Timing of selective basal ganglia white matter loss in premanifest Huntington’s disease

Paul Zeun,Peter Mccolgan,Thijs Dhollander,Sarah Gregory,Eileanoir B Johnson,Marina Papoutsi,Akshay Nair,Rachael I Scahill,Geraint Rees,Sarah J Tabrizi

doi:10.1016/j.nicl.2021.102927

Abstract

ObjectivesTo investigate the timeframe prior to symptom onset when cortico-basal ganglia white matter (white matter) loss begins in premanifest Huntington’s disease (preHD), and which striatal and thalamic sub-region white matter tracts are most vulnerable. MethodsWe performed fixel-based analysis, which allows resolution of crossing white matter fibres at the voxel level, on diffusion tractography derived white matter tracts of striatal and thalamic sub-regions in two independent cohorts; TrackON-HD, which included 72 preHD (approx. 11 years before disease onset) and 85 controls imaged at three time points over two years; and the HD young adult study (HD-YAS), which included 54 preHD (approx. 25 years before disease onset) and 53 controls, imaged at one time point. Group differences in fibre density and cross section (FDC) were investigated. ResultsWe found no significant group differences in cortico-basal ganglia sub-region FDC in preHD gene carriers 25 years before onset. In gene carriers 11 years before onset, there were reductions in striatal (limbic and caudal motor) and thalamic (premotor, motor and sensory) FDC at baseline, with no significant change over 2 years. Caudal motor-striatal, pre-motor-thalamic, and primary motor-thalamic FDC at baseline, showed significant correlations with the Unified Huntington’s disease rating scale (UHDRS) total motor score (TMS). Limbic cortico-striatal FDC and apathy were also significantly correlated. ConclusionsOur findings suggest that limbic and motor white matter tracts to the striatum and thalamus are most susceptible to early degeneration in HD but that approximately 25 years from onset, these tracts appear preserved. These findings may have importance in determining the optimum time to initiate future disease modifying therapies in HD.

Highlights

Huntington’s disease (HD) is a neurodegenerative condition caused by a trinucleotide repeat expansion in the huntingtin gene
By using detailed tractography-based striatum and thalamus connectivity atlases, we show that specific basal ganglia sub-region white matter tracts are more susceptible in premanifest Huntington’s disease (preHD)
Our findings indicate that there is no detectable developmental abnormality in the microstructure of corticostriatal and cortico-thalamic white matter tracts in preHD, using novel fixel-based diffusion Magnetic resonance imaging (MRI) (dMRI) analysis, which has been shown to be more sensitive to neurodegeneration of white matter in Alzheimer’s disease (Mito et al, 2018) when compared to standard diffusion tensor imaging (DTI) approaches

Summary

Introduction

Huntington’s disease (HD) is a neurodegenerative condition caused by a trinucleotide repeat expansion in the huntingtin gene. This results in degeneration of the cortico-basal ganglia white matter circuits resulting in progressive motor, cognitive and neuropsychiatric distur bance (McColgan and Tabrizi, 2018). The basal-ganglia shows some of the earliest changes in premanifest (preHD), with loss of striatal grey matter grey matter (Tabrizi et al, 2011) and white matter (McColgan et al, 2015) occurring 15 years. In manifest HD diffusion tractography (Bohanna et al, 2011; Marrakchi-Kacem et al, 2013) and anatomically based parcellations (Douaud et al, 2009) of striatal grey matter show group differences in cognitive and motor sub-regions.

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