Virginija Danylaité Karrenbauer

Plasma cerebrosterol and magnetic resonance imaging measures in multiple sclerosis

OBJECTIVES The concentration in plasma of the brain-specific cholesterol metabolite cerebrosterol has been proposed as a biomarker of neurodegeneration in multiple sclerosis (MS) and other neurological diseases. It is unknown, however, which pathophysiological process in MS best accounts for variations in plasma cerebrosterol. PATIENTS AND METHODS In this study, we related plasma cerebrosterol concentrations in 46 MS patients - 27 with a relapsing-remitting (RR) disease course and 19 with a primary progressive (PP) course - to three conventional magnetic resonance imaging measures: on T(1)-weighted brain scans, volume of gadolinium-enhanced lesions (a marker of active inflammation) and hypointense lesions (a marker of edema or axonal loss) and on T(2)-weighted scans, volume of hyperintense lesions (a marker of disease extent). RESULTS By multiple-regression analysis, we uncovered negative correlations between the cerebrosterol-cholesterol ratio in plasma and both age at sampling (beta=-0.35 and p=0.079 in RRMS; beta=-0.76 and p=0.006 in PPMS) and volume of T(2)-weighted lesions (beta=-0.52 and p=0.078 in RRMS; beta=-0.50 and p=0.247 in PPMS). CONCLUSION We hypothesize that decreases in plasma cerebrosterol may reflect the total spatiotemporal burden of MS-the cumulative effects of its dissemination in space and its duration in time.

Multiple sclerosis patients lacking oligoclonal bands in the cerebrospinal fluid have less global and regional brain atrophy

To investigate whether multiple sclerosis (MS) patients with and without cerebrospinal fluid (CSF) oligoclonal immunoglobulin G bands (OCB) differ in brain atrophy. Twenty-eight OCB-negative and thirty-five OCB-positive patients were included. Larger volumes of total CSF and white matter (WM) lesions; smaller gray matter (GM) volume in the basal ganglia, diencephalon, cerebellum, and hippocampus; and smaller WM volume in corpus callosum, periventricular-deep WM, brainstem, and cerebellum, were observed in OCB-positives. OCB-negative patients, known to differ genetically from OCB-positives, are characterized by less global and regional brain atrophy. This finding supports the notion that OCB-negative MS patients may represent a clinically relevant MS subgroup.

Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society.

Multiple sclerosis (MS) is associated with inflammatory lesions in the brain and spinal cord. The detection of such inflammatory lesions using magnetic resonance imaging (MRI) is important in the consideration of the diagnosis and differential diagnoses of MS, as well as in the monitoring of disease activity and predicting treatment efficacy. Although there is strong evidence supporting the use of MRI for both the diagnosis and monitoring of disease activity, there is a lack of evidence regarding which MRI protocols to use, the frequency of examinations, and in what clinical situations to consider MRI examination. A national workshop to discuss these issues was held in Stockholm, Sweden, in August 2015, which resulted in a Swedish consensus statement regarding the use of MRI in the care of individuals with MS. The aim of this consensus statement is to provide practical advice for the use of MRI in this setting. The recommendations are based on a review of relevant literature and the clinical experience of workshop attendees. It is our hope that these recommendations will benefit individuals with MS and guide healthcare professionals responsible for their care.

Increased Soluble 4‐1BB Ligand (4‐1BBL) Levels in Peripheral Blood of Patients with Multiple Sclerosis

4‐1BB ligand (4‐1BBL; CD137L) is a member of the tumour necrosis factor superfamily expressed primarily on antigen presenting cells such as B cells, macrophages and dendritic cells. Its engagement with the receptor 4‐1BB (CD137) has been shown to promote T‐cell activation and regulate proliferation and survival of T cells. The role of the costimulatory molecule in multiple sclerosis (MS) remains unclear. In this study, the expression of 4‐1BBL and soluble 4‐1BBL (s4‐1BBL) protein levels were analysed in peripheral blood of MS patients. Compared with healthy controls, MS patients had an increase in both plasma s4‐1BBL protein levels and expression of 4‐1BBL in CD14+ monocytes. In contrast, myelin basic protein‐reactive T‐cell proliferation was not found to be inhibited by the use of an anti‐4‐1BBL antibody. The elevated s4‐1BBL protein levels in the MS patients may function as a self‐regulatory mechanism of 4‐1BB/4‐1BBL interaction and costimulation.

Reduced cerebrospinal fluid concentrations of oxysterols in response to natalizumab treatment of relapsing remitting multiple sclerosis

BACKGROUND Natalizumab therapy reduces inflammation and degeneration of the CNS in relapsing-remitting multiple sclerosis (RRMS). In cerebrospinal fluid (CSF) the concentration of 24S-hydroxycholesterol (24OHC) reflect neurodegeneration, whereas 27-hydroxycholesterol (27OHC) is dependent on the integrity of the blood-brain barrier (BBB). OBJECTIVE To measure the impact from natalizumab treatment on 24OHC and 27OHC concentrations in serum and CSF of RRMS. METHODS In serum and CSF obtained from 31 patients before and following 12 months of natalizumab treatment, 24OHC and 27OHC were analyzed by isotope-dilution mass spectrometry. RESULTS Natalizumab treatment reduced CSF-24OHC concentrations (p=0.002), CSF-27OHC concentrations (p=0.01) and serum-24OHC concentrations (p=0.029). There was no significant effect of the treatment on serum-27OHC concentrations. Serum concentrations of 24OHC correlated with Symbol Digit Modalities Test scores before (r=0.5, p=0.007) and after natalizumab treatment (r=0.403, p=0.033). CONCLUSIONS We showed for the first time that natalizumab treatment of RRMS reduced the concentrations of 24- and 27OHC in CSF, indicating reduced neurodegeneration and improved integrity of the BBB, respectively. Our results imply a role for serum 24OHC as a biomarker of cognition (visuo-spatial ability and processing speed) in RRMS.

Hereditary diffuse leukoencephalopathy with spheroids - a volumetric and radiological comparison with multiple sclerosis patients and healthy controls.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder caused by colony‐stimulating factor 1 receptor (CSF1R) gene mutations, resulting in demyelination and axonal degeneration with spheroids. The clinical expression is variable, including behavioral changes, cognitive impairment, motor symptoms and parkinsonism. Magnetic resonance imaging (MRI) reveals white matter (WM) changes and atrophy. The indistinct phenotype has led to misdiagnoses. This studys aim was to compare brain volumetry and radiological ratings in HDLS with multiple sclerosis (MS) patients and controls.

Cognitive function is a major determinant of income among multiple sclerosis patients in Sweden acting independently from physical disability

Background: In multiple sclerosis (MS), various aspects of cognitive function can be detrimentally affected, thus patients’ employment and social functioning is commonly impacted. Objective: To analyse income among MS patients in relation to cognitive function, assessed with the Symbol Digit Modalities Test (SDMT). Methods: A cross-sectional study including 2080 MS patients was conducted linking national register-based data. Descriptive statistics and a two-part model were used to estimate differences in earnings and social benefits. Results: MS patients in the highest SDMT score quartile earned more than twice annually compared to patients in the lowest quartile, whereas patients in the lowest quartile received three times more income through social benefits. The difference in earnings and benefits across the SDMT performance quartiles remained statistically significant after adjusting for various clinical and socio-demographic variables, including physical disability. The corrected prevalence ratios for MS patients in the highest quartile for having income from earnings and benefits were 1.40 (95% confidence interval (CI): 1.29–1.49) and 0.81 (95% CI: 0.71–0.90), respectively, when compared to the patients in the lowest quartile. Conclusion: Cognitive function affects the financial situation of MS patients negatively and independently of physical disability. This warrants cognitive testing as a routine measure in health care services for MS patients.

Income in Multiple Sclerosis Patients with Different Disease Phenotypes

Background Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course. Objective To analyze sources and levels of income among MS patients in relation to disease phenotype with a special focus on identifying differences/similarities between primary progressive MS (PPMS) and secondary progressive MS (SPMS). Methods A total of 6890 MS patients aged 21−64 years and living in Sweden in 2010 were identified for this cross-sectional study. Descriptive statistics, logistic, truncated linear, and zero-inflated negative binomial regression models were used to estimate differences in income between SPMS, PPMS and relapsing-remitting MS (RRMS) patients. Results RRMS patients earned almost twice as much as PPMS and SPMS patients (on average SEK 204,500, SEK 114,500, and SEK 79,800 in 2010, respectively). The difference in earnings between PPMS and SPMS was not statistically significant when analyzed with multivariable regression. The estimated odds ratio for PPMS patients to have income from earnings was not significantly different from SPMS patients (95% CI 0.98 to 1.59). PPMS and RRMS patients were less likely to receive benefits when compared to SPMS patients (by 6% and 27% lower, respectively). Conclusion Our findings argue for similarities between PPMS and SPMS and highlight the socioeconomic importance of preventing RRMS patients convert to SPMS.

Number of OCBs in CSF at diagnosis timepoint,— predictor of long term radiological outcome in MS?

evidence for B cell antigen presentation during EAE and MS, we chose to explore the role of antigen presentation by myelin antigen-specific B cells. We hypothesized that antigen presentation by cognate antigen-specific B cells during EAE is sufficient to support CD4mediated neuroinflammation. We induced active EAE using MOG protein or peptide immunization and induced passive EAE using encephalitogenic CD4 T cell lines in mice expressing MHCII by DCs alone and those in which B cells are deficient in MHCII expression. Further, we examined mice expressing MHCII by B cells alone with or without an increase in precursor frequency for MOG-specific B cell receptors. We found that maximal disease in protein-induced active EAE models is dependent upon B cell antigen presentation. Further, increasing the precursor frequency of MOG-specific B cells, but not the addition of soluble MOG-specific antibody, is sufficient to facilitate passive EAE in mice expressing MHCII by B cells alone. This is the first direct demonstration in vivo that B cells can serve as the sole APC and coordinate CD4 T cell autoreactivity to myelin antigens during EAE. These data support a model in which expansion of antigen-specific B cells during CNS autoimmunity amplifies cognate interactions between B and CD4 T cells and independently drives neuro-inflammation at later stages of disease.