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.

The structural correlates of functional deficits in early huntington's disease

“…We also found increased FA and MD in the caudate nucleus and the putamen bilaterally, in line with the higher MD [Douaud et al, 2009;Henley et al, 2009;Mascalchi et al, 2004] and FA [Douaud et al, 2009] reported in both HD and presymptomatic gene carriers [Rosas et al, 2006]. FA increase in the striatum and globus pallidus was attributed to a decreased dispersion of fiber orientation, with a preferential loss of connections along specific radiating directions from the striatum while other fibers were relatively spared [Douaud et al, 2009].…”

Brain Diffusivity and Structural Changes in the R6/2 Mouse Model of Huntington Disease

“…Despite the structural changes in HD tissue, we have not seen a significant change in the diffusion anisotropy among matched axes between HD and WT mice. In contrast, other studies report an increased FA in the GP (Douaud et al, 2009;Antonsen et al, 2013). Douaud and colleagues (2009) proposed that increased FA in striatal gray matter structures is due to the loss of efferent fibers, which in turn leads to increased coherence.…”

“…A number of quantitative magnetic resonance (MR) studies on HD patients and mouse models of HD have used diffusion-weighted magnetic resonance (DW-MR) for assessing gray matter changes (Rosas et al, 2006;Seppi et al, 2006;Douaud et al, 2009;Sanchez-Castaneda et al, 2013), with more and less inconsistent results. DW-MR describes the molecular aspects of water diffusion, which consequently leads to information about tissue microstructure.…”

Functional magnetic resonance imaging of working memory in Huntington's disease: Cross‐sectional data from the IMAGE‐HD study

“…Dumas et al [2012] has observed more widespread microstructural deficits in white matter pathways of the prefrontal cortex in symp-HD. Increased diffusivity in frontal and parietal white matter, together with higher diffusivity in prefrontal afferents to the putamen has also been reported in HD [Douaud et al, 2009]. Moreover, Klö ppel et al [2008] reported reduction of DLPFC projections to posterior parts of the striatum in pre-HD, compared with controls.…”