Multifaceted Biomarkers Suggest a Similar Profile of CNS Pathology in Relapsing and Progressive MS

Katelijn M Blok; Romy A M Klein Kranenbarg; Kirtana Ananth; Hendrik J Engelenburg; Aletta van den Bosch; Lucia A A Giannini; Janet de Beukelaar; Harro Seelaar; Inge Huitinga; Ari Green; Beatrijs Wokke; Ahmed Abdelhak; Joost Smolders

doi:10.1111/ene.70052

Multifaceted Biomarkers Suggest a Similar Profile of CNS Pathology in Relapsing and Progressive MS

Katelijn M Blok, Romy A M Klein Kranenbarg, Kirtana Ananth, Hendrik J Engelenburg, Aletta van den Bosch, Lucia A A Giannini, Janet de Beukelaar, Harro Seelaar, Inge Huitinga, Ari Green, Beatrijs Wokke, Ahmed Abdelhak, Joost Smolders

Netherlands Institute for Neuroscience (NIN)

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

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Abstract

BACKGROUND: Relapsing-remitting (RR) and primary progressive (PP) multiple sclerosis (MS) have distinct clinical courses, but underlying pathophysiological differences remain unclear. We compared pathological components between RRMS, PPMS, and other inflammatory and neurodegenerative disorders, leveraging soluble biomarkers and post-mortem pathology.

METHODS: Serum and cerebrospinal fluid (CSF) of people diagnosed with (pw) PPMS (n = 104), RRMS (n = 38), Alzheimer's disease (AD, n = 22), neuromyelitis optica spectrum disorder (NMOSD, n = 10), and myelin oligodendrocyte glycoprotein-associated disease (MOGAD, n = 10) were collected. B-cell maturation antigen (BCMA), soluble CD27 (sCD27), osteopontin (OPN), chitinase-3-like-1 (CHI3L1), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and synaptosomal-associated protein-25 (SNAP25) were measured. Lymphocytes (CD20+, CD138+, CD3+) and pyramidal-tract axonal density in RR-onset (n = 86) and PPMS (n = 45) post-mortem brain tissue were quantified.

RESULTS: Soluble and post-mortem tissue biomarkers did not differ between pwRRMS and pwPPMS. Compared to AD, MS had higher CSF sCD27 (p < 0.001) but lower serum CHI3L1 and GFAP, and CSF OPN and SNAP25 (all p < 0.05). Serum OPN was lower in RRMS than NMOSD (p = 0.013). Principal component analyses and K-means clustering showed substantial overlap of RRMS and PPMS biomarkers, distinct from AD. In all pwMS, serum NfL and CSF BCMA correlated with clinical/radiological disease activity, CSF BCMA and sCD27 with inflammatory parameters, and serum GFAP, CSF GFAP, and CSF NfL with Expanded Disability Status Scale (EDSS) score.

CONCLUSIONS: Serum and CSF soluble biomarker profiles and post-mortem pathology do not differentiate RRMS from PPMS diagnoses but reflect the extent of inflammation and tissue damage. Detailed assessment of MS-associated inflammation and tissue damage may enhance classification and therapeutic strategies.

Original language	English
Pages (from-to)	e70052
Journal	European Journal of Neurology
Volume	32
Issue number	2
DOIs	https://doi.org/10.1111/ene.70052
Publication status	Published - Feb 2025

Keywords

Humans
Biomarkers/cerebrospinal fluid
Multiple Sclerosis, Chronic Progressive/blood
Male
Female
Multiple Sclerosis, Relapsing-Remitting/cerebrospinal fluid
Middle Aged
Adult
Aged
Alzheimer Disease/blood
Chitinase-3-Like Protein 1/blood
Neuromyelitis Optica/blood
Neurofilament Proteins/blood
Glial Fibrillary Acidic Protein/blood
Osteopontin/blood

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10.1111/ene.70052

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Blok, K. M., Klein Kranenbarg, R. A. M., Ananth, K., Engelenburg, H. J., van den Bosch, A., Giannini, L. A. A., de Beukelaar, J., Seelaar, H., Huitinga, I., Green, A., Wokke, B., Abdelhak, A., & Smolders, J. (2025). Multifaceted Biomarkers Suggest a Similar Profile of CNS Pathology in Relapsing and Progressive MS. European Journal of Neurology, 32(2), e70052. https://doi.org/10.1111/ene.70052

@article{8292f926869f43d280a0842a5af235d2,

title = "Multifaceted Biomarkers Suggest a Similar Profile of CNS Pathology in Relapsing and Progressive MS",

abstract = "BACKGROUND: Relapsing-remitting (RR) and primary progressive (PP) multiple sclerosis (MS) have distinct clinical courses, but underlying pathophysiological differences remain unclear. We compared pathological components between RRMS, PPMS, and other inflammatory and neurodegenerative disorders, leveraging soluble biomarkers and post-mortem pathology.METHODS: Serum and cerebrospinal fluid (CSF) of people diagnosed with (pw) PPMS (n = 104), RRMS (n = 38), Alzheimer's disease (AD, n = 22), neuromyelitis optica spectrum disorder (NMOSD, n = 10), and myelin oligodendrocyte glycoprotein-associated disease (MOGAD, n = 10) were collected. B-cell maturation antigen (BCMA), soluble CD27 (sCD27), osteopontin (OPN), chitinase-3-like-1 (CHI3L1), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and synaptosomal-associated protein-25 (SNAP25) were measured. Lymphocytes (CD20+, CD138+, CD3+) and pyramidal-tract axonal density in RR-onset (n = 86) and PPMS (n = 45) post-mortem brain tissue were quantified.RESULTS: Soluble and post-mortem tissue biomarkers did not differ between pwRRMS and pwPPMS. Compared to AD, MS had higher CSF sCD27 (p < 0.001) but lower serum CHI3L1 and GFAP, and CSF OPN and SNAP25 (all p < 0.05). Serum OPN was lower in RRMS than NMOSD (p = 0.013). Principal component analyses and K-means clustering showed substantial overlap of RRMS and PPMS biomarkers, distinct from AD. In all pwMS, serum NfL and CSF BCMA correlated with clinical/radiological disease activity, CSF BCMA and sCD27 with inflammatory parameters, and serum GFAP, CSF GFAP, and CSF NfL with Expanded Disability Status Scale (EDSS) score.CONCLUSIONS: Serum and CSF soluble biomarker profiles and post-mortem pathology do not differentiate RRMS from PPMS diagnoses but reflect the extent of inflammation and tissue damage. Detailed assessment of MS-associated inflammation and tissue damage may enhance classification and therapeutic strategies.",

keywords = "Humans, Biomarkers/cerebrospinal fluid, Multiple Sclerosis, Chronic Progressive/blood, Male, Female, Multiple Sclerosis, Relapsing-Remitting/cerebrospinal fluid, Middle Aged, Adult, Aged, Alzheimer Disease/blood, Chitinase-3-Like Protein 1/blood, Neuromyelitis Optica/blood, Neurofilament Proteins/blood, Glial Fibrillary Acidic Protein/blood, Osteopontin/blood",

author = "Blok, {Katelijn M} and {Klein Kranenbarg}, {Romy A M} and Kirtana Ananth and Engelenburg, {Hendrik J} and {van den Bosch}, Aletta and Giannini, {Lucia A A} and {de Beukelaar}, Janet and Harro Seelaar and Inge Huitinga and Ari Green and Beatrijs Wokke and Ahmed Abdelhak and Joost Smolders",

note = "{\textcopyright} 2025 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.",

year = "2025",

month = feb,

doi = "10.1111/ene.70052",

language = "English",

volume = "32",

pages = "e70052",

journal = "European Journal of Neurology",

issn = "1351-5101",

publisher = "Wiley-Blackwell",

number = "2",

}

Blok, KM, Klein Kranenbarg, RAM, Ananth, K, Engelenburg, HJ, van den Bosch, A, Giannini, LAA, de Beukelaar, J, Seelaar, H, Huitinga, I, Green, A, Wokke, B, Abdelhak, A & Smolders, J 2025, 'Multifaceted Biomarkers Suggest a Similar Profile of CNS Pathology in Relapsing and Progressive MS', European Journal of Neurology, vol. 32, no. 2, pp. e70052. https://doi.org/10.1111/ene.70052

TY - JOUR

T1 - Multifaceted Biomarkers Suggest a Similar Profile of CNS Pathology in Relapsing and Progressive MS

AU - Blok, Katelijn M

AU - Klein Kranenbarg, Romy A M

AU - Ananth, Kirtana

AU - Engelenburg, Hendrik J

AU - van den Bosch, Aletta

AU - Giannini, Lucia A A

AU - de Beukelaar, Janet

AU - Seelaar, Harro

AU - Huitinga, Inge

AU - Green, Ari

AU - Wokke, Beatrijs

AU - Abdelhak, Ahmed

AU - Smolders, Joost

PY - 2025/2

Y1 - 2025/2

N2 - BACKGROUND: Relapsing-remitting (RR) and primary progressive (PP) multiple sclerosis (MS) have distinct clinical courses, but underlying pathophysiological differences remain unclear. We compared pathological components between RRMS, PPMS, and other inflammatory and neurodegenerative disorders, leveraging soluble biomarkers and post-mortem pathology.METHODS: Serum and cerebrospinal fluid (CSF) of people diagnosed with (pw) PPMS (n = 104), RRMS (n = 38), Alzheimer's disease (AD, n = 22), neuromyelitis optica spectrum disorder (NMOSD, n = 10), and myelin oligodendrocyte glycoprotein-associated disease (MOGAD, n = 10) were collected. B-cell maturation antigen (BCMA), soluble CD27 (sCD27), osteopontin (OPN), chitinase-3-like-1 (CHI3L1), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and synaptosomal-associated protein-25 (SNAP25) were measured. Lymphocytes (CD20+, CD138+, CD3+) and pyramidal-tract axonal density in RR-onset (n = 86) and PPMS (n = 45) post-mortem brain tissue were quantified.RESULTS: Soluble and post-mortem tissue biomarkers did not differ between pwRRMS and pwPPMS. Compared to AD, MS had higher CSF sCD27 (p < 0.001) but lower serum CHI3L1 and GFAP, and CSF OPN and SNAP25 (all p < 0.05). Serum OPN was lower in RRMS than NMOSD (p = 0.013). Principal component analyses and K-means clustering showed substantial overlap of RRMS and PPMS biomarkers, distinct from AD. In all pwMS, serum NfL and CSF BCMA correlated with clinical/radiological disease activity, CSF BCMA and sCD27 with inflammatory parameters, and serum GFAP, CSF GFAP, and CSF NfL with Expanded Disability Status Scale (EDSS) score.CONCLUSIONS: Serum and CSF soluble biomarker profiles and post-mortem pathology do not differentiate RRMS from PPMS diagnoses but reflect the extent of inflammation and tissue damage. Detailed assessment of MS-associated inflammation and tissue damage may enhance classification and therapeutic strategies.

AB - BACKGROUND: Relapsing-remitting (RR) and primary progressive (PP) multiple sclerosis (MS) have distinct clinical courses, but underlying pathophysiological differences remain unclear. We compared pathological components between RRMS, PPMS, and other inflammatory and neurodegenerative disorders, leveraging soluble biomarkers and post-mortem pathology.METHODS: Serum and cerebrospinal fluid (CSF) of people diagnosed with (pw) PPMS (n = 104), RRMS (n = 38), Alzheimer's disease (AD, n = 22), neuromyelitis optica spectrum disorder (NMOSD, n = 10), and myelin oligodendrocyte glycoprotein-associated disease (MOGAD, n = 10) were collected. B-cell maturation antigen (BCMA), soluble CD27 (sCD27), osteopontin (OPN), chitinase-3-like-1 (CHI3L1), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and synaptosomal-associated protein-25 (SNAP25) were measured. Lymphocytes (CD20+, CD138+, CD3+) and pyramidal-tract axonal density in RR-onset (n = 86) and PPMS (n = 45) post-mortem brain tissue were quantified.RESULTS: Soluble and post-mortem tissue biomarkers did not differ between pwRRMS and pwPPMS. Compared to AD, MS had higher CSF sCD27 (p < 0.001) but lower serum CHI3L1 and GFAP, and CSF OPN and SNAP25 (all p < 0.05). Serum OPN was lower in RRMS than NMOSD (p = 0.013). Principal component analyses and K-means clustering showed substantial overlap of RRMS and PPMS biomarkers, distinct from AD. In all pwMS, serum NfL and CSF BCMA correlated with clinical/radiological disease activity, CSF BCMA and sCD27 with inflammatory parameters, and serum GFAP, CSF GFAP, and CSF NfL with Expanded Disability Status Scale (EDSS) score.CONCLUSIONS: Serum and CSF soluble biomarker profiles and post-mortem pathology do not differentiate RRMS from PPMS diagnoses but reflect the extent of inflammation and tissue damage. Detailed assessment of MS-associated inflammation and tissue damage may enhance classification and therapeutic strategies.

KW - Humans

KW - Biomarkers/cerebrospinal fluid

KW - Multiple Sclerosis, Chronic Progressive/blood

KW - Male

KW - Female

KW - Multiple Sclerosis, Relapsing-Remitting/cerebrospinal fluid

KW - Middle Aged

KW - Adult

KW - Aged

KW - Alzheimer Disease/blood

KW - Chitinase-3-Like Protein 1/blood

KW - Neuromyelitis Optica/blood

KW - Neurofilament Proteins/blood

KW - Glial Fibrillary Acidic Protein/blood

KW - Osteopontin/blood

U2 - 10.1111/ene.70052

DO - 10.1111/ene.70052

M3 - Article

C2 - 39907163

SN - 1351-5101

VL - 32

SP - e70052

JO - European Journal of Neurology

JF - European Journal of Neurology

IS - 2

ER -