Evaluation of Biochemical and Epigenetic Measures of Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker in Huntington's Disease Patients.

Ashley Gutierrez,Jody Corey-Bloom,Elizabeth A Thomas,Paula Desplats

doi:10.3389/fnmol.2019.00335

Abstract

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative movement disorder that presents with prominent cognitive and psychiatric dysfunction. Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of HD, as well as other neurodegenerative and psychiatric disorders, and epigenetic alterations in the complex BDNF promoter have been associated with its deregulation in pathological conditions. BDNF has gained increased attention as a potential biomarker of disease; but currently, the conflicting results from measurements of BDNF in different biofluids difficult the assessment of its utility as a biomarker for HD. Here, we measured BDNF protein levels in plasma (n = 85) and saliva (n = 81) samples from premanifest and manifest HD patients and normal controls using ELISA assays. We further examined DNA methylation levels of BDNF promoter IV using DNA derived from whole blood of HD patients and healthy controls (n = 40) using pyrosequencing. BDNF protein levels were not significantly different in plasma samples across diagnostic groups. Plasma BDNF was significantly correlated with age in control subjects but not in HD patients, nor were significant gender effects observed. Similar to plasma, salivary BDNF was correlated with age only in control subjects, with no gender effects observed. Importantly, we detected significantly lower levels of salivary BDNF in premanifest and manifest HD patients compared to control subjects, with lower BDNF levels being observed in premanifest patients within a predicted 10 years to disease onset. Salivary and plasma BDNF levels were not significantly correlated with one another, suggesting different origins. DNA methylation at four out of the 12 CpG sites studied in promoter IV were significantly altered in HD patients in comparison to controls. Interestingly, methylation at three of these CpG sites was inversely correlated to the Hospital Anxiety and Depression Scale (HADS) scores. BDNF promoter methylation was not correlated with motor or cognitive scores in HD patients, and was not associated with sex or age in neither disease nor control groups. Conclusion: Our studies show that BDNF protein levels are decreased in saliva; and BDNF promoter methylation increased in blood in HD subjects when compared to controls. These findings suggest that salivary BDNF measures may represent an early marker of disease onset and DNA methylation at the BDNF promoter IV, could represent a biomarker of psychiatric symptoms in HD patients.

Highlights

Huntington’s disease is an inherited, progressive neurodegenerative disorder characterized by chorea, movement dysfunction, cognitive impairment, and behavioral disturbances (The Huntington’s Disease Collaborative Research Group, 1993)
The samples [plasma (n = 85), saliva (n = 81), and whole blood (n = 39)] used in this study correspond to Huntington’s disease (HD) patients and healthy controls recruited from the University of California, San Diego (UCSD) HD Clinical Research Center over a period of 3 years
There were no significant differences in sex ratios or age between the HD and control groups

Summary

Introduction

Huntington’s disease is an inherited, progressive neurodegenerative disorder characterized by chorea, movement dysfunction, cognitive impairment, and behavioral disturbances (The Huntington’s Disease Collaborative Research Group, 1993). HD is caused by a CAG trinucleotide repeat expansion in the first exon of the HTT gene encoding the HTT (The Huntington’s Disease Collaborative Research Group, 1993). Because the gene mutation is known, diagnostic and predictive genetic testing is available for HD; biomarkers for HD are still greatly needed to predict disease onset, to assess the diversity and severity of symptoms and to monitor disease progression (Ross et al, 2014). Cerebral spinal fluid (CSF) is thought to represent the biofluid most similar to the brain environment, CSF collection is an invasive technique that requires a lumbar puncture, which can be painful and lead to side effects and complications (Evans, 1998). With regards to peripheral sources, investigations in blood have dominated the field for decades, other peripheral fluids for biomarker studies have included saliva, urine, and sweat

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Conclusion