Signs of HD found 24 years before symptoms

Wed June, 17th 2020

Small changes in the brain caused by Huntington’s disease are detectable 24 years before symptoms emerge, new research shows.

Researchers believe the findings will assist in identifying how early treatment should begin for people who have the faulty HD gene.

They come at the same time as clinical trials in Australia and across the world are testing promising new drugs designed to slow and possibly reverse the progress of the disease.

A team led by Professor Sarah Tabrizi from the Huntington’s disease Centre at the University College London (UCL) conducted the HD Young Adult Study (YAS), and the results were recently published in the Lancet Neurology journal.

“As the field makes great strides with the drug development, these findings provide vital new insights informing the best time to initiate treatments in the future, and represent a significant advance in our understanding of early Huntington’s,” Professor Tabrizi said in a UCL news article.

She said the ultimate aim was the find the ideal drug and the ideal time to deliver it to delay or prevent the brain degeneration people with HD experience.

A group of 64 young people who have the faulty HD gene were recruited for the UK research along with a control group of 67 people who do not. The average age of the participants was 29.

The aim was to look for the earliest signs of the disease in people who were still functioning at full capacity.

The HD positive participants were judged to be, on average, 24 years away from the onset of the disease, based on their age and earlier genetic test results.

Tests in the study included cognition (planning, attention, memory) and psychiatric condition (depression, anxiety, behaviour) along with MRI scans to map the brain, look for signs of the disease and see how different areas were connecting. Blood and cerebrospinal fluid samples were tested to look for biomarkers, which are measurable indicators of a disease.

Researchers found the participants with the HD gene did not show any changes in thinking or behaviour and there was no evidence of the involuntary movement that is characteristic of the disease.

However, they did detect “significantly higher concentrations” in the cerebrospinal fluid of a protein called neurofilament light (NfL). Increases in NfL are viewed by researchers as a sign of nerve cell damage in the brain. Levels were higher in participants closer to the estimated onset of symptoms of the disease.

Just under half the HD positive group had NfL levels above that of the control group, leading to the conclusion that small brain changes were occurring, on average, 24 years before the onset of the disease.

Why this matters

Firstly it is good news that there is no evidence of any cognitive, functional or psychiatric differences in people with the HD gene at this point in their lives.

Secondly, before this study the earliest detected brain changes in people with the HD gene were around 15 to 18 years before the predicted onset of symptoms, Professor Tabrizi told a conference earlier this year.

With this study confirming changes occur earlier, that can be taken into account in determining the ideal time to start treatment, prevent neurodegeneration and preserve people’s quality of life.

Interestingly, the study did not find significant levels of the mutant huntingtin protein in gene positive participants. That protein is believed to cause the damage to the brain that people with HD experience.

But by identifying that NfL levels in the cerebrospinal fluid are rising 24 years before onset, it gives researchers a promising biomarker that can be used to measure disease progression and people’s response to new treatments.

One of the other researchers leading the study, Dr Rachael Scahill from UCL, said starting treatment before any changes were detectable in the brain might be ideal, although there may be a “complex trade-off between the benefits of slowing the disease at that point and any negative effects of long-term treatment”.

Clinical trials, underway in Australia and many other countries around the world are testing new DNA-based drugs targeting either the faulty HD gene or the mutant huntingtin protein.

Participants in those trials are all in the early stages of the disease where symptoms are visible.

The first phases of both the Roche and Wave Life Science trials have produced evidence that levels of the mutant huntingtin protein in the cerebrospinal fluid of people with HD can be reduced. In the next few years it will become clear from the trials whether that reduction correlates with a slowing of the progression of the disease and improved function and cognitive capacity in participants.