Cerebrospinal fluid total tau concentration predicts clinical phenotype in Huntington's disease.

Filipe Brogueira Rodrigues,Peter Mccolgan,Blair R Leavitt,Sarah J Tabrizi,Lauren Byrne,Henrik Zetterberg,Nicola Robertson,Edward J Wild

doi:10.1111/jnc.13719

Filipe Brogueira Rodrigues, Peter Mccolgan + Show 6 more

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https://doi.org/10.1111/jnc.13719

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Abstract

Huntington's disease (HD) is a hereditary neurodegenerative condition with no therapeutic intervention known to alter disease progression, but several trials are ongoing and biomarkers of disease progression are needed. Tau is an axonal protein, often altered in neurodegeneration, and recent studies pointed out its role on HD neuropathology. Our goal was to study whether cerebrospinal fluid (CSF) tau is a biomarker of disease progression in HD. After informed consent, healthy controls, pre‐symptomatic and symptomatic gene expansion carriers were recruited from two HD clinics. All participants underwent assessment with the Unified HD Rating Scale ’99 (UHDRS). CSF was obtained according to a standardized lumbar puncture protocol. CSF tau was quantified using enzyme‐linked immunosorbent assay. Comparisons between two groups were tested using ancova. Pearson's correlation coefficients were calculated for disease progression. Significance level was defined as p < 0.05. Seventy‐six participants were included in this cross‐sectional multicenter international pilot study. Age‐adjusted CSF tau was significantly elevated in gene expansion carriers compared with healthy controls (p = 0.002). UHDRS total functional capacity was significantly correlated with CSF tau (r = −0.29, p = 0.004) after adjustment for age, and UHDRS total motor score was significantly correlated with CSF tau after adjustment for age (r = 0.32, p = 0.002). Several UHDRS cognitive tasks were also significantly correlated with CST total tau after age‐adjustment. This study confirms that CSF tau concentrations in HD gene mutation carriers are increased compared with healthy controls and reports for the first time that CSF tau concentration is associated with phenotypic variability in HD. These conclusions strengthen the case for CSF tau as a biomarker in HD. In the era of novel targeted approaches to Huntington's disease, reliable biomarkers are needed. We quantified Tau protein, a marker of neuronal death, in cerebrospinal fluid and found it was increased in patients with Huntington's disease and predicted motor, cognitive, and functional disability in patients. It is therefore likely to be a biomarker of disease progression, and possibly of therapeutic response. Read the Editorial Highlight for this article on page 9.

Highlights

EJW was the guarantor of this project
The development of sensitive biomarkers of disease progression that reflect neuropathology and treatment response is of vital importance to empower clinical trials
It has been shown that Huntington’s disease (HD) patients have higher cerebrospinal fluid (CSF) total tau concentrations compared with healthy controls (Constantinescu et al 2011), but no associations with phenotype or independent validation were made

Summary

Introduction

EJW was the guarantor of this project. EJW, HZ, BL, and SJT conceptualized the project. All authors reviewed and authorized the final version of the manuscript. The progression of HD is slow, with half of the patients surviving at least 24 years after the motor diagnosis (Rodrigues et al 2014). This makes studying the efficacy of disease-modifying compounds challenging. It has been shown that tau concentration in cerebrospinal fluid (CSF) of patients with Alzheimer’s disease is associated with disease progression (Blom et al 2009). It has been shown that HD patients have higher CSF total tau concentrations compared with healthy controls (Constantinescu et al 2011), but no associations with phenotype or independent validation were made

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