Abstract
Huntington's disease (HD) is an inherited, autosomal dominant disorder that is characteristically thought of as a degenerative disorder. Despite cellular and molecular grounds suggesting HD could also impact normal development, there has been scarce systems-level data obtained from in vivo human studies supporting this hypothesis. Sulcus-specific morphometry analysis may help disentangle the contribution of coexisting neurodegenerative and neurodevelopmental processes, but such an approach has never been used in HD. Here, we investigated cortical sulcal depth, related to degenerative process, as well as cortical sulcal length, related to developmental process, in early-stage HD and age-matched healthy controls. This morphometric analysis revealed significant differences in the HD participants compared with the healthy controls bilaterally in the central and intra-parietal sulcus, but also in the left intermediate frontal sulcus and calcarine fissure. As the primary visual cortex is not connected to the striatum, the latter result adds to the increasing in vivo evidence for primary cortical degeneration in HD. Those sulcal measures that differed between HD and healthy populations were mainly atrophy-related, showing shallower sulci in HD. Conversely, the sulcal morphometry also revealed a crucial difference in the imprint of the Sylvian fissure that could not be related to loss of grey matter volume: an absence of asymmetry in the length of this fissure in HD. Strong asymmetry in that cortical region is typically observed in healthy development. As the formation of the Sylvian fissure appears early in utero, and marked asymmetry is specifically found in this area of the neocortex in newborns, this novel finding likely indicates the foetal timing of a disease-specific, genetic interplay with neurodevelopment.
Highlights
Cortical sulcal analysis has for long solely relied on the empirical description of the cortical foldings investigated post mortem (Dareste, 1852; Broca, 1878)
While most of the measures that differed between the two populations were atrophy-related, showing shallower sulci in Huntington's disease (HD) (8 out of 9 of the significant findings), one measure could not be related to loss of grey matter volume seen in this neurodegenerative disorder: the length of the left posterior Sylvian fissure
As the length of the left posterior Sylvian fissure seemed to be a hallmark of abnormal asymmetry in HD, we further investigated within this group if it was associated with their striatal volumetric asymmetry, as measured using careful manual segmentation of the subcortical structures (Douaud et al, 2006)
Summary
Cortical sulcal analysis has for long solely relied on the empirical description of the cortical foldings investigated post mortem (Dareste, 1852; Broca, 1878). We expected that sulcal morphometry analysis might reveal evidence for coexisting abnormal degenerative and developmental processes, in line with the duality, observed for the mutant protein, of both gain-of-function and loss-of-function (effects which are in turn thought to play a distinct role in brain degeneration and abnormal development respectively) (Marder and Mehler, 2012) As this exploratory, yet region-of-interest based approach provides information on the shape of sulci complementary to information obtained with voxelwise techniques, we anticipated that it should in particular detect subtle abnormalities not identified using an approach such as VBM (Mangin et al, 2004; Douaud et al, 2006) and that it might, crucially, reveal novel abnormalities related to altered neurodevelopment in HD
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