients.

Genetic variations in the SULF1 gene alter the risk of cervical cancer and precancerous lesions

Human papillomavirus (HPV) infection alone is not sufficient to explain the development of cervical cancer. Genetic variants have been linked to the development of precancerous lesions and cervical cancer. In this study, we aimed to evaluate the association of 10 single nucleotide polymorphisms (SNPs) of the Fas cell surface death receptor (FAS), trinucleotide repeat containing 6C (TNRC6C), transmembrane channel like 8 (TMC8), DNA meiotic recombinase 1 (DMC1), deoxyuridine triphosphatase (DUT), sulfatase 1 (SULF1), 2′-5-oligoadenylate synthetase 3 (OAS3), general transcription factor IIH subunit 4 (GTF2H4) and interferon gamma (IFNG) genes with susceptibility to precancerous lesions and cervical cancer. In total, 608 female participants, consisting of 199 patients with persistent low-grade precancerous lesions (CIN1), 100 with high-grade precancerous lesions (CIN2/3), 17 patients with cervical cancer and 292 healthy controls, were enrolled in this study. SNPs were tested for associations with each of the above-mentioned cervical group lesions or when considering an overall patient group. A significant difference for rs4737999 was observed between the controls and the overall patient group considering the recessive mode of inheritance [odds ratio (OR), 0.48; 95% confidence interval (CI), 0.24–0.96; P=0.033]. This effect was even stronger on the risk of CIN1 lesions. Carriers of the rs4737999 AA genotype were almost 3-fold less likely of having low grade lesions compared to the other genotypes. On the whole, this study provides evidence of an influence of the SULF1 gene rs4737999 SNP in the development of precancerous lesions/cervical cancer.

Body mass index and survival from amyotrophic lateral sclerosis: A meta-analysis

Background Several studies have examined the relationship between body mass index (BMI) and survival from amyotrophic lateral sclerosis (ALS). Many indicate that low BMI at diagnosis or during follow-up may be associated with accelerated progression and shortened survival. This study systematically evaluated the relationship between BMI and survival in patients with ALS. Methods The PubMed database was searched to identify all available studies reporting time-to-event data. Eight studies with 6,098 patients fulfilled the eligibility criteria. BMI was considered a continuous and ordered variable. Interstudy heterogeneity was assessed by the Cochran Q test and quantified by the I2 metric. Fixed- or random-effects odds ratios summarized pooled effects after taking interstudy variability into account. Significance was set at p < 0.05. Results The ALS survival hazard ratio (HR) decreased approximately by 3% (95% confidence interval [CI]: 2%–5%) for each additional BMI unit when BMI was considered a continuous variable. When BMI was considered a categorical variable, the HRs for “normal” BMI vs “overweight” BMI and “obese” BMI were estimated to be as high as 0.91 (95% CI: 0.79–1.04) and 0.78 (95% CI: 0.60–1.01), respectively. The HR for the comparison of the “normal” BMI vs “underweight” BMI was estimated to be as high as 1.94 (95% CI: 1.42–2.65). Conclusions BMI is significantly and inversely associated with ALS survival.

Replication study of GWAS risk loci in Greek multiple sclerosis patients

ObjectivesTo validate in an ethnically homogeneous Greek multiple sclerosis (MS) cohort, genetic risk factors for the disease, identified through a number of previous multi-ethnic genome-wide association studies (GWAS).MethodsA total of 1228 MS cases and 1014 controls were recruited in the study, from 3 MS centers in Greece. We genotyped 35 susceptibility SNPs that emerged from previous GWAS or meta-analyses of GWAS. Allele and genotype single locus regression analysis, adjusted for gender and site, was performed. Permutation testing was applied to all analyses.ResultsSix polymorphisms reached statistical significance (permutation p value < 0.05). In particular, rs2760524 of LOC105371664, near RGS1 (permutation p value 0.001), rs3129889 of HLA-DRA, near HLA-DRB1 (permutation p value < 1.00e-04), rs1738074 of TAGAP (permutation p value 0.007), rs703842 of METTL1/CYP27B1 (permutation p value 0.008), rs9596270 of DLEU1 (permutation p value < 1.00e-04), and rs17445836 of LincRNA, near IRF8 (permutation p value 0.001) were identified as susceptibility risk factors in our group.ConclusionThe current study replicated a number of GWAS susceptibility SNPs, which implies that some similarities between the examined Greek population and the MS genetic architecture of the GWAS populations do exist.

Beneficial Effect of Multidomain Cognitive Training on the Neuropsychological Performance of Patients with Early-Stage Alzheimer’s Disease

Background and Purpose There is an increasing interest in the effect of nonpharmacological interventions on the course of patients with Alzheimers disease (AD). The objective of the present study is to determine the benefits of a structured, multidomain, mostly computer-based, cognitive training (MCT) οn the cognitive performance of patients with early-stage AD. Method Fifty patients with early-stage AD participated in the study. Patients were randomly allocated either to the training program group (n = 25) or to a wait list control group (n = 25). The training program group received computer-assisted MCT and linguistic exercises utilizing pen and paper supplemented by cognitive-linguistic exercises for homework. The duration of the MCT intervention program was 15 weeks, and it was administered twice a week. Each session lasted for approximately one hour. Objective measures of episodic memory, delayed memory, word recognition, attention, executive function, processing speed, semantic fluency, and naming were assessed at baseline and after the completion of the program in both groups. Results Analysis showed that in controls, delayed memory and executive function had deteriorated over the observation period of 15 weeks, while the training group improved their performance in word recognition, Boston Naming Test (BNT), semantic fluency (SF), clock-drawing test (CDT), digit span forward (DSF), digit span backward (DSB), trail-making test A (TMT A), and trail-making test B (TMT B). Comparison between the training group and the controls showed that MCT had a significant beneficial effect in delayed memory, naming, semantic fluency, visuospatial ability, executive functions, attention, and processing speed. Conclusions The study provides evidence of a beneficial effect of MCT with an emphasis on cognitive-language performance of patients with early-stage AD. Considering the limited efficacy of current pharmacological therapies in AD, concurrent computer-based MCT may represent an additional enhancing treatment option in early-stage AD patients.