Naghmeh Jafari

Genetic variation in the KIF1B locus influences susceptibility to multiple sclerosis.

The few loci associated with multiple sclerosis (MS) are all related to immune function. We report a GWA study identifying a new locus replicated in 2,679 cases and 3,125 controls. An rs10492972[C] variant located in the KIF1B gene was associated with MS with an odds ratio of 1.35 (P = 2.5 × 10−10). KIF1B is a neuronally expressed gene plausibly implicated in the irreversible axonal loss characterizing MS in the long term.

Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes.

Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 × 10(-11)). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 × 10(-5) using Poser criteria; hazard ratio = 1.6; P = 3.7 × 10(-6) for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 × 10(-8)). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 × 10(-9) using Poser criteria; P = 5.6 × 10(-11) for McDonald criteria) and more rapid development of disability (P = 1.8 × 10(-10)). These findings validate cerebrospinal fluid CHI3L1 as a biomarker associated with the conversion to multiple sclerosis and development of disability and reinforce the prognostic role of CHI3L1 in patients with clinically isolated syndrome. We propose that determining cerebrospinal fluid chitinase 3-like 1 levels at the time of a clinically isolated syndrome event will help identify those patients with worse disease prognosis.

No evidence for intrathecal IgG synthesis to Epstein Barr virus nuclear antigen-1 in multiple sclerosis

BACKGROUND Recent studies suggest an intrathecal IgG response against Epstein Barr virus (EBV) in multiple sclerosis (MS), implicating a pathogenic role for the virus in MS. OBJECTIVES To determine the spectrum of anti-EBV antibodies and B-cell epitopes within EBV nuclear antigen-1 (EBNA-1). Furthermore, to determine whether EBNA-1-specific IgG is produced intrathecally. STUDY DESIGN Immunoblot analysis was used to study the anti-EBV IgG response in serum and cerebral spinal fluid (CSF) in MS and controls. EBNA-1 B-cell epitopes were identified by immunoscreening of 12 residue long peptides, with 11 residue overlap, spanning EBNA-1. Thirteen peptides containing all immunoreactive regions were constructed and used in paired serum and CSF of MS patients (n=17) and controls (n=18). Subsequently, reactivity to the identified immunodominant peptide was analysed in a large cohort of serum and CSF of MS patients (n=114) and disease controls (n=62). RESULTS No difference was observed in the overall anti-EBV antibody diversity, but EBNA-1 reactivity was increased in MS patients versus controls for immunoblot and ELISA (p<0.0001). Epitope analysis on EBNA-1 revealed one immunodominant region covering residues 394-451: EBNA-1(394-451). Anti-EBNA-1(394-451) IgG levels in serum and CSF were significantly higher in MS patients compared to controls. However, normalization for total IgG content of paired serum and CSF samples abrogated this disease association. CONCLUSIONS MS patients have normal overall anti-EBV antibody responses with increased reactivity to EBNA-1(394-451). No evidence was found for intrathecal EBNA-1-specific IgG synthesis in MS.

Cigarette smoking and risk of MS in multiplex families

Recent studies suggest that a history of cigarette smoking is a risk factor for multiple sclerosis (MS). We aimed to test the smoking effect in multiplex families, matching for both environmental and genetic factors. In a matched case-control study, 136 MS patients from 106 multiplex MS families were compared with their 204 healthy siblings as controls. Participants completed self-report questionnaires. Conditional logistic regression was used to analyse smoking and MS risk association while controlling for confounding by age and sex. Smoking history was classified in different variables. Within our survey the smoking history of MS patients and the controls did not differ. The odds of MS were comparable for different smoking levels. However, more intense exposure and women showed higher odds ratios, although non-significant. Association studies in families with relatively high genetic loading are unlikely to be confounded by smoking history.

Fatigue at time of CIS is an independent predictor of a subsequent diagnosis of multiple sclerosis

Objective Fatigue is a common, disabling symptom of multiple sclerosis (MS), but little is known about fatigue in patients with clinically isolated syndrome (CIS), often the presenting symptom of MS. We aimed to investigate the prevalence and severity of fatigue in patients with CIS, and its association with a diagnosis of clinically definite MS (CDMS). Methods 127 patients were consecutively included in our ongoing prospective CIS study. At baseline, clinical, demographic, laboratory and MRI data were collected, and fatigue severity was assessed using Krupps Fatigue Severity Scale (FSS); fatigue was defined as FSS≥5.0. Fatigue scores were compared with scores of 113 healthy controls and with scores from the literature. The association of fatigue with CDMS was calculated using Cox regression models. Results The mean FSS of patients with CIS was 4.3, similar to MS patients, and significantly higher than that of healthy individuals (p<0.001). Fatigue prevalence in patients with CIS (46.5%) was significantly higher than in controls (p<0.001). Fifty-two patients (40.9%) reached CDMS during follow-up. Fatigue was associated with a diagnosis of CDMS in univariate analysis (HR 2.6, 95% CI 1.5 to 4.6) and in multivariate analysis correcting for sex, age, neuroanatomical localisation of CIS, 25-OH-vitamin D, anxiety, depression, MRI dissemination in space and gadolinium enhancement (HR 4.5, 95% CI 1.9 to 10.6). Conclusions Already at the stage of CIS, fatigue is a very common symptom, with a severity similar to fatigue in MS patients. This fatigue seems unrelated to the type or severity of the attack. Importantly, we found that fatigue was an independent predictor of a subsequent diagnosis of MS.

Callosal lesion predicts future attacks after clinically isolated syndrome

Background: Current MRI criteria can help predict a second attack after a clinically isolated syndrome (CIS). Given the known association between corpus callosum lesions (CC) and multiple sclerosis (MS), such lesions on MRI could provide additional predictive information. This study assessed whether the presence of CC lesion on MRI could, next to the modified Barkhof criteria, further enhance prediction of conversion from CIS to MS. Methods: Follow-up study of 158 patients with CIS who underwent MRI after CIS was performed. MRI were scored for the Barkhof criteria and CC lesion. Patients were classified as having MS according to Poser criteria. Cox regression models were used for the time to conversion from CIS to MS. Results: The Barkhof criteria and CC lesion were strongly associated with conversion to MS with hazard ratios (HR), respectively, of 2.6 (95% confidence interval [CI] 1.5–4.3) and 2.7 (95% CI 1.6–4.5). The HRs of CC lesion adjusted for the Barkhof criteria and the Barkhof criteria adjusted for CC lesion were similar (HRs 1.8, not significant). The combined prediction of the Barkhof criteria and CC lesion was 3.3 (95% CI 1.9–5.7). Patients not fulfilling the Barkhof criteria had a fourfold increased risk of MS (HR 3.8, 95% CI 1.5–9.3) when they had a lesion in the CC. Conclusions: Corpus callosum (CC) lesion and the Barkhof criteria both predicted conversion to multiple sclerosis (MS). When both variables were combined, the association was stronger. The assessment of CC lesion may be a useful additional tool for predicting conversion to MS in patients with clinically isolated syndrome.

Application of the 2010 revised criteria for the diagnosis of multiple sclerosis to patients with clinically isolated syndromes

Recently, the McDonald criteria for the diagnosis of multiple sclerosis (MS) have been revised, with the aims to diagnose earlier and to simplify the use of brain MRI. To validate the 2010 revised criteria they were applied to a cohort of patients with clinically isolated syndromes (CIS).

Perspectives on the Use of Multiple Sclerosis Risk Genes for Prediction

Objective A recent collaborative genome-wide association study replicated a large number of susceptibility loci and identified novel loci. This increase in known multiple sclerosis (MS) risk genes raises questions about clinical applicability of genotyping. In an empirical set we assessed the predictive power of typing multiple genes. Next, in a modelling study we explored current and potential predictive performance of genetic MS risk models. Materials and Methods Genotype data on 6 MS risk genes in 591 MS patients and 600 controls were used to investigate the predictive value of combining risk alleles. Next, the replicated and novel MS risk loci from the recent and largest international genome-wide association study were used to construct genetic risk models simulating a population of 100,000 individuals. Finally, we assessed the required numbers, frequencies, and ORs of risk SNPs for higher discriminative accuracy in the future. Results Individuals with 10 to 12 risk alleles had a significantly increased risk compared to individuals with the average population risk for developing MS (OR 2.76 (95% CI 2.02–3.77)). In the simulation study we showed that the area under the receiver operating characteristic curve (AUC) for a risk score based on the 6 SNPs was 0.64. The AUC increases to 0.66 using the well replicated 24 SNPs and to 0.69 when including all replicated and novel SNPs (n = 53) in the risk model. An additional 20 SNPs with allele frequency 0.30 and ORs 1.1 would be needed to increase the AUC to a slightly higher level of 0.70, and at least 50 novel variants with allele frequency 0.30 and ORs 1.4 would be needed to obtain an AUC of 0.85. Conclusion Although new MS risk SNPs emerge rapidly, the discriminatory ability in a clinical setting will be limited.

Soluble CD27 Levels in Cerebrospinal Fluid as a Prognostic Biomarker in Clinically Isolated Syndrome

Importance There is a growing number of therapies that could be administered after the first symptom of central nervous system demyelination. These drugs can delay multiple sclerosis (MS) diagnosis and slow down future disability. However, treatment of patients with benign course may not be needed; therefore, there is a need for biomarkers to predict long-term prognosis in patients with clinically isolated syndrome (CIS). Objective To investigate whether the T-cell activation marker soluble CD27 (sCD27) measured in cerebrospinal fluid of patients at time of a first attack is associated with a subsequent diagnosis of MS and a higher relapse rate. Design, Setting, and Participants This prospective study included 77 patients with CIS between March 2002 and May 2015 in a tertiary referral center for multiple sclerosis, in collaboration with several regional hospitals. Patients with CIS underwent a lumbar puncture and magnetic resonance imaging scan within 6 months after first onset of symptoms. Main Outcomes and Measures Soluble CD27 levels were determined in cerebrospinal fluid using a commercially available enzyme-linked immunosorbent assay. Cox regression analyses was used to calculate univariate and multivariate hazard ratios for MS diagnosis. Association between sCD27 levels and relapse rate was assessed using a negative binomial regression model. Results Among 77 patients with CIS, 50 were female (79.5%), and mean (SD) age was 32.7 (7.4) years. Mean (SD) age in the control individuals was 33.4 (9.5) years, and 20 were female (66.7%).Patients with CIS had higher cerebrospinal fluid sCD27 levels than control individuals (geometric mean, 31.3 U/mL; 95% CI, 24.0-40.9 vs mean, 4.67 U/mL; 95% CI, 2.9-7.5; P < .001). During a mean (SD) follow-up of 54.8 (35.1) months, 39 of 77 patients (50.6%) were diagnosed as having MS. In a model adjusted for magnetic resonance imaging and cerebrospinal fluid measurements, sCD27 levels were associated with a diagnosis of MS (hazard ratio, 2.4 per 100 U/mL increase in sCD27 levels; 95% CI, 1.27-4.53; P = .007). Additionally, patients with MS with high sCD27 levels (median, >31.4 U/mL) at the time of CIS had a 5.5 times higher annualized relapse rate than patients with low sCD27 levels (annualized relapse rate, 0.06 vs 0.33; P = .02). Conclusions and Relevance Soluble CD27 in cerebrospinal fluid of patients with CIS was associated with MS diagnosis and a high relapse rate. Therefore, sCD27 is an activation molecule directly related to the immunopathology of the disease and is a potential clinical marker to help in treatment decisions after a first attack of suspected MS.

No influence of KIF1B on neurodegenerative markers in multiple sclerosis

In search of genetic causes of multiple sclerosis (MS), a number of genes have consistently shown association with MS susceptibility in the past couple of years.1 All of these identified genes are directly or indirectly involved with the inflammatory process. However, it has become increasingly clear that MS consists of both an inflammatory and a progressive neurodegenerative process,2 which is illustrated by the fact that new and potent anti-inflammatory drugs have been unable to halt neurodegeneration. The relation between episodes of inflammation and the neurodegenerative component characterized by irreversible axonal loss are far from clear at this point. Some authors have argued that neurodegeneration is independent of inflammation, while others argue that the 2 components are closely associated and are actually interdependent.2,3 The neurodegenerative component is clinically highly relevant since it is held predominantly responsible for disability accumulation, although several questions regarding this issue remain.2 Until recently, no genetic marker for neurodegeneration in MS was identified. However, in 2008, it was reported for the first time that a “neurodegenerative gene,” i.e., the KIF1B rs10492972 [C] variant, was associated with MS susceptibility.4 KIF1B is involved in axonal transport of mitochondria and synaptic vesicle precursors. Dysregulation of axonal transport plays a role in several neurodegenerative diseases.4 The authors suggested that KIF1B could be the first gene involved in MS susceptibility with a possible neurodegenerative effect.4 Unfortunately, this finding could later not be confirmed in other …