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Background Detection of intrathecal immunoglobulin G (IgG) synthesis by gold standard oligoclonal bands (OCB) or IgG index remains an integral part of multiple sclerosis (MS) diagnostics, although both methods have weaknesses. Emerging evidence suggests that automated detection of free light chains (FLC) in the cerebrospinal fluid (CSF) has diagnostic performance equal to OCB. The objective of this study was to compare the diagnostic performance of CSF FLC with OCB and IgG index in a large cohort of Scandinavian patients referred for MS evaluation. Methods We prospectively included 230 patients suspected for MS. They are composed of patients with MS (n=96), clinically isolated syndrome (n=37), other neurological diseases (OND, n=31) and symptomatic controls (SC, n=66). CSF and serum samples were analyzed for kappa and lambda FLC, OCB and IgG index. Diagnostic performance was evaluated by receiver operating characteristic (ROC) analysis. Results Both the absolute concentration of CSF-kappa and the kappa index had excellent MS diagnostic performances with ROC area under the curve of 0.93 and 0.94 (MS vs. SC+OND). At the 0.42 mg/L cutoff, CSF-kappa had sensitivity and specificity of 93.8% and 85.6%, whereas sensitivity and specificity for OCB was 82.3% and 93.8% (72.9% and 95.9% for IgG index at cutoff 0.64). CSF-lambda and lambda index performed inferior to CSF-kappa and kappa index. Conclusions CSF-kappa and kappa index represent automated, rapid and low-cost alternatives to OCB. Using merely the absolute concentration of CSF-kappa is a logistic advantage in the clinical laboratories.

Objectives: Neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) may be misdiagnosed as multiple sclerosis. The aim of this study was to (i) to measure AQP4-IgG in patients who fulfilled the clinical and radiological criteria of NMOSD in the Central Denmark Region and (ii) to estimate the incidence of NMOSD in the region, according to both the 2006 Wingerchuk criteria and the 2015 International Panel for NMO Diagnosis criteria., Materials and Methods: Medical records of all patients diagnosed with a demyelinating disorder in the region from 1 January 2012 to 31 December 2013 were reviewed. Patients were classified as having (i) "NMO" if the 2006 criteria were met, (ii) "NMOSD with AQP4-IgG" or (iii) "NMOSD without/unknown AQP-IgG" if the new 2015 NMOSD criteria were met. Patients with core symptoms were invited to provide a blood sample for AQP4-IgG analysis with an enzyme-linked immunosorbent assay and a cell-based indirect immunofluorescence assay., Results: In 191 patients with core symptoms, one met the 2015 NMOSD with AQP4-IgG criteria. Two patients met the 2006 NMO and 2015 NMOSD without/unknown AQP4-IgG criteria. Among 108 patients providing a blood sample, all were seronegative. The estimated incidence of NMO (2006 criteria) and NMOSD (2015 criteria) was 0.08 and 0.12 per 100 000 person-years, respectively., Conclusion: NMO/NMOSD is a rare disease in the Central Denmark Region, with a considerably lower incidence rate than previously estimated in a neighbouring region., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Multiple sclerosis (MS) is an immune mediated, inflammatory and demyelinating disease of the central nervous system (CNS). Substantial evidence points toward monocytes and macrophages playing prominent roles early in disease, mediating both pro- and anti-inflammatory responses. Monocytes are subdivided into three subsets depending on the expression of CD14 and CD16, representing different stages of inflammatory activation. To investigate their involvement in MS, peripheral blood mononuclear cells from 40 patients with incipient or progressed MS and 20 healthy controls were characterized ex vivo. In MS samples, we demonstrate a highly significant increase in nonclassical monocytes (CD14+CD16++), with a concomitant significant reduction in classical monocytes (CD14++CD16-) compared with healthy controls. Also, a significant reduction in the surface expression of CD40, CD163, and CD192 was found, attributable to the upregulation of the nonclassical monocytes. In addition, significantly increased levels of human endogenous retrovirus (HERV) envelope (Env) epitopes, encoded by both HERV-H/F and HERV-W, were specifically found on nonclassical monocytes from patients with MS; emphasizing their involvement in MS disease. In parallel, serum and cerebrospinal fluid (CSF) samples were analyzed for soluble biomarkers of inflammation and neurodegeneration. For sCD163 versus CD163, no significant correlations were found, whereas highly significant correlations between levels of soluble neopterine and the intermediate monocyte (CD14++CD16+) population was found, as were correlations between levels of soluble osteopontin and the HERV Env expression on nonclassical monocytes. The results from this study emphasize the relevance of further focus on monocyte subsets, particularly the nonclassical monocytes in monitoring of inflammatory diseases., (© 2017 The Authors Immunology and Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of Australasian Society for Immunology Inc.)

Objectives: This study aimed to examine the levels of the macrophage marker sCD163 and other biomarkers at the time of diagnosis of patients with either clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (RRMS), and assess relation to clinical indicators of prognosis, disease activity (DA), and changes in the levels of these biomarkers at follow-up., Materials and Methods: The clinical status and MRI were reevaluated in 56 patients more than 1 year after diagnosis with a median follow-up time of 2 years. Levels of biomarkers in serum and cerebrospinal fluid (CSF) samples were evaluated by enzyme-linked immunosorbent assays., Results: There was no significant difference in time to DA between patients with CIS and RRMS. A high sCD163 ratio (>0.07) was significantly ( P  = 0.04) associated with time to DA in the untreated patient group. In 21 patients reevaluated with serum and CSF samples, the sCD163 ratio levels decreased from 0.068 to 0.054 ( P  = 0.026) in the CIS/RRMS-treated group. The CSF CXCL13, CXCL13 ratio, CSF neurofilament light polypeptide and osteopontin levels also decreased significantly in the CIS/RRMS-treated group., Conclusions: The levels of all biomarkers changed concurrently with MS treatment. The sCD163 ratio was identified as a potential novel marker for time to DA.

Background and Purpose: Deep brain stimulation (DBS) for severe Parkinson's disease (PD) outperforms the best medical treatment in controlling motor symptoms and improving quality of life. Nevertheless disease progression cannot be controlled, and the development of dementia over time is nearly inevitable, often resulting in nursing home placement. Ten-year survival, development of hallucinations, dementia and nursing home placement were examined and adverse events were assessed., Method: Patient files were scrutinized from baseline up to 10 years of treatment or death on all 79 PD patients treated with DBS of the subthalamic nucleus from 1998 to 2003 at Aarhus University Hospital., Results: Twenty-four patients died during the follow-up period of 10 years. Age above 60 years at surgery increased mortality 2.3-fold (P = 0.04). Of the 55 surviving patients 29 (53%) were demented and 19 (35%) were in nursing homes. Average time from operation to dementia was 5.6 ± 2.9 years. Hallucinations and nursing home placement were associated with increased mortality., Conclusion: Survival of 70% after a mean of 25 years of PD including 10 years with DBS illustrates that this is a selected group of PD patients. The prevalence of dementia steadily increased after surgery as expected from disease progression and can be an early event. Compared with the few similar long-term studies, the present study presents a larger cohort followed at the same DBS center for a longer period of time and none was lost to follow-up, making conclusions more valid. The present findings are of significant prognostic help for the patient, caregiver and physician when treatment with DBS has to be decided., (© 2014 EAN.)

Background: Expression of soluble CD163 (sCD163), a macrophage/microglia biomarker, is increased in inflammatory conditions, and sCD163 levels in the cerebrospinal fluid (CSF) have recently been shown to be elevated in patients with multiple sclerosis (MS): the sCD163 CSF/serum ratio was elevated in patients with relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and clinically isolated syndrome (CIS) compared with symptomatic controls., Objective: To investigate the contributions of the sCD163 CSF/serum ratio to a biomarker panel focusing on inflammation and axonal degeneration in newly diagnosed MS; thus optimising a diagnostic biomarker panel for MS., Methods: After a full MS diagnostic work-up, including collection of paired samples of CSF and serum, 125 patients were included in this study. Patients were divided into groups based on their diagnosis, and patients with normal clinical and paraclinical findings were defined as symptomatic controls. Serum and CSF levels, ratios, and indices of sCD163, CXCL13, osteopontin, neopterin, and CSF levels of neurofilament light polypeptide were determined by enzyme-linked immunosorbent assays (ELISAs). For sCD163 the results constitute a post-hoc analysis of already published data., Results: All tested biomarkers, notably the sCD163 ratio, the CXCL13 ratio, the NEO ratio, the CSF level of NfL, the IgG index, and the serum level of OPN, were significantly correlated to RRMS, PPMS, and/or CIS. The individual biomarkers in single tests had a lower performance than the IgG index, however, their combined receiver operating characteristic (ROC) curve demonstrated excellent diagnostic discriminatory power., Conclusion: The biomarker panel showed distinct profiles for each patient group and could be a valuable tool for clinical differentiation of MS subgroups. The combined ROC analysis showed that sCD163 contributes positively as a diagnostic marker to a panel of established MS biomarkers. Patients with PPMS were demonstrated to have significantly elevated levels of both inflammatory and degenerative markers.

Purpose: In this work we specifically investigate the molecular weight (Mw) dependent combinatorial properties of hyaluronic acid (HA) for exhibiting stealth and targeting properties using different Mw HA nanoshells to tune nanoparticle retargeting to CD44-expressing cancer cells., Methods: HA of different Mw was covalently grafted onto model polystyrene nanoparticles and advanced surface analysis by X-ray photoelectron spectroscopy performed to quantify and evaluate the effect of the coating procedure. Specific CD44-mediated retargeting was investigated by flow cytometry and confocal microscopy using isogenic D44-deficient and CD44-expressing MCF-7 breast adenocarcinoma cells., Results: Surface analysis demonstrated effective surface coating with 33, 260 and 900 kDa HA resulting in increased colloidal stability and highly negative surface charge due to presentation of up to 4.7% carboxyl groups that indicates an extended and non-constricted HA polymer surface. Reduced non-specific particle interaction in CD44(-) cells was shown for all HA nanoshells but CD44-dependent cellular retargeting and internalization in CD44(+) cells was highly dependent on the coating HA Mw properties., Conclusion: The combination of advanced surface characterization and evaluation of particle interactions in isogenic cells with and without CD44 receptor demonstrates direct evidence for the dual capacity of HA for stealth and CD44-mediated retargeting tunable by the HA molecular weight.

Multiple sclerosis (MS) is an inflammatory disease where phagocytic cells infiltrate the nerve tissue and act as terminal agents in destruction of the myelin sheath. However, the mechanism that triggers the ability of these cells to recognize myelin remains obscure. We show that myelin basic protein (MBP), a major autoantigen in MS, is a potent and specific ligand for the integrin alpha(M)beta(2) (Mac-1, CD11b/CD18) expressed mainly on phagocytic cells. MBP undergoes a dramatic conformational change when liberated from the lipid-rich environment of the myelin sheath. The MS drug glatiramer acetate mimics the conformationally labile regions of MBP, interacts in the unfolded state strongly with alpha(M)beta(2), and inhibits the MBP binding to alpha(M)beta(2). Our study reveals a link between MBP, glatiramer acetate, and the alpha(M)beta(2) integrin, and suggests a new model for MS pathogenesis based on the recognition of unfolded MBP by the alpha(M)beta(2) integrin.