Validation of semaphorin 7A and ala-β-his-dipeptidase as biomarkers associated with the conversion from clinically isolated syndrome to multiple sclerosis

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.

Protein-Based Classifier to Predict Conversion from Clinically Isolated Syndrome to Multiple Sclerosis

“…This cohort was independent from that used in our previous discovery study (14), and samples were recruited at the Hospital Ramó n y Cajal (Madrid, Spain). Patients with clinically isolated syndrome were classified according to the following criteria: no conversion to CDMS during the follow-up period, negative IgG oligoclonal bands, and 0 Barkhof criteria at a baseline brain MRI (n ϭ 25) or conversion to CDMS, presence of IgG oligoclonal bands, and an abnormal brain MRI at baseline (2, 3, or 4 Barkhof criteria) (n ϭ 25) (15). A full description of clinical information and cerebrospinal fluid characteristics of all patients included in the present study is provided in Supplemental Table ST1.…”

“…In the initial screening, several proteins exhibited significant differences in abundance when comparing these two groups of patients. The abundance change in one of the altered proteins, chitinase 3-like 1 (CH3L1), was confirmed by ELISA in CSF of individual patients, whereas for others, such as semaphorin 7A (SEM7A) and ala-␤-his-dipeptidase (CNDP1), their abundance changes were confirmed by targeted mass spectrometry in follow-up studies with independent cohorts (15). Moreover, the levels of CH3L1 were associated with brain MRI abnormalities and disability progression during the follow-up period, as well as with shorter time to conversion to clinically definite multiple sclerosis (14).…”

An unconventional cerebrospinal fluid-derived Semaphorin-signalling regulates apical progenitor dynamics in the developing neocortex

“…Interestingly, the release of various additional axon guidance molecules in the CSF, such as Sema4D, Sema7A, Sema3C, and Slits, was already reported 16,76,77 . Our findings bring the first insights into a likely much broader developmental program orchestrating apical dynamics of cortical progenitors.…”

Differential expression of sema3A and sema7A in a murine model of multiple sclerosis: Implications for a therapeutic design

“…However, its function as a negative regulator of T-cell responses has also been reported [36]. In the context of MS, patients with a clinically isolated syndrome who convert to clinically defined MS have diminished levels of sema7A in the cerebrospinal fluid compared to those who do not convert [37,38].…”