Early brain changes in Huntington’s disease detected two decades before symptoms

Subtle changes in the brain, detectable through advanced imaging, blood and spinal fluid analysis, occur around two decades before a clinical motor diagnosis in people with Huntington’s disease, a new study led by UCL researchers has found.

The research, published in Naturopathywas in collaboration with experts from the universities of Glasgow, Gothenburg, Iowa and Cambridge.

The team found that although functions such as movement, thinking or behavior remained normal for a long time before the symptoms of Huntington’s disease developed, subtle changes occurred in the brain up to 20 years earlier.

These findings pave the way for future preventive clinical trials, offering hope for earlier interventions that can preserve brain function and improve outcomes for individuals at risk for Huntington’s disease.

Huntington’s disease is a devastating neurodegenerative disorder that affects movement, thinking and behavior. It is a genetic disease and people with an affected parent have a 50% chance of inheriting the HD mutation, meaning they will develop symptoms of the disease – usually by mid-adulthood.

The disease is caused by repeated expansions of three DNA blocks (C, A and G) in the DNA hunttine gene. This sequence tends to expand continuously in certain cells throughout a person’s life, in a process known as somatic CAG expansion. This continued expansion accelerates neurodegeneration, making brain cells more fragile over time.

For the new study, researchers studied 57 people with gene expansion for Huntington’s disease, who were calculated to be an average of 23.2 years away from a predicted clinical motor diagnosis.

They were examined at two time points over about five years to see how their bodies and brains changed over time. Their results were compared with those of 46 control participants, who were closely matched for age, gender and education level.

As part of the study, all participants volunteered to undergo extensive assessments of their thinking, movement and behavior, in addition to brain scans and blood and spinal fluid samples.

Importantly, the Huntington’s disease gene expansion group showed no decline in any clinical function (thinking, movement or behavior) during the study period, compared to the closely matched control group.

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

Specifically, the researchers identified increased levels of neurofilament light chain (NfL), a protein released into the spinal fluid when neurons are injured, and decreased levels of proenkephalin (PENK), a neuropeptide marker of the state of healthy neurons that could trigger changes in the brain reflect. response to neurodegeneration.

Our study highlights the importance of somatic CAG repeat expansion driving the earliest neuropathological changes of the disease in living humans with Huntington’s disease gene expansion. I would like to thank the participants in our young adult study because their dedication and commitment over the past five years means that we hope that clinical trials aimed at preventing Huntington’s disease will become a reality in the coming years.”

Professor Sarah Tabrizi, lead author, UCL Huntington’s Disease Research Center and UK Dementia Research Institute at UCL

The findings suggest that there is a treatment period, possibly decades before symptoms manifest, during which those at risk of developing Huntington’s disease function normally despite having detectable measures of subtle, early neurodegeneration. Identifying these early disease markers is essential for future clinical trials to determine whether a treatment has any effect.

Co-first author of the study, Dr. Rachael Scahill (UCL Huntington’s Disease Research Center and UCL Queen Square Institute of Neurology) said: “This unique cohort of individuals with Huntington’s disease gene expansion and control participants provides us with unprecedented insights into the very earliest disease processes prior to the onset of clinical symptoms. , which has implications not only for Huntington’s disease, but also for other neurodegenerative disorders such as Alzheimer’s.”

This study is the first to directly link somatic CAG repeat expansion, measured in blood, and early brain changes in humans, decades before the clinical motor diagnosis in Huntington’s disease.

While somatic CAG expansion was already known to accelerate neurodegeneration, this study shows how it actively drives the earliest observable changes in the brain, particularly in the caudate and putamen, areas crucial for movement and thinking.

By demonstrating that changes in somatic CAG repeat expansion measured in blood predict changes in brain volume and other markers of neurodegeneration, the findings provide crucial evidence supporting 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 crucial advance toward future prevention trials in Huntington’s disease.

Co-first author of the study, Dr Mena Farag (UCL Huntington’s Disease Research Center and UCL Queen Square Institute of Neurology) added: “These findings are particularly timely as the HD therapeutic landscape expands and evolves in the towards preventive clinical trials.”

Funding for this work comes from Wellcome and the CHDI Foundation. The research was also supported by the Biomedical Research Center at UCLH’s National Institute for Health and Care Research (NIHR), and involved UCLH’s NIHR Clinical Research Facility.

Professor Sarah Tabrizi will discuss this research and its implications with Jenna Heilman of the HD Youth Organization (HDYO) in a film ‘Breaking Down Barriers’ released on Tuesday 21 May.^st January 2025.