Plasma Neurofilament Light Chain Levels Are Elevated in Children and Young Adults With Wolfram Syndrome

Abstract

Wolfram syndrome is a rare disease caused by pathogenic variants in the WFS1 gene with progressive neurodegeneration. As an easily accessible biomarker of progression of neurodegeneration has not yet been found, accurate tracking of the neurodegenerative process over time requires assessment by costly and time-consuming clinical measures and brain magnetic resonance imaging (MRI). A blood-based measure of neurodegeneration, neurofilament light chain (NfL), is relatively inexpensive and can be repeatedly measured at remote sites, standardized, and measured in individuals with MRI contraindications. To determine whether NfL levels may be of use in disease monitoring and reflect disease activity in Wolfram syndrome, plasma NfL levels were compared between children and young adults with Wolfram syndrome (n = 38) and controls composed of their siblings and parents (n = 35) and related to clinical severity and selected brain region volumes within the Wolfram group. NfL levels were higher in the Wolfram group [median (interquartile range) NfL = 11.3 (7.8–13.9) pg/mL] relative to controls [5.6 (4.5–7.4) pg/mL]. Within the Wolfram group, higher NfL levels related to worse visual acuity, color vision and smell identification, smaller brainstem and thalamic volumes, and faster annual rate of decrease in thalamic volume over time. Our findings suggest that plasma NfL levels can be a powerful tool to non-invasively assess underlying neurodegenerative processes in children, adolescents and young adults with Wolfram syndrome.

Genotype and clinical characteristics of patients with Wolfram syndrome and WFS1-related disorders

“…Prior studies have explored WFS1 expression levels and their correlations with clinical progression ( Hu et al, 2022 ). Similarly, biomarkers for neurodegeneration, such as neurofilament light chain and myelin basic protein, and inflammatory cytokine levels have been shown to be elevated in patients with Wolfram ( Abreu et al, 2021 ; Panfili et al, 2021 ; Eisenstein et al, 2022 ). Establishing correlations between these biomarker levels and phenotype severity may eventually pave the way for their validation and use as prognostic tools.…”

Genotype and Clinical Characteristics of Patients with Wolfram Syndrome and WFS1-related Disorders

“…Additional directions for research include exploring the correlation between levels of biomarkers and severity of disease. Biomarkers for neurodegeneration, such as neurofilament light chain and myelin basic protein, and inflammatory cytokine levels have been shown to be elevated in patients with Wolfram [23; 24]. The use of functional assays could be helpful in this regard to further explore the role of these biomarkers in the pathogenesis of Wolfram.…”

“…The use of functional assays could be helpful in this regard to further explore the role of these biomarkers in the pathogenesis of Wolfram. Establishing a correlation between biomarker levels and phenotype severity will aid in the prediction of clinical outcomes and disease progression in patients with Wolfram syndrome [23].…”

Benchmarking of a multi-biomarker low-volume panel for Alzheimer’s Disease and related dementia research

“…Other emerging AD biomarkers were quantified using a variety of immunoassays. CSF NfL was measured using commercially available immunoassays kits (Uman Diagnostics AB, Umea, Sweden) as previously described [29][30][31], whereas plasma levels were assessed using Quanterix [32]. CSF NRGN, SNAP25, and VILIP1 were performed using Single Molecule Counting (SMC) technology (EMD Millipore, Burlington, MA) as previously described [33][34][35][36].…”