The Hunt for an HD Blood Test

Huntington’s disease (HD) is a devastating neurodegenerative disorder with no cure or disease-modifying treatments. Caused by an expanded trinucleotide repeat of the DNA bases cytosine-adenine-guanine (CAG) in the Huntingtin gene, it is primarily an inherited disease. Symptoms commonly arise between the ages of 30 and 50, but can begin as early as infancy. When it comes to diagnosis, there are well-established clinical and neuroimaging markers of disease and progression – but few useful biochemical markers exist.

Lauren Byrne is a researcher at University College London Huntington’s Disease Centre who is working on a blood test that can predict the onset and progression of HD – and she has personal reasons for doing so. “I grew up in a HD family, and have several family members affected by the disease. I always loved science and was fascinated by the brain, so it was a natural progression for me to get involved in HD research. I find translational research – for example, the development of biomarkers of disease progression that could directly benefit patients – particularly enticing”, she says.

“The hunt for a blood test has been going on for decades,” says Byrne. Efforts began in earnest in the 1990s, after the causative gene behind HD was identified. Byrne and her colleagues have been focusing on neurofilament light protein (NfL) – a subunit found in neurons that helps them hold their structure. NfL is released when neuronal damage occurs, and is found at increased concentrations in the cerebrospinal fluid (CSF) of people with diseases such as Alzheimer’s, ALS, and dementia; previous studies have also found raised concentrations in CSF in individuals with HD. NfL has also been measured in the blood in several neurodegenerative disorders, and in the blood of athletes in high impact sports like boxing. But this new project is the first to study the blood of HD patients, using an ultrasensitive single-molecule array method.

“We found blood levels of NfL to be raised in HD and even in HD gene mutation carriers that were over 10 years from showing any symptoms of HD. NfL levels from the first baseline visit were associated with decline in cognitive and functional measures as well as global and regional brain atrophy,” says Byrne. “Individuals who progressed from premanifest to manifest HD within the three years of our study had higher levels of NfL at baseline. Most of these associations survived adjustment for age and CAG interactions, which are the best predictors of disease progression currently available.”

As this is the first blood marker to show such predictive value for disease onset and progression, the potential implications for patients are huge. The research group now plans to measure NfL in different animal models, including those treated with Huntington-lowering therapies, and to study the marker in larger patient cohorts at more time points, to better understand individual variation.

“We have presented the results at two scientific meetings and had a great response. Several groups want to collaborate with us by sending us their own samples to quantify NfL,” says Byrne. “And the public have also been excited. I think researchers and patients alike understand that this could be very important for the success of future trials.”