Cerebrospinal fluid GAP-43 in early multiple sclerosis.

BACKGROUND/OBJECTIVE: Novel biomarkers identifying and predicting disease activity in multiple sclerosis (MS) would be valuable for primary diagnosis and as outcome measures for monitoring therapeutic effects in clinical trials. Axonal loss is present from the earliest stages of MS and correlates with disability measures. Growth-associated protein 43 (GAP-43) is a presynaptic protein with induced expression during axonal growth. We hypothesized this protein could serve as a biomarker of axonal regeneration capacity in MS. METHODS: We developed a novel GAP-43 enzyme-linked immunosorbent assay for quantification in cerebrospinal fluid (CSF) and measured GAP-43 levels in 71 patients with clinically isolated syndrome, 139 MS patients and 51 controls. RESULTS: GAP-43 concentrations were similar in patients and controls. Nevertheless, GAP-43 levels were higher in patients with >10 T2-magnetic resonance imaging (MRI) lesions (p = 0.005). CSF GAP-43 concentrations correlated with CSF mononuclear cell counts (p = 0.031) and were inversely correlated with patient age (p = 0.038) with a trend for higher CSF GAP-43 concentrations in patients with gadolinium-enhancing MRI lesions and positive CSF oligoclonal immunoglobulin G status. CONCLUSION: Our results suggest that axonal regeneration capacity is relatively preserved in early MS. CSF GAP-43 concentration is positively associated with markers of inflammation, suggesting possible inflammatory-driven expression of this growth-associated protein in early MS.

Step initiation interferes with working memory in nondisabled patients with the earliest multiple sclerosis-A dual-task study.

Balance and cognition are affected by multiple sclerosis (MS). Cognitive-motor interference (CMI) is important for balance impairment in MS, however little is known about CMI at the earliest stages of the disease. Step initiation (SI) with anticipatory postural adjustments (APAs) has been linked to postural instability and falls in subjects with MS, therefore we aimed to assess CMI between SI and the two storage systems of working memory in patients with clinically isolated syndrome (presented as optic neuritis-ON) suggestive of MS. Twenty patients with normal/near normal visual acuity and 20 age-, weight-, height-, sex- and education-matched control subjects were included. APAs were studied using center of pressure measures in three conditions: SI alone, SI+Brooks' spatial- and SI+2-back verbal working memory task. Decrements (% change) in performance on cognitive tasks and in APA parameters were calculated. CMI was assessed combining the two decrements scores. Performance on both cognitive tasks was more affected by dual-tasking in patients compared to healthy subjects. In both groups APA parameters were not influenced by dual-tasking. CMI was higher in patients compared to healthy subjects. Our results suggest that the disease affects CMI in its earliest stages. Since both cognitive tasks were similarly affected by dual-tasking in patients and controls central executive seems to play the major role in CMI between SI and working memory. Patients prioritizing motor over cognitive task for balance maintenance suggests reduced divided attention capacity as a cause of increased CMI in the earliest MS.

Pulmonary arterial hypertension associated with interferon beta treatment for multiple sclerosis: a case report.

A 23-year-old woman with multiple sclerosis developed respiratory symptoms 3 years after introduction of interferon beta-1b. The diagnosis of pulmonary arterial hypertension (PAH) was established. The patient partially responded to sildenafil and bosetan treatment. This is the first report of PAH, associated with interferon beta therapy. As shown in experimental models, interferon treatment can induce PAH by stimulation of thromboxane cascade and secretion of various inflammatory mediators.

Impression of clinical worsening fails to predict interferon-beta neutralizing antibody status.

The development of neutralizing antibodies (NAbs) against interferon-beta(IFNbeta) reduces clinical efficacy and markers of bioactivity in patients with multiple sclerosis (MS), although it has also been shown that a poor response to IFNbeta coincided with unexpectedly low NAb levels. To try and resolve this incoherency, this study investigated 2822 patients referred to a NAb testing facility. The reason for NAb testing was indicated for 2506 patients: routine testing (76%), worsening of disease (14%) and other reasons (10%). Overall, 31% of patients were NAb positive and 17% had titres high enough to obliterate IFNbeta bioactivity. The frequency of NAbs was similar in patients in the routine testing group compared with the worsening group. Samples showing high titres failed to be associated with worsening of symptoms. The study failed to show low NAb levels in patients responding poorly to IFNbeta. It is concluded that it is not possible to predict NAb status by clinical impression of treatment response. This is likely to be an effect of the partial efficacy of IFNbeta. Thus routine testing for NAbs must be carried out in order to identify NAb status in patients with MS.

Interferon beta preparations for the treatment of multiple sclerosis patients differ in neutralizing antibody seroprevalence and immunogenicity.

Development of neutralizing antibodies (NAbs) reduces the clinical efficacy of interferon beta (IFNbeta) treatment in multiple sclerosis (MS) patients. The aim of this study was to evaluate NAb seroprevalence (frequency of patients with NAbs) and immunogenicity (titer levels) of IFNbeta preparations in a clinical setting. We analysed 1115 consecutive MS patients, treated with one of the three available IFNbeta preparations, for an average of 40 months (1-120 months), for the presence of NAbs with the MxA protein induction assay. Overall, 32% of patients were positive for NAbs with neutralizing titers above 10. The frequency of NAbs, ie, the seroprevalence, was 13% in Avonex-treated patients, 43% for Betaferon, 39% for Rebif22 and 30% for Rebif44. In addition, the potential to induce high titer levels, ie, the immunogenicity, was observed to differ between preparations. Avonex, showing the lowest seroprevalence, also showed low immunogenicity and typically induced low titers. Betaferon, showing the highest seroprevalence when inducing NAbs, induced lower titers compared to Rebif22 and Rebif44. Treatment duration over five years only marginally correlated with decreased seroprevalence and titer levels. In conclusion, NAbs to IFNbeta are common in a clinical setting and the IFNbeta preparations differ not only in NAb seroprevalence, but also in immunogenicity.