Brain changes in Huntington’s disease decades before diagnosis will guide future prevention trials

Subtle changes in the brain, detectable through advanced imaging, blood and spinal fluid analysis, happen around twenty years before a clinical motor diagnosis in people with Huntington’s disease, a new study at UCLH and UCL has found.

The findings suggest there is a treatment window, potentially decades before symptoms are present, where those at risk of developing Huntington’s disease are functioning normally despite having detectable measures of early neurodegeneration.

Huntington’s disease is a devastating neurodegenerative condition affecting movement, thinking and behaviour. It is a genetic disease – caused by a mutation to the huntingtin gene – and people with an affected parent have a 50% chance of inheriting this mutation, meaning they will develop disease symptoms – typically in mid-adulthood.

The early markers of disease identified in the study were signs of brain shrinkage in areas that control movement, and changes to certain proteins in the brain which relate to brain health.

Knowing about these early markers will be vital in future research involving people at risk of Huntington’s disease, as these markers can be monitored to determine whether a treatment is having any effect.

The study is the first to show that a process behind the genetic mutation in Huntington’s disease – called somatic CAG repeat expansion, measured in blood – is directly linked with the early markers of disease in the brain. Until now, it was known that somatic CAG repeat expansion was responsible for accelerating neurodegeneration. Now researchers believe it drives early neurological changes.

Lead author, Professor Sarah Tabrizi, said: “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.”

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

The research is published in Nature Medicine.