Elena Garcia-Montoya1, Dr Matthias Machacek1, Dr Peter McColgan2, Dr Patricia Sanwald-Ducray3, Dr Norman Alan Mazer4
1LYO-X AG, 2Roche Products Limited, 3Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Homann La Roche Ltd, 4NAM Consulting
Introduction and Objectives: Neurofilament light chain (NfL) is a structural protein of the neuronal cytoskeleton that is released into the cerebrospinal fluid (CSF) following axonal damage or neuronal death. Increased NfL levels in CSF and plasma have been established as biomarkers of neurodegeneration and are associated with various neurodegenerative diseases, including Huntington’s disease (HD). Nonetheless, the relationship between the dynamics of NfL concentrations in CSF and the time-course of neurodegeneration (whole brain atrophy) has not yet been described in a quantitative and mechanistic manner. We developed a novel semi-mechanistic model, which postulated that the amount of NfL entering the CSF equals the amount of NfL released from damaged neurons, whose degeneration results in a decrease in brain volume. Additionally, we explored the influence of cytosine-adenine-guanine (CAG) repeat length on the huntingtin gene (HTT) on neurodegeneration in HD. Methods: We use a compartmental non-linear mixed effects approach to analyse individual CSF NfL concentrations and brain volume data from a 24-month study involving an 80-participant cohort of HD mutation carriers and healthy controls from ages 26 to 77 years. The model linked changes in brain volume, the NfL content per brain volume assuming a homogenous distribution, and the CSF outflow rate with the CSF NfL concentrations using a set of ordinary differential equations. The time-course of the whole brain volume was represented empirically by a 2nd order polynomial. CSF flow rates in healthy and HD populations were taken from recent literature data. For model validation, individual post-mortem brain mass data was obtained from another study of 184 participants ranging in age from 20 to 100 years, with no prior history or pathological evidence of neurological disease. Results: The model successfully described the brain volume changes and the longitudinal trajectory of CSF NfL concentrations in both HD patients and healthy controls. The model predicted a brain NfL concentration of 15.5 µg/g, which compared well with the reported experimental NfL concentration range of 10 to 47 µg/g. In HD subjects, the brain volume shrinkage, hence the NfL release rate, significantly increased with the number of CAG repeats on HTT. The predicted age-related brain volume changes and CSF NfL concentration time profiles agreed well with the independent validation data set. Our findings suggested that the NfL concentration in CSF reflects the rate of neurodegeneration rather than the extent of it. Conclusions: For healthy subjects and for HD subjects these results supported a relationship between neuronal death, brain volume shrinkage and the NfL in CSF based on mass conservation. This further suggested that transport via CSF flow was the only elimination mechanism and contribution through the immune system was negligible. However, evidence suggested that the mass-balance principle of this model may not hold in all neurological conditions. For example, in Alzheimer’s disease, increased cortical microglia activation has been associated with low plasma NfL levels suggesting that the brain immune system can participates in control of released NfL in some cases. The relationship with the release rate of NfL imply that NfL CSF levels are a measure of ongoing neuronal damage, and as such is more indicative of future rather than past neurological damage. References: Machacek M, Garcia-Montoya E, McColgan P, Sanwald-Ducray P and Mazer NA (2024) NfL concentration in CSF is a quantitative marker of the rate of neurodegeneration in aging and Huntington’s disease: a semi-mechanistic model-based analysis. Front. Neurosci. 18:1420198. doi: 10.3389/fnins.2024.1420198
Reference: PAGE 33 (2025) Abstr 11439 [www.page-meeting.org/?abstract=11439]
Poster: Drug/Disease Modelling - CNS