Multiparametric characterization of white matter alterations in early stage Huntington disease

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.

Figure 1

Diffusion tensor analysis showing altered brain white matter microstructure in patients with HD using tract-based spatial statistics. Reduced fractional anisotropy (FA), increased mean diffusivity (MD) and increased radial diffusivity (RD) were observed in the corpus callosum, sagittal stratum, thalamic radiation bundle, superior longitudinal fasciculus, external and internal capsules, corona radiata, and the cingulum. FA was also reduced in the corticospinal tract, and pontine crossing tract. FA and RD were also altered in the cerebellar and cerebral peduncles. The color bar represents significant regions (p < 0.05) of alterations in DTI metrics.

Figure 2

Fixel-based analysis showing significantly reduced fiber density (FD), fiber bundle cross-section (FC) and fiber density and cross-section (FDC) in patients with HD. Reduction in FD was limited to the corticospinal tract while FC and FDC were significantly reduced in the corticospinal tract, cerebellar peduncles, pontine crossing tracts, internal and external capsules, medial lemniscus, cerebral peduncles, sagittal stratum, and corona radiata. FDC was also reduced in the fornix/stria terminalis and the corpus callosum in patients with HD. Significantly reduced streamlines are directionally colored (red: left–right, green: anterior–posterior, blue: superior-inferior).

Figure 3

Diffusivity of metabolites and the representation of diffusion-weighted magnetic resonance spectroscopy (DW-MRS) acquisition. (a) Average diffusivity of total N-acetylaspartate (tNAA) and total choline (tCho) between patients and controls. Significantly lower average diffusivity of tNAA was observed in patients with HD while no difference in diffusivity was observed in tCho. (b) Position of the 15 × 32 × 8 mm³ voxel for DW-MRS acquisitions in the corpus callosum. (c) Signal attenuation in relation to an increase in the b values used in DW-MRS acquisitions.