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

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

Subtle changes in the brain, detectable through advanced imaging, blood and spinal fluid analysis, occur approximately twenty years before a clinical motor diagnosis in people with Huntington's disease, a new study led by UCL researchers suggests.

The research, published inNatural medicinewas in collaboration with experts at the universities of Glasgow, Gothenburg, Iowa and Cambridge.

The team found that functions such as movement, thinking or behavior remained normal long before the onset of symptoms in Huntington's disease, but subtle brain changes took place up to two decades before that.

These results pave the way for future preventive clinical trials, offering hope for earlier interventions that could preserve brain function and improve outcomes for people at risk of developing Huntington's disease.

Huntington's disease is a devastating neurodegenerative disease that affects movement, thinking and behavior. It is a genetic disease, and people with an affected parent have a 50% chance of inheriting the Huntington's disease mutation, meaning they will develop symptoms of the disease - typically mid-presidency.

The disease is caused by repeated expansions of three DNA blocks (c, a and g) in theHuntingtinGene. This sequence tends to expand continuously in certain cells throughout a person's life, in a process known as somatic CAG expansion. This ongoing expansion accelerates neurodegeneration and makes brain cells more vulnerable over time.

For the new study, researchers looked at 57 people with the expansion of the Huntington's disease gene, calculated on average 23.2 years after a predicted clinical motor diagnosis.

They were examined twice over about five years to see how their bodies and brains changed over time. Their results were compared to 46 control participants closely matched on age, gender and education level.

As part of the study, all participants volunteered to undergo comprehensive assessments of their thinking, movement and behavior, as well as their brain scan and blood and spinal fluid samples.

Importantly, the expansion of the HD gene group during the study period showed no decline in clinical function (thinking, movement, or behavior) compared to the closely matched control group.

However, subtle changes were detected in brain scans and spinal fluid biomarkers of those with HD compared to the control group. This suggests that the neurodegenerative process occurs long before symptoms are 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 reduced levels of prorenkephalin (PENK), a neuropeptide marker of healthy neuron state that may reflect changes in the brain response to neurodegeneration.

Our study supports the importance of somatic CAG repeat expansion driving the earliest neuropathological changes of the disease in humans with the HD expansion of the HD gene. I would like to thank the participants in our young adult study for their dedication and commitment over the past five years, we hope to make clinical trials to prevent Huntington's disease a reality in the next few years. “

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

The results suggest that there is a treatment window, potentially decades before symptoms are present, at risk of developing the disease and functioning normally, despite evidence of subtle, early neurodegeneration. Identifying these early disease markers is essential for future clinical trials to determine whether a treatment has an effect.

The study's co-first author, Dr. Rachael Scahill (UCL Huntington Research Center and UCL Queen Square Institute of Neurology), said: “This unique cohort of people with the HD expansion and control participants provides us with unprecedented insights into the very earliest disease processes, before the onset of clinical symptoms, which is relevant not only to HD but also to others neurodegenerative diseases such as Alzheimer's disease. “

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 the clinical motor diagnosis in Huntington's disease.

While somatic CAG expansion was already known to accelerate neurodegeneration, this research shows how it actively responds to the earliest detectable changes in the brain in the caudate and putamen, regions critical for movement and thought.

By showing that somatic CAG expansion changes measured in blood predict brain volume changes and other neurodegeneration markers, the results provide crucial evidence to support the hypothesis that somatic CAG expansion is an important driver of neurodegeneration.

With treatments to suppress CAG somatic repeat expansion currently in development, this work validates this mechanistic process as a promising therapeutic target and represents a critical advance toward future prevention attempts in Huntington's disease.

Dr. Mena Farag (UCL Huntington's Disease Research Center and UCL Queen Square Institute of Neurology), the study's co-first author, added: "These results are particularly timely as the HD therapeutic landscape is expanding and moving towards preventative clinical trials."

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

Professor Sarah Tabrizi discuss this research and its implications for Jenna Heilman of the HD Youth Organization (HDYO) in a film, “Breaking Barriers,” released on Tuesday, January 21, 2025.

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