Multiparametric characterization of white matter alterations in early stage Huntington disease

Isaac M Adanyeguh,Francesca Branzoli,Marie-Lorraine Monin,Alexandra Durr,Fanny Mochel,Cécile Delorme,Emanoel Sabidussi,Aurélie Méneret,Marie-Pierre Luton

doi:10.1038/s41598-021-92532-1

Abstract

Huntington’s disease (HD) is a monogenic, fully penetrant neurodegenerative disorder. Widespread white matter damage affects the brain of patients with HD at very early stages of the disease. Fixel-based analysis (FBA) is a novel method to investigate the contribution of individual crossing fibers to the white matter damage and to detect possible alterations in both fiber density and fiber-bundle morphology. Diffusion-weighted magnetic resonance spectroscopy (DW-MRS), on the other hand, quantifies the motion of brain metabolites in vivo, thus enabling the investigation of microstructural alteration of specific cell populations. The aim of this study was to identify novel specific microstructural imaging markers of white matter degeneration in HD, by combining FBA and DW-MRS. Twenty patients at an early stage of HD and 20 healthy controls were recruited in a monocentric study. Using diffusion imaging we observed alterations to the brain microstructure and their morphology in patients with HD. Furthermore, FBA revealed specific fiber populations that were affected by the disease. Moreover, the mean diffusivity of the intra-axonal metabolite N-acetylaspartate, co-measured with N-acetylaspartylglutamate (tNAA), was significantly reduced in the corpus callosum of patients compared to controls. FBA and DW-MRS of tNAA provided more specific information about the biological mechanisms underlying HD and showed promise for early investigation of white matter degeneration in HD.

Highlights

Huntington’s disease (HD) is a monogenic, fully penetrant neurodegenerative disorder
Most studies have reported reduced fractional anisotropy (FA) and elevated mean diffusivity (MD) in the white matter (WM) of patients with HD compared to controls, suggesting axonal degeneration
In order to achieve a specific in vivo characterization of WM axonal pathology in patients with HD, we applied for the first time in this disease two innovative methods – Fixel-based analysis (FBA) and Diffusion-weighted magnetic resonance spectroscopy (DW-MRS)

Summary

Introduction

Huntington’s disease (HD) is a monogenic, fully penetrant neurodegenerative disorder. The aim of this study was to identify novel specific microstructural imaging markers of white matter degeneration in HD, by combining FBA and DW-MRS. FBA and DW-MRS of tNAA provided more specific information about the biological mechanisms underlying HD and showed promise for early investigation of white matter degeneration in HD. Alterations in tissue microstructure evaluated with FBA can be attributed to a reduced amount of intra-axonal volume (fiber density, FD), to a similar fiber density but reduced total area occupied by the axons (fiber-bundle cross-section, FC), or to a combination of both processes (fiber density and cross-section, FDC)[16] This method overcomes the limitations associated with other diffusion MRI approaches that cannot differentiate between multiple fiber populations in a single v oxel[15,17], which is of crucial relevance especially in brain regions with crossing fibers. The diffusion of the intra-neuronal metabolite N-acetylaspartate was suggested as a marker of intra-axonal damage before irreversible loss in multiple s clerosis[21]

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Conclusion