Taha Gholipour

Circulating MicroRNAs as biomarkers for disease staging in multiple sclerosis

MicroRNAs (miRNAs) are single‐stranded, small noncoding RNAs that regulate gene expression. Because they are stable in serum, they are being developed as biomarkers for cancer and other diseases. In multiple sclerosis (MS), miRNAs have been studied in cell populations but not in the circulation. In MS, a major challenge is to develop immune biomarkers to monitor disease. We asked whether circulating miRNAs could be identified in MS and whether they are linked to disease stage and/or disability.

Functional connectivity in patients with idiopathic generalized epilepsy

Purpose:  Idiopathic generalized epilepsy (IGE) is characterized by electroencephalography (EEG) recordings with generalized spike wave discharges (GSWDs) arising from normal background activity. Although GSWDs are the result of highly synchronized activity in the thalamocortical network, EEG without GSWDs is believed to represent normal brain activity. The aim of this study was to investigate whether thalamocortical interactions are altered even during GSWD‐free EEG periods in patients with IGE.

Effect of gender on late-onset multiple sclerosis

Objectives: We aimed to examine the incidence and disease course of late-onset multiple sclerosis (LOMS) compared with adult-onset MS (AOMS) in our clinic cohort, stratified based on gender and race, since both have been reported as important modifiers of disease outcomes in MS. Methods: Patients with LOMS and AOMS were compared in terms of demographic characteristics and disease course characteristics. Combined effects were investigated with a logistic regression model. Time from disease onset to sustained Expanded Disability Status Scale (EDSS) score of 6 was investigated using an extension of log-rank test appropriate for interval-censored data. Results: Some 7.96% of 4273 patients studied had an onset of MS after the age of 50 years (LOMS), and 1.33% experienced an onset after age 60. Progressive onset was more common in LOMS relative to AOMS. The proportion of women with progressive-onset disease was similar in AOMS and LOMS. Time to EDSS 6 was delayed in AOMS females compared with males; however, it was similar between males and females in the LOMS group. Conclusions: Women with LOMS have a different trajectory in terms of disease progression than women with AOMS. The effect of menopause combined with race/ethnicity on the MS disease course requires further investigation.

Demographic and clinical characteristics of malignant multiple sclerosis

Objective: Multiple sclerosis (MS) that causes patients to require assistance for ambulation (Expanded Disability Status Scale [EDSS] ≥6) within 5 years from symptom onset is generally termed malignant. Malignant status can be transient (TM) or sustained until year 5 (SM). We studied the incidence, predictors, and demographic and clinical characteristics of malignant MS. Methods: Patients with symptom onset in 2002–2005 and 5-year follow-up were selected from the Partners Multiple Sclerosis Center database. Patients with TM were further grouped into TM and SM. The mechanism of reaching EDSS 6 (relapse- vs progression-related) was determined. Results: A total of 487 patients were included (17 TM, 42 SM). The incidence proportion of ever malignant (EM = SM+TM) was estimated as 12.11% and SM as 8.62%. Patients with older age at onset, male gender, and positive smoking history were more likely to become SM. Compared to nonmalignant patients, the proportion of progressive-onset MS in the SM group was significantly higher, but not different in TM. Within relapsing-onset patients, most of TM, and a smaller proportion of the SM group had a relapse-related as opposed to progression-related mechanism. The final model predictors for EM vs nonmalignant were older age at onset, motor symptoms at onset, and progressive disease onset. Within the malignant patients, predictors of TM vs SM were younger age and brainstem symptoms at onset. Conclusions: Over 10% of patients with MS experience a malignant course as defined above. Some demographic and clinical factors are found to predict a malignant outcome. MS in patients who reach a high EDSS based on disease progression is more likely to remain malignant.

Elevated relapse rates in pediatric compared to adult MS persist for at least 6 years

OBJECTIVE To compare relapse rates in pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (AOMS) over the first 6-years of disease. METHODS Patients with relapsing-remitting disease onset were identified from the Partners Pediatric MS Center, Massachusetts General Hospital and Partners MS Center, Brigham and Womens Hospital. 84 POMS and 258 AOMS patients were included. Annualized relapse rates (ARR) for each individual year from year 1 to year 6, after first attack were compared using Poisson regression, as was expanded disability status scale (EDSS) score at the visit closest to each year interval. RESULTS ARR was significantly higher in POMS compared to AOMS at individual years (except year 4), and was not significantly affected by adjustment for gender, race and proportion of time on treatment. Despite a 2.30 times higher relapse rate over 6-years, EDSS between groups did not differ. ARR in years 1-5 did not impact year 5 disability measured by EDSS in POMS. CONCLUSIONS Our findings demonstrate that higher ARR in POMS relative to AOMS is sustained over 6-years, suggesting a more inflammatory nature and potential disconnect between relapses and disability measured by EDSS early in POMS. This data may be useful when designing clinical trials for POMS.

Reproducibility of interictal EEG-fMRI results in patients with epilepsy

Purpose:  Combined electroencephalography (EEG) and functional MRI (EEG‐fMRI) can be useful in the evaluation of epilepsy patients. The reproducibility of EEG‐fMRI findings needs to be established to consider it as a clinically valuable method. We addressed the intrasubject reproducibility of EEG‐fMRI and the possible superiority of higher magnetic field strength in patients who were scanned twice.

Evaluation of circulating osteopontin levels in an unselected cohort of patients with multiple sclerosis: relevance for biomarker development.

Background: Osteopontin (OPN) is a pleiotropic protein with important roles in inflammation and immunity that has been suggested as a candidate biomarker for disease activity in multiple sclerosis (MS). Objective: We evaluated plasma levels of OPN in an unselected cohort of MS patients, to determine its potential as a biomarker for disease subtype and/or disease activity in a regular clinical setting. Methods: We analyzed OPN plasma levels in 492 consecutive MS patients, using a commercial enzyme-linked immunosorbent assay (ELISA). Results: OPN levels were higher in relapsing–remitting and secondary progressive MS, compared to healthy controls. Treatment with natalizumab or glatiramer acetate was associated with lower OPN levels. There was no significant association between the OPN levels and disease activity, as measured by clinical or radiological criteria. One-third of patients with high OPN levels had concurrent disorders that may also be associated with increased OPN expression, and which may mask a modest effect of MS disease activity on OPN levels. Conclusion: Our data do not support a role for circulating OPN levels as a biomarker for disease activity in a heterogeneous clinical setting, but does not rule out a potential role in the cerebrospinal fluid, in a controlled setting such as a clinical trial, or in concert with other biomarkers.

Seizure susceptibility alteration through 5-HT3 receptor: Modulation by nitric oxide

There is some evidence that epileptic seizures could be induced or increased by 5-hydroxytryptamine (5-HT) attenuation, while augmentation of serotonin functions within the brain (e.g. by SSRIs) has been reported to be anticonvulsant. This study was performed to determine the effect of selective 5-HT(3) channel/receptor antagonist granisetron and agonist SR57227 hydrochloride on the pentylenetetrazole (PTZ)-induced seizure threshold in mice. The possible interaction of this effect with nitrergic system was also examined using the nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) and the NO precursor l-arginine. SR57227 (10mg/kg, i.p.) significantly increased the seizure threshold compared to control group, while high dose granisetron (10mg/kg, i.p.) proved proconvulsant. Co-administration of sub-effective doses of the 5-HT(3) agonist with l-NAME (5 and 60mg/kg, i.p., respectively) exerted a significant anticonvulsive effect, while sub-effective doses of granisetron (3mg/kg) was observed to have a proconvulsive action with the addition of l-arginine (75mg/kg, i.p.). Our data demonstrate that enhancement of 5-HT(3) receptor function results in as anticonvulsant effect in the PTZ-induced seizure model, and that selective antagonism at the 5-HT(3) receptor yields proconvulsive effects. Furthermore, the NO system may play a role in 5-HT(3) receptor function.

Changes preceding interictal epileptic EEG abnormalities: comparison between EEG/fMRI and intracerebral EEG.

Purpose:  In simultaneous scalp electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), blood oxygen level dependent (BOLD) changes occurring before the spike have been sometimes described but could not be explained. To characterize the origin of this prespike BOLD signal change, we looked for electrographic changes in stereo‐EEG (SEEG) possibly preceding the scalp spike in patients that showed early BOLD response in EEG/fMRI.

Role of the nitric oxide pathway and the endocannabinoid system in neurogenic relaxation of corpus cavernosum from biliary cirrhotic rats

Relaxation of corpus cavernosum, which is mediated by nitric oxide (NO) released from non‐adrenergic non‐cholinergic (NANC) neurotransmission, is critical for inducing penile erection and can be affected by many pathophysiological conditions. However, the peripheral effect of liver cirrhosis on erectile function is as yet unknown. The aim of the present study was to investigate the effect of biliary cirrhosis on NANC‐mediated relaxation of rat corpus cavernosum and the possible roles of endocannabinoid and nitric oxide systems in this model.