Elsevier

NeuroImage

Volume 32, Issue 4, 1 October 2006, Pages 1562-1575
NeuroImage

Distribution of grey matter atrophy in Huntington’s disease patients: A combined ROI-based and voxel-based morphometric study

https://doi.org/10.1016/j.neuroimage.2006.05.057Get rights and content

Abstract

The striatum, a subcortical structure, is the principal target of the neurodegenerative process in Huntington’s disease (HD). The measurement of striatal atrophy using the bicaudate ratio on CT scanner images has therefore been used for years to assess disease progression, but this measure only takes into account unidimensional changes in the head of the caudate nucleus. Recently, voxel-based morphometry (VBM), which permits automated statistical comparisons of whole-brain MRI images, has been proposed to quantify striatal atrophy. However, VBM was not originally designed to study subcortical structures, and severe deep brain deformations that occur in HD may hamper the automatic processing of VBM. Here, we validate the use of the optimised protocol of VBM to quantify subcortical atrophy in HD by comparing results obtained with this method to those provided by manual segmentation of subcortical structures. We studied 20 patients with early HD and 12 controls matched for age, sex and handedness using an improved T1-weighted sequence that eased grey matter segmentation. Both manual and automated methods evidenced the dorso-ventral gradient of striatal atrophy, a loss of grey matter in the globus pallidus and the thalamus, and similar correlations between clinical scores and subcortical atrophy. Furthermore, we were able to detect with VBM grey matter loss in the substantia nigra, the hypothalamus, the amygdala, the insular cortex and the premotor and sensorimotor cortices. Finally, VBM provided results consistent with previous post mortem results and proved to be a sensitive biomarker capable of correctly managing subcortical distortions throughout HD patients’ brains.

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.

References (55)

  • G.M. Halliday et al.

    Regional specificity of brain atrophy in Huntington’s disease

    Exp. Neurol.

    (1998)
  • P.Y. Herve et al.

    Finger hand-arm, handedness and grey matter amount in the Rolando’s genu area

    NeuroImage

    (2005)
  • T.L. Jernigan et al.

    Cerebral structure on MRI: Part II. Specific changes in Alzheimer’s and Huntington’s diseases

    Biol. Psychiatry

    (1991)
  • H.P. Kremer et al.

    The hypothalamic lateral tuberal nucleus and the characteristics of neuronal loss in Huntington’s disease

    Neurosci. Lett.

    (1991)
  • H. Lange et al.

    Morphometric studies of the neuropathological changes in choreatic diseases

    J. Neurol. Sci.

    (1976)
  • A.G. Lasker et al.

    Ocular motor abnormalities in Huntington’s disease

    Vision Res.

    (1997)
  • L.L. Murray et al.

    Productive syntax abilities in Huntington's and Parkinson's diseases

    Brain Cogn.

    (2001)
  • K.A. Sieradzan et al.

    Huntington’s disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein

    Exp. Neurol.

    (1999)
  • R.H. Wurtz et al.

    Role of the basal ganglia in the initiation of saccadic eye movements

    Prog. Brain Res.

    (1986)
  • E.H. Aylward et al.

    Longitudinal change in basal ganglia volume in patients with Huntington’s disease

    Neurology

    (1997)
  • J. Bloch et al.

    Neuroprotective gene therapy for Huntington’s disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study

    Hum. Gene Ther.

    (2004)
  • G.T. Bots et al.

    Neuropathological changes of the nucleus accumbens in Huntington’s chorea

    Acta Neuropathol. (Berl.)

    (1981)
  • M. Brett et al.

    Region of interest analysis using an SPM toolbox

  • A.J. Calder et al.

    Impaired recognition and experience of disgust following brain injury

    Nat. Neurosci.

    (2000)
  • S.M. de la Monte et al.

    Morphometric demonstration of atrophic changes in the cerebral cortex, white matter, and neostriatum in Huntington’s disease

    J. Neuropathol. Exp. Neurol.

    (1988)
  • E. Duchesnay et al.

    Population classification based on structural morphometry of cortical sulci

  • C. Fennema-Notestine et al.

    In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease

    Neurology

    (2004)
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