Brain-derived neurotrophic factor in cerebrospinal fluid and plasma is not a biomarker for Huntington\u2019s disease

Zhen-Yi Andy Ou,Edward J Wild,Marzena Arridge,Henrik Zetterberg,Filipe B Rodrigues,Enrico De Vita,Martha S Foiani,Lauren M Byrne,Rosanna Tortelli,Rachael I Scahill,Amanda Heslegrave,Eileanoir B Johnson

doi:10.1038/s41598-021-83000-x

Abstract

Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington’s disease (HD), possibly because mutant huntingtin impairs its cortico-striatal transport, contributing to striatal neurodegeneration. The BDNF trophic pathway is a therapeutic target, and blood BDNF has been suggested as a potential biomarker for HD, but BDNF has not been quantified in cerebrospinal fluid (CSF) in HD. We quantified BDNF in CSF and plasma in the HD-CSF cohort (20 pre-manifest and 40 manifest HD mutation carriers and 20 age and gender-matched controls) using conventional ELISAs and an ultra-sensitive immunoassay. BDNF concentration was below the limit of detection of the conventional ELISAs, raising doubt about previous CSF reports in neurodegeneration. Using the ultra-sensitive method, BDNF concentration was quantifiable in all samples but did not differ between controls and HD mutation carriers in CSF or plasma, was not associated with clinical scores or MRI brain volumetric measures, and had poor ability to discriminate controls from HD mutation carriers, and premanifest from manifest HD. We conclude that BDNF in CSF and plasma is unlikely to be a biomarker of HD progression and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF.

Highlights

Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons
cerebrospinal fluid (CSF) levels were below the limit of detection (LOD) in all 20 samples on the Promega assay, while 16 (80%) out of 20 samples were between the LOD and the LOQ on the Sigma-Aldrich assay
With an ultra-sensitive assay, BDNF levels were measurable in both CSF and plasma but did not reflect Huntington’s disease (HD) or its progression and were not associated with the examined clinical and imaging measures

Summary

Introduction

Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a mutation in the gene encoding mutant huntingtin protein (mHTT). It causes behavioural, cognitive, and motor dysfunctions and no diseasemodifying treatment has yet demonstrated e fficacy[1]. In HD, the selective vulnerability and degeneration of striatal neurons may be caused by the depletion of brain-derived neurotrophic factor (BDNF)[2]. BDNF concentration in cerebrospinal fluid (CSF) or blood could be an accessible means of quantifying dysfunction of this pathogenic pathway, could be a useful monitoring or prognosis biomarker, and could elucidate target engagement by therapeutics expected to restore the pathway. BDNF deficiency in serum has been observed in HD p atients[14]

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Results

Conclusion