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Contactin-1 and contactin-2 in cerebrospinal fluid as potential biomarkers for axonal domain dysfunction in multiple sclerosis.

ABSTRACT: Background:Contactin-1 and contactin-2 are important for the maintenance of axonal integrity. Objective:To investigate the cerebrospinal fluid levels of contactin-1 and contactin-2 in multiple sclerosis patients and controls, and their potential use as prognostic markers for neurodegeneration. Methods:Cerebrospinal fluid contactin-1 and contactin-2 were measured in relapsing-remitting multiple sclerosis (n?=?41), secondary progressive multiple sclerosis (n?=?26) and primary progressive multiple sclerosis patients (n?=?13) and controls (n?=?18), and in a second cohort with clinically isolated syndrome patients (n?=?88, median clinical follow-up period of 2.3 years) and controls (n?=?20). Correlations/linear regressions were analysed with other baseline cerebrospinal fluid axonal damage markers and cross-sectional/longitudinal magnetic resonance imaging features. Results:Contactin-1 and contactin-2 levels were up to 1.4-fold reduced in relapsing-remitting multiple sclerosis (contactin-1: p?=?0.01, contactin-2: p?=?0.02) and secondary progressive multiple sclerosis (contactin-1: p?=?0.05, contactin-2: p?=?0.02) compared to controls. In clinically isolated syndrome patients, contactin-1 tended to increase when compared to controls (p?=?0.07). Both contactin-1 and contactin-2 correlated with neurofilament light, neurofilament heavy and magnetic resonance imaging metrics differently depending on the disease stage. In clinically isolated syndrome patients, baseline contactin-2 level (??=?-0.42, p?=?0.04) predicted the longitudinal decline in cortex volume. Conclusion:Cerebrospinal fluid contactin-1 and contactin-2 reveal axonal dysfunction in various stages of multiple sclerosis and their inclusion to the biomarker panel may provide better insight into the extent of axonal damage/dysfunction.

SUBMITTER: Chatterjee M

PROVIDER: S-EPMC6305953 | biostudies-literature | 2018 Oct-Dec

REPOSITORIES: biostudies-literature

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Contactin-1 and contactin-2 in cerebrospinal fluid as potential biomarkers for axonal domain dysfunction in multiple sclerosis.

Chatterjee Madhurima M Koel-Simmelink Marleen Ja MJ Verberk Inge Mw IM Killestein Joep J Vrenken Hugo H Enzinger Christian C Ropele Stefan S Fazekas Franz F Khalil Michael M Teunissen Charlotte E CE

Multiple sclerosis journal - experimental, translational and clinical 20181001 4

<h4>Background</h4>Contactin-1 and contactin-2 are important for the maintenance of axonal integrity.<h4>Objective</h4>To investigate the cerebrospinal fluid levels of contactin-1 and contactin-2 in multiple sclerosis patients and controls, and their potential use as prognostic markers for neurodegeneration.<h4>Methods</h4>Cerebrospinal fluid contactin-1 and contactin-2 were measured in relapsing-remitting multiple sclerosis (<i>n = </i>41), secondary progressive multiple sclerosis (<i>n = </i>2 ...[more]

PMID: 30627437

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Project description:BackgroundVerification of cerebrospinal fluid (CSF) biomarkers for multiple sclerosis and other neurological diseases is a major challenge due to a large number of candidates, limited sample material availability, disease and biological heterogeneity, and the lack of standardized assays. Furthermore, verification studies are often based on a low number of proteins from a single discovery experiment in medium-sized cohorts, where antibodies and surrogate peptides may differ, thus only providing an indication of proteins affected by the disease and not revealing the bigger picture or concluding on the validity of the markers. We here present a standard approach for locating promising biomarker candidates based on existing knowledge, resulting in high-quality assays covering the main biological processes affected by multiple sclerosis for comparable measurements over time.MethodsBiomarker candidates were located in CSF-PR (proteomics.uib.no/csf-pr), and further filtered based on estimated concentration in CSF and biological function. Peptide surrogates for internal standards were selected according to relevant criteria, parallel reaction monitoring (PRM) assays created, and extensive assay quality testing performed, i.e. intra- and inter-day variation, trypsin digestion status over time, and whether the peptides were able to separate multiple sclerosis patients and controls.ResultsAssays were developed for 25 proteins, represented by 72 peptides selected according to relevant guidelines and available literature and tested for assay peptide suitability. Stability testing revealed 64 peptides with low intra- and inter-day variations, with 44 also being stably digested after 16 h of trypsin digestion, and 37 furthermore showing a significant difference between multiple sclerosis and controls, thereby confirming literature findings. Calibration curves and the linear area of measurement have, so far, been determined for 17 of these peptides.ConclusionsWe present 37 high-quality PRM assays across 21 CSF-proteins found to be affected by multiple sclerosis, along with a recommended workflow for future development of new assays. The assays can directly be used by others, thus enabling better comparison between studies. Finally, the assays can robustly and stably monitor biological processes in multiple sclerosis patients over time, thus potentially aiding in diagnosis and prognosis, and ultimately in treatment decisions.

Project description:Eighty-five percent of multiple sclerosis cases begin with a discrete attack termed clinically isolated syndrome, but 37% of clinically isolated syndrome patients do not experience a relapse within 20 years of onset. Thus, the identification of biomarkers able to differentiate between individuals who are most likely to have a second clinical attack from those who remain in the clinically isolated syndrome stage is essential to apply a personalized medicine approach. We sought to identify biomarkers from biochemical, metabolic and proteomic screens that predict clinically defined conversion from clinically isolated syndrome to multiple sclerosis and generate a multi-omics-based algorithm with higher prognostic accuracy than any currently available test. An integrative multi-variate approach was applied to the analysis of cerebrospinal fluid samples taken from 54 individuals at the point of clinically isolated syndrome with 2-10 years of subsequent follow-up enabling stratification into clinical converters and non-converters. Leukocyte counts were significantly elevated at onset in the clinical converters and predict the occurrence of a second attack with 70% accuracy. Myo-inositol levels were significantly increased in clinical converters while glucose levels were decreased, predicting transition to multiple sclerosis with accuracies of 72% and 63%, respectively. Proteomics analysis identified 89 novel gene products related to conversion. The identified biochemical and protein biomarkers were combined to produce an algorithm with predictive accuracy of 83% for the transition to clinically defined multiple sclerosis, outperforming any individual biomarker in isolation including oligoclonal bands. The identified protein biomarkers are consistent with an exaggerated immune response, perturbed energy metabolism and multiple sclerosis pathology in the clinical converter group. The new biomarkers presented provide novel insight into the molecular pathways promoting disease while the multi-omics algorithm provides a means to more accurately predict whether an individual is likely to convert to clinically defined multiple sclerosis.

Project description:BACKGROUND:Synaptic and axonal loss are two major mechanisms underlying Alzheimer's disease (AD) pathogenesis, and biomarkers reflecting changes in these cellular processes are needed for early diagnosis and monitoring the progression of AD. Contactin-2 is a synaptic and axonal membrane protein that interacts with proteins involved in the pathology of AD such as amyloid precursor protein (APP) and beta-secretase 1 (BACE1). We hypothesized that AD might be characterized by changes in contactin-2 levels in the cerebrospinal fluid (CSF) and brain tissue. Therefore, we aimed to investigate the levels of contactin-2 in the CSF and evaluate its relationship with disease pathology. METHODS:Contactin-2 was measured in CSF from two cohorts (selected from the Amsterdam Dementia Cohort), comprising samples from controls (cohort 1, n?=?28; cohort 2, n?=?20) and AD (cohort 1, n?=?36; cohort 2, n?=?70) using an analytically validated commercial enzyme-linked immunosorbent assay (ELISA). The relationship of contactin-2 with cognitive decline (Mini-Mental State Examination (MMSE)) and other CSF biomarkers reflecting AD pathology were analyzed. We further characterized the expression of contactin-2 in postmortem AD human brain (n?=?14) versus nondemented controls (n?=?9). RESULTS:CSF contactin-2 was approximately?1.3-fold reduced in AD patients compared with controls (p?<?0.0001). Overall, contactin-2 levels correlated with MMSE scores (r?=?0.35, p?=?0.004). We observed that CSF contactin-2 correlated with the levels of phosphorylated tau within the control (r?=?0.46, p?<?0.05) and AD groups (r?=?0.31, p?<?0.05). Contactin-2 also correlated strongly with another synaptic biomarker, neurogranin (control: r?=?0.62, p?<?0.05; AD: r?=?0.60, p?<?0.01), and BACE1, a contactin-2 processing enzyme (control: r?=?0.64, p?<?0.01; AD: r?=?0.46, p?<?0.05). Results were further validated in a second cohort (p?<?0.01). Immunohistochemical analysis revealed that contactin-2 is expressed in the extracellular matrix. Lower levels of contactin-2 were specifically found in and around amyloid plaques in AD hippocampus and temporal cortex. CONCLUSIONS:Taken together, these data reveal that the contactin-2 changes observed in tissues are reflected in CSF, suggesting that decreased contactin-2 CSF levels might be a biomarker reflecting synaptic or axonal loss.

Dataset Information

Contactin-1 and contactin-2 in cerebrospinal fluid as potential biomarkers for axonal domain dysfunction in multiple sclerosis.

Publications

Contactin-1 and contactin-2 in cerebrospinal fluid as potential biomarkers for axonal domain dysfunction in multiple sclerosis.

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