CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

Abstract

Objective Evidence for a role of microglia in the pathogenesis of multiple sclerosis (MS) is growing. We investigated association of microglial markers at time of diagnostic lumbar puncture (LP) with different aspects of disease activity (relapses, disability, magnetic resonance imaging parameters) up to 6 years later in a cohort of 143 patients. Methods In cerebrospinal fluid (CSF), we measured 3 macrophage and microglia‐related proteins, chitotriosidase (CHIT1), chitinase‐3–like protein 1 (CHI3L1 or YKL‐40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), as well as a marker of neuronal damage, neurofilament light chain (NfL), using enzyme‐linked immunosorbent assay and electrochemiluminescence. We investigated the same microglia‐related markers in publicly available RNA expression data from postmortem brain tissue. Results CHIT1 levels at diagnostic LP correlated with 2 aspects of long‐term disease activity after correction for multiple testing. First, CHIT1 increased with reduced tissue integrity in lesions at a median 3 years later (p = 9.6E‐04). Second, CHIT1 reflected disease severity at a median 5 years later (p = 1.2E‐04). Together with known clinical covariates, CHIT1 levels explained 12% and 27% of variance in these 2 measures, respectively, and were able to distinguish slow and fast disability progression (area under the curve = 85%). CHIT1 was the best discriminator of chronic active versus chronic inactive lesions and the only marker correlated with NfL (r = 0.3, p = 0.0019). Associations with disease activity were, however, independent of NfL. Interpretation CHIT1 CSF levels measured during the diagnostic LP reflect microglial activation early on in MS and can be considered a valuable prognostic biomarker for future disease activity. ANN NEUROL 2020;87:633–645

Quantitative MRI phenotypes capture biological heterogeneity in multiple sclerosis patients

“…In MS active lesions, these innate immune cells increase already in initial lesion stages and reach their peak in early/late active lesion areas 47 . Microglia-related CSF biomarkers at diagnosis correlate with MTR measured more than 3 years later in a subset of the current study population 13 . In particular, chitotriosidase or CHIT1 levels increase with increasing MTR abnormalities (decreasing MTR) in lesions, and explain 12% of variance in median lesion MTR across patients.…”

“…We obtained and analysed the images as we described previously 13 . MRI data were acquired on a 3T MRI scanner (Intera, Ingenia, or Achieva; Philips, Best, The Netherlands) equipped with an 8-, 15- or 32-channel head coil using parameters corresponding to 6 different MRI protocols as summarized in Supplementary Table S1 .…”

“…DNA was extracted from total blood using standard methods with an in-house protocol. Genotyping for 700,078 variants using the Infinium HTS assay on Global Screening Array bead-chips (Illumina) followed by genotype calling and quality control (QC) using PLINK v1.9 was done as described previously 13 , 18 , 19 . For one patient no genetic data were available, and three samples were excluded because of cryptic relatedness (identity by descent > 0.1875).…”

“…A total of 502,527 SNPs remained in the analysis. Strand alignment, pre-phasing and imputation were done as described previously 13 , 18 . Classical Human Leukocyte Antigen (HLA) alleles, amino acid polymorphisms and SNPs were imputed with SNP2HLA v1.0.3 and the T1DGC reference panel (build 37) 20 .…”

Identification of Key Pathways and Genes in Dementia via Integrated Bioinformatics Analysis

“…[76], BTK (Bruton tyrosine kinase) [77], C7 [78], PLA2G7 [79], SOCS3 [80], OLR1 [81], LIPA (lipase A, lysosomal acid type) [82], CD86 [83], TLR5 [ [100], AGRN (agrin) [101] and GP6 [102] have been shown as a promising biomarkers in Alzheimer's disease. Field et al [103], Lincoln et al [104], Ziliotto et al [105], El Sharkawi et al [106], Cossins et al [107], Mirowska-Guzel et al [108], Asouri et al [109], Cardamone et al [110], Begovich et al [111], Bennetts et al [112], Iparraguirre et al [113] and Oldoni et al [114] reported that HLA-DPB1, HLA-DQA1, CCL18, CCL20, MMP7, IL1A, IL2RA, CYBB (cytochrome b-245 beta chain), PTPN22, HLA-DMB, ANXA2 and CHIT1expression were associated with progression of multiple sclerosis, but these genes might be liable for advancement of dementia. Chang et al [115], Jamshidi et al [116], Campolo et al [117], Bottero et al [118], Gao et al [119], Haga et al [120], Klaver et al [121], Greenbaum et al [122] and Aguirre et al [123] reported that expression of HLA-DQB1, HLA-DRA, TLR7, TLR8, PTPRC (protein tyrosine phosphatase receptor type C), OSMR (oncostatin M receptor), FABP5, LAMP2, CHRNA5 and IL13RA1 could be an index for Parkinson's disease progression, but these genes might be responsible for progression of dementia.…”