Neurofilament light protein in CSF and blood is associated with neurodegeneration and disease severity in Huntington\u2019s disease R6/2 mice

Rana Soylu-Kucharz,Åsa Sandelius,Henrik Zetterberg,Edward J Wild,Marie Sjögren,Maria Björkqvist,Kaj Blennow

doi:10.1038/s41598-017-14179-1

Abstract

There is an unmet need to reliably and non-invasively monitor disease progression in preclinical Huntington’s disease (HD) models. As a marker of axonal damage, neurofilament light chain (NfL) has been suggested a marker for neurodegeneration. NfL concentrations in blood and CSF were recently shown to have prognostic value for clinical HD progression and brain atrophy. We therefore hypothesized that CSF and blood NfL concentrations could be useful preclinical HD markers, reflecting underlying pathology. To test our hypothesis we utilized the R6/2 mouse model of HD and measured NfL concentrations in CSF and serum using the ultrasensitive Single molecule array (Simoa) platform. In addition, we assessed HD mouse disease characteristics. We found robust increases of NfL in CSF and serum in R6/2 mice compared to wild-type littermates. CSF and serum concentrations of NfL were significantly correlated, suggesting similar marker potential of serum NfL. CSF and serum concentrations of NfL correlated with disease severity, as assessed by striatal volume and body weight loss. We here provide evidence that CSF and blood NfL concentrations can be used as accessible and reliable pre-clinical HD markers. This will be of potential use for monitoring HD mouse model disease progression and evaluating preclinical disease-modifying treatment response.

Highlights

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a CAG triplet repeat expansion in the gene encoding huntingtin[1]
We found that Neurofilament light chain (NfL) was elevated in R6/2 mice in both fluids; its level was significantly associated with measures of clinical and pathological severity; and cerebrospinal fluid (CSF) NfL level increase precedes HD pathology
Byrne and co-workers recently presented convincing data on NfL concentrations in CSF and plasma with striking prognostic power for progression in clinical HD12. We here validate this strategy in an animal model of HD used in drug design strategies, showing that monitoring NfL levels in CSF and plasma may be a marker of relevance in pre-clinical studies

Summary

Introduction

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a CAG triplet repeat expansion in the gene encoding huntingtin[1]. Clinical HD is characterised by a variable phenotypic expression of motor, cognitive and psychiatric symptoms[2], middle age onset and slow disease progression[3]. Mouse models of HD recapitulate many clinical HD features, such as progressive loss of memory and motor dysfunction. The transgenic R6/2 mouse model, first developed in 19965, displays rapid and reproducible progression of HD-like symptoms, such as motor dysfunction, weight loss and striatal volume reduction[5,6]. NfL concentration in cerebrospinal fluid (CSF) has been shown to be a marker of axonal injury in several neurological disorders[9,10,11]. Neurofilament light chain (NfL) concentrations in body fluids have been shown to reflect pathology and symptoms in proteinopathy mouse models of neurodegeneration[14] but have never been examined in an HD animal model before. We found that NfL was elevated in R6/2 mice in both fluids; its level was significantly associated with measures of clinical and pathological severity; and CSF NfL level increase precedes HD pathology

Methods

Results

Conclusion