Plasma Concentration of the Neurofilament Light Protein (NFL) is a Biomarker of CNS Injury in HIV Infection: A Cross-Sectional Study

Abstract

Background: Cerebrospinal fluid (CSF) neurofilament light chain protein (NFL) is a sensitive marker of neuronal injury in a variety of neurodegenerative conditions, including the CNS dysfunction injury that is common in untreated HIV infection. However, an important limitation is the requirement for lumbar puncture. For this reason, a sensitive and reliable blood biomarker of CNS injury would represent a welcome advance in both clinical and research settings.

Methods: To explore whether plasma concentrations of NFL might be used to detect CNS injury in HIV infection, an ultrasensitive Single molecule array (Simoa) immunoassay was developed. Using a cross-sectional design, we measured NFL in paired CSF and plasma samples from 121 HIV-infected subjects divided into groups according to stage of their systemic disease, presence of overt HIV-associated dementia (HAD), and after antiretroviral treatment (ART)-induced viral suppression. HIV-negative controls were also examined.

Findings: Plasma and CSF NFL concentrations were very highly correlated (r = 0.89, P < 0.0001). While NFL was more than 50-fold lower plasma than CSF it was within the quantifiable range of the new plasma assay in all subjects, including the HIV negatives and the HIV positives with normal CSF NFL concentrations. The pattern of NFL changes were almost identical in plasma and CSF, both exhibiting similar age-related increases in concentrations along with highest values in HAD and substantial elevations in ART-naïve neuroasymptomatic subjects with low blood CD4(+) T cells.

Interpretation: These results show that plasma NFL may prove a valuable tool to evaluate ongoing CNS injury in HIV infection that may be applied in the clinic and in research settings to assess the presence if active CNS injury. Because CSF NFL is also elevated in a variety of other CNS disorders, sensitive measures of plasma NFL may similarly prove useful in other settings.

Keywords: Antiretroviral Treatment; Biomarker; CNS; CSF; Central Nervous System; Cerebrospinal Fluid; HAD; HIV; HIV Associated Dementia; NFL; Neurofilament Light Chain; Plasma.

Fig. 1

Association between CSF and plasma NFL and concentrations of biomarkers in 8 subject groups. Panels a–b and d–f, plot concentrations of different markers for the 8 subject groups, HIV-negative controls (HIV-neg); primary HIV infection (PHI); untreated neuroasymptomatic subjects in different CD4 cell strata (Asympt); HIV-associated dementia (HAD); and subjects on suppressive antiretroviral treatment (ART). Boxes depict median and IQR, whiskers show 10–90 percentiles and ‘+’ designates the means. Dotted horizontal lines in panels d–e show the limit of detection for HIV RNA (40 copies/mL), and in panel f the upper limit of normal for CSF neopterin (5.8 nmol/L). Panel c plots the correlation between log CSF and log plasma NFL.

Fig. 2

Association between NFL and age. Panel a displays the regression lines for age to log plasma and log CSF NFL in HIV-negative controls. Age was closely correlated with plasma NFL (r = 0.79, p < 0.0001).