Compensation in Preclinical Huntington's Disease: Evidence From the Track-On HD Study

• Published in: EBioMedicine 2015-10, Vol.2 (10), p.1420-1429
• Main Authors: Klöppel, Stefan, Gregory, Sarah, Scheller, Elisa, Minkova, Lora, Razi, Adeel, Durr, Alexandra, Roos, Raymund A.C., Leavitt, Blair R., Papoutsi, Marina, Landwehrmeyer, G. Bernhard, Reilmann, Ralf, Borowsky, Beth, Johnson, Hans, Mills, James A., Owen, Gail, Stout, Julie, Scahill, Rachael I., Long, Jeffrey D., Rees, Geraint, Tabrizi, Sarah J.
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Brain Mapping; Case-Control Studies; Cognitive; Connectome; Female; Heterozygote; Humans; Huntingtin Protein; Huntington Disease - diagnosis; Huntington Disease - genetics; Huntington Disease - pathology; Huntington Disease - physiopathology; Huntington's disease; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Memory, Short-Term; Motor; MRI; Mutation; Nerve Tissue Proteins - genetics; Neural compensation; Preclinical; Psychomotor Performance
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2015.08.002

Cognitive and motor task performance in premanifest Huntington's disease (HD) gene-carriers is often within normal ranges prior to clinical diagnosis, despite loss of brain volume in regions involved in these tasks. This indicates ongoing compensation, with the brain maintaining function in the presence of neuronal loss. However, thus far, compensatory processes in HD have not been modeled explicitly. Using a new model, which incorporates individual variability related to structural change and behavior, we sought to identify functional correlates of compensation in premanifest-HD gene-carriers. We investigated the modulatory effects of regional brain atrophy, indexed by structural measures of disease load, on the relationship between performance and brain activity (or connectivity) using task-based and resting-state functional MRI. Consistent with compensation, as atrophy increased performance-related activity increased in the right parietal cortex during a working memory task. Similarly, increased functional coupling between the right dorsolateral prefrontal cortex and a left hemisphere network in the resting-state predicted better cognitive performance as atrophy increased. Such patterns were not detectable for the left hemisphere or for motor tasks. Our findings provide evidence for active compensatory processes in premanifest-HD for cognitive demands and suggest a higher vulnerability of the left hemisphere to the effects of regional atrophy. •Huntington's disease (HD) is an ideal model for studying the earliest stages of neurodegeneration.•Pre-clinical HD gene-carriers maintain normal behavior across motor and cognitive domains despite neuronal degeneration.•We characterized neural compensation using functional MRI in combination with measures of disease load and task performance.•Evidence of hemisphere-specific compensation provides potential targets for future therapeutic trials in neurodegeneration. We have developed a model which characterizes compensation in preclinical HD using functional MRI, volumetric disease load and task performance. By explicitly testing the relationship between cognitive performance and brain activity or connectivity, we have demonstrated that those closest to clinical diagnosis experience functional deterioration within the left hemisphere of the brain and localized compensation in the right. This pattern provides potential targets for future testing of HD modifying agents. Furthermore, HD acts as a model for studying th