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

Abstract

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.

Chitotriosidase 1 in the cerebrospinal fluid as a putative biomarker for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) progression

“…Recently, neopterin and CXCL10 have been shown as promising biomarkers for HAM/TSP progression evaluated with the Osame Motor Disability Score ( 24 ), and confirmed in this study population using the IPEC-2 disability scale ( 25 ). Neopterin is a byproduct of immune responses mediated by monocytes/macrophages.…”

“…Distinct biomarkers of neuroinflammation and neuronal death were previously evaluated in this study population ( 25 ). In HAM/TSP patients, CSF levels of CHIT1 positively correlated with neopterin, a byproduct from the monocyte/macrophage inflammatory response (Spearman R = 0.603, p = 0.005), and with the phosphorylated neurofilament heavy protein (pNfH), a biomarker for neuronal damage (Spearman R = 0.627, p = 0.003).…”

“…The correlation between the CSF concentration of (A–E) CHIT1 and (F–L) sVCAM-1 with neopterin, phosphorylated neurofilament heavy chain (pNfH) protein, and proinflammatory chemokines (CCL2, CCL3, CCL4, CXCL1, CXCL5, CXCL8, CXCL10, and CXCL11) was performed with Spearman’s rank of correlations test. The biomarkers of neuroinflammation or neuronal damage were assessed in this population in a previous study ( 25 ). The concentration values were log 2 -transformed and p -values <0.05 were considered significant.…”

“…Study participants were distributed in groups as HTLV-1 AC (n=13) and HAM/TSP patients (n=21). Patients with HAM/TSP were further subdivided according to the rate of disease progression, as previously described ( 25 ). Briefly, HAM/TSP patients were evaluated with the IPEC-2 disability scale ( Supplementary Table 1 ), which was performed by at least one of the four trained and experienced neurologists who participated in this study, and the disease progression index was obtained by the quotient between the scores and the time of disease in years.…”

“…The presence of elevated levels of inflammatory factors such as neopterin, CXCL10, and CXCL9 in the cerebrospinal fluid (CSF) have been shown to strongly correlate with HAM/TSP development and progression ( 23 – 25 ). Increased CSF levels of interleukin (IL)-1β, IL-6, granulocyte/macrophage-colony stimulating factor (GM-CSF), IFN-γ, and chemokines such as CCL3, CCL5, and CCL11 were also associated with HAM/TSP ( 26 ).…”