Following the Clues: Usefulness of Biomarkers of Neuroinflammation and Neurodegeneration in the Investigation of HTLV-1-Associated Myelopathy Progression

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease due to axonal damage of the corticospinal secondary to an inflammatory response against infected T-cells. In the present work, we aimed to evaluate biomarkers of neurodegeneration and neuroinflammation in the definition of HAM/TSP prognosis. Neurofilament light (NfL) and phosphorylated heavy (pNfH) chains, total Tau protein, cellular prion protein (PrPc), inflammatory chemokines, and neopterin were quantified in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n=21), HTLV-1 asymptomatic carriers (AC) (n=13), and HTLV-1 seronegative individuals with non-inflammatory non-degenerative neurological disease (normal-pressure hydrocephalus) (n=9) as a control group. HTLV-1 proviral load in peripheral blood mononuclear cells and the expression of chemokine receptors CCR4, CCR5, and CXCR3 in infected CD4+ T-cells (HTLV-1 Tax+ cells) were also assessed. CSF levels of Tau, NfL, and pNfH were similar between groups, but PrPc and neopterin were elevated in HAM/TSP patients. Most individuals in the control group and all HTLV-1 AC had CSF/serum neopterin ratio < 1.0, and two-thirds of HAM/TSP patients had ratio values > 1.0, which positively correlated with the speed of disease progression and pNfH levels, indicating active neuroinflammation. HAM/TSP patients showed high serum levels of CXCR3-binding chemokines (CXCL9, CXCL10, and CXCL11) and elevated CSF levels of CCL2, CCL3, CCL4, CCL17, CXCL5, CXCL10, and CXCL11. Indeed, CXCL10 concentration in CSF of HAM/TSP patients was 5.8-fold and 8.7-fold higher in than in HTLV-1 AC and controls, respectively, and correlated with CSF cell counts. HAM/TSP patients with typical/rapid disease progression had CSF/serum CXCL10 ratio > 1.0 and a higher frequency of CXCR3+Tax+CD4+ T-cells in blood, which indicated a positive gradient for the migration of infected cells and infiltration into the central nervous system. In conclusion, the slow progression of HAM/TSP abrogates the usefulness of biomarkers of neuronal injury for the disease prognosis. Thus, markers of inflammation provide stronger evidence for HAM/TSP progression, particularly the CSF/serum neopterin ratio, which may contribute to overcome differences between laboratory assays.

Elevated levels of neopterin and pentraxin 3 in patients with rheumatoid arthritis

Objectives As a systemic inflammatory disease, rheumatoid arthritis (RA) is the most common inflammatory arthritis in the population and there is no specific diagnostic marker in laboratory tests. The purpose of the study was to determine whether serum neopterin and pentraxin 3 (PTX3) levels may be a marker of increased inflammation in RA patients. Materials and methods The study were consist of 30 RA patients and 30 healthy controls who were admitted to the department of rheumatology. Blood specimens were taken from both group, and the levels of neopterin were analyzed by chromatography method (HPLC) and the PTX 3 levels were measured by enzyme-linked immunosorbent assay (ELISA). All data and demographic characteristics of participants were also recorded. Results Serum neopterin and PTX 3 levels of the patient group (25.99 ± 7.24 ng/mL and 4.19 ± 1.01 ng/dL, respectively) was higher than the control group (9.55 ± 0.74 ng/mL and 2.23 ± 0.39 ng/dL, respectively). These results were remarkable significant (p<0.01). No statistically significant correlation was found between age-PTX 3, age-neopterin and PTX 3-neopterin parameters in the patient group. In the control group, a significant negative correlation was found between age and PTX 3 (p<0.05), and a positive correlation between neopterin and PTX 3. Conclusions Consequently, the serum neopterin and PTX 3 levels were higher in RA patients as compared to the healthy individuals. Our study suggest that there is a relation between neopterin and PTX 3 levels with RA patients. These findings suggest that neopterin and PTX 3 are important markers in the monitoring of RA disease.

Circulating concentrations of citrulline, neopterin, kynurenine, and tryptophan during chemoradiation in patients with cervical carcinoma

The aim of this study was to investigate the changes in circulating concentrations of citrulline, neopterin, kynurenine, and tryptophan during the course of chemoradiation in patients with cervical cancer. Sixteen patients with histologically confirmed carcinoma of the uterine cervix, aged 53 ± 15 years (range 29–76 years), were included in this study. Plasma neopterin, kynurenine, and tryptophan were determined with an enzyme-linked immunosorbent assay. Plasma citrulline was measured with high-performance liquid chromatography. Compared to baseline, citrulline concentration was markedly and statistically significantly decreased at visits 2, 3, and 4, while returning to pretreatment concentrations at visit 5. A significant increase in serum neopterin concentrations was observed at visits 4 and 5. With the exception of decreased kynurenine/tryptophan ratio at visit 3, no significant changes were observed in the concentrations of kynurenine, tryptophan, and kynurenine/tryptophan ratio throughout the course of the treatment. In conclusion, present data demonstrate that citrulline concentrations decrease early and neopterin concentrations increase late during the course of chemoradiation in patients with cervical carcinoma. Citrulline represents a biomarker of intestinal toxicity in this population.

Serum Neopterin Levels and the Clinical Presentation of COVID-19

In Coronavirus disease 2019 (COVID-19), it is important to evaluate disease activity and investigate possible biomarkers. Therefore, in this study, we investigated the relationship between disease activity and serum levels of possible immune activation marker neopterin in patients with COVID-19. The study enrolled 45 patients (23 females, 51.1%) treated for COVID-19. The patients were divided into two groups according to their clinical presentation: those who recovered quickly (Group 1) and those who worsened progressively (Group 2). The neopterin and C-reactive protein levels were high in all patients on admission. In Group 1, neopterin concentrations and serum neopterin/creatinine ratios were significantly higher on admission compared to Day 14 of the disease, whereas in Group 2, levels were significantly higher at Day 14 of the disease than on admission. Neopterin levels at admission were significantly higher in Group 1. The serum neopterin concentrations at admission were markedly higher in patients with a derived neutrophil–lymphocyte ratio (dNLR) > 2.8 compared to those with a dNLR ≤ 2.8 (p < 0.05). Serum neopterin levels can be used as a prognostic biomarker in predicting disease activity in COVID-19.

Serum neopterin levels in relation to mild and severe COVID-19

Background The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, is rapidly spreading worldwide. There is limited information about prognostic markers that could help clinicians to identify COVID-19 patients with a poor prognosis. Serum levels of the immune activation marker neopterin has shown to be of prognostic value in patients with SARS. The aim of this study was to investigate whether serum neopterin is associated with the severity of COVID-19. Methods We included 34 patients with confirmed COVID-19 between March 3 and March 30, 2020. Fifteen patients had mild disease and did not require hospitalization, whereas 19 patients developed severe COVID-19 requiring intensive care. Concentrations of serum neopterin, tryptophan, and kynurenine were measured at and repeatedly after inclusion. Results We found a more than two-fold higher mean concentration of neopterin in severely ill patients (mean value 42.0 nmol/L (SD 18.2)) compared to patients with mild symptoms (16.9 nmol/L (SD 11.0)). All of the severe cases had elevated neopterin concentrations (> 9.1 nmol/L) at the initial sampling with values ranging from 17.2 to 86.7 nmol/L. In comparison, 10 of 15 patients with mild disease had neopterin levels above 9.1 nmol/L, with concentrations in the range from 4.9 to 31.6 nmol/L. Neopterin levels gradually decreased during the course of COVID-19, but severe cases maintained elevated levels for a longer period. Moreover, lower levels of tryptophan and higher levels of kynurenine, indicating an increased tryptophan catabolism, were seen in the group with severe cases. Conclusions In conclusion, we found that serum neopterin levels are associated with the severity of COVID-19. Our findings suggest that neopterin could be used as a prognostic marker, but further studies are needed to elucidate how it can be used in the clinic.

Neopterin and biopterin levels and tryptophan degradation in patients with diabetes

This study aimed to evaluate the possible changes of neopterin, biopterin levels and tryptophan degradation in diabetes and to compare the results within diabetes groups and with healthy subjects. Diabetes mellitus patients and healthy controls were recruited the study. Patients were further subgrouped according to their drug therapy. Serum neopterin concentrations were detected by ELISA. Urinary neopterin, biopterin, serum tryptophan (Trp) and kynurenine (Kyn) levels were detected by HPLC. There was no difference between controls and diabetes patients in serum neopterin, urinary neopterin and biopterin levels (p > 0.05, all). Serum Trp and Kyn levels were significantly different in type 1 diabetes (T1DM) patients compared to controls (p < 0.05, both). Serum neopterin levels were significantly higher in type 2 diabetes patients (T2DM) compared to T1DM (p < 0.05). Urinary biopterin levels of T2DM patients using both metformin and vildagliptin were significantly higher than T1DM patients (p < 0.05). The correlations between serum neopterin and urinary neopterin, Kyn and Kyn/Trp were statistically significant in control and patient groups (p < 0.05, all). The study showed that Kyn/Trp was altered in diabetes patients due to immune modulation. On the other hand, although xenobiotic exposure may change pteridine levels, metformin and/or vildagliptin use in T2DM patients did not have any effect on the measured parameters.