Distribution of grey matter atrophy in Huntington’s disease patients: A combined ROI-based and voxel-based morphometric study
Introduction
Huntington’s disease (HD) is a lethal autosomic dominant degenerative disease resulting from an expansion of a CAG repeat within the IT15 gene on chromosome 4. The striatum is known to be the principal affected structure in HD patients. Indeed, the post mortem analysis of brain serial sections, providing the first measurements of neuropathological changes in Huntington’s disease, demonstrated marked atrophy of the striatum (de la Monte et al., 1988, Lange et al., 1976). Besides, Vonsattel et al. (1985) showed that this striatal atrophy displayed a dorso-ventral gradient, and established a 5-point grading scale that has become the gold standard for neuropathological classification of HD. In this study, they found no discernible gross or microscopic neuropathological abnormalities in several cases of clinically diagnosed Huntington’s disease. These cases were therefore labeled as ‘grade 0’. Nevertheless, a recent whole-brain magnetic resonance imaging study has shown significant grey matter loss in the striatum of asymptomatic gene-positive subjects (Thieben et al., 2002). This suggests that striatal atrophy is an early marker of the neurodegenerative process in subjects carrying the HD mutation. Furthermore, it confirms that the measurement of striatal atrophy is relevant to monitor disease progression and therefore to identify the potential action of new treatments aiming to slow disease progression (Bloch et al., 2004) or at replace degenerated neurones (Bachoud-Lévi et al., 2000). The bicaudate ratio is the technique most commonly used to assess striatal atrophy in HD patients’ in vivo images. This ratio is defined as the distance between the heads of the caudate nuclei at their narrowest separation as a percentage of the width of the brain along the same line. This method is, however, not satisfactory as it only takes into account unidimensional changes in a single structure of the striatum, the head of caudate. Moreover, although the striatum is the main target of the neurodegenerative process, the mutation is distributed ubiquitously and several studies have reported the occurrence of atrophy in other subcortical and cortical regions in carriers of the HD mutation, either symptomatic or not (Kassubek et al., 2004, Rosas et al., 2003, Thieben et al., 2002). The quantification of atrophy in Huntington’s disease subjects should therefore make use of imaging tools assessing whole-brain changes in three dimensions.
Voxel-based morphometry (VBM) permits an automated voxel-wise whole-brain statistical comparison of MRI scans using the statistical parametric mapping (SPM) software (Wellcome Department of Cognitive Neurology, London) (Ashburner and Friston, 2000). As such, VBM could afford clinicians of HD a unique biomarker, unbiased, reproducible and sensitive to infra-clinical manifestations (Thieben et al., 2002), which could both assess disease progression from an asymptomatic stage and refine inclusion criteria for experimental treatment protocols. However, VBM was not originally designed for the analysis of subcortical structures. In addition, even at an early stage of the disease, the deep brain regions already show severe deformations that may hamper the automatic processing of VBM analysis.
The aim of this work is therefore to validate the use of VBM for the quantification of subcortical atrophy in early HD patients, by comparison with regions of interest (ROI)-based morphometric measurements. More precisely, we investigated whether these two techniques provided similar results and whether they reproduced the data obtained in previous post mortem studies.
Section snippets
Methods
This study was part of the MIG-HD (Multicentric Intracerebral Grafting in Huntington’s Disease) project and was approved by the ethics committee of Henri Mondor Hospital in Créteil. All subjects gave written informed consent.
Improvement of the MRI acquisition sequence
Improvement of the T1-weighted sequence facilitated the manual segmentation because the outlines of several structures, including the posterior putamen, the globus pallidus and the thalamus, appeared more clearly. This sequence improvement also allowed the visualisation of the globus pallidus, which was not visible in all patients with the standard acquisition sequence (Fig. 7). Finally, it came out that this improvement also benefited to the automated segmentation in the optimised VBM
Discussion
This is the first study comparing two different methods for quantifying the atrophy of subcortical grey nuclei associated with Huntington’s disease: a manual segmentation and the voxel-based morphometry. These two approaches were previously compared in Alzheimer’s disease and schizophrenia but showed some discrepancies in the results concerning the presence or the significance of volume reductions in cortical grey matter (Giuliani et al., 2005, Good et al., 2002, Testa et al., 2004). We show
Conclusion
This is the first study comparing a manual ROI-based approach and optimised VBM for the quantification of subcortical atrophy in Huntington’s disease patients. Although VBM involves spatial deformation to register all the scans into a common space, it happens to correctly handle the principal distortions in the subcortical grey nuclei and ventricles. We thus find that if both techniques provide comparable results, the optimised VBM method presents several advantages. This method is indeed less
Acknowledgments
We thank Jean-François Mangin at the Service Hospitalier Frédéric Joliot for providing helpful advice and comments. This study is part of the MIG-HD program and is supported by the Délégation Régionale à la Recherche Clinique (PHRC AOM0039), the Association Française contre les Myopathies and the Etablissement Français des Greffes.
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