Chitotriosidase - a putative biomarker for sporadic amyotrophic lateral sclerosis

Varghese, Anu; Sharma, Aparna; Mishra, Pooja-Shree; Vijayalakshmi, K.; Harsha, H. C.; Sathyaprabha, Talakad N.; Bharath, Srinivas; Nalini, Atchayaram; Alladi, Phalguni Anand; Raju, T.R.

doi:10.1186/1559-0275-10-19

Cited by 98 publications

(103 citation statements)

References 32 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%

“…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]. Previous reports showed chitin-like glucosamine polymers in amyloid plaques in AD suggesting a role in the pathogenesis of neurodegeneration [36][37][38].…”

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: 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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“…While reasons for these observations need clarification, they demonstrate that cytokines and chemokines may play a role in the pathogenesis of ALS. For example, NSC-34 cells treated with CSF from patients with ALS exhibited decreased cell viability and increased lactate dehydrogenase activity [48], suggesting that factors within or released to the CSF contribute to neurodegeneration. Further analyses in the same study also showed that Chit-1 increased expression in microglia upon exposure to CSF from patients with ALS, suggesting its role in microglial activation.…”

Section: Biomarkers Of Inflammationmentioning

confidence: 99%

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.

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“…Both animal models and postmortem tissue from ALS patients shows infiltration of activated microglia and T cells into affected areas, which correlates with progression rate. 10,11 We applied a state-of-the-art high-throughput MS method to enable in-depth characterization of individual longitudinal CSF samples from a large, clinically well-characterized ALS cohort, in comparison to healthy and disease control groups. 6,7 Differential expression of cytokines, including factors specifically involved in microglial activation, have been observed in enzyme-linked immunosorbent assay (ELISA)-based studies of CSF from ALS patients.…”

mentioning

confidence: 99%