Neurofilament light protein as a biomarker for spinal muscular atrophy: a review and reference ranges.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, characterized by progressive neuromuscular degeneration resulting from mutations in the survival motor neuron (SMN1) gene. The availability of disease-modifying therapies for SMA therapies highlights the pressing need for easily accessible and cost-effective blood biomarkers to monitor treatment response and for better disease management. Additionally, the wide implementation of newborn genetic screening programs in Western countries enables presymptomatic diagnosis of SMA and immediate treatment administration. However, the absence of monitoring and prognostic blood biomarkers for neurodegeneration in SMA hinders effective disease management. Neurofilament light protein (NfL) is a promising biomarker of neuroaxonal damage in SMA and reflects disease progression in children with SMA undergoing treatment. Recently, the European Medicines Agency issued a letter of support endorsing the potential utilization of NfL as a biomarker of pediatric neurological diseases, including SMA. Within this review, we comprehensively assess the potential applications of NfL as a monitoring biomarker for disease severity and treatment response in pediatric-onset SMA. We provide reference ranges for normal levels of serum based NfL in neurologically healthy children aged 0-18 years. These reference ranges enable accurate interpretation of NfL levels in children and can accelerate the implementation of NfL into clinical practice.

Plasma Lipidomic Profiles in cART-Treated Adolescents with Perinatally Acquired HIV Compared to Matched Controls.

Children with perinatally acquired human immunodeficiency virus (PHIV) are growing into adulthood with HIV and treatment-associated comorbidities, such as dyslipidemia and insulin resistance. HIV is identified as independent risk factor for cardiovascular disease (CVD). The hypothesis behind increased CVD risk associated with HIV includes vascular inflammation, dyslipidemia and combination antiretroviral therapy (cART) metabolomic toxicity. To investigate differences in lipid profiles and pathophysiological mechanisms of CVD risk in adolescents with PHIV, we compared the plasma lipidome of PHIV adolescents and HIV-negative controls. We additionally investigated the influence of current cART regimens and increased lipoprotein(a) (Lp(a)) levels on the plasma lipidome. We included 20 PHIV-infected adolescents and 20 HIV-negative controls matched for age, sex, ethnic origin and socio-economic status. Plasma lipidome was measured using Thermo Scientific Ultimate 3000 binary high-performance liquid chromatography (HPLC)-mass spectrometry. We evaluated the plasma lipidome in PHIV adolescents using different cART regimens (including those known to be associated with lipid alterations). The median age was 17.5 years (15.5-20.7) and 16.5 years (15.7-19.8) for PHIV adolescents and controls, respectively. Of PHIV adolescents, 45% used a non-nucleotide reverse transcriptase inhibitor (NNRTI)-based (25%) or protease inhibitor (PI)-based (20%) cART regimen. In this pilot study, we observed no significant differences between lipidomic profiles between PHIV adolescents and controls. We observed no differences in the plasma lipidome in participants with increased versus normal Lp(a) levels. Different cART regimens appear to influence chain length differences in the plasma lipidome of PHIV adolescents; however, the significance and causality of this observation remains undetermined. Further research on the influence of cART on lipid composition could further identify these alterations.

Plasma Neurofilament Light Is Not Associated with Ongoing Neuroaxonal Injury or Cognitive Decline in Perinatally HIV Infected Adolescents: A Brief Report.

Despite combination antiretroviral therapy (cART), adolescents with perinatally acquired human immunodeficiency virus (PHIV) exhibit cerebral injury and cognitive impairment. Plasma neurofilament light (pNfL) is a biomarker identified as a promising marker associated with neuroaxonal injury and cognitive impairment. To investigate whether cerebral injury in cART-treated PHIV adolescents is persistent, we longitudinally measured pNfL. We included 21 PHIV adolescents and 23 controls, matched for age, sex, ethnic origin and socio-economic status. We measured pNfL in both groups and CSF NfL in PHIV adolescents using a highly sensitive Single Molecule Array (Simoa) immunoassay. We compared pNfL between groups over time with a mean follow-up time of 4.6 years and assessed its association with MRI outcomes, cognitive function and HIV-related characteristics using linear mixed models. The median age was 17.5 years (15.5-20.7) and 16.4 years (15.8-19.6) at the second assessment for PHIV adolescents and controls, respectively. We found comparable pNfL (PHIV vs. controls) at the first (2.9 pg/mL (IQR 2.0-3.8) and 3.0 pg/mL (IQR 2.3-3.5), p = 0.499) and second assessment (3.3 pg/mL (IQR 2.5-4.1) and 3.0 pg/mL (IQR 2.5-3.7), p = 0.658) and observed no longitudinal change (coefficient; -0.19, 95% -0.5 to 0.1, p = 0.244). No significant associations were found between pNfL and HIV- or cART-related variables, MRI outcomes or cognitive function. We observed low CSF NfL concentrations at the baseline in PHIV adolescents (100.8 pg/mL, SD = 47.5). Our results suggest that there is no ongoing neuroaxonal injury in cART-treated PHIV adolescents and that the neuroaxonal injury is acquired in the past, emphasizing the importance of early cART to mitigate HIV-related neuroaxonal damage.