Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression

Steinacker, Petra; Verde, Federico; Fang, Lubin; Feneberg, Emily; Oeckl, Patrick; Roeber, Sigrun; Anderl‐Straub, Sarah; Danek, Adrian; Diehl‐Schmid, Janine; Faßbender, Klaus; Fließbach, Klaus; Foerstl, Hans; Giese, Armin; Jahn, Holger; Kassubek, Jan; Kornhuber, Johannes; Landwehrmeyer, G. Bernhard; Lauer, Martin; Pinkhardt, Elmar H.; Prudlo, Johannes; Rosenbohm, Angela; Schneider, Anja; Schroeter, Matthias L.; Tumani, Hayrettin; Arnim, Christine A. F. Von; Weishaupt, Jochen H.; Weydt, Patrick; Ludolph, Albert C.; Yilmazer-Hanke, Deniz; Otto, Markus

doi:10.1136/jnnp-2017-317138

Cited by 107 publications

(144 citation statements)

References 40 publications

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“…On the contrary, we found no association between CCL18 levels in plasma or CSF in cases versus controls. Similar results regarding ChT have been previously reported suggesting that ChT could be a potential CSF marker for sporadic ALS [17][18][19].…”

Section: Discussionsupporting

confidence: 76%

“…Further studies to investigate the presence of ChT substrate in CNS of ALS's patients are necessary. We have not demonstrated any association between ChT activity in CSF with the course, severity or progression of the disease as it has been reported by other authors [18,29], which could be explained for the limited sample size.…”

Section: Discussionmentioning

confidence: 46%

“…Previous reports showed chitin-like glucosamine polymers in amyloid plaques in AD suggesting a role in the pathogenesis of neurodegeneration [36][37][38]. In addition, an interesting recent study has observed ChT immunoreactivity in ALS spinal cord, only partially corresponding to the staining pattern of activated microglia [18].…”

Section: Discussionmentioning

confidence: 95%

“…This evidence suggests the overproduction of this enzyme exerts a deleterious effect in many degenerative disorders [15,[37][38][39][40]. Regarding ALS, some studies have previously shown an increased blood ChT activity suggesting this enzyme as a potential biomarker [29], and elevated ChT levels in ALS-CSF proposing a role for the enzyme in the disease pathogenesis [16,18]. Chitin, the natural substrate of ChT in unvertebrates animals, is an insoluble N-acetylglucosamine polymer and it is uncertain whether ChT activity in CSF reflects only a microglia activation or if some chitin-like polysaccharides at CNS could be the substrate of this enzyme [17].…”

Section: Discussionmentioning

confidence: 99%

“…In the human brain, ChT is proposed to be synthesized by microglia and high CSF ChT levels have been shown in several neurological conditions [14][15][16]. Previous reports revealed that ChT is increased in CSF in patients with ALS and proposed this enzyme as a potential biomarker for ALS [17][18][19]. Nevertheless, in these previous studies, there is no homogeneity in the techniques used to assess ChT or genotype correlation because of the high frequency of null allele in the general population [20].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of Chitotriosidase and CC-Chemokine Ligand 18 as Biomarkers of Microglia Activation in Amyotrophic Lateral Sclerosis

et al. 2018

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Background: The development of biomarkers for use in diagnosing, monitoring disease progression and analyzing therapeutic trials response in amyotrophic lateral sclerosis (ALS) is essential. Objective: The aim of this study was to identify inflammatory factors in plasma or cerebrospinal fluid (CSF) from patients with ALS with particular attention to specific markers of microglia activation as chitotriosidase (ChT) and chemokine (C-C motif) ligand 18 (CCL18) to determine its potential as ALS biomarkers. Methods: We studied CSF and plasma samples from 32 patients and 42 healthy controls. We assayed the ChT activity by a spectrofluorometric method and protein levels of other inflammatory biomarkers (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6 and CCL18) by enzyme-linked immunosorbent assay. CHIT1 gene polymorphism in exon 10 (c.1049_1072dup24) encoding inactive ChT enzyme was genotyped in all subjects. Results: ChT activity and TNF-alpha protein levels were significantly higher in CSF of ALS patients, but we found no correlation with the severity and progression of the disease. Nevertheless, we did not found any differences in CCL18 or IL-6 protein levels between both groups in CSF or plasma. In our sample, only 3% of subjects were homozygous carriers for the CHIT1 exon 10 duplication associated with defective enzyme. Conclusions: High ChT activity in CSF of patients with ALS may reflect microglia activation and could be a potential biomarker of the disease. We did not find any significant difference regarding CCL-18, another specific marker of microglia activation that is related with M2-like microglia phenotype. Deepening the understanding of the activation state of microglia (M1 and M2) may contribute to the knowledge about the specific role of neuroinflammation in ALS and future therapeutic strategies.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 46%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of Chitotriosidase and CC-Chemokine Ligand 18 as Biomarkers of Microglia Activation in Amyotrophic Lateral Sclerosis

et al. 2018

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CSF chitinases before and after symptom onset in amyotrophic lateral sclerosis

Thompson

Wuu

et al. 2020

Ann Clin Transl Neurol

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Objective To evaluate the CSF levels of chitinase proteins during the presymptomatic and early symptomatic phases of amyotrophic lateral sclerosis (ALS). Methods CSF samples were obtained from 16 controls, 55 individuals at‐risk for ALS (including 18 carrying a mutation in C9ORF72, 33 in SOD1), 12 ALS patients, and 7 phenoconverters (individuals diagnosed with ALS during follow‐up). At‐risk individuals and phenoconverters were enrolled through the Pre‐fALS study, which includes individuals carrying an ALS‐associated gene mutation without disease manifestations at initial assessment. Longitudinal CSF collections, where possible, took place every 3‐12 months for ALS patients and every 1‐2 years for others. CSF levels of chitotriosidase 1 (CHIT1), chitinase‐3‐like protein 1 (CHI3L1, YKL‐40) and chitinase‐3‐like protein 2 (CHI3L2, YKL‐39) were measured by ELISA, along with CHIT1 activity. Longitudinal changes in at‐risk individuals and phenoconverters were fitted to linear mixed effects models. Results Slowly rising levels of CHIT1 were observed over time in the at‐risk individuals (slope 0.059 log10[CHIT1] per year, P < 0.001). Among phenoconverters, CHIT1 levels and activity rose more sharply (0.403 log10[CHIT1] per year, P = 0.005; 0.260 log10[CHIT1 activity] per year, P = 0.007). Individual levels of both CHI3L1 and CHI3L2 remained relatively stable over time in all participant groups. Interpretation The CHIT1 neuroinflammatory response is a feature of the late presymptomatic to early symptomatic phases of ALS. This study does not suggest a long prodrome of upregulated glial activity in ALS pathogenesis, but strengthens the place of CHIT1 as part of a panel of biomarkers to objectively assess the impact of immune‐modulatory therapeutic interventions in ALS.

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Chitotriosidase is a biomarker for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia

Hayer

Santhanakumaran

Böhringer

et al. 2022

Ann Clin Transl Neurol

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Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) leads to rapidly progressive dementia and is caused by mutations in the gene CSF1R. Neurodegeneration is driven by dysfunction of microglia, the predominant cell type expressing CSF1R in the brain. We assessed chitotriosidase, an enzyme secreted by microglia, in serum and cerebrospinal fluid of patients with ALSP. Chitotriosidase activity was highly increased in cerebrospinal fluid of patients and correlated inversely with disease duration. Of interest, presymptomatic CSF1R mutation carriers did not show elevated chitotriosidase levels. This makes chitotriosidase a promising new biomarker of disease activity for this rare disease.

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Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression

Cited by 107 publications

References 40 publications

Evaluation of Chitotriosidase and CC-Chemokine Ligand 18 as Biomarkers of Microglia Activation in Amyotrophic Lateral Sclerosis

Evaluation of Chitotriosidase and CC-Chemokine Ligand 18 as Biomarkers of Microglia Activation in Amyotrophic Lateral Sclerosis

CSF chitinases before and after symptom onset in amyotrophic lateral sclerosis

Chitotriosidase is a biomarker for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia

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