Quantitative Studies in Choreaacanthocytosis 21 Voxel Based Morphometry in Choreaacanthocytosis

In contrast to predefined ROI analysis, voxel based morphometry (VBM) is a whole brain-based statistical approach to compare volumes of the complete imaging data set on a voxel basis as described by Ashburner and Friston [3]. VBM offers the possibility of exploring regional brain changes unconstrained by a-priori hypotheses about affected structures by comparing patient brains with normal controls.

Volumetric data were analyzed from six ChAc patients (five male and one female, median age: 37, range: 26-44 years) with a genetically confirmed diagnosis [12]. Disease duration, defined as time since onset of first motor symptoms, was 13 (range: 6-18) years. As an a priori hypothesis, changes were expected to be localized in the striatum, in accordance with the results of former imaging studies. Three-dimensional T1-weighted high-resolution volume-rendering MRI scans were acquired at the Clinical Center, National Institutes of Health (Bethesda, MD, USA), using a 1.5 Tesla MRI scanner and a 3D magnetization prepared rapid gradient echo pulse sequence (MP-RAGE). As the standard tool, the Statistical Parametric Mapping software (SPM Wellcome Department of Imaging Neuroscience Group, London UK.; http//www.fil.ion.ucl.uk/spm) was used. The processing of the imaging data included normalization to the 3D-stereotaxic Montreal Neurological Institute (MNI) standard space, automated segmentation into the compartments of grey matter, white matter and cerebrospinal fluid and smoothing with a 6 mm isotropic Gaussian kernel. The grey matter maps of the patients and 15 age-matched healthy controls were statistically compared voxel-by-voxel in a parametric group analysis to detect differences of grey matter density. Data were thresholded at p < 0.001, and a correction for small volumes was performed.

The relative global brain volume was estimated by calculation of the brain parenchymal fraction (BPF) as described by Kassubek et al. [6, 15]. Different tissue densities were automatically separated into grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF). The BPF is defined as the ratio of brain parenchymal volume (GM and WM) to total brain volume. In the group-comparison of the mean BPF of the six ChAc patients with age-matched controls, no significant reductions of brain volume was found (0.817 vs. 0.837). However, in two of the patients a reduction of more than two standard deviations was detected. Their mean disease duration did not differ significantly from the other four patients (12 vs. 16.7). In summary, this argues against a gross general brain atrophy in the first years of the disease.

In the VBM component of this study, regional atrophy was found almost exclusively in the head of the caudate nucleus (Figs. 1 and 2). The global maxima were

Fig. 1 Overlay of significant atrophic areas of the group analysis on a patient's brain demonstrating alterations in the caudate nucleus bilaterally (crosshair indicating the global maximum. Z-score is indexed by the greyscale)

Fig. 1 Overlay of significant atrophic areas of the group analysis on a patient's brain demonstrating alterations in the caudate nucleus bilaterally (crosshair indicating the global maximum. Z-score is indexed by the greyscale)

Fig. 2 Maximum intensity projection of all areas with significantly decreased grey matter in the SPM group analysis, overlain on the SPM glass brain template localized nearly symmetrically in the head of the caudate nucleus at the Talairach coordinates x,y,z: -8,12,4 and 9,12,4. Z-scores of the global maxima were 5.46 and 5.37, respectively, showing a robust result. Symmetry was shown by the limitation of side difference of the size of the significant voxel clusters to less than 10%. No areas of increased grey matter density were found. The use of a less significant threshold with an uncorrected P < 0.05 led to greater cluster volumes but did not include other cerebral structures, underlining the robustness of the results.

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