A recent study led by researchers at UCL reveals that subtle brain changes can be detected through advanced imaging, blood tests, and spinal fluid analysis roughly twenty years prior to a clinical motor diagnosis in individuals with Huntington’s disease.
Published in Nature Medicine, this research involved collaboration with specialists from the Universities of Glasgow, Gothenburg, Iowa, and Cambridge.
Despite normal functioning in areas like movement, cognition, and behavior for many years before symptoms of Huntington’s disease manifest, the researchers discovered that minor changes in the brain began as much as two decades earlier.
These insights open the door for upcoming preventative clinical trials, providing hope for earlier interventions that could help maintain brain function and enhance outcomes for those at risk of Huntington’s disease.
Huntington’s disease is a severe neurodegenerative disorder that impacts movement, cognitive abilities, and behavior. As a genetic condition, individuals with an affected parent have a 50% chance of inheriting the Huntington’s disease mutation, which typically leads to symptoms appearing in mid-adulthood.
The condition arises from the repetitive expansion of three DNA bases (C, A, and G) in the huntingtin gene. This sequence can expand progressively in certain cells throughout a person’s life, a phenomenon called somatic CAG expansion. Such ongoing expansions contribute to neurodegeneration, making brain cells increasingly susceptible over time.
For this study, the researchers analyzed 57 individuals with the Huntington’s disease gene expansion, who were estimated to be an average of 23.2 years away from a predicted clinical motor diagnosis.
Participants were evaluated at two separate points over the course of about five years to track changes in their bodies and brains. Comparisons were made with a control group of 46 participants closely matched in terms of age, sex, and education level.
All participants voluntarily underwent thorough assessments of their cognitive abilities, movement, and behavior, along with brain scans and samples of blood and spinal fluid.
Significantly, the group with the Huntington’s disease gene expansion did not show any decline in clinical functions (such as thinking, movement, or behavior) during the study period when compared to the closely matched control group.
Nevertheless, the Huntington’s group exhibited detectable changes in brain scans and spinal fluid biomarkers when contrasted with the control group. This suggests that the neurodegenerative process begins considerably ahead of the appearance of symptoms and prior to a clinical motor diagnosis.
Specifically, researchers found increased levels of neurofilament light chain (NfL), a protein released into spinal fluid when neurons are damaged, and decreased levels of proenkephalin (PENK), a neuropeptide marker signaling healthy neuron status that may indicate alterations in the brain’s reaction to neurodegeneration.
Lead author, Professor Sarah Tabrizi from UCL’s Huntington’s Disease Research Centre and the UK Dementia Research Institute, stated: “Our study highlights the crucial role of somatic CAG repeat expansion in driving the earliest neuropathological changes in living humans carrying the Huntington’s disease gene expansion. I extend my gratitude to the participants of our young adult study; their dedication over the last five years brings hope that clinical trials aimed at preventing Huntington’s disease will soon become a reality.”
The findings imply a treatment window that may exist decades before symptoms arise, during which individuals at risk for Huntington’s disease can function normally despite experiencing early, subtle signs of neurodegeneration. Recognizing these early disease markers is vital for future clinical trials to evaluate the effectiveness of treatments.
Co-first author of the study, Dr. Rachael Scahill from UCL’s Huntington’s Disease Research Centre and UCL Queen Square Institute of Neurology, remarked: “This unique cohort of individuals with the Huntington’s disease gene expansion and their control counterparts offers unprecedented insights into the initial disease processes before the onset of clinical symptoms, which may have implications not just for Huntington’s disease but also for other neurodegenerative disorders, such as Alzheimer’s disease.”
This study is the first to establish a clear connection between somatic CAG repeat expansion, as measured in blood, and early brain changes in humans, long before a clinical motor diagnosis for Huntington’s disease.
While it was already known that somatic CAG expansion speeds up neurodegeneration, this research illustrates its active role in triggering the earliest detectable changes in the brain—particularly in the caudate and putamen, which are essential areas for movement and cognition.
By demonstrating that somatic CAG repeat expansion changes in blood predict alterations in brain volume and other neurodegenerative biomarkers, the findings provide crucial evidence that somatic CAG expansion is a significant contributor to neurodegeneration.
With treatments aimed at reducing somatic CAG repeat expansion currently being developed, this research validates this mechanism as a promising therapeutic target, marking an important step toward future prevention trials for Huntington’s disease.
Co-first author Dr. Mena Farag from UCL’s Huntington’s Disease Research Centre and UCL Queen Square Institute of Neurology added: “These findings are especially timely as the landscape for Huntington’s disease therapies expands and progresses toward preventative clinical trials.”
This research was funded by Wellcome and the CHDI Foundation, with support from the National Institute for Health and Care Research (NIHR) Biomedical Research Centre at UCLH, and involved the NIHR Clinical Research Facility at UCLH.
Professor Sarah Tabrizi will discuss this research and its significance with Jenna Heilman from the HD Youth Organisation (HDYO) in a film titled ‘Breaking Down Barriers,’ set to be released on Tuesday, January 21st, 2025.
