Association between cerebrospinal fluid chitotriosidase level and amyotrophic lateral sclerosis: a systematic review

Introduction

One of the fatal and debilitating neurodegenerative diseases is amyotrophic lateral sclerosis (ALS). This disease can progressively affect the upper and lower motor neurons of spinal cord, motor cortex and brainstem areas [1], 2]. Increasing age is one of the risk factors of ALS, and the onset of the disease usually occurs in the age range of 50–79 [2], [3], [4]. ALS is a rare disease; the incidence and prevalence of this disease are 2.8 and 5.4 cases respectively per 100,000 people per year for an average age of 61.8 ± 3.8 [5]. Death from this disease occurs 2–4 years after the onset of the disease due to respiratory failure and swallowing problems [6], [7], [8], [9], [10]. However, 5–10 % of ALS patients survive for more than a decade [9]. Considering that the elderly population in the world is increasing, it is possible that ALS cases will increase by 69 % in the next 25 years [11]. Therefore, now and in the current situation, it is very important to identify the causes of the disease, useful and effective diagnostic and treatment methods.

Currently, diagnosis of ALS is done using revised Gold Coast criteria [12]. But still the early diagnosis of ALS is challenging, because the clinical findings in the early stages of this disease are very diverse [13], 14]. The diagnosis of this disease takes an average of 14 months from the onset of the disease [15]. Diagnostic criteria for ALS disease lack neurochemical biomarkers, but it seems that these biomarkers, especially cerebrospinal fluid (CSF) biomarkers, can be useful in diagnosing this disease [16], [17], [18], [19]. Today, chitotriosidase (CHIT1) is one of the biomarkers that has attracted the attention of many researchers, because it seems that the level of this protein can be related to ALS disease. Chitotriosidase or CHIT1 is expressed by monocytes and macrophages and is the most abundant human chitinase. The purpose of this systematic review is to determine the relationship between CHIT1 protein level and ALS disorder.

Methods

Results

The search was done using keywords and without time limit in Scopus, Web of Science, ScienceDirect and PubMed databases. First, 120 articles were obtained, after deleting 69 duplicate articles, 51 studies remained to review the title and abstract. In this screening step, 26 articles were excluded from our study due to various reasons such as the type of study (case reports, case series, animal experiments, clinical trials, conference abstracts, letter to editor, editorials, systematic review and meta-analysis, narrative reviews), non-human population, and the irrelevance of the topic and outcome. The full text of 25 articles was retrieved and the text and data of the articles were carefully examined. Eleven articles were excluded from our study due to the lack of information and data related to the outcome of our study (chitotriosidase level in the case group and control groups and their comparison with each other). Finally, 14 articles were selected for data and information extraction and included in our study. Search process and the number of selected and excluded articles based on the inclusion and exclusion criteria are summarized in the flow diagram (Figure 1).

Figure 1:

The diagram of study.

Most of the studies (9 out of 14 studies) were conducted in European countries. Italy, Portugal, Germany, the United Kingdom, Belgium, France and the Netherlands are among the European countries where this study has been carried out. In other continents, few studies (5 out of 14) have been conducted. The United States of America, China and India are among the countries that have carried out this study. In total, 1791 participants were present in 14 studies, of which 1,085 participants were in the group of patients with ALS, 391 were in the disease control (patients with other neurological diseases), and 315 were in the healthy control group (without any clinical history of neurological deficits). In Table 1, the summary of all the data and information is shown.

Among the 14 selected studies, 8 studies [18], 19], 21], 23], 27]–30] included 3 groups (ALS patients, healthy control and disease control), and the level of biomarker CHIT1 in the CSF of different groups was compared with each other. Three studies [16], 22], 24] included two groups, i.e. ALS patients and disease control group, and 3 other studies [17], 25], 26] included two groups, i.e. ALS patients and healthy control group. In all 14 selected studies, the level of biomarker CHIT1 in the CSF of ALS patients was significantly higher than that of healthy control and disease control groups. But, in 8 studies that included 3 groups, no significant difference was observed between the CHIT1 levels in the two control groups. In these 8 studies [18], 19], 21], 23], 27]–30], 6 studies [18], 19], 21], 23], 28], 29] have reported the amount of CHIT1 level quantitatively and accurately. Among these 6 studies, in 5 studies [18], 19], 21], 28], 29] CHIT1 level in disease control was higher than healthy control (not significant) and in only one study [23] CHIT1 level was higher in healthy control compared to disease control (not significant).

Discussion

Although today the diagnosis of ALS is done using the Gold Coast criteria [12], early diagnosis of this disease is still a very important challenge in the field of health and treatment. The reason for the challenging diagnosis of this disease is the diversity of clinical findings in the early stages of the disease [13], 14]. Today, based on the studies, it seems that biomarkers in CSF can play an important and useful role in the diagnosis of this disease in the future [16], [17], [18], [19]. Therefore, the purpose of this systematic review was to investigate the relationship between the level of the biomarker CHIT1 in CSF and ALS. Based on the findings of this study, the level of CHIT1 in the CSF of patients with ALS is significantly higher compared to the disease control group and the healthy control group. Therefore, based on the information in Table 1, it seems that the level of this biomarker is related to ALS and plays a role in the pathogenesis of the disease.

In the study by Abu-Rumeileh and et al., in addition to evaluating the level of CHIT1 biomarkers in CSF of ALS patients, ALS mimics and healthy controls, and comparing the biomarker levels of the groups with each other, the amount and level of other biomarkers such as NfL, chitinase-3-like protein 1 (YKL-40) and phosphorylated (p)-tau/total (t)-tau ratio in the CSF of these groups were also evaluated. The level of chitotriosidase, YKL-40 and NfL biomarkers in the CSF of ALS patients was higher than the level of these biomarkers in the healthy control group and ALS mimics. But the ratio of p-tau/t-tau in ALS patients was lower compared to healthy control groups and ALS mimics. Biomarker NfL had the highest diagnostic performance (The specificity and sensitivity were more than 90 %) among other biomarkers in this study [21].

Also, in the study of Chen and et al., the diagnostic performance of CHIT1 biomarker and the combination of CHIT1 and phosphorylated neurofilament heavy chain (pNfH) biomarkers in CSF were evaluated. In this study, the cut-off value of chitotriosidase was determined to be 1,593.779 ng/L, and the patients group was distinguished from the control group with specificity and sensitivity of 81.1 and 83.8 %, respectively. The combination of two biomarkers, chitotriosidase and pNfH, improved the diagnostic accuracy and performance because the specificity of 91.9 % and the sensitivity of 83.8 % were obtained [22].

In another study conducted in 2020, the sensitivity and specificity of biomarker CHIT1 was reported to be over 80 %. In this study, the cut-off value was 1,405.43 pg/mL, and the sensitivity and specificity of biomarker CHIT1 in the diagnosis of ALS patients were mentioned as 87 and 83.3 %, respectively. Also, the combination of CHIT1 level and activity led to the improvement of the diagnostic performance of this biomarker. Negative and positive predictive values were reported as 100 and 97.78 %, respectively. The level of biomarker CHIT1 in ALS patients increased 19 times (p<0.0001) compared to the healthy control group and 24 times (p<0.01) compared to the disease control group. But, no significant correlation was observed between the X level of the healthy control group and the disease control group [23].

Another study was conducted in Germany in 2018 with the aim of investigating the level of CHIT1 in CSF and blood of ALS patients, healthy and disease control groups [18]. Similar to the findings of the previous study [21], the level of CHIT1 in the CSF of ALS patients was significantly higher compared to the healthy control group and the disease control group (p<0.0001 and p<0.05, respectively). Unlike the level of CHIT1 in CSF, the level of this biomarker in the serum of ALS patients was not significantly different from other groups [18].

In the study by Costa and et al. [24], which included two groups of ALS patients and a patient control group, the level of CHIT1 was significantly higher in ALS patients (p<0.0001) and the level of this biomarker in patients compared to the control group was 6.7 times (4,254 pg/mL vs. 638.9 pg/mL). Similar results were observed in another study [16] which, like the previous study (24), included the group of ALS patients and the disease control group. In this study [16], CHIT1 level was significantly higher in ALS patients (p<0.0001).

Based on the study method of Varghese and et al. [25], groups of ALS patients and healthy control were present. Sixteen people were in the group of ALS patients and 13 people were in the healthy control group. Biomarker CHIT1 level was increased 17 times in ALS patients, which level was significantly higher compared to the healthy control group (p<0.01). Similar results were observed in another study conducted in Germany [17]. This study, like the previous study, included a group of ALS patients (n=66) and a healthy control group (n=36), and the level of CHIT1 in the patients increased 9 times (12,668 pg/mL vs. 1 433 pg/mL) and was significantly higher (p<0.001). The findings of Gray and et al.’s study [26] were consistent with the previous two studies [17], 25]. In this study, the number of patients was 11 and the number of healthy control group was 16, and the level of CHIT1 was higher in patients compared to the healthy control group (p<0.001). Three previous studies have been conducted in different countries and continents. Varghese and et al.’s study was conducted in Asia and India [25], Oeckl and et al.’s study in Europe and Germany [17], and Gray and et al.’s study in North America and the USA [26].

Studies 18, 19, 21, 23, 27, 28, 29, 30 included groups of ALS patients, healthy control group and patient control group. In Vu and et al.’s study, the level of biomarker CHIT1 in the CSF of patients was significantly higher compared to healthy and disease control groups (p<0.0001 and p<0.01, respectively(. In this study, the level of CHIT1 in the plasma of the 3 groups was also measured and compared with each other. But unlike the cerebrospinal fluid, no quantitatively significant difference in CHIT1 level was observed between the 3 groups. Therefore, according to the findings of this study, plasma chitinases cannot replace CSF chitinases in the diagnosis and screening of ALS patients [27]. The results of two studies by Thompson and et al. in 2019 and 2022 [19], 28] were consistent with the findings of the previous study [27]. In both studies by Thompson and et al., CHIT1 levels were significantly higher in patients [19], 28]. The results of three studies by Thompson and et al. in 2019 and 2022 [19], 28], 30] were consistent with the findings of the previous study [27]. In all three studies by Thompson and et al., CHIT1 levels were significantly higher in patients [19], 28], 30]. The findings of Steinacker and et al.’s study [29], which was conducted in 2021 in Germany, Belgium, UK, France, Italy and The Netherlands, confirmed the results of previous studies. Biomarker CHIT1 levels were significantly higher in patients (p<0.05) compared to the other two groups [29].

According to the findings of the present study, it seems that the increase in the level of CHIT1 and its release into the CSF can lead to an increase in the severity of neurodegeneration. In all the studies that this systematic review has examined, a multifold increase in CHIT1 levels has been observed in patients compared to healthy and disease control groups. It should be noted that in order to ensure the diagnostic performance of this biomarker, more studies should be conducted to evaluate the sensitivity and specificity of this biomarker.