Brain changes in Huntington’s disease occur decades before diagnosis

Subtle changes in the brain happen approximately twenty years before a clinical motor diagnosis in people with Huntington’s disease, finds a new study led by Prof Sarah Tabrizi (UK DRI at UCL), in collaboration with experts at the Universities of Glasgow, Gothenburg, Iowa, and Cambridge. The research, published in Nature Medicine, paves the way for future preventative clinical trials, offering hope for earlier interventions that could preserve brain function and improve outcomes for individuals at risk of Huntington’s.

Huntington’s disease is a devastating neurodegenerative condition affecting movement, thinking and behaviour. It is caused by repetitive expansions of three DNA blocks (C, A and G) in the huntingtin gene. This sequence tends to continually expand in certain cells over the lifetime of someone with Huntington’s, in a process known as somatic CAG expansion, which accelerates neurodegeneration, making brain cells more vulnerable over time.

This study is the first to establish a direct link between somatic CAG repeat expansion, measured in blood, and early brain changes in humans, decades before clinical motor diagnosis. While somatic CAG expansion was already known to accelerate neurodegeneration, this research demonstrates how it actively drives the earliest detectable changes in the brain—specifically in the caudate and putamen, regions critical to movement and thinking. 

In the new study, the researchers examined 57 people with the Huntington’s disease gene expansion, who were calculated as being on average 23.2 years from a predicted clinical motor diagnosis.  They were studied at two time points over approximately five years to see how their bodies and brains changed over time. Their results were compared to 46 control participants, matched closely for age, sex and educational level.

All participants underwent comprehensive assessments of their thinking, movement and behaviour, alongside brain scans and blood and spinal fluid sampling. Importantly, the group with Huntington’s disease gene expansion showed no decline in any clinical function (thinking, movement or behaviour) during the study period, compared to the control group. 

However, compared to the control group, subtle changes were detected in brain scans and spinal fluid biomarkers of those with Huntington’s disease gene expansion. This indicates that the neurodegenerative process begins long before symptoms are evident and before a clinical diagnosis. 

The findings suggest that there is a treatment window, where those at risk of developing Huntington’s disease are functioning normally despite having 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.

Prof Tabrizi explained: 

“Our study underpins the importance of somatic CAG repeat expansion driving the earliest neuropathological changes of the disease in living humans with the Huntington’s disease gene expansion. I want to thank the participants in our young adult study as their dedication and commitment over the last five years mean we hope that clinical trials aimed at preventing Huntington’s disease will become a reality in the next few years.”

By showing that somatic CAG repeat expansion changes measured in blood predicts brain volume changes and other markers of neurodegeneration, the findings provide crucial evidence to support the hypothesis that somatic CAG expansion 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 represents a critical advance towards future prevention trials in Huntington’s disease.

Co-first author of the study, Dr Rachael Scahill (UCL) said: 

“This unique cohort of individuals with the Huntington’s disease gene expansion 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 Huntington’s disease but for other neurodegenerative conditions such as Alzheimer’s disease.”

Co-first author of the study, Dr Mena Farag (UCL) added:

“These findings are particularly timely as the Huntington’s disease therapeutic landscape expands and progresses toward preventive clinical trials.”

Funding for this work is from Wellcome and the CHDI Foundation. The research was also supported by staff and facilities from the NIHR UCLH Clinical Research Facility as well as from support from the NIHR UCLH Biomedical Research Centre.

Professor Sarah Tabrizi will be discussing this research and its implications with Jenna Heilman from the HD Youth Organisation (HDYO) in a film ‘Breaking Down Barriers’ released on Tuesday 21 January 2025.

Source: University College London