Associations between neurofilament light-chain protein, brain structure, and chronic kidney disease

Abstract

Background: Neurofilament light chain (NfL) protein is a blood-based marker of neuroaxonal injury. We sought to 1) compare plasma NfL levels in children with chronic kidney disease (CKD) and healthy peers, 2) characterize the relationship between NfL level and kidney function, and 3) evaluate NfL as a predictor of abnormal brain structure in CKD. Methods: Sixteen children with CKD due to congenital kidney anomalies and 23 typically developing peers were included. Plasma NfL was quantified using single-molecule array immunoassay. Participants underwent structural magnetic resonance imaging. Multiple linear regression models were used to evaluate the association between plasma NfL levels, kidney function, and brain structure. Results: An age × group interaction was identified whereby NfL levels increased with age in the CKD group only (estimate = 0.65; CI = 0.08–1.22; p = 0.026). Decreased kidney function was associated with higher NfL levels (estimate = −0.10; CI = −0.16 to −0.04; p = 0.003). Lower cerebellar gray matter volume predicted increased plasma NfL levels (estimate = −0.00024; CI = −0.00039–0.00009; p = 0.004) within the CKD group. Conclusion: Children with CKD show accelerated age-related increase in NfL levels. NfL level is associated with lower kidney function and abnormal brain structure in CKD.

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

“…It may be difficult to investigate the dynamics of CSF and serum NfPs in chronic neurodegenerative diseases such as AD and PD without treatments that can cure them. Because it is suggested that serum NfL fragments may be cleared by the kidneys, renal function ought to be considered when interpreting serum NfL levels (Korley et al, 2019;Van Der Plas et al, 2021).…”

Quantitative susceptibility mapping and blood neurofilament light chain differentiate between parkinsonian disorders

“…Third, cutoff of NfL in blood might vary depending on the disease severity and quantification techniques. It should also be noted that blood NfL is relatively low specificity and also abnormal in other conditions including nervous system diseases and renal disease (Gaetani et al, 2019;van der Plas et al, 2021). While these methods are promising, future studies are needed to substantiate their usefulness as biomarker in early parkinsonism.…”

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

“…It is possible that between-group factors other than central axonal injury such as peripheral nerve damage, impaired renal function and/or vascular neuropathy may be responsible for elevated plasma NfL levels in individuals with Wolfram syndrome ( Bischof et al, 2018 ; Khalil et al, 2018 ; Sandelius et al, 2018 ; Akamine et al, 2020 ; Frempong et al, 2021 ). Future studies using CSF NfL samples and MR diffusion studies of tissue microstructural integrity, known to be impaired in Wolfram syndrome ( Lugar et al, 2016 ), will help to determine whether the elevated NfL is primarily due to central axonal injury or other aspects of Wolfram syndrome (e.g., diabetes, ER dysfunction) ( Piehl et al, 2018 ; Akamine et al, 2020 ; van der Plas et al, 2021 ). Unfortunately, the current study was not powered to detect relationships between diffusion MRI-based tissue microstructural integrity and NfL levels since these measures were not always obtained during the same clinic year in individuals with Wolfram syndrome.…”

“…Neurofilament light chain levels fluctuate non-linearly over the lifespan in healthy individuals and, in normal aging, elevated NfL levels cross-sectionally and longitudinally relate to brain volume loss presumably due to increasing levels of neuroaxonal injury ( Bridel et al, 2019 ; Khalil et al, 2020 ; Ashton et al, 2021 ). Risk for or presence of disease often alters the relationship between age and NfL levels ( Bridel et al, 2019 ; Khalil et al, 2020 ; Ashton et al, 2021 ; van der Plas et al, 2021 ). The subset of siblings in our control group, composed of children and adolescents, had plasma NfL levels similar to those of the control parents in our study and to serum NfL levels in similarly aged healthy controls in a pediatric MS study ( Reinert et al, 2020 ).…”

“…NfL levels are not associated with a specific disease etiology but instead are sensitive to progressive neurodegeneration and may predict onset or progression across many diseases, such MS in adults and children, Alzheimer’s disease (AD), Huntington disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia ( Disanto et al, 2017 ; Mattsson et al, 2017 ; Ashton et al, 2019 ; Bridel et al, 2019 ; Gaetani et al, 2019 ; Gordon, 2020 ; Reinert et al, 2020 ; Coarelli et al, 2021 ). In addition, elevated NfL predicts worse cognitive function and smaller brain volume in both AD and frontotemporal dementia ( Rohrer et al, 2016 ; Mattsson et al, 2017 ), decreased cerebellar and pons volumes in spinocerebellar ataxia ( Coarelli et al, 2021 ), decreased cerebellar gray matter volume in children with chronic kidney disease ( van der Plas et al, 2021 ), reduced white matter integrity in dominantly inherited AD ( Schultz et al, 2020 ), and decreased hippocampal volume, cortical thickness, white matter integrity, and worsening cognition in cognitively unimpaired older adults ( Mielke et al, 2019 ). NfL levels are also useful as a biomarker for monitoring therapeutic response.…”