title: Validation of semaphorin 7A and ala-β-his-dipeptidase as biomarkers associated with the conversion from clinically isolated syndrome to multiple sclerosis.
abstract: BACKGROUND
  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). Here, we aimed to validate these results in individual CSF samples using alternative techniques.
  
  
  METHODS
  In 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.
  
  
  RESULTS
  CSF 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.
  
  
  CONCLUSIONS
  These 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.
authors.forename: Ester
authors.initials: E
authors.lastname: Cantó
authors.forename: Mar
authors.initials: M
authors.lastname: Tintoré
authors.forename: Luisa Maria
authors.initials: LM
authors.lastname: Villar
authors.forename: Eva
authors.initials: E
authors.lastname: Borrás
authors.forename: Jose Carlos
authors.initials: JC
authors.lastname: Alvarez-Cermeño
authors.forename: Cristina
authors.initials: C
authors.lastname: Chiva
authors.forename: Eduard
authors.initials: E
authors.lastname: Sabidó
authors.forename: Alex
authors.initials: A
authors.lastname: Rovira
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Ps, Vall d'Hebron 119-129, Barcelona, 08035, Spain. manuel.comabella@vhir.org.
authors.forename: Manuel
authors.initials: M
authors.lastname: Comabella
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D003711:Demyelinating Diseases / Q000134:cerebrospinal fluid*; D004150:Dipeptidases / Q000134:cerebrospinal fluid*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D058851:GPI-Linked Proteins / Q000134:cerebrospinal fluid; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid*; D039961:Semaphorins / Q000134:cerebrospinal fluid*
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D058851:GPI-Linked Proteins; C118753:SEMA7A protein, human; D039961:Semaphorins; D004150:Dipeptidases