Abstract
BackgroundIn a previous proteomics study using pooled cerebrospinal fluid (CSF) samples, we proposed apolipoprotein AI, apolipoprotein AIV, vitronectin, plasminogen, semaphorin 7A, and ala-β-his-dipeptidase as candidate biomarkers associated with the conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndromes (CIS). Here, we aimed to validate these results in individual CSF samples using alternative techniques.MethodsIn a first replication study, levels of apolipoproteins AI and AIV, vitronectin, and plasminogen were measured by ELISA in CSF and serum of 56 CIS patients (29 patients who converted to CDMS (MS converters) and 27 patients who remained with CIS during follow-up (MS non-converters)) and 26 controls with other neurological disorders. Semaphorin 7A and ala-β-his-dipeptidase levels were determined by selected reaction monitoring (SRM) in CSF of 36 patients (18 MS converters, 18 non-converters) and 20 controls. In a second replication study, apolipoprotein AI levels were measured by ELISA in CSF of 74 CIS patients (47 MS converters, 27 non-converters) and 50 individual controls, and levels of semaphorin 7A and ala-beta-his-dipeptidase were determined by SRM in 49 patients (24 MS converters, 25 non-converters) and 22 controls.ResultsCSF levels of apolipoprotein AI were increased (P = 0.043) and levels of semaphorin 7A and ala-β-his-dipeptidase decreased (P = 4.4 × 10−10 and P = 0.033 respectively) in MS converters compared to non-converters. No significant differences were found in serum levels for apolipoproteins AI and AIV, vitronectin, and plasminogen. Findings with semaphorin 7A and ala-β-his-dipeptidase were also validated in the second replication study, and CSF levels for these two proteins were again decreased in MS converters versus non-converters (P = 1.2 × 10−4 for semaphorin 7A; P = 3.7 × 10−8 for ala-β-his-dipeptidase). Conversely, apolipoprotein AI findings were not replicated and CSF levels for this protein did not significantly differ between groups. Furthermore, CSF semaphorin 7A levels were negatively associated with the number of T2 lesions at baseline and one-year follow-up.ConclusionsThese results validate previous findings for semaphorin 7A and ala-β-his-dipeptidase, and suggest that these proteins play a role as CSF biomarkers associated with the conversion to CDMS in CIS patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0181-8) contains supplementary material, which is available to authorized users.
Highlights
In a previous proteomics study using pooled cerebrospinal fluid (CSF) samples, we proposed apolipoprotein AI, apolipoprotein AIV, vitronectin, plasminogen, semaphorin 7A, and ala-β-his-dipeptidase as candidate biomarkers associated with the conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndromes (CIS)
With the aim to identify additional molecular biomarkers associated with the conversion to MS, we recently conducted a mass spectrometry-based proteomic study in pooled CSF samples from patients with CIS who converted to clinically definite MS (CDMS) and patients who remained with CIS [5]
CSF levels of apoAI were determined by ELISA (ELISAPRO kit for Human apolipoprotein AI; 3710-1HP-2; Mabtech AB, Nacka Strand, Sweden) in 74 CIS patients recruited at the Centre d’Esclerosi Múltiple de Catalunya (Cemcat) (27 CIS patients who remained with CIS during the follow-up period and 47 patients who converted to CDMS)
Summary
In a previous proteomics study using pooled cerebrospinal fluid (CSF) samples, we proposed apolipoprotein AI, apolipoprotein AIV, vitronectin, plasminogen, semaphorin 7A, and ala-β-his-dipeptidase as candidate biomarkers associated with the conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndromes (CIS). Chitinase 3-like 1 (CHI3L1), ceruloplasmin, and vitamin D-binding protein were selected for validation in individual CSF samples, and CHI3L1 findings were confirmed in additional cohorts of CIS patients [5] In this initial screening proteomic study, other proteins were identified and proposed to be candidate biomarkers associated with conversion to MS: apolipoprotein AI (apoAI), apolipoprotein AIV (apoAIV), vitronectin, and plasminogen were found to be upregulated, and semaphorin 7A (sema7A) and ala-beta-his-dipeptidase (CNDP1) were found to be downregulated in CSF pools of CIS patients who converted to CDMS [5]. We pursued the validation of these proteins as biomarkers using different techniques in individual CSF samples from CIS patients classified according to their conversion (or lack of ) to CDMS
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