An age‐dependent mathematical model of neurofilament trafficking in healthy conditions

Abstract

Neurofilaments (Nfs) are the major structural component of neurons. Their role as a potential biomarker of several neurodegenerative diseases has been investigated in past years with promising results. However, even under physiological conditions, little is known about the leaking of Nfs from the neuronal system and their detection in the cerebrospinal fluid (CSF) and blood. This study aimed at developing a mathematical model of Nf transport in healthy subjects in the 20-90 age range. The model was implemented as a set of ordinary differential equations describing the trafficking of Nfs from the nervous system to the periphery. Model parameters were calibrated on typical Nf levels obtained from the literature. An age-dependent function modeled on CSF data was also included and validated on data measured in serum. We computed a global sensitivity analysis of model rates and volumes to identify the most sensitive parameters affecting the model's steady state. Age, Nf synthesis, and degradation rates proved to be relevant for all model variables. Nf levels in the CSF and in blood were observed to be sensitive to the Nf leakage rates from neurons and to the blood clearance rate, and CSF levels were also sensitive to rates representing CSF turnover. An additional parameter perturbation analysis was also performed to investigate possible transient effects on the model variables not captured by the sensitivity analysis. The model provides useful insights into Nf transport and constitutes the basis for implementing quantitative system pharmacology extensions to investigate Nf trafficking in neurodegenerative diseases. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?The change of neurofilament (Nf) concentration in the cerebrospinal fluid and blood is a potential marker of several neurodegenerative diseases and brain injury.

The 2022 Lady Estelle Wolfson lectureship on neurofilaments

“…On a group level, there remains a large overlap between health and disease. Overcoming these issues will pave the way for application of Nf to individualised, personal medicine. The causal relationship of Nf body fluid levels with age should be investigated in more detail (Paris et al, 2022). The challenge is to separate physiological ageing from accelerated neurodegeneration.…”

“…8. The causal relationship of Nf body fluid levels with age should be investigated in more detail (Paris et al, 2022). The challenge is to separate physiological ageing from accelerated neurodegeneration.…”

A pediatric quantitative systems pharmacology model of neurofilament trafficking in spinal muscular atrophy treated with the antisense oligonucleotide nusinersen

“…The immunoassays employed to obtain the data used in this work return significantly higher pNfH levels than other assays, 8,22 which are reflected in a lower estimated clearance rate in blood than that originally estimated in the healthy adult model. 10 To parametrize the SMA model, we built a virtual population of 400 subjects compatible with the data from the untreated condition using a method recently reported in literature 23 (see Appendix S1 for further details). Each subject of the population is obtained by estimating a set of four rate values, which includes the three parameters composing r14, representing the additional contribution of SMA to the pNfH trafficking and the clearance of pNfH in blood r13.…”

“…The extension of a previously developed Nf trafficking model in healthy adults 10 to the pediatric scenario required several modifications before including the reactions representing the effect of SMA. Drug modeling in children, in particular estimating organ volumes, T A B L E 1 Estimated model parameters computed from the generated untreated population and from the fit of the individual time series of treated patients (the full list of model parameters is provided in Table S4) direction of longitudinal growth population data 25 and modeling them in a mathematical way by introducing time-dependent volume changes and additional terms in the Nf ODEs.…”

“…8,9 In a previous article, we presented a mathematical model of Nf transport in healthy subjects in the age range of 20-90 years. 10 The aim of this work is to update and extend the model to provide a quantitative systems pharmacology model describing the pNfH trafficking in the SMA condition in the untreated and treated conditions during pediatric ages (0-20 years). We considered the physiological changes typical of the pediatric age that could affect Nf concentrations, in particular the differential growth of the tissue volumes and the peculiar development of the central nervous system (CNS).…”