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

Stefan Klöppel,James A Mills,Beth Borowsky,G Bernhard Landwehrmeyer,Rachael I Scahill,Ralf Reilmann,Marina Papoutsi,Raymund A.C Roos,Adeel Razi,Elisa Scheller,Geraint Rees,Gail Owen,Lora Minkova,Sarah Gregory,Blair R Leavitt,Jeffrey D Long,Alexandra Dürr ,Hans J Johnson ,Julie C Stout

doi:10.1016/j.ebiom.2015.08.002

Abstract

BackgroundCognitive 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. MethodsWe 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. FindingsConsistent 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. InterpretationOur 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.

Highlights

In neurodegenerative disease, progressive degenerative changes can be detected many years prior to the manifestation of clinical symptoms including cognitive and motor deficits
We developed a measure of neural compensation that takes into account the relationships between behavioral performance and brain activity seen in healthy individuals, and applied it to functional MRI measures of brain activity in a large cohort of over 100 individuals with premanifest-Huntington's disease (HD)
There was a relatively strong and positive relationship between Verbal Working Memory (VWM)-task performance and cortex activity for high structural disease load, but the relationship diminished as structural disease load lightened with the lowest structural disease load showing no relationship

Summary

Introduction

Progressive degenerative changes can be detected many years prior to the manifestation of clinical symptoms including cognitive and motor deficits. In Huntington's disease (HD), a fully penetrant monogenic disorder, individuals far from the onset of overt signs and symptoms demonstrate extensive neuroimaging evidence of subcortical and cortical atrophy Such HD expansion mutation carriers perform to healthy controls on a wide variety of motor and cognitive tests and show minimal longitudinal change in performance (Tabrizi et al, 2011; Papoutsi et al, 2014). 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. Interpretation: 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

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