In vivo evidence for the selective subcortical degeneration in Huntington's disease

Abstract

Although Huntington's disease is largely considered to be a subcortical disease, there is no clear consensus on whether all deep grey matter loss is a direct downstream consequence of the massive degeneration of the medium-size spiny neurons in the striatum. Our aim was to characterise in vivo such preferential degeneration by analysing various distinct diffusion imaging measures including mean diffusivity, anisotropy, fibre orientation (using the information of the principal diffusion direction) and white matter tractography.All results converged to demonstrate the selective degeneration of connections in subcortical grey and white matter, degeneration which was likely to originate with the death of the striatal medium-size spiny neurons. Indeed, we found a significant increase of MD and FA in all the subcortical grey matter structures involved in the cortico-striato-thalamo-cortical loops. The atypical striatal and pallidal increase of FA was concurrent to a decrease of the dispersion of the fibre orientation, unambiguously characterising a preferential loss of connections along specific radiating directions from these structures while some others are comparatively spared. Analysis of striatal and pallidal white matter tracts revealed that striato-pallidal projections were the most affected. The ability of DTI to uncover the impact of such neurodegenerative disease on some specific neuronal/axonal populations is a further step towards the future definition of a surrogate marker of this disease. Beyond Huntington's disease, we prove here that diffusion imaging technique, associated to adequate methodological analyses, can provide insight into any neurodegenerative disorder for which some neuronal populations or connections are selectively targeted over others.

Cortical Metabolites as Biomarkers in the R6/2 Model of Huntington's Disease

“…Manual segmentation of the images using commercially available software was sufficient to extract volume measurements and achieve accuracy for large structures. By 12 weeks, volume loss was detectable in subcortical regions consistent with stereological and voxel-based morphometry studies (Kremer et al, 1990;Stack et al, 2005;Douaud et al, 2009).…”

The Corticospinal Tract in Huntington's Disease

“…Nevertheless, although these studies were valuable, they provided only a limited assessment of the CST because they used a whole brain or region of interest approach, with limited DTI parameters. Interestingly, an earlier DTI study showed a selective degeneration in the subcortical gray matter which lead to an increase in FA because of the hypothesized increased orientation of the fibers (Douaud et al 2009). Although our analysis of the CST also showed degeneration, our FA result was in the opposite direction, which emphasizes the importance of caution when interpreting diffusion data (Jones et al 2013).…”

Natural biological variation of white matter microstructure is accentuated in Huntington's disease

“…Diffusivity is an indirect marker of white matter tract organization. Increases of diffusivity across both the whole brain and in select white matter pathways, such as within the sensorimotor network, are suggestive of white matter degeneration in premanifest (preHD) and early manifest HD (Della Nave et al, 2010; Douaud et al, 2009; Dumas et al, 2012; Klöppel et al, 2008; Matsui et al, 2014; Novak et al, 2014; Odish et al, 2015; Poudel et al, 2014, 2015). In a recent study of the sensorimotor network, we observed a broad structural HD phenotype that encompassed gray and white matter volume, cortical thickness, and altered diffusivity in left white matter tracts in the sensorimotor network, which was associated with CAG repeat length (Orth et al, 2016).…”