1 Department of Neurology, University of Ulm, Germany and 2 Department of Nuclear Medicine, University of Bern, Switzerland
Address correspondence to Jan Kassubek, Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany. Email: jan.kassubek{at}medizin.uni-ulm.de.
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Abstract |
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Key Words: basal ganglia executive functions neurodegenerative disease thalamus voxel-based morphometry
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Introduction |
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Patients and Methods
All data are given as arithmetic mean ± standard deviation. Forty-four patients with genetically confirmed HD in early clinical stages [I and II according to the classification of Shoulson (Shoulson and Fahn, 1979)] were investigated (male/female ratio 21/23; mean age 44.7 ± 10.7 years, range 2566 years). None of the patients were treated with psychotropic drugs at the time of scanning. The mean number of CAG repeats in the mutant allele was 45.5 ± 7.8. The age of onset was assessed as the onset of motor signs; this information was obtained through self-reports of patients and their relatives. The mean interval between onset of motor symptoms and imaging was 5.1 ± 3.3 years. Patients were independently rated within one week prior to the studies by two experienced neurologists, using the motor score of the UHDRS and the Total Functional Capacity score (TFC). On the motor subscore of the UHDRS, the mean value was 24.1 ± 12.1. The TFC mean value was 10.9 ± 1.4.
The neuropsychological tests were performed in all 44 HD patients and in 22 age-matched volunteers who constituted the control group both here and in the morphometric MRI analysis. The volunteers (male/female ratio 10/12; mean age 44.1 ± 16.9 years, range 2568 years) had no history of central nervous system disorders and displayed no symptoms and signs of neurological and psychiatric diseases at the time of examination. They were matched to the patients with respect to years of school education. Three timed psychomotor tests, which are part of the UHDRS assessment battery, were used. First, a letter fluency test (LF, Controlled Oral Word Association test) was administered to assess verbal fluency by cueing the subjects with a particular letter and asking them to generate as many words as possible within 1 min (Benton and Hamsher, 1989). Second, the subjects performed the Stroop Color Word test to assess selective attention, perceptual interference and information processing speed (Treisman and Fearnley, 1969
). This test consists of reading words, naming colors and then naming the color of ink of the words describing colors. The score is the number of correctly identified items within 45 s for each condition. Third, the Digit Symbol test (DS) from the Wechsler Adult Intelligence Scale Revised (WAIS-R) (Wechsler, 1981
) was employed under standard rules for administration, and the test was scored according to WAIS-R criteria. The results of the three tests (as scores adjusted for age, sex and education) were summed to generate a global cognitive score as is generally used for the cognitive subscore of the UHDRS. The summary score (as an index of three seperate test among which one the Stroop test is in itself composed of three subtests which tap differentially on executive functions) is referred to as an indicator of executive functioning. This is in line with the (arguably loose) definition of executive function in the clinical literature to emphasize the fact that the common denominator of all tests used is that some aspects of executive function are challenged.
High-resolution whole head 3-D MRI data of all patients were collected on a 1.5 T clinical scanner (Siemens, Erlangen, Germany). Images were acquired using a T1-weighted magnetization-prepared rapid-acquisition gradient echo sequence (MP-RAGE) in the sagittal plane (160180 partitions, repetition time 9.7 ms, echo time 3.93 ms, flip angle 15°, matrix 256 x 256 mm2, field of view 250 mm, voxel size 1 x 1 x 1 mm3). For setting up an age-matched MRI normal data base, 3-D MRI data of the above 22 healthy volunteers were acquired using the same scanning protocol. All MRI data were processed in the same way using methods implemented in the Statistical Parametric Mapping software (SPM99, Wellcome Department of Imaging Neuroscience Group, London). Voxel-based morphometric analysis (VBM) was performed according to the principles first described by Ashburner and Friston (Ashburner and Friston, 2000; Ashburner et al., 2003
). The MRI data were spatially normalized to map each structural MRI to a template in the same standard 3-D stereotaxic space. Since the best matched templates are created from the study group itself so that the template can be considered as customized to the local MRI scanner and disease population, the customized templates in this study were created from the patients and controls (22 subjects each) in order to minimize the degree of non-linear warping required, as previously described as the so-called optimized protocol (Good et al., 2001
, 2002
). As a result of non-linear spatial normalization, the volumes of certain brain regions may grow, whereas others may shrink. In order to preserve the amount of a particular tissue (gray matter) within a voxel, a further processing step was incorporated. This involved modulating voxel values by the Jacobian determinants derived from the spatial normalization step (Ashburner and Friston, 2000
). Modulation effectively converts values of gray and white matter concentration into gray matter mass, i.e. rendering the inferences about the absolute amounts (volume) of gray matter in a voxel as opposed to the relative amounts (concentration) (Good et al., 2001
). Further data processing included automatic segmentation (into gray matter, white matter, cerebrospinal fluid) and smoothing (6 mm isotropic Gaussian kernel). After smoothing, each voxel represents the local average amount of gray matter in the surrounding region, the size of which is determined by the smoothing kernel. The gray matter images of the HD patients were then statistically compared to the gray matter maps of the normal data base in a parametric group analysis to detect whether each voxel had a greater or lesser gray matter density than the controls. Within this approach, the flexible General Linear Model framework allows effects to be partitioned between different explanatory variables in a principled manner. This comparison between the entire patient group and the control group was performed within SPM99 as an analysis of covariance (ANCOVA) using the individual cognitive sum scores for each patient and each control. As nuisance variables, the individual values for age, total gray matter volume, disease duration and UHDRS motor score were included (being 0 for the latter two confounding covariates in the controls); that way, these variables were covaried out. Contrasts were chosen in such a way that the interaction between group and cognitive performance was examined.
As a different approach, a second ANCOVA was performed within SPM99 using only the gray matter images of the patients and individual cognitive scores (including age, total gray matter volume, UHDRS motor score and disease duration as confounding covariates). Finally, an additional ANCOVA was calculated within SPM99 for control purposes as a voxel-based comparison between the patient group and the control group using the individual UHDRS motor scores for the patients (and 0 for controls) as covariates without including the cognitive scores.
Resulting parametric maps were transformed to normal distribution. All data presented were corrected for multiple comparisons by the error correction implemented in SPM99 and were thresholded at a P-value P < 0.001, representing a conservative estimate. The coordinates of significant foci derived from the Montreal Neurological Institute template were transformed to the 3-D standard coordinate system of Talairach and Tournoux for anatomical identification using the appropriate algorithm (Brett et al., 2002). The identification of neuroanatomical regions, e.g. specific thalamic subnuclei, was based on these stereotaxic coordinates as provided by the MNI or Talairach 3-D grid, respectively, gained from the voxel clusters with maximal Z-values (at P < 0.001, corrected).
To further control for possible effects of atrophy on a group analysis of spatially normalized brains, an additional processing step was included: after analysis, the significant voxel clusters were registered back onto individual subjects' brains. For that purpose, the spatial deformation fields applied during the spatial normalization of individual brain data were written out. These deformation fields were then inverted and consecutively applied to the significant voxel clusters. These inversely normalized voxel clusters were then superimposed onto the individual, original structural MRI data (i.e. which were not spatially normalized and thus in native space). This procedure was performed for all patients separately and anatomical localizations of the thalamic clusters were checked for consistency.
In addition, the brain parenchymal fractions (BPF) were calculated from the segmented 3-D MRI data for all HD patients according to a previously described largely automated protocol (Kassubek et al., 2003, 2004b
). BPF, defined as the proportion of brain parenchymal volume to total intracranial volume, is a size-normalized quantification of brain volume and may serve as a marker of global brain atrophy if compared to age-matched healthy volunteers (Juengling and Kassubek, 2003
). Further statistical analysis was performed using the Statistical Package for the Social Sciences software (SPSS, Version 9.0, Chicago, IL).
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Results |
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Mean BPF in the HD patients (mean age 44.7 years) was 0.7629 ± 0.0303 (range 0.69800.8338). This value was significantly decreased both in comparison to the mean BPF of the age-matched normal data base used for the VBM analysis (0.8292 ± 0.0392) and compared to the mean BPF value of healthy controls at ages 4049 years in a previous study (0.8295 ± 0.0055) (Kassubek et al., 2003), indicating substantial global cerebral atrophy. A bivariate correlation analysis between BPF values and overall cognitive performance (including performance in the cognitive subtests separately) did not disclose statistically significant correlations (SPSS).
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Discussion |
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From a methodological point of view, the VBM approach allows for a whole-brain based analysis without a priori assumptions about areas of alteration, in contrast to region-of-interest based approaches. Inherent to VBM, however, there are several properties that may render the interpretation of VBM studies challenging. The individual features of brains, i.e. gyral and sulcal patterns, are not preserved but blurred in the VBM technique by the steps of normalization to a template and smoothing although the anatomical variability across individuals may be difficult to interpret by region-of-interest techniques as well (Steinmetz and Seitz, 1991). Furthermore, the accuracy of registration in terms of spatial normalization in the presence of atrophy is a problem inherent in VBM. The non-linear spatial transformations used do not attempt to match every single structure in the brain exactly, but rather attempt to minimize global brain shape differences. Nevertheless, any differences detected by VBM must be caused by systematic differences in the anatomy of these structures between the groups of subjects to be compared. Several recent studies reported on the application of VBM to markedly atrophic brains (Grossman et al., 2004
), demonstrating that the presence of atrophy per se does not preclude a valid analysis using VBM provided that a number of steps are performed to attenuate the potentially confounding effects of atrophy to the normalization process. In the present study, therefore, customized templates, taking into account the properties of the local MRI scanner and the disease population, were created from patients and controls in order to minimize the degree of non-linear warping required, as previously described by Good et al. (2001)
as the so-called optimized protocol. By this approach, a further potential problem is addressed: the graywhite contrast of the thalamus is poor in T1-weighted images. The classification of gray and white tissue in the segmentation process within SPM is based on a prior probability map, reducing misclassification problems in regions with lower graywhite contrast. To further attenuate these misclassification errors, we used customized age- and disease-matched priors. The application of this protocol should therefore increase the applicability of the VBM approach in the analysis of diseased brains.
Our demonstration of thalamic volume alterations dependent on cognitive performance in early stages of HD appears at first glance to be at odds with recent studies using high-resolution MRI in which no significant atrophy was observed in the region of the thalamus. For example, in a 3-D MRI study using VBM, highly significant regional gray matter atrophy was found bilaterally in striatal areas, whereas extrastriatal gray matter changes were restricted to a small set of areas not involving the thalamus (Kassubek et al., 2004a). Rosas et al. reported a widespread extrastriatal involvement in 18 HD patients using a region-of-interest-based approach of 3-D MRI analysis (Rosas et al., 2003
), but the thalamus appeared to be spared with volumes of 100% relative to normal controls. In addition, a functional imaging study using single photon emission computed tomography (Harris et al., 1996
) could not demonstrate thalamic abnormalities in groups of patients with early HD. All these studies lumped together patients with different degrees of cognitive impairment. Cognitive deficits in early HD patients, although they inevitably develop, vary considerably in severity; therefore, subtle regional structural changes associated with cognitive decline might be missed in imaging studies if unselected large groups of HD patients in early stages are investigated. In the present study, impairment of executive functions was specifically interrogated by three neuropsychological tests, and the test scores in these timed psychomotor tasks were used for an ANCOVA within the morphometric comparison between patients and controls in the sense of voxel-based lesion-symptom mapping as proposed by Bates et al. (2003)
.
The demonstration of thalamic volume loss in the present VBM analysis converges with neuropathological observations (Heinsen et al., 1996, 1999
), indicating neuronal loss within the thalamus in end-stage HD patients at autopsy. At postmortem, two thalamic subregions appear to be most prominently affected: first, the centromedian/parafascicular nuclei (CM) and second, the dorsomedial nuclei (DM) (Heinsen et al., 1999
). In addition, the ventrolateral thalamic subregion, which relays basal ganglia output, may display volume loss (Dom et al., 1976
). The same subnuclei which demonstrated to exhibit the most profound alterations in neuropathological studies of end-stage HD brains (well in access to the global atrophic changes in the thalamus or the brain overall) were shown to be altered in our observer-independent hypothesis-free VBM analysis based on the Talairach coordinates of the maxima of significant voxel-clusters and therefore supports our interpretation that these thalamic changes develop as a feature of HD.
The connectivity of the affected thalamic subnuclei lends further plausibility to the notion that the alteration of the thalamus in HD has functional implications. CM as an efferent thalamic nucleus mainly projects to the striatum (Morel et al., 1997); a retrograde process of degeneration may therefore play a role in the degeneration of CM in HD. In contrast, DM is not synaptically connected to the striatum, but projects preferentially to prefrontal cortical areas. Although several areas in the thalamus might account for executive deficits, especially DM (which was shown to be affected in our study) seems to be an important relay station in executive function as demonstrated by lesion studies (Schuurman et al., 2002
; Van der Werf et al., 2003
).
It is unknown when during the course of HD thalamic degeneration sets in, resulting in volume changes and eventually leading to neuronal loss. In a previous VBM study in 18 presymptomatic HD gene carriers (Thieben et al., 2002), gray matter changes in the tectum of the midbrain were reported among other findings which extended into the left medio-dorsal thalamic nucleus. These findings are compatible with our data since the mutation-positive subjects in the study by Thieben et al. showed some gray matter alterations in the thalamic area (small-volume-corrected P = 0.003, only in the left hemisphere) while scoring significantly lower than controls in, for example, the Stroop word score. A definite answer to the question when in the course of HD thalamic changes begin to be apparent obviously requires a longitudinal study in mutation carriers well before the onset of clinically apparent disease; a large-scale longitudinal study (PREDICT-HD) was launched in 2001 by the Huntington Study Group to address questions of this kind (http://www.huntington-study-group.org). The data of the present study suggest that already in HD stages I and II thalamic alterations can occur, in particular in patients displaying prominent impairment in timed psychomotor tasks. These findings imply that HD is a true multisystem disorder which appears to affect regions outside the striatum at a time when overall functional impairment does not yet preclude independent living.
In addition, the evidence for both striatal and thalamic atrophy in the present study suggests that the basal-ganglia-thalamo-cortical loops engaged in verbal fluency and Stroop tasks may be disrupted at several levels in HD. Our study demonstrates disruptions at the level of both striatum and thalamus. There are several arguments in favor of an important role of thalamic atrophy in cognitive dysfunction present in the HD patients: first, thalamic gray matter changes were only observed when analyzing brain morphology with cognitive functions as a covariate; striatal changes, however, occur as a robust finding in a morphometry without additional covariance (although it is clear that the possibility that striatal alterations in themselves are sufficient to cause the cognitive deficits observed in HD patients cannot be ruled out by the data presented). Second, the results of the additional analyses performed support this interpretation: (i) the within-group analysis of the HD patients with cognitive score as covariates demonstrates the same pattern of thalamic grey matter changes; (ii) in comparison, an analysis using clinical parameters other than cognitive score (e.g. motor score) as covariates demonstrates no thalamic grey matter changes. Concerning the other extrastriatal alterations (i.e. the circumscribed cortical atrophy localized in the opercula bilaterally and in the right paracentral lobule) disclosed by our analysis, it is of note that (i) these alterations were considerably less robust (with respect to the P-values in this study) than the thalamic changes reported and (ii) that we observed these circumscribed cortical changes like the striatal atrophy as well in analyses not using cognitive functions as a covariate. All these points support the view that localized thalamic atrophy in HD does have a functional correlate, i.e. contributes to cognitive impairment. Lastly, it is worth mentioning that the localization of the atrophy within the thalamus (i.e. affecting the medio-dorsal and the ventrolateral subnuclei) is plausible in view of what is known about the connectivity (and hence functional role) of the thalamic subregions disclosed by our analysis. The results of lesion studies emphasize this point, i.e. the observation that impairment in verbal fluency and Stroop tests reminiscent of the pattern found in HD can be brought about by isolated thalamic lesions, e.g. circumscribed infarct (Van der Werf et al., 2000).
To our minds, the fact that no prefrontal cortical areas were shown to display significant atrophy in this VBM analysis does not imply that these areas are structurally intact neuropathological studies (e.g. DiFiglia et al., 1997; Gutekunst et al., 1999
), as well as MRI-based studies (Rosas et al., 2002
) provided evidence to the contrary but indicates that cortical atrophy is variable and does not develop with the same robustness as in striatal and thalamic regions. As a note aside: with respect to thalamic changes, we qualify the thalamic atrophy in cognitively impaired HD patients as robust based on the high P value associated with thalamic alterations; we do not want to imply by robust that multiple other MRI-based studies on HD came to identical conclusions on the contrary, further independent studies are needed to either confirm or refute our findings.
Furthermore, the impairment in executive functions appears to co-vary specifically with regional atrophy in both striatal and thalamic areas. In the present study [as well as in a 3-D MRI study on 70 HD patients (Kassubek et al., 2004b)], no significant correlation between clinical scores and the BPF values was found. This observation indicates that there is no correlation between the impairment of executive functions and overall gross brain atrophy and underscores that regional atrophy appears to underlie diminished cognitive abilities in HD.
Lastly, our findings have implications for the use of HD patients to infer basal ganglia function. In numerous studies, results obtained in HD patients were interpreted solely as a reflection of basal ganglia dysfunction (e.g. Lauterbach et al., 1998; Richer et al., 2002
). Our results caution against this interpretation since the patients who are impaired in executive tests display double lesions both at the striatal and the thalamic level. Our results suggest that neuropsychological tools like verbal fluency and Stroop tests are useful for probing the function of basal-ganglia-thalamo-cortical circuitry, but do not allow to infer specific sites of disruption.
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