Contribution of Blood Biomarkers to Multiple Sclerosis Diagnosis

Manuel Comabella; Agustín Pappolla; Enric Monreal; Nicolás Fissolo; Augusto Cesaar Sao-Avilés; Georgina Arrambide; Pere Carbonell-Mirabent; Lucía Gutierrez; Álvaro Cobo-Calvo; Carmen Tur; Javier Villacieros-Álvarez; Ángela Vidal-Jordana; Joaquín Castilló; Ingrid Galán; Mercedes Espiño; Helena Ariño; Luca Bollo; Marta Rodríguez Barranco; Luciana Soledad Midaglia; René Carvajal; Noelia Villarrubia; José Ignacio Fernández Velasco; Breogán Rodríguez Acevedo; Lucienne F Costa Frossard; Andreu Vilaseca; Cristina Auger; Ana Zabalza; Susana Sainz De La Maza; Neus Mongay-Ochoa; Jordi Río; Jaume Sastre-Garriga; Àlex Rovira; Mar Tintoré; Luisa M Villar; Xavier Montalban

doi:10.1212/NXI.0000000000200370

Contribution of Blood Biomarkers to Multiple Sclerosis Diagnosis

Manuel Comabella, Agustín Pappolla, Enric Monreal, Nicolás Fissolo, Augusto Cesaar Sao-Avilés, Georgina Arrambide, Pere Carbonell-Mirabent, Lucía Gutierrez, Álvaro Cobo-Calvo, Carmen Tur, Javier Villacieros-Álvarez, Ángela Vidal-Jordana, Joaquín Castilló, Ingrid Galán, Mercedes Espiño, Helena Ariño, Luca Bollo, Marta Rodríguez Barranco, Luciana Soledad Midaglia, René CarvajalNoelia Villarrubia, José Ignacio Fernández Velasco, Breogán Rodríguez Acevedo, Lucienne F Costa Frossard, Andreu Vilaseca, Cristina Auger, Ana Zabalza, Susana Sainz De La Maza, Neus Mongay-Ochoa, Jordi Río, Jaume Sastre-Garriga, Àlex Rovira, Mar Tintoré, Luisa M Villar, Xavier Montalban

Department of Medicine

Research output: Contribution to journal › Article › Research › peer-review

Abstract

BACKGROUND AND OBJECTIVES: Invasive procedures may delay the diagnostic process in multiple sclerosis (MS). We investigated the added value of serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), chitinase-3-like 1 (sCHI3L1), and the immune responses to the Epstein-Barr virus-encoded nuclear antigen 1 to current MS diagnostic criteria.

METHODS: In this multicentric study, we selected patients from 2 prospective cohorts presenting a clinically isolated syndrome (CIS). Patients were classified as (1) not presenting dissemination in space (DIS) nor dissemination in time (DIT) (noDIS and noDIT); (2) presenting DIS without DIT (DIS and noDIT); and (3) presenting both (DIS and DIT), which were used as a reference. sNfL, sGFAP, and sCHI3L1 levels were measured with single-molecule array immunoassays and EBNA1-specific IgG levels with ELISA. Biomarker levels were compared between groups using linear regression models. Receiver operating characteristic curve analyses and Youden Index were used to determine cutoff values associated with MS diagnosis during follow-up.

RESULTS: We included 181 patients (66.3% females, mean [SD] age of 35.0 [9.7] years). At baseline, 25 (13.8%) were classified as noDIS and noDIT, 62 (34.3%) as DIS and noDIT, and 94 (51.9%) as DIS and DIT. Only sNfL Z-scores discriminated between groups (DIS and DIT vs DIS and noDIT [ p = 0.002], DIS and DIT vs noDIS and noDIT [ p < 0.001], and DIS and noDIT vs noDIS and noDIT [ p = 0.026]). In noDIS and noDIT patients (median interquartile range [IQR] follow-up of 8.1 [5.0-11.7] years), high sNfL Z-scores best predicted MS diagnosis (specificity [SP] and 95% CI of 93.3% [68.1-99.8] and positive predictive value [PPV] of 87.5% [47.3-99.7]). Among DIS and noDIT patients (median [IQR] follow-up of 6.8 [4.0-9.1] years), high sNfL Z-scores best predicted MS diagnosis (SP of 80% [28.4-99.5] and PPV of 97.3% [85.8-99.9]) without considering oligoclonal band (OB) status. In the subset of patients of this group with negative OBs, a combination of high sNfL Z-scores and sGFAP levels predicted MS diagnosis (SP of 100% [39.8-100] and PPV of 100% [54.1-100]).

DISCUSSION: These results suggest that sNfL and sGFAP may be incorporated in particular scenarios to diagnose MS in patients with CIS not fulfilling current diagnostic criteria.

Original language	English
Article number	e200370
Number of pages	11
Journal	Neurology(R) neuroimmunology & neuroinflammation
Volume	12
Issue number	2
DOIs	https://doi.org/10.1212/NXI.0000000000200370
Publication status	Published - 29 Jan 2025

Keywords

Humans
Female
Male
Adult
Biomarkers/blood
Multiple Sclerosis/blood
Middle Aged
Glial Fibrillary Acidic Protein/blood
Chitinase-3-Like Protein 1/blood
Neurofilament Proteins/blood
Epstein-Barr Virus Nuclear Antigens/blood
Prospective Studies

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Comabella, M., Pappolla, A., Monreal, E., Fissolo, N., Sao-Avilés, A. C., Arrambide, G., Carbonell-Mirabent, P., Gutierrez, L., Cobo-Calvo, Á., Tur, C., Villacieros-Álvarez, J., Vidal-Jordana, Á., Castilló, J., Galán, I., Espiño, M., Ariño, H., Bollo, L., Rodríguez Barranco, M., Midaglia, L. S., ... Montalban, X. (2025). Contribution of Blood Biomarkers to Multiple Sclerosis Diagnosis. Neurology(R) neuroimmunology & neuroinflammation, 12(2), Article e200370. https://doi.org/10.1212/NXI.0000000000200370

@article{dadcd48d94f747f69535554ac68eb6c6,

title = "Contribution of Blood Biomarkers to Multiple Sclerosis Diagnosis",

abstract = "BACKGROUND AND OBJECTIVES: Invasive procedures may delay the diagnostic process in multiple sclerosis (MS). We investigated the added value of serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), chitinase-3-like 1 (sCHI3L1), and the immune responses to the Epstein-Barr virus-encoded nuclear antigen 1 to current MS diagnostic criteria.METHODS: In this multicentric study, we selected patients from 2 prospective cohorts presenting a clinically isolated syndrome (CIS). Patients were classified as (1) not presenting dissemination in space (DIS) nor dissemination in time (DIT) (noDIS and noDIT); (2) presenting DIS without DIT (DIS and noDIT); and (3) presenting both (DIS and DIT), which were used as a reference. sNfL, sGFAP, and sCHI3L1 levels were measured with single-molecule array immunoassays and EBNA1-specific IgG levels with ELISA. Biomarker levels were compared between groups using linear regression models. Receiver operating characteristic curve analyses and Youden Index were used to determine cutoff values associated with MS diagnosis during follow-up.RESULTS: We included 181 patients (66.3% females, mean [SD] age of 35.0 [9.7] years). At baseline, 25 (13.8%) were classified as noDIS and noDIT, 62 (34.3%) as DIS and noDIT, and 94 (51.9%) as DIS and DIT. Only sNfL Z-scores discriminated between groups (DIS and DIT vs DIS and noDIT [ p = 0.002], DIS and DIT vs noDIS and noDIT [ p < 0.001], and DIS and noDIT vs noDIS and noDIT [ p = 0.026]). In noDIS and noDIT patients (median interquartile range [IQR] follow-up of 8.1 [5.0-11.7] years), high sNfL Z-scores best predicted MS diagnosis (specificity [SP] and 95% CI of 93.3% [68.1-99.8] and positive predictive value [PPV] of 87.5% [47.3-99.7]). Among DIS and noDIT patients (median [IQR] follow-up of 6.8 [4.0-9.1] years), high sNfL Z-scores best predicted MS diagnosis (SP of 80% [28.4-99.5] and PPV of 97.3% [85.8-99.9]) without considering oligoclonal band (OB) status. In the subset of patients of this group with negative OBs, a combination of high sNfL Z-scores and sGFAP levels predicted MS diagnosis (SP of 100% [39.8-100] and PPV of 100% [54.1-100]). DISCUSSION: These results suggest that sNfL and sGFAP may be incorporated in particular scenarios to diagnose MS in patients with CIS not fulfilling current diagnostic criteria.",

keywords = "Humans, Female, Male, Adult, Biomarkers/blood, Multiple Sclerosis/blood, Middle Aged, Glial Fibrillary Acidic Protein/blood, Chitinase-3-Like Protein 1/blood, Neurofilament Proteins/blood, Epstein-Barr Virus Nuclear Antigens/blood, Prospective Studies",

author = "Manuel Comabella and Agust{\'i}n Pappolla and Enric Monreal and Nicol{\'a}s Fissolo and Sao-Avil{\'e}s, {Augusto Cesaar} and Georgina Arrambide and Pere Carbonell-Mirabent and Luc{\'i}a Gutierrez and {\'A}lvaro Cobo-Calvo and Carmen Tur and Javier Villacieros-{\'A}lvarez and {\'A}ngela Vidal-Jordana and Joaqu{\'i}n Castill{\'o} and Ingrid Gal{\'a}n and Mercedes Espi{\~n}o and Helena Ari{\~n}o and Luca Bollo and {Rodr{\'i}guez Barranco}, Marta and Midaglia, {Luciana Soledad} and Ren{\'e} Carvajal and Noelia Villarrubia and {Fern{\'a}ndez Velasco}, {Jos{\'e} Ignacio} and {Rodr{\'i}guez Acevedo}, Breog{\'a}n and {Costa Frossard}, {Lucienne F} and Andreu Vilaseca and Cristina Auger and Ana Zabalza and {Sainz De La Maza}, Susana and Neus Mongay-Ochoa and Jordi R{\'i}o and Jaume Sastre-Garriga and {\`A}lex Rovira and Mar Tintor{\'e} and Villar, {Luisa M} and Xavier Montalban",

year = "2025",

month = jan,

day = "29",

doi = "10.1212/NXI.0000000000200370",

language = "English",

volume = "12",

journal = "Neurology(R) neuroimmunology & neuroinflammation",

issn = "2332-7812",

publisher = "Lippincott Williams and Wilkins",

number = "2",

}

Comabella, M, Pappolla, A, Monreal, E, Fissolo, N, Sao-Avilés, AC, Arrambide, G, Carbonell-Mirabent, P, Gutierrez, L, Cobo-Calvo, Á, Tur, C, Villacieros-Álvarez, J, Vidal-Jordana, Á, Castilló, J, Galán, I, Espiño, M, Ariño, H, Bollo, L, Rodríguez Barranco, M, Midaglia, LS, Carvajal, R, Villarrubia, N, Fernández Velasco, JI, Rodríguez Acevedo, B, Costa Frossard, LF, Vilaseca, A, Auger, C, Zabalza, A, Sainz De La Maza, S, Mongay-Ochoa, N, Río, J, Sastre-Garriga, J, Rovira, À, Tintoré, M, Villar, LM & Montalban, X 2025, 'Contribution of Blood Biomarkers to Multiple Sclerosis Diagnosis', Neurology(R) neuroimmunology & neuroinflammation, vol. 12, no. 2, e200370. https://doi.org/10.1212/NXI.0000000000200370

TY - JOUR

T1 - Contribution of Blood Biomarkers to Multiple Sclerosis Diagnosis

AU - Comabella, Manuel

AU - Pappolla, Agustín

AU - Monreal, Enric

AU - Fissolo, Nicolás

AU - Sao-Avilés, Augusto Cesaar

AU - Arrambide, Georgina

AU - Carbonell-Mirabent, Pere

AU - Gutierrez, Lucía

AU - Cobo-Calvo, Álvaro

AU - Tur, Carmen

AU - Villacieros-Álvarez, Javier

AU - Vidal-Jordana, Ángela

AU - Castilló, Joaquín

AU - Galán, Ingrid

AU - Espiño, Mercedes

AU - Ariño, Helena

AU - Bollo, Luca

AU - Rodríguez Barranco, Marta

AU - Midaglia, Luciana Soledad

AU - Carvajal, René

AU - Villarrubia, Noelia

AU - Fernández Velasco, José Ignacio

AU - Rodríguez Acevedo, Breogán

AU - Costa Frossard, Lucienne F

AU - Vilaseca, Andreu

AU - Auger, Cristina

AU - Zabalza, Ana

AU - Sainz De La Maza, Susana

AU - Mongay-Ochoa, Neus

AU - Río, Jordi

AU - Sastre-Garriga, Jaume

AU - Rovira, Àlex

AU - Tintoré, Mar

AU - Villar, Luisa M

AU - Montalban, Xavier

PY - 2025/1/29

Y1 - 2025/1/29

N2 - BACKGROUND AND OBJECTIVES: Invasive procedures may delay the diagnostic process in multiple sclerosis (MS). We investigated the added value of serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), chitinase-3-like 1 (sCHI3L1), and the immune responses to the Epstein-Barr virus-encoded nuclear antigen 1 to current MS diagnostic criteria.METHODS: In this multicentric study, we selected patients from 2 prospective cohorts presenting a clinically isolated syndrome (CIS). Patients were classified as (1) not presenting dissemination in space (DIS) nor dissemination in time (DIT) (noDIS and noDIT); (2) presenting DIS without DIT (DIS and noDIT); and (3) presenting both (DIS and DIT), which were used as a reference. sNfL, sGFAP, and sCHI3L1 levels were measured with single-molecule array immunoassays and EBNA1-specific IgG levels with ELISA. Biomarker levels were compared between groups using linear regression models. Receiver operating characteristic curve analyses and Youden Index were used to determine cutoff values associated with MS diagnosis during follow-up.RESULTS: We included 181 patients (66.3% females, mean [SD] age of 35.0 [9.7] years). At baseline, 25 (13.8%) were classified as noDIS and noDIT, 62 (34.3%) as DIS and noDIT, and 94 (51.9%) as DIS and DIT. Only sNfL Z-scores discriminated between groups (DIS and DIT vs DIS and noDIT [ p = 0.002], DIS and DIT vs noDIS and noDIT [ p < 0.001], and DIS and noDIT vs noDIS and noDIT [ p = 0.026]). In noDIS and noDIT patients (median interquartile range [IQR] follow-up of 8.1 [5.0-11.7] years), high sNfL Z-scores best predicted MS diagnosis (specificity [SP] and 95% CI of 93.3% [68.1-99.8] and positive predictive value [PPV] of 87.5% [47.3-99.7]). Among DIS and noDIT patients (median [IQR] follow-up of 6.8 [4.0-9.1] years), high sNfL Z-scores best predicted MS diagnosis (SP of 80% [28.4-99.5] and PPV of 97.3% [85.8-99.9]) without considering oligoclonal band (OB) status. In the subset of patients of this group with negative OBs, a combination of high sNfL Z-scores and sGFAP levels predicted MS diagnosis (SP of 100% [39.8-100] and PPV of 100% [54.1-100]). DISCUSSION: These results suggest that sNfL and sGFAP may be incorporated in particular scenarios to diagnose MS in patients with CIS not fulfilling current diagnostic criteria.

AB - BACKGROUND AND OBJECTIVES: Invasive procedures may delay the diagnostic process in multiple sclerosis (MS). We investigated the added value of serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), chitinase-3-like 1 (sCHI3L1), and the immune responses to the Epstein-Barr virus-encoded nuclear antigen 1 to current MS diagnostic criteria.METHODS: In this multicentric study, we selected patients from 2 prospective cohorts presenting a clinically isolated syndrome (CIS). Patients were classified as (1) not presenting dissemination in space (DIS) nor dissemination in time (DIT) (noDIS and noDIT); (2) presenting DIS without DIT (DIS and noDIT); and (3) presenting both (DIS and DIT), which were used as a reference. sNfL, sGFAP, and sCHI3L1 levels were measured with single-molecule array immunoassays and EBNA1-specific IgG levels with ELISA. Biomarker levels were compared between groups using linear regression models. Receiver operating characteristic curve analyses and Youden Index were used to determine cutoff values associated with MS diagnosis during follow-up.RESULTS: We included 181 patients (66.3% females, mean [SD] age of 35.0 [9.7] years). At baseline, 25 (13.8%) were classified as noDIS and noDIT, 62 (34.3%) as DIS and noDIT, and 94 (51.9%) as DIS and DIT. Only sNfL Z-scores discriminated between groups (DIS and DIT vs DIS and noDIT [ p = 0.002], DIS and DIT vs noDIS and noDIT [ p < 0.001], and DIS and noDIT vs noDIS and noDIT [ p = 0.026]). In noDIS and noDIT patients (median interquartile range [IQR] follow-up of 8.1 [5.0-11.7] years), high sNfL Z-scores best predicted MS diagnosis (specificity [SP] and 95% CI of 93.3% [68.1-99.8] and positive predictive value [PPV] of 87.5% [47.3-99.7]). Among DIS and noDIT patients (median [IQR] follow-up of 6.8 [4.0-9.1] years), high sNfL Z-scores best predicted MS diagnosis (SP of 80% [28.4-99.5] and PPV of 97.3% [85.8-99.9]) without considering oligoclonal band (OB) status. In the subset of patients of this group with negative OBs, a combination of high sNfL Z-scores and sGFAP levels predicted MS diagnosis (SP of 100% [39.8-100] and PPV of 100% [54.1-100]). DISCUSSION: These results suggest that sNfL and sGFAP may be incorporated in particular scenarios to diagnose MS in patients with CIS not fulfilling current diagnostic criteria.

KW - Humans

KW - Female

KW - Male

KW - Adult

KW - Biomarkers/blood

KW - Multiple Sclerosis/blood

KW - Middle Aged

KW - Glial Fibrillary Acidic Protein/blood

KW - Chitinase-3-Like Protein 1/blood

KW - Neurofilament Proteins/blood

KW - Epstein-Barr Virus Nuclear Antigens/blood

KW - Prospective Studies

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UR - https://www.mendeley.com/catalogue/2671fe81-da67-33c4-b7ed-7d512f43cf46/

U2 - 10.1212/NXI.0000000000200370

DO - 10.1212/NXI.0000000000200370

M3 - Article

C2 - 39879564

SN - 2332-7812

VL - 12

JO - Neurology(R) neuroimmunology & neuroinflammation

JF - Neurology(R) neuroimmunology & neuroinflammation

IS - 2

M1 - e200370

ER -

Contribution of Blood Biomarkers to Multiple Sclerosis Diagnosis

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