The following is a brief survey of HD-related research published during January-March 2021:
Advances in Understanding HD
Biomarkers are defined as a measurable biological trait that can be used to indicate the presence of a disease. Biomarkers are incredibly helpful tools for physicians in order to diagnose and monitor the progression of diseases. As such, research on quantitative biomarkers for HD is an incredibly important medical need.
In a February report published in Movement Disorders, a group of German researchers investigated the use of novel biomarkers for HD.1 The researchers measured the levels of the potential target, PDYN‐derived peptides, in relation to a standard biomarker for neurodegenerative diseases, neurofilament light chain. The rationale behind this choice is based on prior research demonstrating that brain expression of PDYN is decreased in mouse models of HD. The group measured the levels of PDYN-derived peptides and neurofilament light chain in the cerebrospinal fluid of HD patients, controls, and patients with other neurodegenerative disorders. They found that PDYN‐derived peptide levels were significantly decreased specifically in HD patients, whereas neurofilament light chain levels were increased nonspecifically in all neurodegenerative disorders. These promising findings suggest that PDYN-derived peptide levels could be a more specific biomarker for HD compared to neurofilament light chain, although more research is needed to validate PDYN-derived peptide measurements as a marker for HD progression.
In a February report published in Free Radical Biology and Medicine, Naia and colleagues investigated the role of a mitochondrial protein called NAD-dependent deacetylase sirtuin-3 (SIRT3) in HD.2 It has been previously demonstrated that SIRT3 levels and activity is increased in HD. The study expanded on this knowledge by finding that loss of SIRT3 is correlated with increased oxidative stress, which can cause mitochondrial dysfunction. Conversely, the researchers found that SIRT3 overexpression led to enhanced mitochondrial function. In a fly model of HD, SIRT3 overexpression protected against neurodegeneration and extended the lifespan of the flies. These findings can help inform future research investigating novel therapeutic strategies for HD.
Computational methods have and continue to play an increasingly important role in improving our understanding of the pathophysiology of HD and discovering novel therapeutic strategies.
The composite Unified Huntington’s Disease Rating Scale (cUHDRS) is a metric used to track the progression of HD and is heavily relied upon in clinical trials. In a January study published in Movement Disorders, Estevez‐Fraga and colleagues aimed to statistically analyze how well the cUHDRS correlates with imaging biomarkers to track the progression of HD.3 This was done in order to validate cUHDRS as a relevant metric for HD progression. Using two techniques called voxel-based morphometry and tract-based spatial statistics, the researchers looked at the correlation between cUHDRS scores, gray & white matter volumes, and structural connectivity metrics. The group found strong evidence supporting the correlation between cUHDRS scores and longitudinal volume in regions of the brain called the occipito-parietal cortex, centrum semiovale, and the basal ganglia and structural connectivity metrics. These findings support the use of cUHDRS as a valid measurement tool for HD progression.
Given the genetic nature of HD, there exists the possibility for predictive testing. Those who are at risk of HD have the option to choose whether or not to get genetically tested. Learning about genetic predisposition to HD comes with significant psychological burden, including the fear of genetic discrimination. Understanding the sociology behind this phenomenon is an important step in reducing the stereotypes and stigma surrounding genetic diseases like HD.
In a February study published in the European Journal of Human Genetics, two Belgian researchers aimed to better understand why individuals at risk for HD worry about genetic discrimination despite the existence of genetic non-discrimination regulations, and how these individuals cope with their concerns.4 The researchers analyzed semi-structured, in-depth interviews with individuals at risk for HD to fuel their findings. With regards to why these individuals fear genetic discrimination, the study found that these concerns were largely grounded in family backgrounds. These individuals often witnessed symptomatic relatives suffering from discrimination and stigmatization on numerous occasions, fueling their own concerns. The researchers also identified two distinct coping strategies- keeping genetic risk a secret, or explicitly choosing to be transparent. These findings help us gain a better understanding of the social aspects of being at risk for HD.
- Al Shweiki, R., et al., “Cerebrospinal Fluid Levels of Prodynorphin‐Derived Peptides are Decreased in Huntington’s Disease” Movement Disorders.
- Naia, L., et al., “Mitochondrial SIRT3 confers neuroprotection in Huntington’s disease by regulation of oxidative challenges and mitochondrial dynamics” Free Radical Biology and Medicine.
- Estevez‐Fraga, C., et al., “Composite UHDRS Correlates With Progression of Imaging Biomarkers in Huntington’s Disease” Movement Disorders.
- Wauters and Hoyweghan, “Normalizing life at risk of Huntington’s disease. A qualitative study of backgrounds and coping strategies of fears of genetic discrimination” European Journal of Human Genetics.