UCL Queen Square Institute of Neurology


Compensation in Huntington’s disease

17 August 2015

A new measure has been developed which can explicitly characterise compensation in Huntington’s disease (HD) gene-carriers prior to clinical diagnosis. Publishing in EBioMedicine, the research team working on the study hope that identifying patterns of compensation in preclinical HD will not only improve understanding of neural mechanisms underlying HD pathology, but also provide potential targets that can be used in the testing of HD therapeutics.

HD is a neurodegenerative disease and despite considerable neuronal loss, preclinical HD gene-carriers are able to maintain normal behavior during many motor and cognitive tasks. This suggests that some form of compensation is taking place which enables those in the early stages of the disease to function normally. However, until now, there has been no experimentally-testable model of compensation to investigate this.

The international team of scientists from the Department of Neurodegenerative Disease and the Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, UCL Institute of Cognitive Neuroscience, Albert Ludwigs University of Freiburg, University Hospital Salpêtrière Paris, University of Leiden, University of British Columbia, University of Ulm, University of Iowa, and Monash University Melbourne and the CHDI Foundation have developed a new model which uses functional and structural Magnetic Resonance Imaging (MRI) to investigate potential compensatory associations between behaviour and brain activity in preclinical HD patients. Using variability in levels of brain atrophy to mark disease severity, the research team have shown that in those HD gene-carriers with the most significant neuronal loss there is localised compensation in the right hemisphere during cognitive processing, while comparable function in the left hemisphere appears to deteriorate.

In demonstrating hemisphere-specific compensation in preclinical HD gene-carriers, we have provided potential targets for the future planned testing of disease modifying agents in the preclinical phases of HD where it may be important to monitor for preservation of compensatory activity. Professor Sarah Tabrizi, Huntington’s Disease Research Group, UCL Institute of Neurology

Furthermore, as HD is caused by a single gene mutation and fully heritable, it is an ideal model for studying not only the earliest stages of HD, but neurodegeneration generally, as it possible to predict who will develop the disease many years before symptom onset.

By using this model we can gain insight into the more common protein-misfolding neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, which are largely sporadic and are therefore much more challenging to study in the preclinical phases.Professor Tabrizi

This ability to measure compensatory mechanisms within neurodegenerative disease and track disease progression in the preclinical phase provides a unique opportunity to design and evaluate therapies that can be initiated prior to symptom onset.

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