Voxel-based morphometry detects patterns of atrophy that help differentiate progressive supranuclear palsy and Parkinson's disease
Introduction
Progressive supranuclear palsy (PSP) is a neurodegenerative condition which in its classical form presents with postural instability and falls, a supranuclear gaze palsy with early abnormalities of saccadic eye movements, symmetrical bradykinesia, and axial rigidity Lees, 1987, Steele et al., 1964. PSP is characterized pathologically by the presence of tau-positive neurofibrillary tangles, neuropil threads, tufted astrocytes and oligodendroglial coiled bodies in brainstem structures, including the midbrain, cerebellum, and basal ganglia as well as premotor and motor cortical areas (Verny et al., 1996). In the early stages or when the disease is atypical, it can be difficult to distinguish from other neurodegenerative diseases such as multiple system atrophy (MSA), corticobasal degeneration (CBD), and Parkinson's disease (PD).
Various imaging techniques have been used to study PSP and its clinical differentials. Early studies using MRI highlighted signal change and atrophy in the putamen and midbrain as well as an increase in third ventricular size as markers of the disease Drayer et al., 1986, Savoiardo et al., 1994. More recent cross-sectional imaging studies have retrospectively tested the use of these measures as potential aids to diagnosis Schrag et al., 2000, Warmuth-Metz et al., 2001. Over 70% of clinically diagnosed PSP cases can be correctly identified using these markers. Diffusion-weighted MRI studies of the basal ganglia can differentiate cases of PD and PSP with a sensitivity of 90% (Seppi et al., 2003).
The majority of imaging studies have relied on visual observations or linear measurements of regions chosen on the basis of previous imaging work or knowledge of the areas pathologically affected at postmortem in PSP. These studies rely on prior assumptions of regional MRI abnormalities, and hence an inherent bias is introduced by selecting a limited number of brain regions for study.
An MRI comparison of the local composition of different brain tissue types prioritizes a measure of structural differences between subjects. Voxel-based morphometry (VBM) is an unbiased technique designed to detect statistically significant differences in these tissues between subject groups (Ashburner and Friston, 2000). VBM removes positional and global volume differences through spatial normalization and then detects differences in tissue density by comparing local intensities of tissue after smoothing. VBM avoids some of the shortcomings of other methods by being operator-independent and semiautomated, hence avoiding a priori assumptions as to which brain areas should be assessed. VBM has recently demonstrated frontal atrophy in PSP when compared to healthy controls (Brenneis et al., 2004). No studies comparing PSP to another bradykinetic rigid syndrome have been undertaken, and the potential application of VBM results in clinical practice has not been explored. Our first objective was to apply VBM analysis of MRI in PSP and PD to study the morphological alterations in PSP- and PD-affected brains in vivo.
While VBM is cited as supportive of region of interest studies Maguire et al., 2000, Vargha-Khadem et al., 1998 and as a method of identifying affected brain areas with a view to new avenues of research, the clinical utility of VBM findings in bradykinetic rigid syndromes has not been evaluated. Our second objective was to apply the VBM findings as a guide to neuroradiological distinction of PSP from PD and controls.
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Subjects
Twelve patients with PSP (eight clinically definite and four clinically probable) according to the NINDS criteria (Litvan et al., 2003) and twelve patients with Parkinson disease (PD), according to the Queen Square brain bank clinical criteria (Gibb and Lees, 1988), were included in the study as well as twelve controls with no history of neurological illness. The groups were age- and sex-matched. Subjects underwent a detailed clinical assessment including a UPDRS (Cubo et al., 2000) evaluation,
Subjects
The mean ages of the PSP, PD, and control groups were not significantly different; neither was the male to female ratio (see Table 1). The disease duration was significantly longer in the PD group than in the PSP group (P = 0.001). The FAB scores were significantly lower in the PSP than in the PD group (P < 0.001). There was no significant difference in scores on the MMSE, the UPDRS II, or the UPDRS III between the PD and PSP subjects (see Table 1).
VBM
All results are for analysis carried out using
Discussion
To our knowledge, this is the first study using VBM to demonstrate differences in atrophy patterns between PSP and PD as well as normal age-matched controls, suggesting that the changes are relatively specific for PSP. VBM revealed significant group differences with a reduction in gray and white matter in the region of the subthalamic nucleus, midbrain, and cerebral peduncles, particularly evident in the PSP subjects, fitting with the known distribution of pathology in PSP. Review of the
Acknowledgements
DCP is supported by a grant from the PSP (Europe) Association; the imaging work is supported by a grant from the PSP (Europe) Association. NCF holds a MRC Senior Clinical Fellowship.
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