Researchers at University College London and collaborating institutions have uncovered early brain changes in individuals with the Huntington's disease (HD) gene expansion, potentially occurring two decades before the onset of motor symptoms. The study, published in Nature Medicine, highlights the importance of somatic CAG repeat expansion in driving these early neuropathological changes.
The study involved over 150 participants, including individuals with the HD gene expansion and a control group. Participants underwent comprehensive assessments, including clinical measures, MRI brain scans, and analysis of spinal fluid biomarkers, over a 4.5-year period. The research team categorized participants with the HD gene expansion using the HD Integrated Staging System (HD-ISS), which defines stages based on the presence of the HD gene (Stage 0), early brain scan changes (Stage 1), and noticeable changes in movement and thinking (Stage 2).
Early Biomarkers of Disease Progression
While cognitive skills and mental health remained stable in HD gene expansion carriers, subtle changes were detected through MRI and spinal fluid analysis. Researchers observed decreases in the size of the striatum, a brain region affected early in HD, even in individuals 20 years away from expected clinical diagnosis. Furthermore, levels of neurofilament light chain (NfL), a marker of brain health, were elevated in the spinal fluid of HD gene carriers, while levels of proenkephalin (PENK), a marker associated with healthy medium spiny neurons, were reduced.
Somatic Expansion and Brain Changes
The study established a direct link between somatic CAG repeat expansion, measured in blood, and early brain changes. Somatic expansion refers to the phenomenon where the CAG repeat number increases in certain cell types over time. The rate of somatic expansion in blood correlated with brain volume changes and levels of NfL and PENK biomarkers. According to Professor Sarah Tabrizi from UCL, "Our study underpins the importance of somatic expansion driving the earliest neuropathological changes of the disease in living humans carrying the HD genetic expansion."
Implications for Future Trials
These findings have significant implications for the development of preventative treatments for Huntington's disease. Identifying early markers of disease progression, such as NfL, PENK, and somatic CAG expansion, allows for the design of clinical trials in pre-symptomatic individuals. Treatments aimed at suppressing somatic CAG repeat expansion are currently in development, and this research validates this approach as a promising therapeutic target. As stated by Dr. Rachael Scahill (UCL Huntington's Disease Research Centre and UCL Queen Square Institute of Neurology), the study provides "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."
