Objective: The objective of the current study was to assess the potential for saliva to serve as a biospecimen for accessible biomarkers for Huntington’s disease (HD).

Background: Peripheral biomarkers are greatly needed in the field of neurodegenerative disorders to anticipate onset of disease symptoms, monitor disease progression, and track potential therapeutic effects. Huntington’s disease (HD) is a fatal, inherited neurodegenerative disorder caused by a CAG repeat expansion in the gene encoding the protein, huntingtin (Htt). Pathogenesis is associated with expression of the mutant Htt (mHtt) protein in the CNS; however, HD is also associated with abnormalities in peripheral tissues. The Htt protein is the most significant molecular target for disease modifying therapies, and several therapeutic approaches directed at its production, processing, and/or turnover are under development for impending clinical trials in HD. Since non-invasive methods to quantify Htt in the CNS do not exist, measuring Htt and other disease proteins in peripheral cells represents an essential step in biomarker discovery for HD.

Methods: In the current study, we measured Htt protein in saliva from manifest HD patients, gene-positive premanifest HD patients, and age- and sex-matched normal individuals (total n=178) using Western blots and ELISA methods.  Additional salivary analytes, including alpha amylase, cortisol, C-reactive protein (CRP), and uric acid, were also measured using standardized ELISAs.

Results: Salivary total Htt levels were significantly increased (p=0.0012) in saliva from HD individuals (mean=0.775 ng/ml) compared to normal controls (mean=0.359 ng/ml). Salivary total Htt did not vary over time of day or over different days, nor were there age or gender effects.  Additionally, salivary mHtt levels were higher in gene positive premanifest HD subjects compared to normal controls (p<0.05). CRP, a widely used biomarker of systemic inflammation, was found to be significantly (p=0.025) elevated in premanifest HD subjects (9,548 pg/ml) compared to normal controls (3,399 pg/ml) and may be an early marker of disease onset.  Levels of other salivary proteins, alpha amylase and uric acid, were not significantly different between HD patients, premanifest subjects, or normal controls. 

Conclusions: Measurement of salivary Htt and other disease proteins offers significant promise as relevant, non-invasive biomarkers of disease onset and progression in HD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/salivary-biomarkers-for-huntingtons-disease-hd/