Towards endophenotyping multiple sclerosis

promotiedatum: 6-6-2014 � prom-id: 1089

The physiological variation of the retinal nerve fiber layer thickness and macular volume in humans as assessed by spectral domain-optical coherence tomography

PURPOSE. With the introduction of spectral domain-optical coherence tomography (SD-OCT), changes in retinal nerve fiber layer (RNFL) thickness and macular volume (MV) can be detected with high precision. The aim of this study was to determine whether there is a physiological quantifiable degree of variation of these structures in humans. METHODS. This study took place during a 10-km charity run at VU University Medical Center Amsterdam. Weight, height, hydration status, RNFL thickness (ring scan, 12° around the optic nerve head), and MV (20° × 20°) were assessed in 69 subjects (44 runners, 25 controls) using SD-OCT with eye-tracking function. The SD-OCT scans were assessed before running (normal status), after running (more dehydrated status), and 1 to 1.5 hours after finishing the run (rehydrated status). Controls were measured at the same time intervals as the runners but did not participate in the running event. Changes over time were assessed by general linear models, correcting for repeated measurements. RESULTS. In runners, a significant increase in both RNFL thickness (94.4 μm [baseline] to 95.2 μm [rehydration], P = 0.04) and MV (288.9 μm [baseline] to 291.0 μm [rehydration], P < 0.001) over time was observed. Controls did not show significant changes over time. Anatomically, the physiological change of RNFL thickness was most marked in the nasal sectors. CONCLUSIONS. This prospective study demonstrated a significant physiological variation of the RNFL thickness and MV at a proportion that, on an individual patient level, may be relevant for longitudinal studies in neurodegenerative diseases. © 2012 The Association for Research in Vision and Ophthalmology, Inc

Clinical relevance of serum natalizumab concentration and anti-natalizumab antibodies in multiple sclerosis

Background: Antibodies against natalizumab have been found in 4.5-14.1% of natalizumab-treated multiple sclerosis (MS) patients. If antibodies persist, they are associated with an adverse effect on treatment response. However, it has proved to be difficult to standardize anti-drug antibody measurements. Objectives: The purpose of this study was to evaluate the clinical and radiological impact of serum natalizumab concentrations and their relation with anti-natalizumab antibodies in MS patients. Methods: In this prospective observational cohort study of 73 consecutive patients treated with natalizumab, we measured serum natalizumab levels and antibody titers before the start of natalizumab treatment, at weeks 12 and 24 and annually after natalizumab initiation. Antibodies against natalizumab were measured by radioimmunoassay and serum natalizumab concentrations using a newly developed enzyme linked immunosorbent assay (ELISA). Magnetic resonance imaging (MRI) scan and clinical evaluation were performed before the start of natalizumab treatment and subsequently every year. Results: Antibodies were detected in 58% of the natalizumab-treated patients. All patients developed their antibodies before week 24. The large majority of these patients reverted to neutralizing antibody (NAb) negative status during follow-up. The presence of antibodies was inversely correlated with serum natalizumab concentration (p<0.001). Only high antibody titers are associated with very low or undetectable serum natalizumab concentration. Both high antibody titers and low serum natalizumab concentrations are associated with relapses and gadolinium-enhancing lesions on MRI. Conclusions: Our data show that both low natalizumab serum concentration and high antibody titers are associated with a lack of efficacy of natalizumab. Measuring serum natalizumab, using a highly specific assay, might lead to more enhanced precision using natalizumab in individual patients. © The Author(s) 2012

Functional brain network organization predicts cognitive decline in multiple sclerosis: A longitudinal magnetoencephalography study

Item does not contain fulltextIntroduction: Disruptions in functional brain network organization seem to be important underlying mechanisms of cognitive impairment in multiple sclerosis (MS). However, little is known about its longitudinal predictive value and its unique value beyond structural brain pathology. Aim of study: This longitudinal study aimed to investigate the importance of disruptions in functional brain network organization as a predictor of cognitive decline in MS patients, and to explore its unique value irrespective of structural pathology. Methods: Magnetoencephalography (MEG) recordings and magnetic resonance imaging (MRI) were analysed in 100 MS patients at baseline. Neuropsychological assessments were obtained at baseline and after five years. Brain network organization was computed using network properties of the Minimum Spanning Tree (MST; i.e. backbone of the functional brain network). Correlational and regression analyses were performed to relate these measures to cognitive decline, and to explore their effects beyond grey matter and white matter lesion volume. Results: Cognitive decline was best predicted by both a disintegrated network (i.e. a loss of network complexity) in the delta band and a more integrated network (i.e. a larger chance of hub overload) in the beta band at baseline (MEG model: R2=21%). These network measures remained independent predictors of cognitive decline (p< 0.05) when structural brain measures were included (combined MEG and MRI model: R2=27%). Conclusions: In conclusion, disruptions in functional brain network organization can serve as predictive markers of cognitive decline in patients with MS. These disruptions in functional brain network organization may be responsible for cognitive decline irrespective of the accumulation of structural damage.2 p

Ocrelizumab Concentration Is a Good Predictor of SARS-CoV-2 Vaccination Response in Patients with Multiple Sclerosis

Ocrelizumab, an anti-CD20 monoclonal antibody, counteracts induction of humoral immune responses after severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccinations in patients with multiple sclerosis (MS). We aimed to assess if serum ocrelizumab concentration measured at the time of vaccination could predict the humoral response after SARS-CoV-2 vaccination. In 52 patients with MS, we found ocrelizumab concentration at the time of vaccination to be a good predictor for SARS-CoV-2 IgG anti-RBD titers after vaccination (comparable to B-cell count). As the course of ocrelizumab concentration may be predicted using pharmacokinetic models, this may be a superior biomarker to guide optimal timing for vaccinations in B-cell depleted patients with MS. ANN NEUROL 2023;93:103-108