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 (44 MS 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.

Figure 1. Plasma CHI3L1 concentration of patients with MS and HCs. (A) CHI3L1 levels were higher in PMS versus HC and PMS versus RRMS (Mann-Whitney U test). (B) There was no difference in the CHI3L1 concentration between patients with and without gadolinium-enhancing lesions. The CHI3L1 concentration was measured using ELISA. The inner line in the box represents the median of the data. The ends of the box indicate the upper (Q3) and lower (Q1) quartiles. The whiskers mark the 75th percentile +1.5* IQR values and the 25th percentile – 1.5 * IQR. Values greater/lower than the whiskers are marked as outliers and are shown as individual points. n(HC)=17, n(MS)=55, n(PMS)=25, n(RRMS)=30, n(Gadolinium+)=7, n(Gadolinium-)=36. CHI3L1, chitinase-3-like protein 1; HC, healthy control; MS, multiple sclerosis; PMS, progressive MS; RRMS, relapsing-remitting MS. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

Figure 2. Forest plot illustrating the linear regression modelling of CHI3L1 with translocator protein positron emission tomography (TSPO-PET)-related, demographical and clinical, biomarker and volumetric variables among all MS. (A–E) Univariate regression model included all possible observations for each variable A. n=44, B&E. n=55, C. n(GFAP and NfL)=46, and n(iron rims)=43, D. n=47. In the univariate model, brain DVR (A) was a significant predictor of CHI3L1 concentration. When demographical and clinical variables (B&E) were considered, age, disease duration, EDSS and disease type predicted CHI3L1 concentration significantly. However, of the studied biomarkers (C), none predicted CHI3L1 concentration significantly. The brain and thalamus volume (D) had a significant inverse effect on CHI3L1. (F) Multivariate stepwise linear regression model included only those patients with available TSPO-PET imaging (n=44). The model building started with a model without any predictors, and in each step, the most suitable variable according to Bayesian information criterion (BIC) was added to the model. All variables that were used in univariate models were considered when the multivariate model was built. The final multivariate regression model included thalamus volume, BMI and NfL, and it explained 33% of the variance in CHI3L1 among all MS. The dots represent standardised regression coefficients, and the lines represent the confidence intervals of these estimates. Log(CHI3L1-10) was used as a response variable in all models to gain normality of residuals. Logarithm transformation was used for T1 lesion load, NfL and GFAP. ARR, annualised relapse rate; BMI, body mass index; CHI3L1, chitinase-3-like protein 1; DMT, disease modifying treatment; DVR, distribution volume ratio; EDSS, expanded disability status scale; GFAP, glial fibrillary acidic protein; MSSS, multiple sclerosis severity score; NfL, neurofilament light chain; PRL, paramagnetic rim lesion.