Possible Implication of GSTP1 and NQO1 Polymorphisms on Natalizumab Response in Multiple Sclerosis.

Oxidative stress plays a pivotal role in the pathogenesis of multiple sclerosis (MS). Inactivating polymorphism of genes encoding detoxification enzymes, such as NQO1 and GSTP1 could influence susceptibility to MS. The monoclonal antibody natalizumab is an effective treatment in MS. Natalizumab's efficacy in MS patients with regard to NQO1 and GSTP1 genetic polymorphisms is investigated. 130 patients with definite MS according to the Mc Donald's criteria treated monthly with natalizumab were included in the study. MS patients were classified with regard to their clinical subtype, gender and clinical outcome after Natalizumab administration. GSTP1 and NQO1 genotyping was performed using Real-Time PCR and PCR-RFLP assays. Among our cohort of MS patients, 88.5% responded and 11.5% manifested clinical deterioration after natalizumab treatment. Statistical analysis revealed a significantly increased frequency of double NQO1 and GSTP1 mutant polymorphisms in non responders compared to the responders. Therefore, patients who carry the wild type genotype or only one polymorphism for either NQO1 or GSTP1 gene have possibly a better clinical outcome after the natalizumab therapy. Our findings indicate that antioxidant efficiency might reflect a better clinical outcome after natalizumab administration. Hence, oxidative stress reduction might be another mechanism through which natalizumab exerts its protective effect.

Combined GSTP1 and NQO1 germline polymorphisms in the susceptibility to Multiple Sclerosis.

Germline polymorphisms of detoxification genes could influence susceptibility to Multiple Sclerosis (MS). Glutathione-S-transferases (GSTs) and NAD(P)H: quinone oxidoreductase 1 (NQO1) are detoxifying enzymes involved in biotransformation of metabolites preventing cells from oxidative damage. In order to evaluate the possible contribution of the A313G GSTP1 inactivating polymorphism, alone and in combination with the C609T NQO1 genetic variant in MS susceptibility, we performed a case-control study consisting of 254 MS patients and 370 healthy donors. Genotypes were investigated using a new Real-Time PCR and PCR-RFLP assays. The GSTP1 polymorphism was evaluated in relation to patients' characteristics (clinical subtypes, age and gender) and the NQO1 gene status. GSTP1 genotype distribution was similar between cases and controls. Higher frequency of GSTP1 heterozygotes was observed in patients with relapsing remitting disease (RRMS) (p = 0.019), especially in those presenting a benign form (EDSS ≤ 2 after 10-15 years from the disease onset). Interestingly, genotype distribution analysis of combined GSTP1 and NQO1 polymorphisms revealed significantly higher frequency of GSTP1 heterozygous (A/G) and NQO1 variant genotypes (C/T and T/T) in patients as compared to the controls (p = 0.031). The increased incidence of combined GSTP1 and NQO1 variant genotypes in MS patients may suggest that defective function of detoxification enzymes might be an important determinant of susceptibility and clinical manifestation of the disease. Moreover, the results suggest a possible role for the GSTP1 heterozygous background in the development of RRMS.

Observational study assessing demographic, economic and clinical factors associated with access and utilization of health care services of patients with multiple sclerosis under treatment with interferon beta-1b (EXTAVIA).

Multiple sclerosis (MS) results in an extensive use of the health care system, even within the first years of diagnosis. The effectiveness and accessibility of the health care system may affect patients' quality of life. The aim of the present study was to evaluate the health care resource use of MS patients under interferon beta-1b (EXTAVIA) treatment in Greece, the demographic or clinical factors that may affect this use and also patient satisfaction with the health care system. Structured interviews were conducted for data collection. In total, 204 patients (74.02% females, mean age (SD) 43.58 (11.42) years) were enrolled in the study. Analysis of the reported data revealed that during the previous year patients made extensive use of health services in particular neurologists (71.08% visited neurologists in public hospitals, 66.67% in private offices and 48.53% in insurance institutes) and physiotherapists. However, the majority of the patients (52.45%) chose as their treating doctor private practice neurologists, which may reflect accessibility barriers or low quality health services in the public health system. Patients seemed to be generally satisfied with the received health care, support and information on MS (84.81% were satisfied from the information provided to them). Patients' health status (as denoted by disease duration, disability status and hospitalization needs) and insurance institute were found to influence their visits to neurologists. Good adherence (up to 70.1%) to the study medication was reported. Patients' feedback on currently provided health services could direct these services towards the patients' expectations.

Big 5 personality changes in Greek bvFTD, AD, and MCI patients.

Patients with neurodegenerative disease show distinct patterns of personality change, some of which may be traced to focal neurological damage, whereas others may be mediated by cultural reactions to functional impairment. Although such changes are early and pervasive in behavioral variant frontotemporal dementia (bvFTD), and milder changes are seen in Alzheimer disease (AD), no study has examined all Big 5 factors of personality in mild cognitive impairment (MCI) patients. In addition, the influence of culture and ethnicity on disease-related personality changes has seldom been examined. Premorbid and current personality were measured in 47 Greek patients with bvFTD, AD, and MCI on the basis of informant reports using the Traits Personality Questionnaire 5, a 5-factor inventory in the Greek language that accounts for Greek cultural factors. bvFTDs showed greater decreases in conscientiousness compared with ADs and MCIs. ADs and MCIs showed increased neuroticism, whereas the bvFTD patients were rated as having become much less neurotic in the course of their disease. The pattern of personality change in MCIs was very similar to that of ADs, supporting recent evidence that personality changes occur as early as the MCI disease stage. In all the groups, personality changes were similar to those previously described in non-Mediterranean cultures, supporting the hypothesis that they may result directly from disease-specific neurological processes.

The C609T inborn polymorphism in NAD(P)H:quinone oxidoreductase 1 is associated with susceptibility to multiple sclerosis and affects the risk of development of the primary progressive form of the disease.

Oxidative stress plays a pivotal role in the pathogenesis of multiple sclerosis (MS). Inactivating polymorphisms of genes encoding detoxification enzymes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1), could influence susceptibility to MS. To test this hypothesis we performed a case-control study in which we compared the distribution of NQO1 genotypes between 231 MS patients and 380 controls, using both PCR-RFLP and real-time PCR assays. Correlations with MS clinical subtype classification and gender were also evaluated. A significantly higher frequency of the homozygous (T/T) and heterozygous (C/T) NQO1 C(609)T variant genotypes was observed among MS patients compared to controls (P=0.01), with MS patients showing a 1.5-fold increased risk of carrying at least one variant T allele (P=0.009). Interestingly, patients belonging to the primary progressive subgroup exhibited a significantly higher incidence of the heterozygous C/T variant genotype, compared to the other forms of MS (P=0.019). There was no correlation of the NQO1 polymorphism with gender. These results provide the first evidence for a pathogenetic role for the NQO1 C(609)T polymorphism in MS susceptibility and suggest a possible role for the NQO1 genetic background in the development of primary progressive MS.

Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate the feasibility, safety, and immunological effects of intrathecal and intravenous administration of autologous mesenchymal stem cells (MSCs) (also called mesenchymal stromal cells) in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). DESIGN: A phase 1/2 open-safety clinical trial. Patients  Fifteen patients with MS (mean [SD] Expanded Disability Status Scale [EDSS] score, 6.7 [1.0]) and 19 with ALS (mean [SD] Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS] score, 20.8 [8.0]) were enrolled. Intervention  After culture, a mean (SD) of 63.2 × 10(6) (2.5 × 10(6)) MSCs was injected intrathecally (n = 34) and intravenously (n = 14). In 9 cases, MSCs were magnetically labeled with the superparamagnetic iron oxide ferumoxides (Feridex). MAIN OUTCOME MEASURES: The main outcome measure was the recording of side effects. Follow-up (≤25 months) included adverse events evaluation, neurological disability assessment by means of the EDSS, magnetic resonance imaging to exclude unexpected pathologies and track the labeled stem cells, and immunological tests to assess the short-term immunomodulatory effects of MSC transplantation. RESULTS: Twenty-one patients had injection-related adverse effects consisting of transient fever, and 15 reported headache. No major adverse effects were reported during follow-up. The mean ALSFRS score remained stable during the first 6 months of observation, whereas the mean (SD) EDSS score improved from 6.7 (1.0) to 5.9 (1.6). Magnetic resonance imaging visualized the MSCs in the occipital horns of the ventricles, indicating the possible migration of ferumoxides-labeled cells in the meninges, subarachnoid space, and spinal cord. Immunological analysis revealed an increase in the proportion of CD4(+)CD25(+) regulatory T cells, a decrease in the proliferative responses of lymphocytes, and the expression of CD40(+), CD83(+), CD86(+), and HLA-DR on myeloid dendritic cells at 24 hours after MSC transplantation. CONCLUSION: Transplantation of MSCs in patients with MS and ALS is a clinically feasible and relatively safe procedure and induces immediate immunomodulatory effects. Trial Registration  clinicaltrials.gov Identifier: NCT00781872.

Breaking bad news: communication around parental multiple sclerosis with children.

This study investigates the relation of communication around parental multiple sclerosis (MS) to family dysfunction and mental health problems of the children in Greek families. Fifty-six families with a parent with MS were studied regarding emotional well-being of children, parental depression, family functioning, and illness' related impairment, correlated to the amount of information about parental illness provided to children. Significant differences were found in three dimensions of child psychopathology on maternal scores of Child Behavior Checklist, between children who had partial information about parental illness and the other two groups of children who had explicit or no information at all. Differences were also observed in children's scores on (Youth Self Report) social problems between the same groups. The finding that children who had only partial information about their parents' illness presented more problems, illustrates the importance of "how, what, and how much" of information is communicated to children. Clinical implications are discussed in terms of the families' difficulties with communicating parental illness with their children and possible need for professional support.

On the calculation of transcallosal conduction time using transcranial magnetic stimulation.

Transcallosal conduction time (TCT), based on the results of transcranial magnetic stimulation studies, is currently calculated as a function of the ipsilateral silent period (iSP) and of the motor evoked potential (MEP) obtained from a target muscle (TCTcurrent = iSP latency - MEP latency). We argue that this measure overestimates TCT and may lead to a bias in statistical group comparisons. We propose an alternative measure, TCTproposed, which we defined as TCTproposed = iSP latency - cSP latency, where cSP is the contralateral silent period. We report our results on the comparison of the two measures in twenty healthy individuals and provide a theoretical basis for TCTproposed.

A novel CADASIL-causing mutation in a stroke patient.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is an uncommon autosomal dominant genetic disease due to mutations in the Notch3 gene on chromosome 19. The major clinical characteristics of CADASIL are migraine, recurrent ischaemic strokes and dementia. CASE REPORT: We describe the case of a 58-year old man who presented with a minor stroke that occurred in the absence of significant vascular risk factors. His family history included stroke, dementia and early death. An MRI brain scan demonstrated hyperintensities in the white matter on FLAIR images with prominent involvement of the area of the external capsule bilaterally. Based on the family history and the MRI findings, CADASIL was suspected. Mutational analysis of the Notch3 gene disclosed a novel mutation substituting cysteine for glycine at codon 251 in exon 5, confirming the diagnosis of CADASIL. CONCLUSION: This case suggests that CADASIL should be suspected in patients with stroke that arises in the absence of known vascular risk factors, especially if there are typical MRI findings. A strong family history of stroke and dementia are also supportive.

Nonepisodic memory deficits in amnestic MCI.

OBJECTIVE: To (a) compare patients with amnestic Mild Cognitive Impairment (MCI), mild Alzheimer disease (AD), and a group of healthy elderly persons on nonepisodic memory measures; (b) examine which measures are independent of level of education in the groups studied. BACKGROUND: Episodic memory impairment is a cardinal feature of preclinical AD. However, a number of other cognitive measures are also sensitive to the preclinical stage of AD and deficits in multiple domains characterize AD several years before clinical diagnosis. MATERIALS AND METHODS: Patients with amnestic MCI (N=31), patients with mild probable AD (N=15), and healthy elderly controls (N=27) were compared on nonepisodic memory tasks measuring fluid intelligence, working memory, processing speed, verbal fluency, and visual-perceptual and motor functions. Amnestic MCI patients were selected based on clinical criteria and a subgroup was also selected based on psychometric criteria. RESULTS: Multivariate analyses of covariance, controlling for the effects of age, education, and sex, showed that fluid intelligence, working memory, processing speed, semantic fluency, visual-perceptual function, and complex motor function were significantly worse in the MCI than the elderly control group. Working memory, processing speed, semantic fluency, and complex motor tasks were significantly worse in the mild probable AD than the MCI group. The analyses were corroborated using the psychometrically derived MCI group. CONCLUSIONS: (a) Performance on multiple nonepisodic memory measures is affected in the preclinical stage of AD, indicating that broad cognitive impairment characterizes that stage. (b) Complex motor tasks were independent of level of education in our sample, and may have practical utility in the early detection of dementia.

Working-delayed memory difference detects mild cognitive impairment without being affected by age and education.

Performance on neuropsychological tests is affected by age and education, which makes the early detection of cognitive impairment difficult when assessing individuals of varying levels of education. We examined the effects of age, education, and gender on three memory indexes of the Wechsler Memory Scale-III, Delayed Memory, Working Memory and the difference between Working-Delayed Memory in a sample of patients with amnestic Mild Cognitive Impairment, patients with mild probable Alzheimer's disease, and a nondemented elderly comparison group. Whereas Delayed and Working Memory scores were affected by participant type, age, and education, the Working-Delayed Memory difference score was affected by participant type, only. Our preliminary conclusions, pending replication of the findings with a larger sample, are that working-delayed memory difference was sensitive to early memory decline without being affected by age and education.

A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy.

This multicentre randomised double blind crossover trial tested the short term efficacy of intravenous immunoglobulin (IVIg) 2.0 g/kg given over 24 or 48 hours in patients with paraproteinaemic demyelinating neuropathy (PDN). Twenty-two patients were randomised and completed the trial. After 2 weeks, the overall disability grade decreased during both IVIg treatment and placebo but neither change was significant nor was the mean difference between the treatment effects. After 4 weeks the overall disability decreased by a mean of 0.55 [0.67] grades during the IVIg period (p = 0.001) while it was substantially unmodified during the placebo period. The mean difference between the treatment effects was significant (p = 0.05). Overall during the IVIg period 10 patients improved and 11 were stable and one got worse. During the placebo period 4 patients improved, 4 deteriorated and 14 were stable. Many secondary outcome measures, including Rankin scale, time to walk 10 metres, grip strength, sensory symptoms score were significantly better during IVIg treatment. Two serious adverse events occurred during the trial, both during placebo treatment. In conclusion the trial showed some short-term benefit of IVIg in about half of the patients confirming previous observation.