Dynamics of Cortical Degeneration Over a Decade in Huntington’s Disease

Eileanoir B Johnson,Gabriel Ziegler,William Penny,Geraint Rees,Sarah J Tabrizi,Rachael I Scahill,Sarah Gregory

doi:10.1016/j.biopsych.2020.11.009

Abstract

BackgroundCharacterizing changing brain structure in neurodegeneration is fundamental to understanding long-term effects of pathology and ultimately providing therapeutic targets. It is well established that Huntington’s disease (HD) gene carriers undergo progressive brain changes during the course of disease, yet the long-term trajectory of cortical atrophy is not well defined. Given that genetic therapies currently tested in HD are primarily expected to target the cortex, understanding atrophy across this region is essential. MethodsCapitalizing on a unique longitudinal dataset with a minimum of 3 and maximum of 7 brain scans from 49 HD gene carriers and 49 age-matched control subjects, we implemented a novel dynamical systems approach to infer patterns of regional neurodegeneration over 10 years. We use Bayesian hierarchical modeling to map participant- and group-level trajectories of atrophy spatially and temporally, additionally relating atrophy to the genetic marker of HD (CAG-repeat length) and motor and cognitive symptoms. ResultsWe show, for the first time, that neurodegenerative changes exhibit complex temporal dynamics with substantial regional variation around the point of clinical diagnosis. Although widespread group differences were seen across the cortex, the occipital and parietal regions undergo the greatest rate of cortical atrophy. We have established links between atrophy and genetic markers of HD while demonstrating that specific cortical changes predict decline in motor and cognitive performance. ConclusionsHD gene carriers display regional variability in the spatial pattern of cortical atrophy, which relates to genetic factors and motor and cognitive symptoms. Our findings indicate a complex pattern of neuronal loss, which enables greater characterization of HD progression.

Highlights

Characterizing changing brain structure in neurodegeneration is fundamental to understanding longterm effects of pathology and providing therapeutic targets
We investigated in which regions the Huntington’s disease (HD) patients showed lower volume at the point of diagnosis, and how the rates of atrophy varied across the cortex during this period compared with the control participants
To evaluate how regional brain atrophy might contribute to emerging motor and cognitive symptoms, we extended our HD progression model to a longitudinal brain-behavioral framework (Figures S5A and S6; Supplemental Methods and Materials) including 1) brain volumes, 2) Total Motor Score (TMS) motor assessments [29], and 3) cognitive symptoms evaluated using the Symbol Digit Modalities Test (SDMT) [30] in HD participants only

Summary

Introduction

Characterizing changing brain structure in neurodegeneration is fundamental to understanding longterm effects of pathology and providing therapeutic targets. It is well established that Huntington’s disease (HD) gene carriers undergo progressive brain changes during the course of disease, yet the long-term trajectory of cortical atrophy is not well defined. We use Bayesian hierarchical modeling to map participant- and group-level trajectories of atrophy spatially and temporally, relating atrophy to the genetic marker of HD (CAG-repeat length) and motor and cognitive symptoms. We have established links between atrophy and genetic markers of HD while demonstrating that specific cortical changes predict decline in motor and cognitive performance. CONCLUSIONS: HD gene carriers display regional variability in the spatial pattern of cortical atrophy, which relates to genetic factors and motor and cognitive symptoms. Our findings indicate a complex pattern of neuronal loss, which enables greater characterization of HD progression

Objectives

Methods

Results

Conclusion