Plasma CHI3L1 associates with brain volume loss and glial activation in multiple sclerosis

Venla Ahola; Maija Saraste; Marjo Nylund; Markus Matilainen; Amelie Luoma; Anna Vuorimaa; Jussi Lehto; Sini Laaksonen; Eeva Christine Brockmann; Jens Kuhle; David Leppert; Tero Soukka; Urpo Lamminmäki; Laura Airas

doi:10.1136/jnnp-2025-336063

Plasma CHI3L1 associates with brain volume loss and glial activation in multiple sclerosis

Venla Ahola
, Maija Saraste^*
, Marjo Nylund
, Markus Matilainen
, Amelie Luoma
, Anna Vuorimaa
, Jussi Lehto
, Sini Laaksonen
, Eeva Christine Brockmann
, Jens Kuhle
, David Leppert
, Tero Soukka
, Urpo Lamminmäki
, Laura Airas

^*Corresponding author for this work

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

2 Citations (Scopus)

Abstract

Background Multiple sclerosis (MS) progression independent of relapses is driven by brain innate immune cell activation. The aim of this study was to evaluate the association between chitinase-3-like protein 1 (CHI3L1), expressed in brain by astrocytes and microglia, measured from blood and smouldering inflammation measured using 18 kDa translocator protein (TSPO) positron emission tomography (PET) in patients with MS. Methods The study cohort included 55 patients with MS (25 progressive MS (PMS) and 30 relapsing remitting MS (RRMS)) and 17 healthy controls (HC). CHI3L1 was measured with commercial ELISA from plasma samples. A subcohort (44MS and 9 HC) underwent TSPO-PET to assess [¹¹C]PK11195 distribution volume ratio (DVR) and MRI concurrent to blood sampling. These imaging outcomes were used in respective correlation and linear regression analyses. Results CHI3L1 concentration in plasma was higher in PMS (23.5 ng/mL) compared with HC (16.8 ng/mL, p=0.0055) and RRMS (19.3 ng/mL, p=0.049). CHI3L1 associated with brain [¹¹C]PK11195 DVR in all MS (standardised estimate 0.89, 95% CI 0.23 to 1.55, p=0.010) and in PMS (Spearman correlation ρ=0.58, 95% CI 0.058 to 0.86, p=0.032). Additionally, CHI3L1 was associated with smaller brain volume in both MS (−0.75, −1.38 to –0.11, p=0.023) and PMS (ρ=−0.56, –0.83 to –0.095, p=0.021). Furthermore, CHI3L1 was associated with Expanded Disability Status Scale (0.70, 0.12 to 1.28, p=0.019) and age (0.93, 0.37 to 1.48, p=0.002) among all patients with MS. Conclusions Association of CHI3L1 with glial activation and brain volume loss identifies plasma CHI3L1 as a promising biomarker for smouldering inflammation and MS progression-related pathology.

Original language	English
Pages (from-to)	1053-1060
Number of pages	8
Journal	Journal of Neurology, Neurosurgery and Psychiatry
Volume	96
Issue number	11
DOIs	https://doi.org/10.1136/jnnp-2025-336063
Publication status	Published - 1 Nov 2025
MoE publication type	A1 Journal article-refereed

Funding

This work was supported (salary of Venla Ahola) by ImmuDocs National Doctoral Education Pilot Based on the Immune System (decision number OKM/14/523/2024, Document ID 704155), a grant from the National MS Society and the National Stem Cell Foundation (decision number RFA-2203-39281), The Jane and Aatos Erkko Foundation (decision number #220026) and the InFLAMES Flagship Programme of the Research Council of Finland (decision numbers: 337530, 357910 and 358823). All the study participants, the expert staff at Turku PETCentre and members of Airas research group are acknowledged for making thisstudy possible. Doctor Olli Hartiala is acknowledged for his valuable advice duringthe writing process. We thank ImmuDocs National Doctoral Education Pilot Based onthe Immune System for enabling this study. This work was supported (salary of Venla Ahola) by ImmuDocs National Doctoral Education Pilot Based on the Immune System (decision number OKM/14/523/2024, Document ID 704155), a grant from the National MS Society and the National Stem Cell Foundation (decision number RFA-2203-39281), The Jane and Aatos Erkko Foundation (decision number #220026) and the InFLAMES Flagship Programme of the Research Council of Finland (decision numbers: 337530, 357910 and 358823).

Keywords

MRI
MULTIPLE SCLEROSIS
NEUROIMMUNOLOGY
PET

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Ahola, V., Saraste, M., Nylund, M., Matilainen, M., Luoma, A., Vuorimaa, A., Lehto, J., Laaksonen, S., Brockmann, E. C., Kuhle, J., Leppert, D., Soukka, T., Lamminmäki, U., & Airas, L. (2025). Plasma CHI3L1 associates with brain volume loss and glial activation in multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry, 96(11), 1053-1060. https://doi.org/10.1136/jnnp-2025-336063

@article{1f6f0b4de06548e5ba894d8ded681d2c,

title = "Plasma CHI3L1 associates with brain volume loss and glial activation in multiple sclerosis",

abstract = "Background Multiple sclerosis (MS) progression independent of relapses is driven by brain innate immune cell activation. The aim of this study was to evaluate the association between chitinase-3-like protein 1 (CHI3L1), expressed in brain by astrocytes and microglia, measured from blood and smouldering inflammation measured using 18 kDa translocator protein (TSPO) positron emission tomography (PET) in patients with MS. Methods The study cohort included 55 patients with MS (25 progressive MS (PMS) and 30 relapsing remitting MS (RRMS)) and 17 healthy controls (HC). CHI3L1 was measured with commercial ELISA from plasma samples. A subcohort (44MS and 9 HC) underwent TSPO-PET to assess [11C]PK11195 distribution volume ratio (DVR) and MRI concurrent to blood sampling. These imaging outcomes were used in respective correlation and linear regression analyses. Results CHI3L1 concentration in plasma was higher in PMS (23.5 ng/mL) compared with HC (16.8 ng/mL, p=0.0055) and RRMS (19.3 ng/mL, p=0.049). CHI3L1 associated with brain [11C]PK11195 DVR in all MS (standardised estimate 0.89, 95\% CI 0.23 to 1.55, p=0.010) and in PMS (Spearman correlation ρ=0.58, 95\% CI 0.058 to 0.86, p=0.032). Additionally, CHI3L1 was associated with smaller brain volume in both MS (−0.75, −1.38 to –0.11, p=0.023) and PMS (ρ=−0.56, –0.83 to –0.095, p=0.021). Furthermore, CHI3L1 was associated with Expanded Disability Status Scale (0.70, 0.12 to 1.28, p=0.019) and age (0.93, 0.37 to 1.48, p=0.002) among all patients with MS. Conclusions Association of CHI3L1 with glial activation and brain volume loss identifies plasma CHI3L1 as a promising biomarker for smouldering inflammation and MS progression-related pathology.",

keywords = "MRI, MULTIPLE SCLEROSIS, NEUROIMMUNOLOGY, PET",

author = "Venla Ahola and Maija Saraste and Marjo Nylund and Markus Matilainen and Amelie Luoma and Anna Vuorimaa and Jussi Lehto and Sini Laaksonen and Brockmann, \{Eeva Christine\} and Jens Kuhle and David Leppert and Tero Soukka and Urpo Lamminm{\"a}ki and Laura Airas",

note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.",

year = "2025",

month = nov,

day = "1",

doi = "10.1136/jnnp-2025-336063",

language = "English",

volume = "96",

pages = "1053--1060",

journal = "Journal of Neurology, Neurosurgery and Psychiatry",

issn = "0022-3050",

publisher = "BMJ Publishing Group",

number = "11",

}

Ahola, V, Saraste, M, Nylund, M, Matilainen, M, Luoma, A, Vuorimaa, A, Lehto, J, Laaksonen, S, Brockmann, EC, Kuhle, J, Leppert, D, Soukka, T, Lamminmäki, U & Airas, L 2025, 'Plasma CHI3L1 associates with brain volume loss and glial activation in multiple sclerosis', Journal of Neurology, Neurosurgery and Psychiatry, vol. 96, no. 11, pp. 1053-1060. https://doi.org/10.1136/jnnp-2025-336063

TY - JOUR

T1 - Plasma CHI3L1 associates with brain volume loss and glial activation in multiple sclerosis

AU - Ahola, Venla

AU - Saraste, Maija

AU - Nylund, Marjo

AU - Matilainen, Markus

AU - Luoma, Amelie

AU - Vuorimaa, Anna

AU - Lehto, Jussi

AU - Laaksonen, Sini

AU - Brockmann, Eeva Christine

AU - Kuhle, Jens

AU - Leppert, David

AU - Soukka, Tero

AU - Lamminmäki, Urpo

AU - Airas, Laura

PY - 2025/11/1

Y1 - 2025/11/1

N2 - Background Multiple sclerosis (MS) progression independent of relapses is driven by brain innate immune cell activation. The aim of this study was to evaluate the association between chitinase-3-like protein 1 (CHI3L1), expressed in brain by astrocytes and microglia, measured from blood and smouldering inflammation measured using 18 kDa translocator protein (TSPO) positron emission tomography (PET) in patients with MS. Methods The study cohort included 55 patients with MS (25 progressive MS (PMS) and 30 relapsing remitting MS (RRMS)) and 17 healthy controls (HC). CHI3L1 was measured with commercial ELISA from plasma samples. A subcohort (44MS and 9 HC) underwent TSPO-PET to assess [11C]PK11195 distribution volume ratio (DVR) and MRI concurrent to blood sampling. These imaging outcomes were used in respective correlation and linear regression analyses. Results CHI3L1 concentration in plasma was higher in PMS (23.5 ng/mL) compared with HC (16.8 ng/mL, p=0.0055) and RRMS (19.3 ng/mL, p=0.049). CHI3L1 associated with brain [11C]PK11195 DVR in all MS (standardised estimate 0.89, 95% CI 0.23 to 1.55, p=0.010) and in PMS (Spearman correlation ρ=0.58, 95% CI 0.058 to 0.86, p=0.032). Additionally, CHI3L1 was associated with smaller brain volume in both MS (−0.75, −1.38 to –0.11, p=0.023) and PMS (ρ=−0.56, –0.83 to –0.095, p=0.021). Furthermore, CHI3L1 was associated with Expanded Disability Status Scale (0.70, 0.12 to 1.28, p=0.019) and age (0.93, 0.37 to 1.48, p=0.002) among all patients with MS. Conclusions Association of CHI3L1 with glial activation and brain volume loss identifies plasma CHI3L1 as a promising biomarker for smouldering inflammation and MS progression-related pathology.

AB - Background Multiple sclerosis (MS) progression independent of relapses is driven by brain innate immune cell activation. The aim of this study was to evaluate the association between chitinase-3-like protein 1 (CHI3L1), expressed in brain by astrocytes and microglia, measured from blood and smouldering inflammation measured using 18 kDa translocator protein (TSPO) positron emission tomography (PET) in patients with MS. Methods The study cohort included 55 patients with MS (25 progressive MS (PMS) and 30 relapsing remitting MS (RRMS)) and 17 healthy controls (HC). CHI3L1 was measured with commercial ELISA from plasma samples. A subcohort (44MS and 9 HC) underwent TSPO-PET to assess [11C]PK11195 distribution volume ratio (DVR) and MRI concurrent to blood sampling. These imaging outcomes were used in respective correlation and linear regression analyses. Results CHI3L1 concentration in plasma was higher in PMS (23.5 ng/mL) compared with HC (16.8 ng/mL, p=0.0055) and RRMS (19.3 ng/mL, p=0.049). CHI3L1 associated with brain [11C]PK11195 DVR in all MS (standardised estimate 0.89, 95% CI 0.23 to 1.55, p=0.010) and in PMS (Spearman correlation ρ=0.58, 95% CI 0.058 to 0.86, p=0.032). Additionally, CHI3L1 was associated with smaller brain volume in both MS (−0.75, −1.38 to –0.11, p=0.023) and PMS (ρ=−0.56, –0.83 to –0.095, p=0.021). Furthermore, CHI3L1 was associated with Expanded Disability Status Scale (0.70, 0.12 to 1.28, p=0.019) and age (0.93, 0.37 to 1.48, p=0.002) among all patients with MS. Conclusions Association of CHI3L1 with glial activation and brain volume loss identifies plasma CHI3L1 as a promising biomarker for smouldering inflammation and MS progression-related pathology.

KW - MRI

KW - MULTIPLE SCLEROSIS

KW - NEUROIMMUNOLOGY

KW - PET

UR - https://www.scopus.com/pages/publications/105005525253

U2 - 10.1136/jnnp-2025-336063

DO - 10.1136/jnnp-2025-336063

M3 - Article

C2 - 40379482

AN - SCOPUS:105005525253

SN - 0022-3050

VL - 96

SP - 1053

EP - 1060

JO - Journal of Neurology, Neurosurgery and Psychiatry

JF - Journal of Neurology, Neurosurgery and Psychiatry

IS - 11

ER -

Plasma CHI3L1 associates with brain volume loss and glial activation in multiple sclerosis

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