Critical insights into neurodegeneration decades before diagnosis pave the way for preventative treatment trials in Huntington’s disease.

Researchers at UCL, working with their colleagues at the Universities of Glasgow, Gothenburg, Iowa, and Cambridge, have published a breakthrough study in Nature Medicine which helps us understand early mechanistic drivers of neurodegeneration in Huntington’s disease (HD), for the first time in living humans approximately 20 years before the appearance of symptoms. This research paves the way for new avenues in treatment trials to delay or even prevent the the disease.

HD is a devastating neurodegenerative disease affecting movement, thinking, and behaviour. People with an affected parent have a 50% chance of inheriting the HD mutation, meaning they will inevitably develop disease symptoms, typically in mid-adulthood. HD is caused by repetitive expansions of three DNA blocks (C, A and G) in the huntingtin gene. This sequence tends to expand further in certain cells over a person’s life, a process known as somatic CAG expansion. This ongoing expansion accelerates neurodegeneration, making brain cells more vulnerable over time. Those at risk of inheriting the condition can undergo predictive genetic testing, allowing researchers a unique opportunity to study the earliest changes, decades before clinical motor diagnosis.

The researchers, led by Professor Sarah Tabrizi, studied a dedicated cohort of individuals with the HD gene expansion together with controls, who volunteered to undergo comprehensive assessments of thinking, movement, behaviour, brain scans, and blood and spinal fluid sampling. Importantly, over the 4.5-year study period, the HD gene-expanded group showed no signs of decline in any movement, thinking or behavioural function. However, subtle changes in brain scans and spinal fluid measures designed to detect the earliest molecular changes in the brain, indicate that the neurodegenerative process has already started. This suggests a treatment window exists where intact function is coupled with detectable measures of subtle early neurodegeneration; identifying these early markers of disease is essential for future clinical trials in order to determine whether a treatment is having any effect.

Moreover, for the first time in humans, the team established a mechanistic link between somatic CAG repeat expansion measured in blood and these early brain changes occurring approximately 20 years before diagnosis, suggesting this process is a key driver of neurodegeneration. With treatments aimed at suppressing somatic CAG repeat expansion currently in development, this work validates this mechanistic process as a promising therapeutic target and identifies the best time to intervene, representing a critical advance towards future prevention trials in HD.

Professor Sarah Tabrizi, the study lead, said: “Our study underpins the importance of somatic CAG repeat expansion driving the earliest neuropathological changes of the disease in living humans carrying the HD genetic expansion. I want to thank the participants in our young adult study as their dedication and commitment over the last 5 years mean we are truly nearing prevention clinical trials in Huntington’s disease.”

Co-first author of the study, Dr Rachael Scahill (UCL Huntington’s Disease Research Centre) said: “This unique cohort of HD gene expanded and control participants provides us with unprecedented insights into the very earliest disease processes prior to the appearance of clinical symptoms, which has implications not only for HD but for other neurodegenerative conditions.”

Co-first author of the study, Dr Mena Farag (UCL Huntington’s Disease Research Centre) added: “These findings are particularly timely as the HD therapeutic landscape expands and progresses toward preventive clinical trials.”

Funding for this work is from the Wellcome Trust and CHDI Foundation. Professor Sarah Tabrizi will be discussing this research and its implications with Jenna Heilman from the HD Youth Organisation in a film ‘Breaking Down Barriers’ released on Thursday 21st January.

Want to learn more?

Find out more. Email HD-YAS - HD-YASUCLTeam@live.ucl.ac.uk

Links:  Scahill-Farag et al., Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington's disease decades before clinical motor diagnosis. Nature Medicine. Available online: https://www.nature.com/articles/s41591-024-03424-6